Process and intermediates for the production of a jak1 inhibitor

Abstract

A process and intermediates for the production of a compound of Formula (I) or a salt or a hydrate thereof.

Description

[0001] PROCESS AND INTERMEDIATES FOR THE PRODUCTION OF A JAK1 INHIBITOR

[0002] FIELD OF THE INVENTION

[0003] The present disclosure relates to a process and intermediates for the production of a JAK1 inhibitor.

[0004] BACKGROUND

[0005] The JAK (Janus-associated kinase) family includes three receptor bound tyrosine kinases, JAK1 , JAK2 and JAK3, and a non-receptor bound member, Tyk2, which all play a critical role in cytokine and growth factor mediated signal transduction (Schindler et al., (1995), Annu. Rev. Biochem. 64; 621 -651). JAK1 interacts with, among others, the receptors of type I interferon (e.g., IFNa), type II interferon (e.g., IFNy), the common gamma chain yc (e.g., IL-2, IL-4, IL-7, IL-9, IL-15 and IL-21), and the interleukin-6 family (IL-10, IL-13 and IL-22) (O’Shea et al., (2013), N. Engl. J. Med. 368, 161-170). After these cytokines bind to their receptors, receptor oligomerization occurs, resulting in the cytoplasmic tails of associated JAK kinases moving into proximity and facilitating the trans-phosphorylation and activation of tyrosine residues on the JAK kinase. Phosphorylated JAK kinases bind and activate various Signal Transducer and Activator of Transcription (STAT) proteins. These STAT proteins then dimerize and translocate to the nucleus where they function as both signalling molecules and transcription factors and ultimately bind to specific DNA sequences present in the promoters of cytokine-responsive genes (Leonard et al., (2000), J. Allergy Clin. Immunol. 105: 877-888). Various immunodeficiency and autoimmune diseases such as allergies, asthma, alopecia areata, transplant (allograft) rejection, rheumatoid arthritis, amyotrophic lateral sclerosis and multiple sclerosis, and solid and hematologic cancers result from signalling disruption in the JAK / STAT pathway. See for example, Frank, (1999), Mol. Med. 5:432-456; Vijayakriishnan et al., (2011), Trends Pharmacol. Sci. 32, 25-34; and Laurence et al., (2012), Open Rheumatoi d. 6, 232-244; O’Shea et al. (2013), Ghoreschi et al., (2014), Exp. Dermatol. 23 (1), 7-11 ; Clark et al., (2014), J. Med. Chem. 57, 5023-5038, Ashino et al., (2014), J Allergy Clin Immunol. 133, 1162-74; and Herrera et al., (2015), Expert Opinion Orphan Drug 3 (4), 419-431 .

[0006] An important element of JAK1 is the ability to pair with other JAK kinases at the intracellular domains of different subunits of the receptor. For example, JAK3 associates with the common gamma chain (yc) of the various cytokine receptors and pairs with JAK1 (Pesu et al., (2008), Immunol. Rev. 223, 132- 142). It has been indicated that JAK1 is dominant over JAK3, and inhibition of JAK1 is sufficient to inactivate signalling through the common gamma chain despite JAK3 activity (Haan et al., (2011), Chem. Biol. 18 (3), 314-323). Thus, selective inhibition of JAK1 may be sufficient to treat a number of inflammatory and autoimmune diseases associated with cytokine signalling via the JAK1 / JAK3-STAT pathway.

[0007] Examples of JAK1 related disorders include, for example, leukaemia, lymphoma, transplant rejection (e.g., pancreas islet transplant rejection, bone marrow transplant applications (e.g., graft-versus-host disease)) and autoimmune / inflammatory diseases (e.g., Type 1 diabetes, allergic reactions, lupus, multiple sclerosis, rheumatoid arthritis, psoriatic arthritis, juvenile idiopathic arthritis, axial spondy loarthritis, psoriasis, asthma, atopic dermatitis, autoimmune thyroid disorders, ulcerative colitis, Crohn's disease, chronic obstructive pulmonary disease (COPD), vitiligo and alopecia areata.

[0008] Asthma is a heterogenous disease, usually characterised by chronic airway inflammation and bronchial hyperreactivity. It is defined by a history of respiratory symptoms such as wheeze, shortness of breath, chest tightness, and cough that vary over time and in intensity together with variable expiratory airflow obstruction. The JAK1STAT6 pathway is a particularly attractive target in context of T2 asthma, as the key T2 cytokines, IL-4 and IL-13 activate JAK1 , which in turn phosphorylates STAT6 leading to initiation of T2 inflammatory processes including eosinophil recruitment and activation, antibody class switching to immunoglobulin E production, goblet cell hyperplasia and mucus hypersecretion, and airway hyperreactivity and remodelling.

[0009] Examples of compounds that possess selective JAK1 inhibition are disclosed in WO2018 / 134213, including (( / ?)-N-(3-(5-fluoro-2-(2-fluoro-3-(methylsulfonyl)phenylamino)pyrimidin-4-yl)-1 H-indol-7-yl)- 3-methoxy-2-(4-methylpiperazin-1-yl)propanamide with the structure shown below, referred to as "Compound of Formula (I)”:

[0010] WO2018 / 134213, US2019 / 367490A1 and US2021 / 188821A1 , the contents of which are hereby incorporated by reference in their entirety, describe additional JAK inhibiting compounds, including various salts of (R)-N-(3-(5-fluoro-2-(2-fluoro-3-(methylsulfonyl)phenylamino)pyrimidin-4-yl)-1 H-indol- 7-yl)-3-methoxy-2-(4-methylpiperazin-1-yl)propanamide. The synthesis of the compound of Formula (I) is described in WO2018 / 134213 (example 35) and Pithani et al., (2023), Org. Process Res. Dev. 27 (7), 1317-1329.

[0011] W02020 / 016302, US2020 / 062737A1 , and in Nilsson et al., (2022), Drug design, development and therapy 16, 2901 -2917, the contents of which are hereby incorporated by reference in their entirety, disclose a xinafoate salt of the compound of Formula (I) and a process for preparing said salt. The xinafoic acid (1-hydroxy-2-naphthoic acid) salt has the Formula (la) and may be referred to as “Compound of Formula (la)”:

[0012] The compound of Formula (I) possesses a single chiral centre that is incorporated in the manufacture via a final amide bond coupling between the amino indole (III) and the corresponding piperazine substituted amino acid (II):

[0013] Scheme 1

[0014] The method for the production of the compound of Formula (I) described in WO 2018 / 134213 and WO 2020 / 016302 comprises a synthesis of the intermediate amino indole of Formula (III) and of the intermediate piperazine substituted amino acid of Formula (II). A challenge in the synthesis of the compound of Formula (I) is the production of the intermediate compound of Formula (II) in an enantiomeric pure form.

[0015] The synthetic route to the compound of Formula (II) described in WO 2018 / 134213 and WO 2020 / 016302 relies on the resolution of racemic mixtures, resulting in reduced overall yield and efficiency, as described in Example 1 of the present disclosure.

[0016] WO 2020 / 211839 describes JAK1 selective kinase inhibitors and discloses the preparation of a hydrochloric acid salt of the intermediate compound of Formula (II) in Example 1. However, the synthesis is carried out at a small scale. Notably, the reaction conditions are not well suited for large scale manufacturing. In particular the use of a Lewis acid (Mg(OTf)2 in methanol at 50°C for the conversion of the epoxide to the corresponding alcohol takes 3 days and requires chromatography purification (step 4 in Scheme 1 on page 48 of WO 2020 / 211839). In addition, the deprotection of the carboxylic acid in the last step of the synthesis is carried out by hydrolysis of the methyl ester which requires heating at a high temperature of 70°C for 30 hours (step 6 in Scheme 1 on page 48 of WO 2020 / 211839). It is well-known that high temperatures and long reaction conditions are not well suited for large scale production.

[0017] Therefore, there remains a need for a process suitable for large scale production of the compound of Formula (I) and the compound of Formula (la), and in particular for the large-scale enantioselective production of the compound of Formula (II).

[0018] SUMMARY

[0019] An efficient and scalable stereoselective synthesis of the piperazine substituted amino acid of Formula (II), or a salt thereof, is disclosed herein. Also disclosed herein is an efficient and scalable stereoselective synthesis of the JAK1 selective inhibitor of Formula (I), a salt thereof, or a hydrate thereof.

[0020] The present invention is as defined in the claims in combination with the disclosure below, which may be used to further understand the invention.

[0021] Provided herein is a process for the production of a compound of Formula (I): or a salt thereof, comprising reacting a compound of formula (III): or a salt thereof, and a compound of formula (II): or a salt thereof, wherein compound of formula (II), or a salt thereof, is prepared according to a process comprising the following steps: a) reacting a methoxide with a compound of Formula (VI): wherein X is a counter cation, to form a compound of Formula (VII): or a salt thereof, b) protecting the carboxylate group of the compound of Formula (VI I), or a salt thereof, with a benzyl group in the presence of a base, to form a compound of Formula (VIII): c) reacting the compound of Formula (VIII), or a salt thereof, with an electrophilic reagent in the presence of a base to form a compound of Formula (IX): wherein OL is a leaving group, d) reacting the compound of Formula (IX) with 1 -methylpiperazine to form a compound of Formula (X): or a salt thereof, and e) deprotecting the compound Formula (X), or a salt thereof, in the presence of hydrogen to form the compound of Formula (II), or a salt thereof.

[0022] Also provided are uses of intermediate compounds in the synthesis of a compound of Formula (II): or a salt thereof.

[0023] In some embodiments, the counter ion X in step a) is potassium cation. In some embodiments, OL in step c) is selected from triflate, mesylate, tosylate, benzenesulfonates and trifluoroacetate. In some embodiments, OL in step c) is triflate. In some embodiments, the electrophilic reagent in step c) is selected from triflic anhydride, methanesulfonic anhydride, methanesulfonyl chloride, 4-toluenesulfonic anhydride, 4-toluenesulfonyl chloride, benzenesulfonic anhydride, benzenesulfonyl chloride, and trifluoroacetic anhydride. In some embodiments, the electrophilic reagent in step c) is triflic anhydride.

[0024] Provided herein is the use of D-serine in a method of producing a compound of Formula (II), or a salt thereof.

[0025] Also provided herein is the use of a compound of Formula (Vlb): or a salt thereof, in a method of producing a compound of Formula (II), or a salt thereof. In some embodiments, the use is use of a carboxylate salt of Formula (VI): wherein X is a counter cation, optionally the salt is a potassium carboxylate salt of formula (Via):

[0026] Also provided herein is the use of a compound of Formula (VII): or a salt thereof, in a method of producing a compound of Formula (II), or a salt thereof.

[0027] Also provided herein is the use of a compound of Formula (VIII): in a method of producing a compound of Formula (II), or a salt thereof.

[0028] Also provided herein is the use of a compound of Formula (IX): wherein OL is a leaving group in a method of producing a compound of Formula (II), or a salt thereof.

[0029] In some embodiments, OL is selected from triflate, mesylate, tosylate, benzenesulfonate, and trifluoroacetate. In some embodiments, OL is triflate.

[0030] Also provided herein is the use of a compound of Formula (X): .0. or a salt thereof, in a method of producing a compound of Formula (II), or a salt thereof.

[0031] Also provided are procedures for producing intermediate compounds.

[0032] Provided herein is a process for the production of a compound of Formula (VII): or a salt thereof, the process comprising reacting a methoxide with a compound of Formula (VI): wherein X is a counter cation. In some embodiments, X is potassium cation. In some embodiments, the process is carried out in the presence of sodium methoxide in methanol. In some embodiments, from about 3.0 to about 4.5 molar equivalents of methoxide is used, optionally about 3.8 molar equivalents of methoxide is used. In some embodiments, the process is carried out from about 15°C to about 30°C, optionally wherein the process is carried out from about 18°C to about 25°C.

[0033] Also provided herein is a process for the production of a compound of Formula (VIII): the process comprising protecting the carboxylate group of the compound of Formula (VII): or a salt thereof, with a benzyl group in the presence of a base. Advantageously, according to the present process, the compound of Formula (VIII) may be obtained in an enantiomeric purity of at least 95.0%, at least 96.0%, at least 97.0%, at least 98.0%, or at least 99.0%. The compound of Formula (VI 11) may be obtained in an enantiomeric purity of at least 99.5%, at least 99.6%, at least 99.7%, at least 99.8%, or at least 99.9%. In some embodiments, the process further comprises a process for the production of the compound of Formula (VII) as described herein.

[0034] Also provided herein is a process for the production of a compound of Formula (IX): wherein OL is a leaving group, the process comprising reacting the compound of Formula (VIII): or a salt thereof, with an electrophilic reagent in the presence of a base. In some embodiments, OL is selected from tritiate, mesylate, tosylate, benzenesulfonate, and trifluoroacetate. In some embodiments, OL is tritiate. In some embodiments, the electrophilic reagent is selected from triflic anhydride, methanesulfonic anhydride, methanesulfonyl chloride, 4-toluenesulfonic anhydride, 4-toluenesulfonyl chloride, benzenesulfonic anhydride, benzenesulfonyl chloride, and trifluoroacetic anhydride. In some embodiments, the electrophilic reagent is triflic anhydride. In some embodiments, the base is selected from pyridine, triethylamine, diisopropylethylamine, 4-dimethylaminopyridine (DMPA), tetramethylpyridine, N-methylpiperazine, lutidine, 2,6-lutidine, N-methylmorpholine, 1 ,8- diazabicyclo(5.4.0)undec-7-ene (DBU), tetramethylguanidine, and tributylamine. In some embodiments, the base is pyridine. In some embodiments, from about 1.1 to about 2.0 molar equivalents of electrophilic reagent (e.g. triflic anhydride) is used, optionally about 1 .5 molar equivalents of electrophilic reagent (e.g. triflic anhydride) is used. In some embodiments, the process is carried out in a solvent selected from dichloromethane, toluene, acetonitrile, methyl tert-butyl ether, 2- methyltetryhydrofuran, tetrahydrofuran, cyclopentyl methyl ether, anisole, benzonitrile acetone, methyl ethyl ketone, and chlorobenzene, or a mixture thereof. In some embodiments, the process is carried out in dichloromethane. In some embodiments, the process is carried out in toluene. In some embodiments, the process is carried out in a mixture of dichloromethane and toluene. In some embodiments, the process is carried out using a continuous flow process. In some embodiments, a residence time of from about 5 to about 60 seconds is used in the continuous flow process. In some embodiments, the residence time is from about 15 to about 45 seconds, optionally from about 20 to about 40 seconds, more optionally about 30 seconds. In some embodiments, the process further comprises a process for the production of the compound of Formula (VIII) as described herein.

[0035] Also provided herein is a process for the production of a compound of Formula (X):

[0036] .0. or a salt thereof, the process comprising reacting the compound of Formula (IX): wherein OL is a leaving group, with 1 -methylpiperazine. In some embodiments, wherein OL is selected from triflate, mesylate, tosylate, benzenesulfonate, and trifluoroacetate. In some embodiments, OL is triflate. In some embodiments, from about 1.1 to about 2.0 molar equivalents of 1 -methylpiperazine is used, optionally about 1 .5 molar equivalents of 1 -methylpiperazine is used. In some embodiments, the process is carried out in a mixture of dichloromethane and 2-methyltetrahydrofuran. In some embodiments, the process is carried out using a continuous flow process. In some embodiments, a residence time of from about 5 to about 20 minutes is used in the continuous flow process, optionally the residence time is from about 7 to about 15 minutes, optionally the residence time about 10 minutes. According to the present process, the compound of Formula (X) may be obtained in an enantiomeric purity of at least 90.0%, at least 91 .0%, at least 92.0%, at least 93.0%, at least 94.0%, at least 95.0%, at least 96.0%, at least 97.0%, at least 98.0%, or at least 99.0%. The compound of Formula (X) may be obtained in an enantiomeric purity of at least 94.0%, at least 95.0%, at least 96.0%, at least 97.0%, at least 98.0%, or at least 99.0%. In some embodiments, the process further comprises a process for the production of the compound of Formula (IX) as described herein.

[0037] Also provided herein is a process for the production of a compound of Formula (II): or a salt thereof, the process comprising a deprotecting step of hydrogenating the compound of Formula (X): or a salt thereof. In some embodiments, hydrogenating is carried out in the presence of palladium catalyst. In some embodiments, the process further comprises reacting the compound of Formula (II), or a salt thereof, with hydrochloric acid to form the dihydrochloride mohohydrate salt of Formula (Ila):

[0038] According to the present process, the compound of Formula (II) may be obtained in an enantiomeric purity of at least 97.0%, at least 98.0%, or at least 99.0%. The compound of Formula (II) may be obtained in an enantiomeric purity of at least 99.5%, at least 99.6%, at least 99.7%, at least 99.8%, or at least 99.9%. In some embodiments, the process further comprises a process for the production of a compound of Formula (X) as described herein.

[0039] Also provided herein is a process for the production of a compound of Formula (I): or a salt thereof, comprising reacting a compound of formula (III): or a salt thereof, and a compound of formula (II): or a salt thereof, wherein compound of formula (II) is prepared according to a process as described herein. In some embodiments, the process is for the production of a xinafoate salt of Formula (la):

[0040] Also provided are procedures for producing compounds as intermediates in a process of producing a compound of Formula (II): or a salt thereof.

[0041] Provided herein is a process of producing a compound of Formula (VII): or a salt thereof, as an intermediate in a process of producing a compound of Formula (II): or a salt thereof, wherein the process comprises a process for the production of a compound of Formula (VII) as described herein.

[0042] Also provided herein is a process of producing a compound of Formula (VIII): or a salt thereof, as an intermediate in a process of producing a compound of Formula (II): or a salt thereof, wherein the process comprises a process for the production of a compound of Formula (VIII) as described herein.

[0043] Also provided herein is a process of producing a compound of Formula (IX): wherein OL is a leaving group, as an intermediate in a process of producing a compound of Formula

[0044] (II): or a salt thereof, wherein the process comprises a process for the production of a compound of Formula (IX) as described herein.

