Process for forming EP4 antagonists

Abstract

The present invention relates to the formation and isolation of a compound according to Formula (I), its purification including its enantioenrichment, and its use in an improved process for the formation of antagonists of the prostaglandin E2 receptor 4 (EP4) according to Formula (V). The present invention also relates to a solid form of the compound of Formula (I), and to compounds and pharmaceutical compositions obtained by the processes disclosed herein

Description

[0001] PROCESS FOR FORMING EP4 ANTAGONISTS

[0002