[0045] Also provided herein is a process of producing a compound of Formula (IXa): as an intermediate in a process of producing a compound of Formula (II): or a salt thereof, wherein the process comprises a process for the production of a compound of Formula (IXa) as described herein.

[0046] Also provided herein is a process of producing a compound of Formula (X): or a salt thereof, as an intermediate in a process of producing a compound of Formula (II): or a salt thereof, wherein the process comprises a process a process for the production of a compound of Formula (X) as described herein. Also provided are procedures for producing compounds as intermediates in a process of producing a compound of Formula (I): or a salt thereof.

[0047] Provided herein is a process of producing a compound of Formula (VII): or a salt thereof, as an intermediate in a process of producing a compound of Formula (I): or a salt thereof, wherein the process comprises a process for the production of a compound of Formula (VII) as described herein, optionally wherein the process is for the production of a xinafoate salt of Formula (la):

[0048] Also provided herein is a process of producing a compound of Formula (VIII): as an intermediate in a process of producing a compound of Formula (I): or a salt thereof, wherein the process comprises a process for the production of a compound of Formula (VIII) as described herein, optionally wherein the process is for the production of a xinafoate salt of Formula (la):

[0049] Also provided herein is a process of producing a compound of Formula (IX): wherein OL is a leaving group, as an intermediate in a process of producing a compound of Formula (I): or a salt thereof, wherein the process comprises a process for the production of a compound of Formula (IX) as described herein, optionally wherein the process is for the production of a xinafoate salt of Formula (la):

[0050] Also provided herein is a process of producing a compound of Formula (IXa): as an intermediate in a process of producing a compound of Formula (I): or a salt thereof, wherein the process comprises a process for the production of a compound of Formula (IXa) as described herein, optionally wherein the process is for the production of a xinafoate salt of Formula (la):

[0051] Also provided herein is a process of producing a compound of Formula (X): or a salt thereof, as an intermediate in a process of producing a compound of Formula (I): or a salt thereof, wherein the process comprises a process for the production of a compound of Formula (X) as described herein, optionally wherein the process is for the production of a xinafoate salt of Formula (la): Also provided herein is a process of producing a compound of Formula (II): or a salt thereof, as an intermediate in a process of producing a compound of Formula (I): or a salt thereof, wherein the process comprises a process for the production of a compound of Formula (II) as described herein, optionally wherein the process is for the production of a xinafoate salt of Formula (la):

[0052]

[0053] BRIEF DESCRIPTION OF THE DRAWINGS

[0054] FIG. 1 shows a continuous flow diagram for making compound (X). FIG. 2 shows a diagram of initial continuous flow system for generating triflate (IXa) (Example 4).

[0055] FIG. 3 shows a diagram of a continuous flow system for generating triflate (IXa) at different residence times and integrated quench (Example 4).

[0056] FIG. 4 shows a diagram of a telescoped Continuous flow system for generating ester (X) (Example 4).

[0057] DETAILED DESCRIPTION Aspects and embodiments will now be discussed with reference to the accompanying figures. Further aspects and embodiments will be apparent to those skilled in the art. All documents mentioned in this text are incorporated herein by reference.

[0058] As used herein, the term “about”, when used to modify a numeric value or numeric range, indicates that deviations of up to 10% above and down to 10% below the value or range remain within the intended meaning of the recited value or range.

[0059] The present inventors have developed an efficient and scalable stereoselective synthesis of the piperazine substituted amino acid of Formula (II) which is disclosed herein. The stereoselective process is summarised in the retrosynthesis in Scheme 2 below, wherein OL is a leaving group.

[0060]

[0061] Scheme 2

[0062] In some embodiments, the stereoselective process is summarised in the retrosynthesis in Scheme 2a below:

[0063] Scheme 2a

[0064] Advantageously, this approach uses a benzyl protecting group on the carboxylic acid of the compound of Formula (VII) which has been found to be highly effective at preventing racemisation of the downstream intermediates, thereby preserving retention of the stereocentre at the chiral centre during the production of the compound of Formula (II).

[0065] Also advantageously, this approach uses mild and fast reaction conditions which are ideally suited for large scale manufacturing.

[0066] The synthesis of the compound of Formula (II) is described in Scheme 3, wherein X is a counter cation, and wherein OL is a leaving group.

[0067] Scheme 3

[0068] In some embodiments, the synthesis of the compound of Formula (II) is described in Scheme 3a.

[0069] Scheme 3a

[0070] Each of the steps of the synthesis of the compound of Formula (II) are further described in sections 1 to 6 below. Thus, sections 1 to 6 below relate to the individual steps for making the intermediate products in the overall synthesis to make the compound of Formula (II) and the compound of Formula (I). It will be understood that processes 1 to 6 when performed sequentially in combination (i.e. 1 + 2 + 3 + 4 + 5 + 6) constitute a complete synthesis for a compound of Formula (II), a salt thereof or a hydrate thereof. The present disclosure relates to any one of these processes performed individually or in combination with one or more of the other processes.

[0071] The synthesis of the compound of Formula (I) is described in Scheme 4.

[0072] Scheme 4

[0073] Each of the steps of the synthesis of the compound of Formula (I) are further described in sections 1 to 7 below. It will be understood that processes 1 to 7 when performed sequentially in combination (i.e. 1 + 2 + 3 + 4 + 5 + 6 + 7) constitute a complete synthesis for a compound of Formula (I), a salt thereof or a hydrate thereof. The present disclosure relates to any one of these processes performed individually or in combination with one or more of the other processes.

[0074] 1 . Step 1 : production of the epoxide of Formula (Via) or a salt thereof The synthesis of the compound of Formula (VI): wherein X is a counter cation, can be performed using the previously published procedure for conversion of inexpensive D-serine into the required (S)-epoxide which was isolated as the corresponding potassium salt (Via) as shown in Scheme 5.

[0075] Scheme 5

[0076] Accordingly, provided herein is a process for the production of a compound of Formula (Via), (via). from D-serine, the process comprising: a) reacting D-serine with a source of bromide ion in the presence of sodium nitrite to form a bromide intermediate compound of Formula (V), and b) subjecting the reaction mixture to basic conditions in the presence of an alcohol to form the compound of Formula (Via).

[0077] In some embodiments, the source of bromide ion in step (a) is potassium bromide (KBr) in aqueous solution of hydrogen bromide (HBr). In some embodiments, the basic conditions in step (b) is potassium hydroxide (KOH). In some embodiments, the alcohol in step (b) is ethanol.

[0078] Also provided herein is a process for the production of a compound of Formula (VI), wherein X is a counter cation, the process comprising: a) reacting D-serine with a source of bromide ion in the presence of sodium nitrite to form a bromide intermediate compound of Formula (V), and b) subjecting the reaction mixture to basic conditions in the presence of an alcohol to form the compound of Formula (VI).

[0079] In some embodiments, the source of bromide ion in step (a) is potassium bromide (KBr) in aqueous solution of hydrogen bromide (HBr). In some embodiments, the source of bromide ion in step (a) is sodium bromide (KBr) in aqueous solution of hydrogen bromide (HBr). In some embodiments, the basic conditions in step (b) comprise a base selected from potassium hydroxide (KOH) and potassium alkoxides, for example potassium methoxide and potassium ethoxide. In some embodiments, the alcohol in step (b) is a Ci-4alcohol, for example methanol, ethanol, propanol, iso-propanol and / or butanol. In some embodiments, the alcohol in step (b) is ethanol.

[0080] In some embodiments, X is selected from H, K and Na.

[0081] This process is advantageous because it uses the selective formation of the (S) epoxide enantiomer of Formula (VI), (Via) or (Vlb) from the cheap and readily available D-serine.

[0082] Also provided herein is a process of producing a compound of Formula (VI): wherein X is a counter cation, as an intermediate in a process of producing a compound of Formula (II): a salt thereof, or a hydrate thereof, wherein the process comprises a process for the production of a compound of Formula (VI) as described herein.

[0083] Also provided herein is a process of producing a compound of Formula (VI): wherein X is a counter cation, as an intermediate in a process of producing a compound of Formula (I): a salt thereof, or a hydrate thereof, wherein the process comprises a process for the production of a compound of Formula (VI) as described herein.

[0084] In some embodiments, the process is for the production of a salt of a compound of Formula (I), optionally wherein the process is for the production of a xinafoate salt of Formula (la): It will be understood that the present disclosure also relates to the direct products of the processes as described anywhere herein. The present disclosure also relates to products obtainable by processes as described anywhere herein.

[0085] Accordingly, also provided herein is a compound of Formula (VI): wherein X is a counter cation, obtained by the process for the production of a compound of Formula (IV) as described anywhere herein.

[0086] The compound may exhibit characteristics deriving from the process by which it was made, which characteristics will render it possible to determine by routine tests that the compound per se was made by a process according to the disclosure.

[0087] Also provided herein is a compound of Formula (Via): obtained by a process for the production of a compound of Formula (Via) as described anywhere herein.

[0088] The compound may exhibit characteristics deriving from the process by which it was made, which characteristics will render it possible to determine by routine tests that the compound per se was made by a process according to the disclosure.

[0089] 2. Step 2: production of the carboxylic acid of Formula (VII) or a salt thereof

[0090] Conversion of the epoxide of Formula (Via) to the carboxylic acid of Formula (VI I) is shown in Scheme 6.

[0091] (Via) (VII)

[0092] Scheme 6 This process involves ring opening of epoxide of Formula (Via) or an equivalent epoxide of Formula (VI): wherein X is a counter cation, with methoxide to yield the compound of Formula (VII). Preferably, sodium methoxide in methanol is used. Conversion of the alcohol of Formula (VI I) to the corresponding benzyl ester of Formula (VIII) can be achieved under standard conditions using benzyl bromide and a base, e.g. N,N-diisopropyl ethylamine (DIPEA).

[0093] Accordingly, provided herein is a process for the production of a compound of Formula (VII): or a salt thereof, the process comprising reacting a methoxide with a compound of Formula (VI): wherein X is a counter cation. In some embodiments, X is selected from K and Na, optionally X is potassium cation.

[0094] In some embodiments, the source of methoxide is selected from sodium methoxide in methanol, pentane or DMSO. Methoxide may also be produced in situ using methanol in the presence of a base (e.g. sodium tert-butoxide, sodium iso-propoxide or sodium hexamethyldisilazide) or sodium metal. In some embodiments, the process is carried out in the presence of sodium methoxide in methanol. In some embodiments, from about 3.0 to about 4.5 molar equivalents of methoxide is used, optionally about 3.8 molar equivalents of methoxide is used. In some embodiments, about 3.0, about 3.1 , about 3.2, about 3.3, about 3.4, about 3.5, about 3.6, about 3.7, about 3.8, about 3.9, about 4.0, about 4.1 , about 4.2, about 4.3, about 4.4, or about 4.5 molar equivalents of methoxide is used. In some embodiments, about 3.8 molar equivalents of methoxide is used.

[0095] In some embodiments, the process is carried out from about 15°C to about 30°C, optionally wherein the process is carried out from about 18°C to about 25°C. In some embodiments, the process is carried out at about 15°C, about 16°C, about 17°C, about 18°C, about 19°C, about 20°C, about 21 °C, about 22°C, about 23°C, about 24°C, about 25°C, about 26°C, about 27°C, about 28°C, about 29°C, or about 30°C, optionally at about 18°C, about 19°C, about 20°C, about 21 °C, about 22°C, about 23°C, about 24°C, or about 25°C. In some embodiments, the process is carried at about 20°C.

[0096] In some embodiments, the process for the production of a compound of Formula (VI I) further comprises a process for the production of the compound of Formula (VI) as described herein, particularly in section “1 . Process for the production of the epoxide of Formula (Via) or a salt thereof’.

[0097] Also provided herein is a process of producing a compound of Formula (VII): or a salt thereof, as an intermediate in a process of producing a compound of Formula (II): a salt thereof, or a hydrate thereof, wherein the process comprises a process for the production of a compound of Formula (VII) as described herein.

[0098] Also provided herein is a process of producing a compound of Formula (VII): or a salt thereof, as an intermediate in a process of producing a compound of Formula (I): a salt thereof, or a hydrate thereof, 1 wherein the process comprises a process for the production of a compound of Formula (VII) as described herein.

[0099] In some embodiments, the process is for the production of a salt of a compound of Formula (I), optionally wherein the process is for the production of a xinafoate salt of Formula (la):

[0100] It will be understood that the present disclosure also relates to the direct products of the processes as described anywhere herein. The present disclosure also relates to products obtainable by processes as described anywhere herein.

[0101] Accordingly, also provided herein is a compound of Formula (VII): or a salt thereof, obtained by the process for the production of a compound of Formula (VII) as described anywhere herein.

[0102] The compound may exhibit characteristics deriving from the process by which it was made, which characteristics will render it possible to determine by routine tests that the compound per se was made by a process according to the disclosure.

[0103] Advantageously, the opening of the epoxide compound of Formula (VI) can be carried out rapidly (e.g. 3 to 5 hours) under mild conditions (e.g. using a source of methoxide (e.g. sodium methoxide in methanol) at room temperature (e.g. 18 to 25 °C)) to form the alcohol of Formula (VII) where the (S) stereocentre is retained. No chromatography purification is required. These advantageous reaction conditions are key on a large-scale production.

[0104] 3. Step 3: production of the benzyl ester of Formula (VIII) or a salt thereof

[0105] Conversion of the carboxylic acid of Formula (VI I) to the benzyl ester of Formula (VIII) is shown in

[0106] Scheme 7.

[0107] (VIII)

[0108] Scheme 7

[0109] Accordingly, provided herein is a process for the production of a compound of Formula (VIII): or a salt thereof, the process comprising protecting the carboxylate group of the compound of Formula (VII): or a salt thereof, with a benzyl group, in the presence of a base. In some embodiments the protecting group is a benzyl group. In some embodiments, the base is selected from N,N-diisopropylethylamine (DIPEA), pyridine, lutidine, DBU (1 ,8-diazabicyclo(5.4.0)undec-7-ene), guanidine bases and trialkylamines such as triethylamine and tributylamine. In one embodiment, the base is N,N- diisopropylethylamine (DIPEA).

[0110] According to the present process, the compound of Formula (VIII) may be obtained in an enantiomeric purity of at least 95.0%, at least 96.0%, at least 97.0%, at least 98.0%, or at least 99.0%. The compound of Formula (VIII) may be obtained in an enantiomeric purity of at least 99.5%, at least 99.6%, at least 99.7%, at least 99.8%, or at least 99.9%.

[0111] In some embodiments, the process for the production of a compound of Formula (VIII) further comprises a process for the production of the compound of Formula (VII) as described herein, particularly in section “2. Process for the production of the carboxylic acid of Formula (VII) or a salt thereof’.

[0112] Also provided herein is a process of producing a compound of Formula (VIII): or a salt thereof, as an intermediate in a process of producing a compound of Formula (II): a salt thereof, or a hydrate thereof, wherein the process comprises a process for the production of a compound of Formula (VIII) as described herein.

[0113] Also provided herein is a process of producing a compound of Formula (VIII): or a salt thereof, as an intermediate in a process of producing a compound of Formula (I): a salt thereof, or a hydrate thereof, wherein the process comprises a process for the production of a compound of Formula (VIII) as described herein.

[0114] In some embodiments, the process is for the production of a salt of a compound of Formula (I), optionally wherein the process is for the production of a xinafoate salt of Formula (la): It will be understood that the present disclosure also relates to the direct products of the processes as described anywhere herein. The present disclosure also relates to products obtainable by processes as described anywhere herein.

[0115] Accordingly, also provided herein is a compound of Formula (VIII): or a salt thereof, obtained by the process for the production of a compound of Formula (VIII) as described anywhere herein.

[0116] The compound may exhibit characteristics deriving from the process by which it was made, which characteristics will render it possible to determine by routine tests that the compound per se was made by a process according to the disclosure.

[0117] Advantageously, the benzyl protecting group absorbs UV and therefore provides a chromophore for analysis (e.g. chiral UPLC) of all intermediates through to final compound of Formula (II). The benzyl protecting group can also be removed under mild conditions by hydrogenolysis to liberate the desired acid in the final step of the synthesis of the compound of Formula (II), allowing retention of the stereocentre in the compound of Formula (II). Another advantage of the benzyl protecting group is that the only by-product formed upon deprotection is toluene, obviating the need for more complex workups and isolation processes. Thus, the final product is obtained in a neutral form in a solution of toluene which can be used directly, without the need to remove any acid and / or salts.

[0118] 4. Step 4: production of the intermediate of Formula (IX)

[0119] The synthesis of the compound of Formula (IX): wherein OL is a leaving group, can be performed by converting the alcohol of Formula (VIII) into the required compound of Formula (IX) in the presence of a base and an electrophilic agent, as shown in Scheme 8. Scheme 8

[0120] In some embodiments, OL is selected from triflate, mesylate, tosylate, benzenesulfonate, and trifluoroacetate. In some embodiments, OL is triflate. In some embodiments, OL is mesylate. In some embodiments, OL is tosylate. In some embodiments, OL is benzenesulfonate. In some embodiments, OL is trifluoroacetate.

[0121] In some embodiments, the electrophilic reagent is selected from triflic anhydride, methanesulfonic anhydride, methanesulfonyl chloride, 4-toluenesulfonic anhydride, 4-toluenesulfonyl chloride, benzenesulfonic anhydride, benzenesulfonyl chloride, and trifluoroacetic anhydride. In some embodiments, the electrophilic reagent is triflic anhydride. In some embodiments, the electrophilic reagent is methanesulfonic anhydride. In some embodiments, the electrophilic reagent is methanesulfonyl chloride. In some embodiments, the electrophilic reagent is 4-toluenesulfonic anhydride. In some embodiments, the electrophilic reagent is 4-toluenesulfonyl chloride. In some embodiments, the electrophilic reagent is benzenesulfonic anhydride. In some embodiments, the electrophilic reagent is benzenesulfonyl chloride. In some embodiments, the electrophilic reagent is trifluoroacetic anhydride. In some embodiments, the base is selected from pyridine, triethylamine, diisopropylethylamine, 4-dimethylaminopyridine (DMPA), tetramethylpyridine, N-methylpiperazine, lutidine, 2,6-lutidine, N-methylmorpholine, 1 ,8-diazabicyclo(5.4.0)undec-7-ene (DBU), tetramethylguanidine, and tributylamine. In some embodiments, the solvent is selected from dichloromethane, toluene, acetonitrile, methyl tert-butyl ether, 2-methyltetryhydrofuran, tetrahydrofuran, cyclopentyl methyl ether, anisole, benzonitrile acetone, methyl ethyl ketone, and chlorobenzene, or a mixture thereof.

[0122] Conversion of the alcohol of Formula (VI 11) to the triflate of Formula (IXa) is shown in Scheme 8a.

[0123] Tf2O,

[0124] Scheme 8a

[0125] In some embodiments, the process of Scheme 8a involves reacting the compound of Formula (VIII) with triflic anhydride and a base (e.g. pyridine, triethylamine, diisopropylethylamine, 4- dimethylaminopyridine (DMPA), tetramethylpyridine, N-methylpiperazine, lutidine, 2,6-lutidine, N- methylmorpholine, 1 ,8-diazabicyclo(5.4.0)undec-7-ene (DBU), tetramethylguanidine, or tributylamine) in the presence of a solvent (e.g. dichloromethane, toluene, acetonitrile, methyl tert-butyl ether, 2- methyltetryhydrofuran, tetrahydrofuran, cyclopentyl methyl ether, anisole, benzonitrile acetone, methyl ethyl ketone, and chlorobenzene, or a mixture thereof) to form the intermediate mesylate of Formula (IXa). In some embodiments, the process of Scheme 8a involves reacting the compound of Formula (VIII) with triflic anhydride and a base (e.g. pyridine) in the presence of a solvent (e.g. dichloromethane and / or toluene) to form the intermediate mesylate of Formula (IXa). In some embodiments, the process of Scheme 8a involves reacting the compound of Formula (VIII) with an excess of triflic anhydride (e.g. 1.5 to 2 equivalents) and a base (e.g. pyridine) in the presence of dichloromethane to form the intermediate triflate of Formula (IXa). In some embodiments, the process of Scheme 8a involves reacting the compound of Formula (VIII) with an excess of triflic anhydride (e.g. 1.5 to 2 equivalents) and a base (e.g. pyridine) in the presence of toluene to form the intermediate triflate of Formula (IXa). In some embodiments, the process of Scheme 8a involves reacting the compound of Formula (VIII) with an excess of triflic anhydride (e.g. 1.5 to 2 equivalents) and a base (e.g. pyridine) in the presence of a mixture of dichloromethane and toluene to form the intermediate triflate of Formula (IXa). In some embodiments, the intermediate triflate of Formula (IXa) is not isolated but washed with aqueous sodium sulfate (to remove pyridinium salts).

[0126] Conversion of the alcohol of Formula (VI 11) to the tosylate of Formula (IXb) is shown in Scheme 8b.

[0127] Scheme 8b

[0128] In some embodiments, the process of Scheme 8b involves reacting the compound of Formula (VIII) with 4-toluenesulfonyl chloride and a base (e.g. pyridine, triethylamine, diisopropylethylamine, 4- dimethylaminopyridine (DMPA), tetramethylpyridine, N-methylpiperazine, lutidine, 2,6-lutidine, N- methylmorpholine, 1 ,8-diazabicyclo(5.4.0)undec-7-ene (DBU), tetramethylguanidine, or tributylamine) in the presence of a solvent (e.g. dichloromethane, acetonitrile, toluene, methyl tert-butyl ether (MTBE), 2-methyltetrahydrofuran (MeTHF), tetra hydrofuran (THF), cyclopentyl methyl ether (CPME), anisole, benzonitrile acetone, methyl ethyl ketone (MEK), chlorobenzene, or a mixture thereof) to form the intermediate tosylate of Formula (IXb). In some embodiments, the process of Scheme 8b involves reacting the compound of Formula (VIII) with 4-toluenesulfonyl chloride and a base (e.g. triethylamine) in the presence of a solvent (e.g. acetonitrile) to form the intermediate tosylate of Formula (IXb). In some embodiments, the reaction mixture further comprises a catalyst, e.g. 4-dimethylaminopyridine.

[0129] In other embodiments, the tosylate of Formula (IXb) is obtained by reacting 4-toluenesulfonic anhydride and a base (e.g. pyridine, triethylamine, diisopropylethylamine, 4-dimethylaminopyridine (DMPA), tetramethylpyridine, N-methylpiperazine, lutidine, 2,6-lutidine, N-methylmorpholine, 1 ,8- diazabicyclo(5.4.0)undec-7-ene (DBU), tetramethylguanidine, or tributylamine) in the presence of a solvent (e.g. dichloromethane, acetonitrile, toluene, methyl tert-butyl ether (MTBE), 2- methyltetrahydrofuran (MeTHF), tetrahydrofuran (THF), cyclopentyl methyl ether (CPME), anisole, benzonitrile acetone, methyl ethyl ketone (MEK), chlorobenzene, or a mixture thereof). In some embodiments, the tosylate of Formula (IXb) is obtained by reacting 4-toluenesulfonic anhydride and a base (e.g. pyridine) in the presence of a solvent (e.g. dichloromethane and / or toluene).

[0130] In some embodiments, the base is pyridine and the intermediate tosylate of Formula (IXb) is not isolated but washed with aqueous sodium sulfate (to remove pyridinium salts).

[0131] Conversion of the alcohol of Formula (VI 11) to the mesylate of Formula (IXc) is shown in Scheme 8c.

[0132] Scheme 8c

[0133] In some embodiments, the process of Scheme 8c involves reacting the compound of Formula (VIII) with methanesulfonyl chloride and a base (e.g. pyridine, triethylamine, diisopropylethylamine, 4- dimethylaminopyridine (DMPA), tetramethylpyridine, N-methylpiperazine, lutidine, 2,6-lutidine, N- methylmorpholine, 1 ,8-diazabicyclo(5.4.0)undec-7-ene (DBU), tetramethylguanidine, or tributylamine) in the presence of a solvent (e.g. dichloromethane, acetonitrile, toluene, methyl tert-butyl ether (MTBE), 2-methyltetrahydrofuran (MeTHF), tetra hydrofuran (THF), cyclopentyl methyl ether (CPME), anisole, benzonitrile acetone, methyl ethyl ketone (MEK), chlorobenzene, or a mixture thereof) to form the intermediate mesylate of Formula (IXc). In some embodiments, the process of Scheme 8c involves reacting the compound of Formula (VIII) with methanesulfonyl chloride and a base (e.g. diisopropylethylamine) in the presence of a solvent (e.g. 2-methyl tetrahydrofuran).

[0134] In other embodiments, the mesylate of Formula (IXc) is obtained by reacting methanesulfonic anhydride and a base (e.g. pyridine, triethylamine, diisopropylethylamine, 4-dimethylaminopyridine (DMPA), tetramethylpyridine, N-methylpiperazine, lutidine, 2,6-lutidine, N-methylmorpholine, 1 ,8- diazabicyclo(5.4.0)undec-7-ene (DBU), tetramethylguanidine, or tributylamine) in the presence of a solvent (e.g. dichloromethane, acetonitrile, toluene, methyl tert-butyl ether (MTBE), 2- methyltetrahydrofuran (MeTHF), tetrahydrofuran (THF), cyclopentyl methyl ether (CPME), anisole, benzonitrile acetone, methyl ethyl ketone (MEK), chlorobenzene, or a mixture thereof). In some embodiments, the mesylate of Formula (IXc) is obtained by reacting methanesulfonic anhydride and a base (e.g. pyridine) in the presence of a solvent (e.g. dichloromethane and / or toluene).

[0135] In some embodiments, the base is pyridine and the intermediate mesylate of Formula (IXc) is not isolated but washed with aqueous sodium sulfate (to remove pyridinium salts).

[0136] Conversion of the alcohol of Formula (VIII) to the benzene sulfonate of Formula (IXd) is shown in Scheme 8d.

[0137] Scheme 8d

[0138] In some embodiments, the process of Scheme 8d involves reacting the compound of Formula (VIII) with benzenesulfonyl chloride and a base (e.g. pyridine, triethylamine, diisopropylethylamine, 4- dimethylaminopyridine (DMPA), tetramethylpyridine, N-methylpiperazine, lutidine, 2,6-lutidine, N- methylmorpholine, 1 ,8-diazabicyclo(5.4.0)undec-7-ene (DBU), tetramethylguanidine, or tributylamine) in the presence of a solvent (e.g. dichloromethane, acetonitrile, toluene, methyl tert-butyl ether (MTBE), 2-methyltetrahydrofuran (MeTHF), tetra hydrofuran (THF), cyclopentyl methyl ether (CPME), anisole, benzonitrile acetone, methyl ethyl ketone (MEK), chlorobenzene, or a mixture thereof) to form the intermediate benzenesulfonate of Formula (IXd). In some embodiments, the process of Scheme 8d involves reacting the compound of Formula (VIII) with benzenesulfonyl chloride and a base (e.g. triethylamine) in the presence of a solvent (e.g. dichloromethane) to form the intermediate benzenesulfonate of Formula (IXd). In some embodiments, the process of Scheme 8d involves reacting the compound of Formula (VIII) with benzenesulfonyl chloride and a base (e.g. pyridine) in the presence of a solvent (e.g. dichloromethane) to form the intermediate benzenesulfonate of Formula (IXd).

[0139] In other embodiments, the benzenesulfonate of Formula (IXd) is obtained by reacting benzenesulfonic anhydride and a base (e.g. pyridine, triethylamine, diisopropylethylamine, 4-dimethylaminopyridine (DMPA), tetramethylpyridine, N-methylpiperazine, lutidine, 2,6-lutidine, N-methylmorpholine, 1 ,8- diazabicyclo(5.4.0)undec-7-ene (DBU), tetramethylguanidine, or tributylamine) in the presence of a solvent (e.g. dichloromethane, acetonitrile, toluene, methyl tert-butyl ether (MTBE), 2- methyltetrahydrofuran (MeTHF), tetrahydrofuran (THF), cyclopentyl methyl ether (CPME), anisole, benzonitrile acetone, methyl ethyl ketone (MEK), chlorobenzene, or a mixture thereof). In some embodiments, the benzenesulfonate of Formula (IXd) is obtained by reacting benzenesulfonic anhydride and a base (e.g. pyridine) in the presence of a solvent (e.g. dichloromethane and / or toluene).

[0140] In some embodiments, the base is pyridine and the intermediate benzenesulfonate of Formula (IXd) is not isolated but washed with aqueous sodium sulfate (to remove pyridinium salts). Conversion of the alcohol of Formula (VI 11) to the trifluoroacetate of Formula (IXe) is shown in Scheme 8e.

[0141] Scheme 8e

[0142] In some embodiments, the process of Scheme 8e involves reacting the compound of Formula (VIII) with trifluoroacetic anhydride and a base (e.g. pyridine, triethylamine, diisopropylethylamine, 4- dimethylaminopyridine (DMPA), tetramethylpyridine, N-methylpiperazine, lutidine, 2,6-lutidine, N- methylmorpholine, 1 ,8-diazabicyclo(5.4.0)undec-7-ene (DBU), tetramethylguanidine, or tributylamine) in the presence of a solvent (e.g. dichloromethane, acetonitrile, toluene, methyl tert-butyl ether (MTBE), 2-methyltetrahydrofuran (MeTHF), tetra hydrofuran (THF), cyclopentyl methyl ether (CPME), anisole, benzonitrile acetone, methyl ethyl ketone (MEK), chlorobenzene, or a mixture thereof) to form the intermediate trifluoroacetate of Formula (IXe).

[0143] In some embodiments, the base is pyridine and the intermediate trifluoroacetate of Formula (IXe) is not isolated but washed with aqueous sodium sulfate (to remove pyridinium salts).

[0144] Accordingly, provided herein is a process for the production of a compound of Formula (IX): wherein OL is a leaving group, the process comprising reacting the compound of Formula (VIII): or a salt thereof, with an electrophilic reagent in the presence of a base.

[0145] In some embodiments, OL is selected from triflate, mesylate, tosylate, benzenesulfonate, and trifluoroacetate. In some embodiments, OL is triflate. In some embodiments, OL is mesylate. In some embodiments, OL is tosylate. In some embodiments, OL is benzenesulfonate. In some embodiments, OL is trifluoroacetate.

[0146] In some embodiments, the electrophilic reagent is selected from triflic anhydride, methanesulfonic anhydride, methanesulfonyl chloride, 4-toluenesulfonic anhydride, 4-toluenesulfonyl chloride, benzenesulfonic anhydride, benzenesulfonyl chloride, and trifluoroacetic anhydride. In some embodiments, the electrophilic reagent is triflic anhydride. In some embodiments, the electrophilic reagent is methanesulfonic anhydride. In some embodiments, the electrophilic reagent is methanesulfonyl chloride. In some embodiments, the electrophilic reagent is 4-toluenesulfonic anhydride. In some embodiments, the electrophilic reagent is 4-toluenesulfonyl chloride. In some embodiments, the electrophilic reagent is benzenesulfonic anhydride. In some embodiments, the electrophilic reagent is benzenesulfonyl chloride. In some embodiments, the electrophilic reagent is trifluoroacetic anhydride.

[0147] In some embodiments, the electrophilic reagent is triflic anhydride and OL is tritiate. Accordingly, provided herein is a process for the production of a compound of Formula (IXa): the process comprising reacting the compound of Formula (VIII): or a salt thereof, with triflic anhydride in the presence of a base.

[0148] In some embodiments, the base used in the process for the production of a compound of Formula (IX) (IXa), (IXb), (IXc), (IXd) or (IXe), is selected from pyridine, 4-dimethylaminopyridine (DMPA), tetramethylpyridine, N-methylpiperazine, lutidine, 2,6-lutidine, N-methylmorpholine, DBU (1 ,8- diazabicyclo(5.4.0)undec-7-ene), guanidine bases such as tetramethylguanidine, and trialkylamines such as triethylamine, tributylamine and diisopropylethylamine. In some embodiments, the base is selected from pyridine, lutidine, DBU (1 ,8-diazabicyclo(5.4.0)undec-7-ene), guanidine bases and trialkylamines such as triethylamine and tributylamine. In some embodiments, the base is pyridine. In some embodiments, the base is triethylamine. In some embodiments, the base is diisopropylethylamine. In some embodiments, the base used in the process for the production of a compound of Formula (IXa) is pyridine. In some embodiments, the base used in the process for the production of a compound of Formula (IXb) is pyridine. In some embodiments, the base used in the process for the production of a compound of Formula (IXb) is triethylamine. In some embodiments, the base used in the process for the production of a compound of Formula (IXc) is pyridine. In some embodiments, the base used in the process for the production of a compound of Formula (IXc) is diisopropylethylamine. In some embodiments, the base used in the process for the production of a compound of Formula (IXd) is pyridine. In some embodiments, the base used in the process for the production of a compound of Formula (IXd) is triethylamine. In some embodiments, the base used in the process for the production of a compound of Formula (IXe) is pyridine. In some embodiments, in the process for the production of a compound of Formula (IX), from about 1.1 to about 2.0 molar equivalents of electrophilic reagent is used, optionally about 1.5 molar equivalents of electrophilic reagent is used. In some embodiments, about 1.1 , about 1 .2, about 1 .3, about 1 .4, about 1.5, about 1.6, about 1.7, about 1.8, about 1.9, or about 2.0 molar equivalents of electrophilic reagent is used. In some embodiments about 1 .5 molar equivalents of electrophilic reagent is used.

[0149] In some embodiments, in the process for the production of a compound of Formula (IXa), from about

[0150] 1 .1 to about 2.0 molar equivalents of triflic anhydride is used, optionally about 1 .5 molar equivalents of triflic anhydride is used. In some embodiments, about 1.1 , about 1.2, about 1.3, about 1.4, about 1.5, about 1 .6, about 1 .7, about 1 .8, about 1.9, or about 2.0 molar equivalents of triflic anhydride is used. In some embodiments about 1 .5 molar equivalents of triflic anhydride is used.

[0151] In some embodiments, in the process for the production of a compound of Formula (IXb), from about

[0152] 1.1 to about 2.0 molar equivalents of 4-toluenesulfonyl chloride is used, optionally about 1.5 molar equivalents of 4-toluenesulfonyl chloride is used. In some embodiments, about 1.1 , about 1.2, about 1 .3, about 1 .4, about 1 .5, about 1 .6, about 1 .7, about 1 .8, about 1 .9, or about 2.0 molar equivalents of 4-toluenesulfonyl chloride is used. In some embodiments about 1.5 molar equivalents of 4- toluenesulfonyl chloride is used.

[0153] Alternatively, in some embodiments, in the process for the production of a compound of Formula (IXb), from about 1 .1 to about 2.0 molar equivalents of 4-toluenesulfonic anhydride is used, optionally about 1.5 molar equivalents of 4-toluenesulfonic anhydride is used. In some embodiments, about 1.1 , about 1.2, about 1.3, about 1.4, about 1.5, about 1.6, about 1.7, about 1.8, about 1 .9, or about 2.0 molar equivalents of 4-toluenesulfonic anhydride is used. In some embodiments about 1.5 molar equivalents of 4-toluenesulfonic anhydride is used.

[0154] In some embodiments, in the process for the production of a compound of Formula (IXc), from about

[0155] 1.1 to about 2.0 molar equivalents of methanesulfonyl chloride is used, optionally about 1.5 molar equivalents of methanesulfonyl chloride is used. In some embodiments, about 1 .1 , about 1 .2, about 1 .3, about 1.4, about 1.5, about 1.6, about 1.7, about 1.8, about 1.9, or about 2.0 molar equivalents of methanesulfonyl chloride is used. In some embodiments about 1.5 molar equivalents of methanesulfonyl chloride is used.

[0156] Alternatively, in some embodiments, in the process for the production of a compound of Formula (IXc), from about 1.1 to about 2.0 molar equivalents of methanesulfonic anhydride is used, optionally about 1.5 molar equivalents of methanesulfonic anhydride is used. In some embodiments, about 1.1 , about 1.2, about 1.3, about 1.4, about 1.5, about 1.6, about 1.7, about 1.8, about 1 .9, or about 2.0 molar equivalents of methanesulfonic anhydride is used. In some embodiments about 1.5 molar equivalents of methanesulfonic anhydride is used.

[0157] In some embodiments, in the process for the production of a compound of Formula (IXd), from about

[0158] 1.1 to about 2.0 molar equivalents of benzenesulfonyl chloride is used, optionally about 1.5 molar equivalents of benzenesulfonyl chloride is used. In some embodiments, about 1.1 , about 1 .2, about 1 .3, about 1.4, about 1.5, about 1.6, about 1.7, about 1.8, about 1.9, or about 2.0 molar equivalents of benzenesulfonyl chloride is used. In some embodiments about 1.5 molar equivalents of benzenesulfonyl chloride is used.

[0159] Alternatively, in some embodiments, in the process for the production of a compound of Formula (IXd), from about 1 .1 to about 2.0 molar equivalents of benzenesulfonic anhydride is used, optionally about 1.5 molar equivalents of benzenesulfonic anhydride is used. In some embodiments, about 1.1 , about 1.2, about 1.3, about 1.4, about 1.5, about 1.6, about 1.7, about 1.8, about 1 .9, or about 2.0 molar equivalents of benzenesulfonic anhydride is used. In some embodiments about 1.5 molar equivalents of benzenesulfonic anhydride is used.

[0160] In some embodiments, in the process for the production of a compound of Formula (IXe), from about 1.1 to about 2.0 molar equivalents of trifluoroacetic anhydride is used, optionally about 1.5 molar equivalents of trifluoroacetic anhydride is used. In some embodiments, about 1.1 , about 1 .2, about 1 .3, about 1.4, about 1.5, about 1.6, about 1.7, about 1.8, about 1.9, or about 2.0 molar equivalents of trifluoroacetic anhydride is used. In some embodiments about 1.5 molar equivalents of trifluoroacetic anhydride is used.

[0161] In some embodiments, the process for the production of a compound of Formula (IX), (IXa), (IXb), (IXc), (IXd) or (IXe) is carried out in an aprotic solvent or in a mixture of aprotic solvents. In some embodiments, the process is carried out in an aprotic solvent or mixture thereof, for example, where the one or more aprotic solvent(s) is / are selected from dichloromethane, toluene, acetonitrile, dimethylformamide, ethyl acetate, pyridine, tetrahydrofuran and 2-methyl tetra hydrofuran. In some embodiments, the process is carried out in dichloromethane. In some embodiments, the process is carried out in a solvent selected from dichloromethane, toluene, acetonitrile, methyl tert-butyl ether, 2- methyltetryhydrofuran, tetrahydrofuran, cyclopentyl methyl ether, anisole, benzonitrile acetone, methyl ethyl ketone, and chlorobenzene, or a mixture thereof. In some embodiments, the process is carried out in toluene. In some embodiments, the process is carried out in a mixture of dichloromethane and toluene. In some embodiments, the process is carried out in a mixture of dichloromethane and toluene.

[0162] In some embodiments, the process for the production of a compound of Formula (IXa) is carried out in a solvent selected from dichloromethane, toluene, acetonitrile, methyl tert-butyl ether, 2- methyltetryhydrofuran, tetrahydrofuran, cyclopentyl methyl ether, anisole, benzonitrile acetone, methyl ethyl ketone, and chlorobenzene, or a mixture thereof. In some embodiments, the process for the production of a compound of Formula (IXa) is carried out in dichloromethane. In some embodiments, the process for the production of a compound of Formula (IXa) is carried out in toluene. In some embodiments, the process for the production of a compound of Formula (IXa) is carried out in a mixture of dichloromethane and toluene.

[0163] In some embodiments, the process for the production of a compound of Formula (IXb) is carried out in a solvent selected from dichloromethane, toluene, acetonitrile, methyl tert-butyl ether, 2- methyltetryhydrofuran, tetrahydrofuran, cyclopentyl methyl ether, anisole, benzonitrile acetone, methyl ethyl ketone, and chlorobenzene, or a mixture thereof. In some embodiments, the process for the production of a compound of Formula (IXb) is carried out in acetonitrile. In some embodiments, the process for the production of a compound of Formula (IXb) is carried out in dichloromethane. In some embodiments, the process for the production of a compound of Formula (IXb) is carried out in toluene. In some embodiments, the process for the production of a compound of Formula (IXb) is carried out in a mixture of dichloromethane and toluene.

[0164] In some embodiments, the process for the production of a compound of Formula (IXc) is carried out in a solvent selected from dichloromethane, toluene, acetonitrile, methyl tert-butyl ether, 2- methyltetryhydrofuran, tetrahydrofuran, cyclopentyl methyl ether, anisole, benzonitrile acetone, methyl ethyl ketone, and chlorobenzene, or a mixture thereof. In some embodiments, the process for the production of a compound of Formula (IXc) is carried out in 2-methyl tetrahydrofuran. In some embodiments, the process for the production of a compound of Formula (IXc) is carried out in dichloromethane. In some embodiments, the process forthe production of a compound of Formula (IXc) is carried out in toluene. In some embodiments, the process for the production of a compound of Formula (IXc) is carried out in a mixture of dichloromethane and toluene.

[0165] In some embodiments, the process for the production of a compound of Formula (IXd) is carried out in a solvent selected from dichloromethane, toluene, acetonitrile, methyl tert-butyl ether, 2- methyltetryhydrofuran, tetrahydrofuran, cyclopentyl methyl ether, anisole, benzonitrile acetone, methyl ethyl ketone, and chlorobenzene, or a mixture thereof. In some embodiments, the process for the production of a compound of Formula (IXd) is carried out in dichloromethane. In some embodiments, the process for the production of a compound of Formula (IXd) is carried out in toluene. In some embodiments, the process for the production of a compound of Formula (IXd) is carried out in a mixture of dichloromethane and toluene.

[0166] In some embodiments, the process for the production of a compound of Formula (IXe) is carried out in a solvent selected from dichloromethane, toluene, acetonitrile, methyl tert-butyl ether, 2- methyltetryhydrofuran, tetrahydrofuran, cyclopentyl methyl ether, anisole, benzonitrile acetone, methyl ethyl ketone, and chlorobenzene, or a mixture thereof. In some embodiments, the process for the production of a compound of Formula (IXe) is carried out in dichloromethane. In some embodiments, the process for the production of a compound of Formula (IXe) is carried out in toluene. In some embodiments, the process for the production of a compound of Formula (IXe) is carried out in a mixture of dichloromethane and toluene. In some embodiments, the process for the production of a compound of Formula (IX), (IXa), (IXb), (IXc), (IXd) or (IXe) is carried out in batch manufacture. Alternatively, in some embodiments, the process is carried out using a continuous flow process. In some embodiments, a residence time of from about 5 to about 60 seconds is used in the continuous flow process. In some embodiments, the residence time is from about 15 to about 45 seconds, optionally from about 20 to about 40 seconds, more optionally about 30 seconds. In some embodiments, the residence time is about 15 seconds, about 20 seconds, about 25 seconds, about 30 seconds, about 35 seconds, about 40 seconds, or about 45 seconds. In some embodiments, the residence time is about 25 seconds, about 26 seconds, about 27 seconds, about 28 seconds, about 29 seconds, about 30 seconds, about 31 seconds, about 32 seconds, about 33 seconds, about 34 seconds, or about 35 seconds. In some embodiments, the residence time is about 30 seconds.

[0167] In some embodiments, the process for the production of a compound of Formula (IX) further comprises a process for the production of the compound of Formula (VIII) as described herein, particularly in section “3. Process for the production of the benzyl ester of Formula (VI 11) or a salt thereof’.

[0168] In some embodiments, the process for the production of a compound of Formula (IXa) further comprises a process for the production of the compound of Formula (VIII) as described herein, particularly in section “3. Process for the production of the benzyl ester of Formula (VI 11) or a salt thereof’.

[0169] In some embodiments, the process for the production of a compound of Formula (IXb) further comprises a process for the production of the compound of Formula (VIII) as described herein, particularly in section “3. Process for the production of the benzyl ester of Formula (VI 11) or a salt thereof’.

[0170] In some embodiments, the process forthe production of a compound of Formula (IXc) further comprises a process for the production of the compound of Formula (VIII) as described herein, particularly in section “3. Process for the production of the benzyl ester of Formula (VI 11) or a salt thereof’.

[0171] In some embodiments, the process for the production of a compound of Formula (IXd) further comprises a process for the production of the compound of Formula (VIII) as described herein, particularly in section “3. Process for the production of the benzyl ester of Formula (VI 11) or a salt thereof’.

[0172] In some embodiments, the process for the production of a compound of Formula (IXe) further comprises a process for the production of the compound of Formula (VIII) as described herein, particularly in section “3. Process for the production of the benzyl ester of Formula (VI 11) or a salt thereof’.

[0173] Also provided herein is a process of producing a compound of Formula (IX): wherein OL is a leaving group, as an intermediate in a process of producing a compound of Formula (II): a salt thereof, or a hydrate thereof, wherein the process comprises a process for the production of a compound of Formula (IX) as described herein. In some embodiments, OL is selected from triflate, mesylate, tosylate, benzenesulfonate, and trifluoroacetate.

[0174] In some embodiments, OL is triflate. Accordingly, also provided herein is a process of producing a compound of Formula (IXa): as an intermediate in a process of producing a compound of Formula (II): a salt thereof, or a hydrate thereof, wherein the process comprises a process for the production of a compound of Formula (IXa) as described herein.

[0175] In some embodiments, OL is tosylate. Accordingly, also provided herein is a process of producing a compound of Formula (IXb): as an intermediate in a process of producing a compound of Formula (II): a salt thereof, or a hydrate thereof, wherein the process comprises a process for the production of a compound of Formula (IXb) as described herein. In some embodiments, OL is mesylate. Accordingly, also provided herein is a process of producing a compound of Formula (IXc): as an intermediate in a process of producing a compound of Formula (II): a salt thereof, or a hydrate thereof, wherein the process comprises a process for the production of a compound of Formula (IXc) as described herein.

[0176] In some embodiments, OL is benzenesulfonate. Accordingly, also provided herein is a process of producing a compound of Formula (IXd): as an intermediate in a process of producing a compound of Formula (II): a salt thereof, or a hydrate thereof, wherein the process comprises a process for the production of a compound of Formula (IXd) as described herein.

[0177] In some embodiments, OL is trifluoroacetate. Accordingly, also provided herein is a process of producing a compound of Formula (IXe): as an intermediate in a process of producing a compound of Formula (II): a salt thereof, or a hydrate thereof, wherein the process comprises a process for the production of a compound of Formula (IXe) as described herein.

[0178] Also provided herein is a process of producing a compound of Formula (IX): wherein OL is a leaving group, as an intermediate in a process of producing a compound of Formula (I): a salt thereof, or a hydrate thereof, wherein the process comprises a process for the production of a compound of Formula (IX) as described herein. In some embodiments, OL is selected from triflate, mesylate, tosylate, benzenesulfonate, and trifluoroacetate.

[0179] In some embodiments, OL is triflate. Accordingly, also provided herein is a process of producing a compound of Formula (IXa): as an intermediate in a process of producing a compound of Formula (I): a salt thereof, or a hydrate thereof, wherein the process comprises a process for the production of a compound of Formula (IXa) as described herein.

[0180] In some embodiments, OL is tosylate. Accordingly, also provided herein is a process of producing a compound of Formula (IXb): as an intermediate in a process of producing a compound of Formula (I): a salt thereof, or a hydrate thereof, wherein the process comprises a process for the production of a compound of Formula (IXb) as described herein. In some embodiments, OL is mesylate. Accordingly, also provided herein is a process of producing a compound of Formula (IXc): as an intermediate in a process of producing a compound of Formula (I): a salt thereof, or a hydrate thereof, wherein the process comprises a process for the production of a compound of Formula (IXc) as described herein.

[0181] In some embodiments, OL is benzenesulfonate. Accordingly, also provided herein is a process of producing a compound of Formula (IXd): as an intermediate in a process of producing a compound of Formula (I): a salt thereof, or a hydrate thereof, wherein the process comprises a process for the production of a compound of Formula (IXd) as described herein. In some embodiments, OL is trifluoroacetate. Accordingly, also provided herein is a process of producing a compound of Formula (IXe): as an intermediate in a process of producing a compound of Formula (I): a salt thereof, or a hydrate thereof, wherein the process comprises a process for the production of a compound of Formula (IXe) as described herein.

[0182] In some embodiments, the process is for the production of a salt of a compound of Formula (I), optionally wherein the process is for the production of a xinafoate salt of Formula (la):

[0183] It will be understood that the present disclosure also relates to the direct products of the processes as described anywhere herein. The present disclosure also relates to products obtainable by processes as described anywhere herein. Accordingly, also provided herein is a compound of Formula (IX): wherein OL is a leaving group, obtained by the process for the production of a compound of Formula (IX) as described anywhere herein.

[0184] Accordingly, also provided herein is a compound of Formula (IXa): obtained by the process for the production of a compound of Formula (IXa) as described anywhere herein.

[0185] Accordingly, also provided herein is a compound of Formula (IXb): obtained by the process for the production of a compound of Formula (IXb) as described anywhere herein.

[0186] Accordingly, also provided herein is a compound of Formula (IXc): obtained by the process for the production of a compound of Formula (IXc) as described anywhere herein. Accordingly, also provided herein is a compound of Formula (IXd): obtained by the process for the production of a compound of Formula (IXd) as described anywhere herein.

[0187] Accordingly, also provided herein is a compound of Formula (IXe): obtained by the process for the production of a compound of Formula (IXe) as described anywhere herein.

[0188] The compound may exhibit characteristics deriving from the process by which it was made, which characteristics will render it possible to determine by routine tests that the compound per se was made by a process according to the disclosure.

[0189] 5. Step 5: production of the benzyl protected amino acid of Formula (X) or a salt thereof

[0190] Conversion of the triflate of Formula (IX) to the benzyl protected amino acid of Formula (X) is shown in Scheme 9, wherein OL is a leaving group.

[0191] Scheme 9

[0192] In some embodiments, OL is selected from triflate, mesylate, tosylate, benzenesulfonate, and trifluoroacetate. In some embodiments, OL is triflate. In some embodiments, OL is mesylate. In some embodiments, OL is tosylate. In some embodiments, OL is benzenesulfonate. In some embodiments, OL is trifluoroacetate.

[0193] Accordingly, provided herein is a process for the production of a compound of Formula (X): or a salt thereof, the process comprising reacting the compound of Formula (IX): wherein OL is a leaving group, with 1 -methylpiperazine. In some embodiments, OL is selected from tritiate, mesylate, tosylate, benzenesulfonate, and trifluoroacetate. In some embodiments, OL is triflate. In some embodiments, OL is mesylate. In some embodiments, OL is tosylate. In some embodiments, OL is benzenesulfonate. In some embodiments, OL is trifluoroacetate.

[0194] Conversion of the triflate of Formula (IXa) to the benzyl protected amino acid of Formula (X) is shown in Scheme 9a.

[0195] Scheme 9a

[0196] This process involves using a SN2 displacement of a chiral triflate of Formula (IXa) with N- methylpi perazine to form the compound of Formula (X) in very high levels of stereocontrol. Reaction of the compound of Formula (IXa) with N-methyl piperazine was initially demonstrated in batch providing the benzyl protected amino acid of Formula (X) in 92% e.p. This transformation was further improved by application of continuous manufacture to provide the benzyl protected amino acid of Formula (X) in > 99% e.p.

[0197] Conversion of the tosylate of Formula (IXb) to the benzyl protected amino acid of Formula (X) is shown in Scheme 9b. This process involves using a SN2 displacement of a chiral tosylate of Formula (IXb) with N-methylpiperazine to form the compound of Formula (X).

[0198] Scheme 9b

[0199] Conversion of the mesylate of Formula (IXc) to the benzyl protected amino acid of Formula (X) is shown in Scheme 9c. This process involves using a SN2 displacement of a chiral mesylate of Formula (IXc) with N-methylpiperazine to form the compound of Formula (X).

[0200] Scheme 9c

[0201] Conversion of the benzenesulfonate of Formula (IXd) to the benzyl protected amino acid of Formula (X) is shown in Scheme 9d. This process involves using a SN2 displacement of a chiral bezenesulfonate of Formula (IXd) with N-methylpiperazine to form the compound of Formula (X).

[0202] Scheme 9d

[0203] Conversion of the tri fluoroacetate of Formula (IXe) to the benzyl protected amino acid of Formula (X) is shown in Scheme 9e. This process involves using a SN2 displacement of a chiral trifluoroacetate of Formula (IXe) with N-methylpiperazine to form the compound of Formula (X).

[0204] Scheme 9e

[0205] Accordingly, provided herein is a process for the production of a compound of Formula (X): or a salt thereof, the process comprising reacting the compound of Formula (IX): wherein OL is a leaving group, with 1 -methylpiperazine. In some embodiments, OL is selected from tritiate, mesylate, tosylate, benzenesulfonate, and trifluoroacetate.

[0206] In some embodiments, OL is tritiate. Accordingly, provided herein is a process for the production of a compound of Formula (X): or a salt thereof, the process comprising reacting the compound of Formula (IXa): with 1-methylpiperazine. In some embodiments, OL is tosylate. Accordingly, provided herein is a process for the production of a compound of Formula (X): or a salt thereof, the process comprising reacting the compound of Formula (IXb): with 1-methylpiperazine.

[0207] In some embodiments, OL is mesylate. Accordingly, provided herein is a process for the production of a compound of Formula (X): or a salt thereof, the process comprising reacting the compound of Formula (IXc): with 1-methylpiperazine. In some embodiments, OL is benzenesulfonate. Accordingly, provided herein is a process for the production of a compound of Formula (X): or a salt thereof, the process comprising reacting the compound of Formula (IXd): with 1-methylpiperazine.

[0208] In some embodiments, OL is trifluoroacetate. Accordingly, provided herein is a process for the production of a compound of Formula (X): or a salt thereof, the process comprising reacting the compound of Formula (IXe): with 1-methylpiperazine.

[0209] In some embodiments, from about 1.1 to about 2.0 molar equivalents of 1-methylpiperazine is used, optionally about 1 .5 molar equivalents of 1-methylpiperazine is used. In some embodiments, about 1.1 , about 1 .2, about 1 .3, about 1 .4, about 1 .5, about 1 .6, about 1 .7, about 1 .8, about 1 .9, or about 2.0 molar equivalents of 1-methylpiperazine is used. In some embodiments, about 1.5 molar equivalents of 1- methylpi perazine is used.

[0210] In some embodiments, the process is carried out in an aprotic solvent or mixture thereof, for example, where the one or more aprotic solvent(s) is / are selected from dichloromethane, dimethylformamide, ethyl acetate, pyridine, tetrahydrofuran and 2-methyl tetra hydrofuran. In some embodiments, the process is carried out in a mixture of dichloromethane and 2-methyltetrahydrofuran.

[0211] In some embodiments, the process is carried out in batch manufacture. Alternatively, in some embodiments, the process is carried out using a continuous flow process. In some embodiments, a residence time of from about 5 to about 20 minutes is used in the continuous flow process, optionally the residence time is from about 7 to about 15 minutes, optionally the residence time about 10 minutes. In some embodiments, a residence time of about 5, about 6, about 7, about 8, about 9, about 10, about 11 , about 12, about 13, about 14, about 15, about 16, about 17, about 18, about 19, or about 20 minutes is used in the continuous flow process. In some embodiments, a residence time of about 10 minutes is used in the continuous flow process.

[0212] According to the present process, the compound of Formula (X) may be obtained in an enantiomeric purity of at least 90.0%, at least 91 .0%, at least 92.0%, at least 93.0%, at least 94.0%, at least 95.0%, at least 96.0%, at least 97.0%, at least 98.0%, or at least 99.0%. The compound of Formula (X) may be obtained in an enantiomeric purity of at least 94.0%, at least 95.0%, at least 96.0%, at least 97.0%, at least 98.0%, or at least 99.0%.

[0213] In some embodiments, the process for the production of a compound of Formula (X) further comprises a process for the production of the compound of Formula (IX) as described herein, particularly in section “4. Process for the production of the intermediate of Formula (IX)”. In some embodiments, the process for the production of a compound of Formula (X) further comprises a process for the production of the compound of Formula (IXa) as described herein, particularly in section “4. Process for the production of the intermediate of Formula (IX)”. In some embodiments, the process for the production of a compound of Formula (X) further comprises a process for the production of the compound of Formula (IXb) as described herein, particularly in section “4. Process for the production of the intermediate of Formula (IX)”. In some embodiments, the process for the production of a compound of Formula (X) further comprises a process for the production of the compound of Formula (IXc) as described herein, particularly in section “4. Process for the production of the intermediate of Formula (IX)”. In some embodiments, the process for the production of a compound of Formula (X) further comprises a process for the production of the compound of Formula (IXd) as described herein, particularly in section “4. Process for the production of the intermediate of Formula (IX)”. In some embodiments, the process for the production of a compound of Formula (X) further comprises a process for the production of the compound of Formula (IXe) as described herein, particularly in section “4. Process for the production of the intermediate of Formula (IX)”.

[0214] Also provided herein is a process of producing a compound of Formula (X): or a salt thereof, as an intermediate in a process of producing a compound of Formula (II): a salt thereof, or a hydrate thereof, wherein the process comprises a process for the production of a compound of Formula (X) as described herein.

[0215] Also provided herein is a process of producing a compound of Formula (X): or a salt thereof, as an intermediate in a process of producing a compound of Formula (I): a salt thereof, or a hydrate thereof, wherein the process comprises a process for the production of a compound of Formula (X) as described herein. In some embodiments, the process is for the production of a salt of a compound of Formula (I), optionally wherein the process is for the production of a xinafoate salt of Formula (la):

[0216] It will be understood that the present disclosure also relates to the direct products of the processes as described anywhere herein. The present disclosure also relates to products obtainable by processes as described anywhere herein.

[0217] Accordingly, also provided herein is a compound of Formula (X): or a salt thereof, obtained by the process for the production of a compound of Formula (X) as described anywhere herein. The compound may exhibit characteristics deriving from the process by which it was made, which characteristics will render it possible to determine by routine tests that the compound per se was made by a process according to the disclosure. 6. Step 6: production of the amino acid of Formula (II), a salt thereof, or a hydrate thereof

[0218] Conversion of the benzyl ester of Formula (X) to the compound of Formula (II) is shown in Scheme 10.

[0219] Scheme 10

[0220] Deprotection of the benzyl ester group by hydrogenolysis of the benzyl ester followed by isolation of the amino acid of Formula (II) as the corresponding dihydrochloride salt provided a scalable and efficient synthesis of (R)-3-methoxy-2-(4-methylpiperazin-1-yl)propanoic acid (compound of Formula (II)) in good overall yield (32%) and very high optical purity (> 99.5% e.p.).

[0221] Accordingly, provided herein is a process for the production of a compound of Formula (II): a salt thereof, or a hydrate of the salt thereof, the process comprising a deprotecting step of hydrogenating the compound of Formula (X):

[0222] .0. or a salt thereof.

[0223] In some embodiments, hydrogenating is carried out in the presence of palladium catalyst. In some embodiments, palladium on carbon (Pd / C) is used. Optionally, 10% palladium on carbon (Pd / C) is used.

[0224] In some embodiments, the process further comprises reacting the compound of Formula (II), or a salt thereof, with hydrochloric acid to form the dihydrochloride monohydrate salt of Formula (Ila):

[0225] Alternatively, in some embodiments, the salt is selected from an HBr, HI, sulphonate, phosphate and carboxylate salt.

[0226] According to the present process, the compound of Formula (II) may be obtained in an enantiomeric purity of at least 97.0%, at least 98.0%, or at least 99.0%. The compound of Formula (II) or a salt thereof may be obtained in an enantiomeric purity of at least 99.5%, at least 99.6%, at least 99.7%, at least 99.8%, or at least 99.9%.

[0227] In some embodiments, the process for the production of a compound of Formula (II) further comprises a process for the production of a compound of Formula (X) as described herein, particularly in section “5. Process for the production of the benzyl protected amino acid of Formula (X) or a salt thereof

[0228] Also provided herein is a process of producing a compound of Formula (II): a salt thereof, or a hydrate thereof, as an intermediate in a process of producing a compound of Formula (I): a salt thereof, or a hydrate thereof, wherein the process comprises a process for the production of a compound of Formula (II) as described herein.

[0229] In some embodiments, the process is for the production of a salt of a compound of Formula (I), optionally wherein the process is for the production of a xinafoate salt of Formula (la):

[0230] It will be understood that the present disclosure also relates to the direct products of the processes as described anywhere herein. The present disclosure also relates to products obtainable by processes as described anywhere herein. Accordingly, also provided herein is a compound of Formula (II): or a salt thereof, or a hydrate thereof, obtained by the process for the production of a compound of Formula (II) as described anywhere herein.

[0231] The compound may exhibit characteristics deriving from the process by which it was made, which characteristics will render it possible to determine by routine tests that the compound per se was made by a process according to the disclosure.

[0232] Also provided herein is a compound of Formula (Ila): obtained by the process for the production of a compound of Formula (Ila) as described anywhere herein.

[0233] The compound may exhibit characteristics deriving from the process by which it was made, which characteristics will render it possible to determine by routine tests that the compound per se was made by a process according to the disclosure. 7. Process for the production of a compound of Formula (I), a salt thereof, or a hydrate thereof

[0234] Also provided herein is a process for the production of a compound of Formula (I): a salt thereof, a hydrate thereof, or a hydrate of the salt thereof, comprising reacting a compound of formula (III): or a salt thereof, and a compound of formula (II): a salt thereof, or a hydrate thereof, wherein compound of formula (II) is prepared according to a process as described herein, particularly in section “6. Process for the production of the amino acid of Formula (II), a salt thereof, or a hydrate thereof’. In some embodiments, the process is for the production of a compound of Formula (I) or a salt thereof.

[0235] In some embodiments, the compound of Formula (III) is reacted with the compound of Formula (II) in the presence of a base, optionally wherein the base is N,N-Diisopropylethylamine (DIPEA). In some embodiments, the compound of Formula (III) is reacted with the compound of Formula (II) in the presence of HATU along with DIPEA or triethylamine in a polar aprotic solvent, such as DMF.

[0236] In some embodiments, the process is for the production of a salt of a compound of Formula (I). In some embodiments, the process is for the production of a xinafoate salt of Formula (la):

[0237] Also provided herein is a process for the production of a compound of Formula (I): a salt thereof, or a hydrate thereof, comprising reacting a compound of formula (III): or a salt thereof, and a compound of formula (II): a salt thereof, or a hydrate thereof, wherein compound of formula (II), a salt thereof, or a hydrate thereof, is prepared according to a process comprising the following steps: a) reacting a methoxide with a compound of Formula (VI): wherein X is a counter cation, to form a compound of Formula (VII): or a salt thereof, b) protecting the carboxylate group of the compound of Formula (VII), or a salt thereof, with a benzyl group in the presence of a base, to form a compound of Formula (VIII): or a salt thereof, c) reacting the compound of Formula (VIII), or a salt thereof, with an electrophilic reagent in the presence of a base to form a compound of Formula (IX): wherein OL is a leaving group, d) reacting the compound of Formula (IX) with 1 -methylpiperazine to form a compound of Formula (X): or a salt thereof, and e) deprotecting the compound Formula (X), or a salt thereof, in the presence of hydrogen to form the compound of Formula (II), or a salt thereof.

[0238] Optionally, the process further comprises the following step: f) reacting the compound of Formula (II), or a salt thereof, with hydrochloric acid to form the dihydrochloride mohohydrate salt of Formula (Ila):

[0239] In some embodiments, OL is selected from triflate, mesylate, tosylate, benzenesulfonate, and trifluoroacetate. In some embodiments, OL is triflate. In some embodiments, OL is mesylate. In some embodiments, OL is tosylate. In some embodiments, OL is benzenesulfonate. In some embodiments, OL is trifluoroacetate.

[0240] In some embodiments, the electrophilic reagent is selected from triflic anhydride, methanesulfonic anhydride, methanesulfonyl chloride, 4-toluenesulfonic anhydride, 4-toluenesulfonyl chloride, benzenesulfonic anhydride, benzenesulfonyl chloride, and trifluoroacetic anhydride. In some embodiments, the electrophilic reagent is triflic anhydride. In some embodiments, the electrophilic reagent is methanesulfonic anhydride. In some embodiments, the electrophilic reagent is methanesulfonyl chloride. In some embodiments, the electrophilic reagent is 4-toluenesulfonic anhydride. In some embodiments, the electrophilic reagent is 4-toluenesulfonyl chloride. In some embodiments, the electrophilic reagent is benzenesulfonic anhydride. In some embodiments, the electrophilic reagent is benzenesulfonyl chloride. In some embodiments, the electrophilic reagent is trifluoroacetic anhydride.

[0241] In some embodiments, OL is triflate and the electrophilic reagent is triflic anhydride. Accordingly, also provided herein is a process for the production of a compound of Formula (I): a salt thereof, or a hydrate thereof, comprising reacting a compound of formula (III): or a salt thereof, and a compound of formula (II): a salt thereof, or a hydrate thereof, wherein compound of formula (II), a salt thereof, or a hydrate thereof, is prepared according to a process comprising the following steps: a) reacting a methoxide with a compound of Formula (VI): wherein X is a counter cation, to form a compound of Formula (VII): or a salt thereof, b) protecting the carboxylate group of the compound of Formula (VII), or a salt thereof, with a benzyl group in the presence of a base, to form a compound of Formula (VIII): or a salt thereof, C) reacting the compound of Formula (VIII), or a salt thereof, with triflic anhydride in the presence of a base to form a compound of Formula (IXa): d) reacting the compound of Formula (IXa) with 1 -methylpiperazine to form a compound of Formula (X): or a salt thereof, and e) deprotecting the compound Formula (X), or a salt thereof, in the presence of hydrogen to form the compound of Formula (II), or a salt thereof.

[0242] Optionally, the process further comprises the following step: f) reacting the compound of Formula (II), or a salt thereof, with hydrochloric acid to form the dihydrochloride mohohydrate salt of Formula (Ila):

[0243] In some embodiments, OL is tosylate and the electrophilic reagent is 4-toluenesulfonyl chloride. Alternatively, in some embodiments, OL is tosylate and the electrophilic reagent is 4-toluenesulfonic anhydride. Accordingly, also provided herein is a process for the production of a compound of Formula (I): a salt thereof, or a hydrate thereof, comprising reacting a compound of formula (III): or a salt thereof, and a compound of formula (II): a salt thereof, or a hydrate thereof, wherein compound of formula (II), a salt thereof, or a hydrate thereof, is prepared according to a process comprising the following steps: a) reacting a methoxide with a compound of Formula (VI): wherein X is a counter cation, to form a compound of Formula (VII): or a salt thereof, b) protecting the carboxylate group of the compound of Formula (VII), or a salt thereof, with a benzyl group in the presence of a base, to form a compound of

[0244] Formula (VIII): or a salt thereof, c) reacting the compound of Formula (VIII), or a salt thereof, with 4- toluenesulfonyl chloride or 4-toluenesulfonic anhydride in the presence of a base to form a compound of Formula (IXb): d) reacting the compound of Formula (IXb) with 1-methylpiperazine to form a compound of Formula (X): or a salt thereof, and e) deprotecting the compound Formula (X), or a salt thereof, in the presence of hydrogen to form the compound of Formula (II), or a salt thereof.

[0245] Optionally, the process further comprises the following step: f) reacting the compound of Formula (II), or a salt thereof, with hydrochloric acid to form the dihydrochloride mohohydrate salt of Formula (Ila):

[0246] In some embodiments, OL is mesylate and the electrophilic reagent is methanesulfonyl chloride. Alternatively, in some embodiments, OL is mesylate and the electrophilic reagent is methanesulfonic anhydride. Accordingly, also provided herein is a process for the production of a compound of Formula (I): a salt thereof, or a hydrate thereof, comprising reacting a compound of formula (III): or a salt thereof, and a compound of formula (II): a salt thereof, or a hydrate thereof, wherein compound of formula (II), a salt thereof, or a hydrate thereof, is prepared according to a process comprising the following steps: a) reacting a methoxide with a compound of Formula (VI): wherein X is a counter cation, to form a compound of Formula (VII): or a salt thereof, b) protecting the carboxylate group of the compound of Formula (VII), or a salt thereof, with a benzyl group in the presence of a base, to form a compound of Formula (VIII): or a salt thereof, c) reacting the compound of Formula (VIII), or a salt thereof, with methanesulfonyl chloride or methanesulfonic anhydride in the presence of a base to form a compound of Formula (IXc): d) reacting the compound of Formula (IXc) with 1 -methylpiperazine to form a compound of Formula (X): or a salt thereof, and e) deprotecting the compound Formula (X), or a salt thereof, in the presence of hydrogen to form the compound of Formula (II), or a salt thereof.

[0247] Optionally, the process further comprises the following step: f) reacting the compound of Formula (II), or a salt thereof, with hydrochloric acid to form the dihydrochloride mohohydrate salt of Formula (Ila):

[0248] In some embodiments, OL is benzenesulfonate and the electrophilic reagent is benzenesulfonyl chloride. Alternatively, in some embodiments, OL is benzenesulfonate and the electrophilic reagent is benzenesulfonic anhydride. Accordingly, also provided herein is a process for the production of a compound of Formula (I): a salt thereof, or a hydrate thereof, comprising reacting a compound of formula (III): or a salt thereof, and a compound of formula (II): a salt thereof, or a hydrate thereof, wherein compound of formula (II), a salt thereof, or a hydrate thereof, is prepared according to a process comprising the following steps: a) reacting a methoxide with a compound of Formula (VI): wherein X is a counter cation, to form a compound of Formula (VII): or a salt thereof, b) protecting the carboxylate group of the compound of Formula (VII), or a salt thereof, with a benzyl group in the presence of a base, to form a compound of Formula (VIII): or a salt thereof, c) reacting the compound of Formula (VIII), or a salt thereof, with benzenesulfonyl chloride or benzenesulfonic anhydride in the presence of a base to form a compound of Formula (IXd): d) reacting the compound of Formula (IXd) with 1-methylpiperazine to form a compound of Formula (X): or a salt thereof, and e) deprotecting the compound Formula (X), or a salt thereof, in the presence of hydrogen to form the compound of Formula (II), or a salt thereof.

[0249] Optionally, the process further comprises the following step: f) reacting the compound of Formula (II), or a salt thereof, with hydrochloric acid to form the dihydrochloride mohohydrate salt of Formula (Ila):

[0250] In some embodiments, OL is trifluoroacetate and the electrophilic reagent is trifluoroacetic anhydride.

[0251] Accordingly, also provided herein is a process for the production of a compound of Formula (I): a salt thereof, or a hydrate thereof, comprising reacting a compound of formula (III): or a salt thereof, and a compound of formula (II): a salt thereof, or a hydrate thereof, wherein compound of formula (II), a salt thereof, or a hydrate thereof, is prepared according to a process comprising the following steps: a) reacting a methoxide with a compound of Formula (VI): wherein X is a counter cation, to form a compound of Formula (VII): or a salt thereof, b) protecting the carboxylate group of the compound of Formula (VII), or a salt thereof, with a benzyl group in the presence of a base, to form a compound of Formula (VIII): or a salt thereof, c) reacting the compound of Formula (VIII), or a salt thereof, with trifluoroacetic anhydride in the presence of a base to form a compound of Formula (IXe): d) reacting the compound of Formula (IXe) with 1-methylpiperazine to form a compound of Formula (X): or a salt thereof, and e) deprotecting the compound Formula (X), or a salt thereof, in the presence of hydrogen to form the compound of Formula (II), or a salt thereof.

[0252] Optionally, the process further comprises the following step: f) reacting the compound of Formula (II), or a salt thereof, with hydrochloric acid to form the dihydrochloride mohohydrate salt of Formula (Ila):

[0253] In some embodiments, the process is for the production of a JAK1 inhibitor compound of Formula (I) or a salt thereof. In some embodiments, the process is for the production of a salt of a compound of Formula (I). In some embodiments, the process is for the production of a xinafoate salt of Formula (la):

[0254] Accordingly, also provided herein is a compound of Formula (I): or a salt thereof, or a hydrate thereof, obtained by the process for the production of a compound of Formula (I) as described anywhere herein.

[0255] The compound may exhibit characteristics deriving from the process by which it was made, which characteristics will render it possible to determine by routine tests that the compound per se was made by a process according to the disclosure. Also provided herein is a compound of Formula (la): obtained by the process for the production of a compound of Formula (la) as described anywhere herein.

[0256] The compound may exhibit characteristics deriving from the process by which it was made, which characteristics will render it possible to determine by routine tests that the compound per se was made by a process according to the disclosure.

[0257] Uses of intermediate compounds in the synthesis of a compound of Formula (II) or salts thereof

[0258] Provided herein is the use of D-serine in a method of producing a compound of Formula (II), or a salt thereof. Also provided herein is the use of a compound of Formula (Vlb): or a salt thereof, in a method of producing a compound of Formula (II), or a salt thereof. In some embodiments, the use is use of a carboxylate salt of Formula (VI): wherein X is a counter cation, optionally the salt is a potassium carboxylate salt of formula (Via):

[0259] Also provided herein is the use of a compound of Formula (VII): or a salt thereof, in a method of producing a compound of Formula (II), or a salt thereof.

[0260] Also provided herein is the use of a compound of Formula (VIII): or a salt thereof, in a method of producing a compound of Formula (II), or a salt thereof.

[0261] Also provided herein is the use of a compound of Formula (IX): wherein OL is a leaving group, or a salt thereof, in a method of producing a compound of Formula (II), or a salt thereof. In some embodiments, OL is selected from triflate, mesylate, tosylate, benzenesulfonate, and trifluoroacetate. In some embodiments, OL is triflate. Accordingly, also provided herein is the use of a compound of Formula (IXa): or a salt thereof, in a method of producing a compound of Formula (II), or a salt thereof.

[0262] In some embodiments, OL is tosylate. Accordingly, also provided herein is the use of a compound of Formula (IXb): or a salt thereof, in a method of producing a compound of Formula (II), or a salt thereof.

[0263] In some embodiments, OL is mesylate. Accordingly, also provided herein is the use of a compound of Formula (IXc): or a salt thereof, in a method of producing a compound of Formula (II), or a salt thereof.

[0264] In some embodiments, OL is benzenesulfonate. Accordingly, also provided herein is the use of a compound of Formula (IXd): or a salt thereof, in a method of producing a compound of Formula (II), or a salt thereof.

[0265] In some embodiments, OL is trifluoroacetate. Accordingly, also provided herein is the use of a compound of Formula (IXe): or a salt thereof, in a method of producing a compound of Formula (II), or a salt thereof.

[0266] Also provided herein is the use of a compound of Formula (X): .0. or a salt thereof, in a method of producing a compound of Formula (II), or a salt thereof.

[0267] While the present disclosure has been particularly shown and described with reference to specific embodiments, it should be understood by those skilled in the art that various changes may be made therein without departing from the spirit and scope of the present disclosure as disclosed herein.

[0268] Additional embodiments of the invention

[0269] The present invention may be described according to the following numbered statements: S1 . A process for the production of a compound of Formula (I): or a salt thereof, comprising reacting a compound of formula (III): or a salt thereof, and a compound of formula (II): or a salt thereof, wherein compound of formula (II), or a salt thereof, is prepared according to a process comprising the following steps: a) reacting a methoxide with a compound of Formula (VI): wherein X is a counter cation, to form a compound of Formula (VII): or a salt thereof, b) protecting the carboxylate group of the compound of Formula (VII), or a salt thereof, with a benzyl group in the presence of a base, to form a compound of Formula (VIII): c) reacting the compound of Formula (VIII), or a salt thereof, with triflic anhydride in the presence of a base to form a compound of Formula (IXa): d) reacting the compound of Formula (IXa) with 1 -methylpiperazine to form a compound of Formula (X): or a salt thereof, and e) deprotecting the compound Formula (X), or a salt thereof, in the presence of hydrogen to form the compound of Formula (II), or a salt thereof.

[0270] S2. Use of D-serine in a method of producing a compound of Formula (II): or a salt thereof.

[0271] S3. Use of a compound of Formula (Vlb): or a salt thereof, in a method of producing a compound of Formula (II): or a salt thereof. S4. Use according to statement 3, wherein the use is use of a carboxylate salt of Formula (VI): wherein X is a counter cation, optionally the salt is a potassium carboxylate salt of formula (Via): S5. Use of a compound of Formula (VII): or a salt thereof, in a method of producing a compound of Formula (II): or a salt thereof.

[0272] S6. Use of a compound of Formula (VIII): or a salt thereof, in a method of producing a compound of Formula (II): or a salt thereof. S7. Use of a compound of Formula (IXa): or a salt thereof, in a method of producing a compound of Formula (II): or a salt thereof. S8. Use of a compound of Formula (X): or a salt thereof, in a method of producing a compound of Formula (II): or a salt thereof. S9. A process for the production of a compound of Formula (VII): or a salt thereof, the process comprising reacting a methoxide with a compound of Formula (VI): wherein X is a counter cation.

[0273] 510. The process of statement 9, wherein X is potassium cation.

[0274] 511 . The process of statement 9 or statement 10, wherein the process is carried out in the presence of sodium methoxide in methanol.

[0275] S12. The process of any one of statements 9 to 11 , wherein from about 3.0 to about 4.5 molar equivalents of methoxide is used, optionally about 3.8 molar equivalents of methoxide is used.

[0276] S13. The process of any one of statements 9 to 12, wherein the process is carried out from about 15°C to about 30°C, optionally wherein the process is carried out from about 18°C to about 25°C.

[0277] S14. A process for the production of a compound of Formula (VIII): the process comprising protecting the carboxylate group of the compound of Formula (VII): or a salt thereof, with a benzyl group in the presence of a base. S15. The process of statement 14, wherein the compound of Formula (VIII) is obtained in an enantiomeric purity of at least 95.0%, at least 96.0%, at least 97.0%, at least 98.0%, or at least 99.0%.

[0278] S16. The process of statement 14 or statement 15, wherein the compound of Formula (VIII) is obtained in an enantiomeric purity of at least 99.5%, at least 99.6%, at least 99.7%, at least 99.8%, or at least 99.9%.

[0279] S17. The process of any one of statements 14 to 16 further comprising a process for the production of the compound of Formula (VII) according to any one of statements 9 to 13.

[0280] S18. A process for the production of a compound of Formula (IXa): the process comprising reacting the compound of Formula (VIII): with triflic anhydride in the presence of a base.

[0281] 519. The process of statement 18, wherein the base is pyridine.

[0282] 520. The process of statement 18 or statement 19, wherein from about 1.1 to about 2.0 molar equivalents of triflic anhydride is used, optionally about 1.5 molar equivalents of triflic anhydride is used.

[0283] 521 . The process of any one of statements 18 to 20, wherein the process is carried out in dichloromethane.

[0284] 522. The process of any one of statements 18 to 21 , wherein the process is carried out using a continuous flow process.

[0285] 523. The process of statement 22, wherein a residence time of from about 5 to about 60 seconds is used in the continuous flow process.

[0286] 524. The process of statement 23, wherein the residence time is from about 15 to about 45 seconds, optionally from about 20 to about 40 seconds, more optionally about 30 seconds. S25. The process of any one of statements 18 to 24, further comprising a process for the production of the compound of Formula (VIII) according to any one of statements 14 to 17.

[0287] S26. A process for the production of a compound of Formula (X): or a salt thereof, the process comprising reacting the compound of Formula (IXa): with 1-methylpiperazine.

[0288] S27. The process of statement 26, wherein from about 1.1 to about 2.0 molar equivalents of 1-methylpiperazine is used, optionally about 1.5 molar equivalents of 1-methylpiperazine is used.

[0289] 528. The process of statement 26 or statement 27, wherein the process is carried out in a mixture of dichloromethane and 2-methyltetrahydrofuran.

[0290] 529. The process of any one of statements 26 to 28, wherein the process is carried out using a continuous flow process.

[0291] 530. The process of statement 29, wherein a residence time of from about 5 to about 20 minutes is used in the continuous flow process, optionally the residence time is from about 7 to about 15 minutes, optionally the residence time about 10 minutes.

[0292] 531 . The process of any one of statements 26 to 30, wherein the compound of Formula (X) is obtained in an enantiomeric purity of at least 90.0%, at least 91.0%, at least 92.0%, at least 93.0%, at least 94.0%, at least 95.0%, at least 96.0%, at least 97.0%, at least 98.0%, or at least 99.0%.

[0293] 532. The process of any one of statements 26 to 31 , wherein the compound of Formula (X) is obtained in an enantiomeric purity of at least 94.0%, at least 95.0%, at least 96.0%, at least 97.0%, at least 98.0%, or at least 99.0%. S33. The process of any one of statements 26 to 32, further comprising a process for the production of the compound of Formula (IXa) according to any one of statements 18 to 25.

[0294] S34. A process for the production of a compound of Formula (II): or a salt thereof, the process comprising a deprotecting step of hydrogenating the compound of Formula (X): or a salt thereof.

[0295] S35. The process of statement 34, wherein hydrogenating is carried out in the presence of palladium catalyst.

[0296] S36. The process of statement 34 or statement 35, further comprising reacting the compound of Formula (II), or a salt thereof, with hydrochloric acid to form the dihydrochloride mohohydrate salt of Formula (Ila):

[0297] 537. The process of any one of statements 34 to 36, wherein the compound of Formula (II) is obtained in an enantiomeric purity of at least 97.0%, at least 98.0%, or at least 99.0%.

[0298] 538. The process of any one of statements 34 to 37, wherein the compound of Formula (II) is obtained in an enantiomeric purity of at least 99.5%, at least 99.6%, at least 99.7%, at least 99.8%, or at least 99.9%.

[0299] 539. The process of any one of statements 34 to 38, further comprising a process for the production of a compound of Formula (X) according to any one of statements 26 to 33. S40. A process for the production of a compound of Formula (I): or a salt thereof, comprising reacting a compound of formula (III): or a salt thereof, and a compound of formula (II): or a salt thereof, wherein compound of formula (II) is prepared according to the process of any one of statements 34 to 39.

[0300] S41 . The process of statement 40, wherein the process is for the production of a xinafoate salt of Formula (la):

[0301] S42. A process of producing a compound of Formula (VII): or a salt thereof, as an intermediate in a process of producing a compound of Formula (II): or a salt thereof, wherein the process comprises a process according to any one of statements 9 to 13.

[0302] S43. A process of producing a compound of Formula (VIII): as an intermediate in a process of producing a compound of Formula (II): or a salt thereof, wherein the process comprises a process according to any one of statements 14 to 17.

[0303] S44. A process of producing a compound of Formula (IXa): as an intermediate in a process of producing a compound of Formula (II): or a salt thereof, wherein the process comprises a process according to any one of statements 18 to 25.

[0304] S45. A process of producing a compound of Formula (X): or a salt thereof, as an intermediate in a process of producing a compound of Formula (II): or a salt thereof, wherein the process comprises a process according to any one of statements 26 to 33.

[0305] S46. A process of producing a compound of Formula (VII): or a salt thereof, as an intermediate in a process of producing a compound of Formula (I): or a salt thereof, wherein the process comprises a process according to any one of statements 9 to 13, optionally wherein the process is for the production of a xinafoate salt of Formula (la):

[0306]

[0307] S47. A process of producing a compound of Formula (VIII): or a salt thereof, as an intermediate in a process of producing a compound of Formula (I): or a salt thereof, wherein the process comprises a process according to any one of statements 14 to 17, optionally wherein the process is for the production of a xinafoate salt of Formula (la):

[0308] S48. A process of producing a compound of Formula (IXa): as an intermediate in a process of producing a compound of Formula (I): or a salt thereof, wherein the process comprises a process according to any one of statements 18 to 25, optionally wherein the process is for the production of a xinafoate salt of Formula (la):

[0309] S49. A process of producing a compound of Formula (X): or a salt thereof, as an intermediate in a process of producing a compound of Formula (I):

[0310] or a salt thereof, wherein the process comprises a process according to any one of statements 26 to 33, optionally wherein the process is for the production of a xinafoate salt of Formula (la):

[0311] S50. A process of producing a compound of Formula (II): or a salt thereof, as an intermediate in a process of producing a compound of Formula (I): or a salt thereof, wherein the process comprises a process according to any one of statements 34 to 39, optionally wherein the process is for the production of a xinafoate salt of Formula (la):

[0312] EXAMPLES

[0313] Abbreviations:

[0314] EtOH - Ethanol

[0315] DCM - Dichloromethane

[0316] DIPEA - A / , A / -diisopropylethylamine

[0317] HATU - 1-[Bis(dimethylamino)methylene]-1 H-1 ,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate

[0318] HCI - Hydrochloric acid

[0319] THF - Tetrahydrofuran

[0320] DMSO - Dimethylsulfoxide

[0321] MTBE - Methyl tert-buty I ether f-BuOH - te / Y-Butanol

[0322] 2-MeTHF - 2-Methyltetrahydrofuran

[0323] MeOH - Methanol

[0324] 2-PrOH - 2-Propanol

[0325] 1 ,2-DME - 1 ,2-Dimethoxyethane

[0326] DMF - A / ,A / -Dimethylformamide IPA - Isopropyl alcohol w / w - weight / weight weq. - weight equivalents v / v - volume / volume veq. - volume equivalents

[0327] IUPAC names were generated using Biovia Draw 2020 version 20.1

[0328] Example 1 : Previous manufacturing route to the compound of Formula (II)

[0329] A synthetic route was previously developed to supply up to 1 kg of amino acid of Formula (II), also named as amino acid Ila in this example, as shown in Scheme A. This method is disclosed in WO 2018 / 134213 and WO 2020 / 016302.

[0330] This route started with methyl acrylate XI which undergoes ready bromination to provide intermediate dibromo-ester XII. This ester was converted to the corresponding methyl ether XIII by reaction with sodium methoxide in methanol. Subsequent reaction with 1 -methylpiperazine provided ester XIV. Base mediated hydrolysis then provided the racemic lithium carboxylate lib. Access to the enantiomerically pure amino acid Ila was provided through resolution of this racemic mixture by application of preparative super critical fluid chromatography (SFC). Despite extensive investigations into the optimization of SFC for this purification, the method was found to suffer from low throughput and high solvent (MeOH) consumption. Also, the resolved amino acid was found to form a stable carbonate salt He under the chromatography conditions (Thunberg et al., (2020), J. Chromatogr. A 1624, 461172; Pithani et al., (2023), and Nilsson et al. (2023), Journal of Medicinal Chemistry 66 (19), 13400-13415). Subsequent treatment of this carbonate salt with aqueous hydrochloric acid allowed for isolation of the corresponding crystalline hydrated dihydrochloride salt of amino acid Ila (Scheme A). The dihydrochloride salt was successfully used in the subsequent amide coupling and formation of the compound of Formula (I). Resolution by SFC allowed for manufacture on a kilo scale of enantiomerically pure amino acid Ila.

[0331] Scheme A. Initial manufacturing route to amino acid Ila using resolution by supercritical fluid chromatography (SFC).

[0332] With throughput limitations identified with the application of SFC, an alternative approach was sought for resolution of amino acid lib. Extensive salt screening demonstrated that the amino acid could be isolated in high optical purity via formation of the corresponding crystalline L-tartrate salt (Scheme B). Recrystallisation of this salt from ethanol resulted in isolation of the L-tartrate dihydrate salt of amino acid lid with > 99% enantiomeric purity (e.p.). Furthermore, if required, a re-slurry of this isolated salt in ethanol could be performed, providing improvement in optical purity to > 99.5% e.p. Due to the high water solubility associated with amino acid lid and associated difficulties with its isolation, a salt break of the L-tartrate salt was achieved by ion exchange chromatography. To avoid having the tartrate salt carrying through into the subsequent amide coupling stage, the salt was adsorbed on to an acidic 50WX2 ion-exchange resin and eluted with water to remove the L-tartrate counterion. Subsequent washing of the resin with aqueous hydrochloric acid allowed for elution of the required amino acid lib as the dihydrochloride salt. This salt was isolated from the acidic aqueous ion exchange fractions by concentration and subsequent solvent swap into ethanol, resulting in crystallization of the corresponding dihydrochloride monohydrate salt of amino acid lib.

[0333] Scheme B. Manufacture of amino acid lib by resolution of the corresponding L-tartrate salt and ion exchange chromatography. The L-tartrate salt resolution method was successfully scaled to deliver 6 kg of enantiomerically pure amino acid lib. However, this resolution method exhibited a number of issues on scale including:

[0334] • Requirement for removal of large volumes of water post ion-exchange chromatography.

[0335] • Variation in the chloride and water content of the isolated salt of amino acid lib (The calculated assay for Amino acid lib as 2HCI H2O salt is as follows: Freebase = 69.0%; Chloride = 24.2%; Water = 6.1%). This varying salt stoichiometry required further modification of the downstream amide coupling chemistry to support manufacture of the compound of Formula (I) on scale.

[0336] The above issues, in conjunction with a maximum theoretical yield of 50% for resolution of carboxylate lib, resulted in the investigation of enantioselective routes to amino acid lib.

[0337] A large-scale enantioselective manufacturing route to the unusual piperazine-substituted amino acid lib was developed and is described in Examples 2 to 5. The new enantioselective route to amino acid lib uses the SN2 displacement of a chiral triflate IXa with A / -methylpiperazine that proceeds with very high levels of stereocontrol (Example 4). The key chiral triflate IXa is prepared in five synthetic steps in 38% overall yield and > 99% enantiomeric purity (e.p.), starting from cheap and readily available D-serine (Example 1). Subsequent reaction with A / -methyl piperazine was initially demonstrated in batch providing the benzyl protected amino acid X in 83% e.p. on a 3 kg scale. This transformation was further improved by application of continuous manufacture to provide the benzyl protected ester X in > 99% e.p. on an 80 kg scale. Simple deprotection of the benzyl ester group by hydrogenolysis, followed by isolation of the amino acid as the corresponding dihydrochloride salt, provided a scalable and efficient synthesis of (R)-3-methoxy-2-(4-methylpiperazin-1-yl)propanoic acid lib in good overall yield (33%) and very high optical purity (> 99.5% e.p.).

[0338] Example 2: Synthesis of potassium (S)-oxirane-2 -carboxylate (Via)

[0339] KBr (3.4 eq.)

[0340] Scheme C: Synthetic scheme for making carboxylate Via.

[0341] Method

[0342] Vessel 1 was charged with D-Serine IV (56.9 kg, 541 .4 mol, 1.0 eq.), KBr (214 kg, 1798.3 mol, 3.4 eq.), process water (321 L, 5.7 RV (relative volumes)) and 48%wt aqueous hydrobromic (193 kg, 1145 mol, 2.1 eq). The contents of the vessel were agitated and the temperature of the contents of the vessel adjusted to 10 to 20°C. A NaNO2solution (100 kg, 1449.3 mol, 2.7 eq. NaNO2dissolved in 142.3 L, 2.5 RV process water) was then charged into the vessel at < 0°C. After complete addition the contents of the vessel were adjusted to -5 to 5°C and agitated for a further 20 hrs at this temperature. MTBE (462 kg, 8.1 RV) was charged into the vessel and the temperature adjusted to 15-25°C. The contents of the vessel were agitated for 1 hour at 20-25°C then the agitation was stopped and the layers allowed to separate for 1 h. The lower aqueous phase was removed. The aqueous phase was extracted with further MTBE (3 x 462 kg, 8.1 RV). The combined organic extracts were concentrated to 1-2 RV to obtain intermediate bromide V as a solution in MTBE. Further MTBE (200 kg, 3.5 RV) was charged and the mixture concentrated to 1-2 RV (57-114 L). This concentrated solution of bromide V in MTBE was then diluted with EtOH (210 kg, 3.7 RV) and telescoped directly into the next stage as follows:

[0343] Vessel 2 was charged with EtOH (210 kg, 3.7 RV) followed by solid KOH (86 kg, 1532.7 mol, 2.8 eq.). The contents of Vessel 2 were agitated at 20°C until a clear solution was formed. The temperature of the contents of Vessel 2 was adjusted -20°C. The contents of Vessel 1 were then added to Vessel 2 with agitation at a rate to maintain the temperature of the contents of Vessel 2 at approximately 0°C. After complete addition the contents of Vessel 2 were adjusted to 15-25°C and agitated for a further 3hrs. The mixture was filtered and the cake was washed (x3) with cold (0°C) MTBE (24 kg). The wet cake was dried at 5-15°C to obtain 116.70 kg of a crystalline solid that was a mixture of potassium bromide (56% w / w) and potassium (S)-oxirane-2-carboxylate Via (41 .2% w / w, 48 kg, 380.5 mol, 70.3% yield).

[0344] Analytical data for potassium (S)-oxirane-2-carboxylate Via

[0345] 1H NMR (400 MHz / D2O): 3.55 (1 H, m, 2-H), 3.03 (1 H, m, 1-H), 2.90 (1 H, m, 1-H).

[0346] Quantitative NMR (q NMR) = 41% w / w (400 MHz I D2O) with maleic acid as internal standard.

[0347] Results and discussion

[0348] Initial diazotisation in the presence of a high concentration of bromide ion resulted in formation of enantiomerically pure (R)-bromide V with overall retention of stereochemistry. The stereochemical outcome of the reaction has been rationalized in terms of a double inversion mechanism invoking an a- acetolacetone intermediate (Scheme D).

[0349] Scheme D. Double inversion mechanism for stereo-controlled formation of bromide V.

[0350] The intermediate bromide V was not isolated but extracted from the aqueous reaction mixture using methyl te / Y-butyl ether (MTBE) and subsequently solvent swapped into ethanol for use in the next manufacturing stage. Treatment of the ethanolic solutions of bromide V with potassium hydroxide resulted in clean conversion to the desired epoxide Via. Potassium hydroxide (2.84 eq.) was initially added to ethanol at 20°C and the mixture agitated until a complete solution had formed. This solution was then added to the ethanolic solution of bromide V with agitation at an addition rate to control the temperature to 0°C. On complete addition, the reaction mixture was warmed to 20°C and the mixture agitated for a further 3 hours. The resulting suspension was filtered and the cake washed with MTBE. Initial hazards assessment demonstrated a low temperature (128°C) onset for the exothermic decomposition (262 J / g) of the epoxide Via; thus, the epoxide was dried on the filter at a temperature not exceeding 20°C. Residual ethanol in the isolated epoxide Via resulted in formation of the undesired ethyl ether XVI: in the next manufacturing stage. Thus, removal of residual ethanol from epoxide Via was required. This was achieved by washing of the filter cake with cold (5°C) MTBE to displace any residual solvent. Filter cake washing in this manner provided a residual ethanol content of < 0.1 % w / w (weight / weight) in the isolated epoxide Via.

[0351] The epoxide Via was isolated as a white solid in low NMR assay (see Table 1), the residual mass balance being potassium bromide (approx. 50% w / w) and water (approx. 4% w / w). Further purification of the epoxide Via was not undertaken at this stage as residual bromide salts could be accommodated in the next manufacturing stage (vide infra). The final manufacturing results for epoxide Via are summarized in Table 1 .

[0352] Table 1 : Manufacturing results for epoxide Via. Example 3: Synthesis of benzyl (S)-2-hvdroxy-3-methoxypropanoate (VIII)

[0353] BnBr,

[0354] N OM 3 8 DIPEA

[0355] (Via) (VII) (VIII)

[0356] Scheme E: Synthetic scheme for making compound VIII.

[0357] Method

[0358] Vessel 1 was charged with potassium (S)-2-oxiran-2-carboxylate (108.85 kg, 50.6 kg assay corrected, 327.3 mol) and anhydrous MeOH (99 kg, 2 RV) and the contents of the vessel agitated at 15-25°C. A solution of sodium methoxide in methanol (27% wt, 251 kg, 1254 mol) was then added into vessel 1 maintaining the internal temperature at 15-25°C. The mixture was agitated at 15-25°C until the reaction is complete. The contents of the vessel were cooled to 5-15°C. Diluted sulfuric acid (25%wt, 303 kg) was added at 15-25°C to adjust the pH of the contents of vessel 1 to 5-7. The mixture was filtered to remove inorganics. The filtrate was transferred to Vessel 2 and concentrated to 100-125 L (4-5 RV). The temperature of the contents of Vessel 2 were adjusted to 5-15°C. Diluted sulfuric acid (25%wt, 120 kg) was added to Vessel 2 with agitation maintaining the temperature below 15°C until a pH of 1-2 was achieved. This aqueous mixture was subsequently extracted into isopropyl acetate (5 x 629 kg). The combined organic extracts were concentrated to 150-200 L (6-8 RV) to obtain an approximately 10% w / w solution of (S)-2-hydroxy-3-methoxypropanoic acid VII in isopropyl acetate (0.02% w / w water) for direct use in the next stage.

[0359] Vessel 1 is charged with a 9% w / w solution of (S)-2-hydroxy-3-methoxypropanoic acid VII in isopropyl acetate (318 kg, 273.3 mol) and agitated at 20°C. A / ,A / -Diisopropylethylamine (38.0 kg, 246.7 mol) was then added to Vessel 1 at a rate to maintain the temperature of the contents at 15-30°C. Benzyl bromide (42.2 kg, 246.7 mol) was then added to Vessel 1 again maintaining the temperature of the contents at 15-30°C. The contents of Vessel 1 were heated to 80°C and with agitation for 16 hrs. The contents of Vessel 1 were cooled to 20°C and the reaction mixture was quenched by addition of a 7% w / w aqueous solution of sodium hydrogen carbonate (144 kg, 120 mol). The biphasic mixture was then agitated for a further 0.5h at 20°C and the agitation was stopped. The layers were allowed to separate and the aqueous phase discarded. The organic phase was washed three (x3) times with 10% w / w aqueous sodium sulfate solution (141 kg, 98.6 mol at 20°C. The resulting organic phase was concentrated and solvent swapped into dichloromethane (271 kg) to provide benzyl (S)-2-hydroxy-3-methoxypropanoate VIII (38.5 kg, 77.4% yield) as a 14.2% w / w solution in dichloromethane.

[0360] Analytical data for benzyl (S)-2-hvdroxy-3-methoxypropanoate (VIII)

[0361] Chiral purity = 99.5%

[0362]

[0363] HPLC conditions for release analysis of (VIII)

[0364] Purity = 91 % (X bridge C8 method)

[0365] Results and discussion

[0366] Ring opening of epoxide Via was carried out with methoxide. Under these conditions, the presence of the anionic carboxylate instead of the ester circumvented the transesterification issue and suppressed racemisation at the a-stereocentre. This was achieved readily through the use of sodium methoxide in methanol. A 27% w / w solution of sodium methoxide in methanol was added to a solution of the epoxide Via in methanol at 20 °C. After agitation for 4 hours the mixture was cooled to 10 °C and dilute sulfuric acid was added until a pH of 5-7 was achieved. The mixture was filtered to remove inorganic salts and the filtrate concentrated. Further dilute sulfuric acid was then added until a pH of 1-2 was achieved and the mixture subsequently extracted with isopropyl acetate. The isopropyl acetate extracts were then concentrated to lower volume to provide the alcohol VII in 73% yield as a 10% w / w solution in isopropyl acetate.

[0367] Conversion of alcohol VII to the corresponding benzyl ester VIII was readily achieved under standard conditions using benzyl bromide and N, A / -diisopropy I ethylamine (DIPEA) as base; providing 88.4 kg of the benzyl ester VIII in good yield and exceptionally high optical purity (99.6% e.p.).

[0368] Example 4: Synthesis of benzyl ( / ?)-3-methoxy-2-(4-methylpiperazin-1-yl)propanoate (X), in Continuous Flow.

[0369] Scheme F: Synthetic scheme for making compound X. A continuous flow diagram for making compound X is shown in FIG. 1 .

[0370] Method

[0371] Equipment used:

[0372] A Dynamic magnetic mixer was a customized SS316L with a PTFE coated cross stirrer bar.

[0373] Feed 1 pump (P1): LEWA diaphragm pump and MicroMotion mass flow meter with mass flow control and interlock, 25-600 mL / min, 0-10 MPa.

[0374] Feed 2 pump (P2): HPLC style high pressure piston pump from Tauto with PFTE pump head for corrosion resistance, 0-200 mL / min, 0-2 MPa.

[0375] Feed 3 pump (P6): HPLC style high pressure piston pump from Hanbon Sci.&Tech. with SS pump head, 0-100 mL / min, 0-25 MPa.

[0376] Aqueous H2SO4 and NaHCOs feeds (P3, P4 and P5): Peristaltic pumps from Cole Parmer.

[0377] The multi-stage centrifugal extractors (CE1 , CE2 and CE3) used were from TIEI EXTRACTION. Flow rate range: 0-800ml / min. Stirring rate: 0-3000r / min. A lab scale extractor was used from CINC V02.

[0378] Reaction: Feed solution 1 of Compound VIII (79.2 kg, 1.0 eq), pyridine (61 kg, 2.0 eq) in DCM (1053 kg, 10 RV) was prepared. Then Feed solution 2 of Tf20 (159.4 kg, 1.5 eq) in DCM (1580kg, 15 RV) was pumped through P1 (213 mL / min) and mixed with feed solution 1 which was pumped through P2 (213 mL / min) to react in the PFR reactor R1 (3 / 8”, PFA, 7 m) at 0-10 °C. 5% H2SO4 aq. (5V) was pumped through P3 and P4 at 66 mL / min to wash the reaction mixture twice using centrifugal extractor (CE1 and CE2) to separate the aqueous and organic mixtures. The resultant organic mixture was washed with NaHCOs aq. (5V) in flow mode through P5 at 66 mL / min to obtain the compound IXa as a DCM solution. The solution of IXa in DCM was pumped through P7 (270 mL / min) and mixed with Feed solution 3 of 1 -methylpiperazine (44.35 kg, 1.2 eq) in 2-Me-THF (204 kg, 3V) which was pumped through P6 (45 mL / min) into PFR reactor R3 (3 / 8”, SS, 100 m) to react at 20-25 °C. The output reaction solution was quenched by 5% HCI aqueous solution which was pumped through P9 (87.7 mL / min) into a mixing vessel (R4). The quenched reaction mixture was transferred into drums using pump P4 (flow rate varies depending on fill volumes but not relevant to the process).

[0379] Workup: The reaction quenched biphasic solution was separated, the organic phase was extracted with HCI aq. (2M, 10V). The aqueous phase was combined and treated with 10%wt NaOH solution to adjust the pH to 8-9. The solution was extracted with DCM (2 x 10 RV). The DCM solution was then swap with IPA (10 RV followed by 5 RV) to afford 710 kg of 10.8% w / w X as an IPA solution in 69.6% yield with 94.4% chiral purity.

[0380] Results and discussion The N-methyl piperazine was efficiently inserted at the chiral centre through the use of a chiral triflate with no loss of optical purity.

[0381] Batch Manufacture

[0382] Initial development work demonstrated that the required intermediate triflate IXa could be generated using an excess (1 .7 equivalents) of triflic anhydride and pyridine as base. The intermediate triflate was not isolated, but initially washed with aqueous sodium sulfate (to remove pyridinium salts). The resulting solution of triflate IXa in dichloromethane was then reacted with 1 -methylpiperazine (1.5 eq.) at 0 °C. On reaction completion, the organic mixture was washed with 2M hydrochloric acid and the organic phase discarded. The pH of the acidic aqueous extracts were adjusted to 7-8 and the desired ester X solvent lutidine to hydrogenation.

[0383] During development, ester X was obtained in 92% e.p., demonstrating that some loss (7%) of optical purity had occurred during the batch process. A possible explanation for loss of enantiomeric purity is reaction of the intermediate triflate with the pyridine base (Scheme G), with subsequent formation of the opposite enantiomer of ester 29 on reaction of the pyridinium species 30 with 1-methylpiperazine. This rationale for reduction in chiral purity was confirmed during further investigations of the stage in flow (vide infra).

[0384] On scale up of the batch process, further degradation in e.p. was also observed with an average of 83% e.p. over three batches and an average yield of 77% , which highlighted the need to change the process before bigger campaigns were manufactured.

[0385] Scheme G. Initially proposed mechanism for observed loss of enantiomeric purity for ester X.

[0386] Continuous Manufacture

[0387] With the reduction in optical purity observed for the transformation of chiral alcohol VIII to piperazine X (Scheme F) via this batch process, further investigations were initiated to establish whether improved control of this process could be achieved via a continuous manufacturing process.

[0388] A proof of concept was used to show that the chirality is retained with improved mass transfer due to the better mixing in flow chemistry.

[0389] The initial conditions for the continuous flow process employed triflic anhydride in dichloromethane and pyridine as base to convert the chiral alcohol VIII into intermediate IXa. A magnetic dynamic mixer was used to combine the two feed solutions before they go through a short tube out of the reactor. However, an impurity was observed at levels of ~25 %A (area percent by UPLC) with a m / z of 272, consistent with a pyridinium XV. Replacing pyridine with lutidine, to reduce the nucleophilicity of the base, gave IXa and the equivalent lutidinium impurity was not observed. The reaction mixture generated using lutidine was processed to generate piperazine X. The subsequent debenzylation to generate acid II did not go to completion and the reaction stalled, consistent with palladium poisoning caused by an unidentified minor impurity.

[0390] As lutidine was not compatible with downstream palladium chemistry, pyridine was further investigated to try and reduce the impurity XV. As the formation of impurity XV was attributed to long residence times, the residence time for the formation of triflate IXa was investigated further. By screening residence times (5s, 15s 30s, 60s) it was determined that 30s gave the optimum conversion and purity of triflate IXa. More importantly, impurity 30 was not detected (Table 3). For this screening, a quench and work up was also introduced, where a pre-cooled aqueous sodium sulfate solution was used as a quench over a static mixer and a short reactor. The resultant biphasic mixture was extracted using a centrifugal extractor (CE). The organic layer was further washed with an aqueous sodium sulfate solution and the biphasic mixture extracted using a second centrifugal extractor.

[0391] Table 3. Formation of intermediate IXa in continuous flow at difference residence times.

[0392] Having shown that the impurity XV can be successfully controlled in continuous flow, the generation of XV was combined with the addition of 1 -methylpiperazine to form ester X. The initial setup made use of aqueous sodium sulfate solution for the quench as previously shown in FIG. 3. However, blockages were observed and the sodium sulfate was replaced with sulfuric acid solution to prevent solid formation (FIG. 4). After intermediate IXa was quenched and washed with a solution of sulfuric acid, the organic layer was washed with an aqueous solution of sodium hydrogen carbonate. The dichloromethane solution of intermediate IXa was then telescoped into the next reactor through a precooled loop at 20- 25°C before joining a precooled (20-25°C) solution of 1 -methylpiperazine. As for the first reaction, a magnetic dynamic mixer was used followed by a tube reactor, both at 20-25°C. For the 1- methylpi perazine addition, an initial residence time of 5 minutes was used. This was increased to 10 minutes since -6.5% of intermediate IXa was still remaining. The crude solution of ester X was added into a stirred vessel at 20-25°C to which a solution of hydrochloric acid in water was added to obtain a biphasic solution of ester X.

[0393] After checking the stability of all feed solutions over up to 10 days, a 100 g batch was run before the scale up manufacture. No blockages were observed and the crude material was obtained in 93.4 A% purity and 99.9% chiral purity. A workup was developed where the biphasic solution of crude X reaction was separated and the organic phase was extracted with 2 M HCI aqueous solution. The aqueous phase was combined and treated with 10%wt NaOH solution to adjust the pH to 8-9. The solution was then extracted with dichloromethane and solvent swapped to IPAto afford ester X. 80 kg of chiral alcohol

[0394] Example 5: Synthesis of ( / ?)-3-methoxy-2-(4-methylpiperazin-1-yl) propanoic acid dihydrochloride monohydrate Ila

[0395] Scheme H: Synthetic scheme for making compound Ila.

[0396] Method

[0397] Vessel 1 was charged with 10% Pd on carbon (3.5 kg) followed by the 10.8% w / w solution of benzyl (R)-3-methoxy-2-(4-methylpiperzin-1yl)propanoate in propan-2-ol X (352.15 kg, 130 mol). The contents of the vessel were agitated at 20-30°C for 30 minutes and then subjected to a hydrogen atmosphere at 0.28 - 0.35 MPa for 12 hours. The agitation rate was reduced and the vessel purged with nitrogen. The resulting suspension was filtered through a pad of diatomaceous earth into Vessel 2. The filter cake was subsequently washed with further propan-2-ol (107 kg) into Vessel 2 and the filtrates concentrated at 50°C under reduced pressure to an approximate final volume of 200 L. The contents of Vessel 2 were agitated at 30°C and 35% aqueous hydrochloric acid (34 kg) was then added over 2 hours maintaining the temperature of the contents of the vessel at 30 - 40°C. The contents of Vessel 2 were agitated at 30 - 40°C for a further 4 hours then cooled to 5°C over 8 hours providing a white slurry of the salt. The slurry was filtered and the filter cake washed with propan-2-ol (53 kg). The resulting filter cake was dried to constant weight to provide (R)-3-methoxy-2-(4-methylpiperazin-1-yl) propanoic acid dihydrochloride monohydrate Ila as a white crystalline solid (33.15 kg, 85% yield, 68% w / w as free base, 99.8% ep).

[0398] 1H NMR (500 MHz / DMSO-cfe) 5 ppm 2.8 (s, 3H), 3.3 (s, 3H), 3.3-3.5 (m, 2H), 3.5-3.7 (m, 6H), 3.8 (dd, J=11 .8, 3.6 Hz, 1 H), 3.9 (dd, J=11 .8, 2.3 Hz, 1 H), 4.4-4.5 (m, 1 H). Analytical data for ( / ?)-3-methoxy-2-(4-methylpiperazin-1-yl) propanoic acid dihydrochloride monohydrate Ila

[0399] A single crystal of compound Ila was disclosed in WO 2020 / 016302, the contents of which is hereby incorporated by reference in its entirety,

[0400] Space Group: P 21 (4), Cell: a 6.9252(2)A b 13.9904(3)A c 7.7452(2)A, a 90° p 96.072(2)° y 90°

[0401] Results and discussion

[0402] Debenzylation of ester X by hydrogenation in methanol over a palladium catalyst, followed by crystallization of the product as the stable dihydrochloride monohydrate salt provided the chiral amino acid Ila in excellent optical purity and moderate yield (Scheme I).

[0403] 92% e.p. 98.5% e.p.

[0404] Scheme I. Debenzylation of ester Ila and corresponding improvement in optical purity of acid 4 through salt formation.

[0405] The moderate yield observed in the final stage salt formation and isolation was a consequence of requirement to improve the optical purity of amino acid Ila from 83% e.p. to 99% e.p. when using (X) made through a batch process. This resulted in relatively high losses to liquors during the salt formation and isolation. However, this batch process was initially used to manufacture 6.8 kg of the amino acid salt Ila of the required quality for Phase I product development studies in an overall yield of 28% from D-serine (IV) (Table 4).

[0406] Table 4. Initial manufacturing results for amino acid Ila using a batch manufacturing process.

[0407] * Calculated assay for amino acid Ila as dihydrochloride monohydrate salt: freebase = 69% w / w; chloride = 24% w / w; water = 6% w / w.

[0408] When using (X) made from the continuous flow process, The overall process resulted in an efficient manufacture of 50 kg of amino acid Ila as the corresponding crystalline dihydrochloride salt, in excellent optical purity (> 99.5% e.p.) and overall yield (33%), from cheap and readily available D-serine (IV).

Claims

WHAT IS CLAIMED IS:1 . A process for the production of a compound of Formula (I):or a salt thereof, comprising reacting a compound of formula (III):or a salt thereof, and a compound of formula (II):or a salt thereof, wherein compound of formula (II), or a salt thereof, is prepared according to a process comprising the following steps: a) reacting a methoxide with a compound of Formula (VI):wherein X is a counter cation, to form a compound of Formula (VII):or a salt thereof, b) protecting the carboxylate group of the compound of Formula (VII), or a salt thereof, with a benzyl group in the presence of a base, to form a compound of Formula (VIII):c) reacting the compound of Formula (VIII), or a salt thereof, with an electrophilic reagent in the presence of a base to form a compound of Formula (IX):wherein OL is a leaving group, d) reacting the compound of Formula (IX) with 1 -methylpiperazine to form a compound of Formula (X):or a salt thereof, and e) deprotecting the compound Formula (X), or a salt thereof, in the presence of hydrogen to form the compound of Formula (II), or a salt thereof.

2. The process of claim 1 , wherein X in step a) is a potassium cation.

3. The process of claim 1 or claim 2, wherein OL in step c) is selected from triflate, mesylate, tosylate, benzenesulfonate, and trifluoroacetate.

4. The process of claim 3, wherein OL in step c) is triflate.

5. The process of any one of claims 1 to 3, wherein the electrophilic reagent in step c) is selected from triflic anhydride, methanesulfonic anhydride, methanesulfonyl chloride, 4-toluenesulfonic anhydride, 4-toluenesulfonyl chloride, benzenesulfonic anhydride, benzenesulfonyl chloride, and trifluoroacetic anhydride.

6. The process of any one of claims 1 to 5, wherein the electrophilic reagent in step c) is triflic anhydride.

7. Use of D-serine in a method of producing a compound of Formula (II):or a salt thereof.

8. Use of a compound of Formula (Vlb):or a salt thereof, in a method of producing a compound of Formula (II):or a salt thereof.

9. Use according to claim 8, wherein the use is use of a carboxylate salt of Formula (VI):wherein X is a counter cation, optionally the salt is a potassium carboxylate salt of formula (Via):

10. Use of a compound of Formula (VII):or a salt thereof, in a method of producing a compound of Formula (II):or a salt thereof.11 . Use of a compound of Formula (VIII):or a salt thereof, in a method of producing a compound of Formula (II):or a salt thereof.

12. Use of a compound of Formula (IX):wherein OL is a leaving group, in a method of producing a compound of Formula (II):or a salt thereof.

13. Use according to claim 12, wherein OL is selected from tritiate, mesylate, tosylate, benzenesulfonate, and trifluoroacetate.

14. Use according to claim 13, wherein OL is tritiate.

15. Use of a compound of Formula (X):or a salt thereof, in a method of producing a compound of Formula (II):or a salt thereof.

16. A process for the production of a compound of Formula (VII):or a salt thereof, the process comprising reacting a methoxide with a compound of Formula (VI):wherein X is a counter cation.

17. The process of claim 16, wherein X is a potassium cation.

18. The process of claim 16 or claim 17, wherein the process is carried out in the presence of sodium methoxide in methanol.

19. The process of any one of claims 16 to 18, wherein from about 3.0 to about 4.5 molar equivalents of methoxide is used.

20. The process of claim 19, wherein 3.8 molar equivalents of methoxide is used.21 . The process of any one of claims 16 to 20, wherein the process is carried out from about 15°C to about 30°C.

22. The process of claim 21 , wherein the process is carried out from about 18°C to about 25°C.

23. A process for the production of a compound of Formula (VIII):the process comprising protecting the carboxylate group of the compound of Formula (VII):or a salt thereof, with a benzyl group in the presence of a base.

24. The process of claim 23, wherein the compound of Formula (VI 11) is obtained in an enantiomeric purity of at least 95.0%, at least 96.0%, at least 97.0%, at least 98.0%, or at least 99.0%.

25. The process of claim 23 or claim 24, wherein the compound of Formula (VIII) is obtained in an enantiomeric purity of at least 99.5%, at least 99.6%, at least 99.7%, at least 99.8%, or at least 99.9%.

26. The process of any one of claims 23 to 25 further comprising a process for the production of the compound of Formula (VII) according to any one of claims 16 to 22.

27. A process for the production of a compound of Formula (IX):wherein OL is a leaving group, the process comprising reacting the compound of Formula (VIII):or a salt thereof, with an electrophilic reagent in the presence of a base.

28. The process of claim 27, wherein OL is selected from triflate, mesylate, tosylate, benzenesulfonate, and trifluoroacetate.

29. The process of claim 28, wherein OL is triflate.

30. The process of any one of claims 27 to 28, wherein the electrophilic reagent is selected from triflic anhydride, methanesulfonic anhydride, methanesulfonyl chloride, 4-toluenesulfonic anhydride, 4-toluenesulfonyl chloride, benzenesulfonic anhydride, benzenesulfonyl chloride, and trifluoroacetic anhydride.31 . The process of any one of claims 27 to 30, wherein the electrophilic reagent is triflic anhydride.

32. The process of any one of claims 27 to 31 , wherein the base is selected from pyridine, triethylamine, diisopropylethylamine, 4-dimethylaminopyridine (DMPA), tetramethylpyridine, N- methylpiperazine, lutidine, 2,6-lutidine, N-methylmorpholine, 1 ,8-diazabicyclo(5.4.0)undec-7- ene (DBU), tetramethylguanidine, and tributylamine,33. The process of claim 32, wherein the base is pyridine.

34. The process of any one of claims 27 to 33, wherein from about 1.1 to about 2.0 molar equivalents of electrophilic reagent is used.

35. The process of claim 34, wherein about 1 .5 molar equivalents of electrophilic reagent is used.

36. The process of any one of claims 27 to 35, wherein the process is carried out in a solvent selected from dichloromethane, toluene, acetonitrile, methyl tert-butyl ether, 2- methyltetryhydrofuran, tetra hydrofuran, cyclopentyl methyl ether, anisole, benzonitrile acetone, methyl ethyl ketone, and chlorobenzene or a mixture thereof.

37. The process of claim 36, wherein the solvent is dichloromethane.

38. The process of claim 36, wherein the solvent is toluene.

39. The process of claim 36, wherein the solvent is a mixture of dichloromethane and toluene.

40. The process of any one of claims 27 to 39, wherein the process is carried out using a continuous flow process.41 . The process of claim 40, wherein a residence time of from about 5 to about 60 seconds is used in the continuous flow process.

42. The process of claim 41 , wherein the residence time is from about 15 to about 45 seconds.

43. The process of claim 42, wherein the residence time is from about 20 to about 40 seconds.

44. The process of claim 43, wherein the residence time is about 30 seconds.

45. The process of any one of claims 27 to 44, further comprising a process for the production of the compound of Formula (VIII) according to any one of claims 23 to 26.

46. A process for the production of a compound of Formula (X):or a salt thereof, the process comprising reacting the compound of Formula (IX):wherein OL is a leaving group, with 1 -methylpiperazine.

47. The process of claim 46, wherein OL is selected from triflate, mesylate, tosylate, benzenesulfonate, and trifluoroacetate.

48. The process of claim 47, wherein OL is triflate.

49. The process of any one of claims 46 to 48 wherein from about 1 .1 to about 2.0 molar equivalents of 1 -methylpiperazine is used,50. The process of claim 49, wherein about 1.5 molar equivalents of 1 -methylpiperazine is used.

51. The process of any one of claims 46 to 50, wherein the process is carried out in a mixture of dichloromethane and 2- methyltetra hydrofuran.

52. The process of any one of claims 46 to 51 , wherein the process is carried out using a continuous flow process.

53. The process of claim 52, wherein a residence time of from about 5 to about 20 minutes is used in the continuous flow process.

54. The process of claim 53, wherein the residence time is from about 7 to about 15 minutes.

55. The process of claim 54, wherein the residence time is about 10 minutes.

56. The process of any one of claims 46 to 55, wherein the compound of Formula (X) is obtained in an enantiomeric purity of at least 90.0%, at least 91 .0%, at least 92.0%, at least 93.0%, at least 94.0%, at least 95.0%, at least 96.0%, at least 97.0%, at least 98.0%, or at least 99.0%.

57. The process of claim 56, wherein the compound of Formula (X) is obtained in an enantiomeric purity of at least 94.0%, at least 95.0%, at least 96.0%, at least 97.0%, at least 98.0%, or at least 99.0%.

58. The process of any one of claims 46 to 57, further comprising a process for the production of the compound of Formula (IX) according to any one of claims 27 to 45.

59. A process for the production of a compound of Formula (II):or a salt thereof, the process comprising a deprotecting step of hydrogenating the compound of Formula (X):or a salt thereof.

60. The process of claim 59, wherein hydrogenating is carried out in the presence of palladium catalyst.61 . The process of claim 59 or claim 60, further comprising reacting the compound of Formula (II), or a salt thereof, with hydrochloric acid to form the dihydrochloride mohohydrate salt of Formula (Ha):

62. The process of any one of claims 59 to 61 , wherein the compound of Formula (II) is obtained in an enantiomeric purity of at least 97.0%, at least 98.0%, or at least 99.0%.

63. The process of any one of claims 59 to 62, wherein the compound of Formula (II) is obtained in an enantiomeric purity of at least 99.5%, at least 99.6%, at least 99.7%, at least 99.8%, or at least 99.9%.

64. The process of any one of claims 59 to 63, further comprising a process for the production of a compound of Formula (X) according to any one of claims 46 to 58.

65. A process for the production of a compound of Formula (I):or a salt thereof, comprising reacting a compound of formula (III):or a salt thereof, and a compound of formula (II):or a salt thereof, wherein compound of formula (II) is prepared according to the process of any one of claims 59 to 64.

66. The process of claim 65, wherein the process is for the production of a xinafoate salt of Formula (la):

67. A process of producing a compound of Formula (VII):or a salt thereof, as an intermediate in a process of producing a compound of Formula (II):or a salt thereof, wherein the process comprises a process according to any one of claims 16 to 22.

68. A process of producing a compound of Formula (VIII):as an intermediate in a process of producing a compound of Formula (II):or a salt thereof, wherein the process comprises a process according to any one of claims 23 to 26.

69. A process of producing a compound of Formula (IX):wherein OL is a leaving group, as an intermediate in a process of producing a compound of Formula (II):or a salt thereof, wherein the process comprises a process according to any one of claims 27 to 45.

70. A process of producing a compound of Formula (X):or a salt thereof, as an intermediate in a process of producing a compound of Formula (II):or a salt thereof, wherein the process comprises a process according to any one of claims 46 to 58.71 . A process of producing a compound of Formula (VI I):or a salt thereof, as an intermediate in a process of producing a compound of Formula (I):or a salt thereof, wherein the process comprises a process according to any one of claims 16 to 22.

72. A process of producing a compound of Formula (VIII):or a salt thereof, as an intermediate in a process of producing a compound of Formula (I):or a salt thereof, wherein the process comprises a process according to any one of claims 23 to 26.

73. A process of producing a compound of Formula (IX):wherein OL is a leaving group, as an intermediate in a process of producing a compound of Formula (I):or a salt thereof, wherein the process comprises a process according to any one of claims 27 to 45.

74. A process of producing a compound of Formula (X):or a salt thereof, as an intermediate in a process of producing a compound of Formula (I):or a salt thereof,wherein the process comprises a process according to any one of claims 46 to 58.

75. A process of producing a compound of Formula (II):or a salt thereof, as an intermediate in a process of producing a compound of Formula (I):or a salt thereof.

76. A process of producing a compound of Formula (VII):or a salt thereof, as an intermediate in a process of producing a xinafoate salt of Formula (la):wherein the process comprises a process according to any one of claims 16 to 22.

77. A process of producing a compound of Formula (VIII):or a salt thereof, as an intermediate in a process of producing a xinafoate salt of Formula (la):wherein the process comprises a process according to any one of claims 23 to 26.

78. A process of producing a compound of Formula (IX):wherein OL is a leaving group, as an intermediate in a process of producing a xinafoate salt of Formula (la):wherein the process comprises a process according to any one of claims 27 to 45.

79. A process of producing a compound of Formula (X):or a salt thereof, as an intermediate in a process of producing a xinafoate salt of Formula (la):wherein the process comprises a process according to any one of claims 46 to 58.

80. A process of producing a compound of Formula (II):or a salt thereof, as an intermediate in a process of producing a xinafoate salt of Formula (la):wherein the process comprises a process according to any one of claims 59 to 64.

Images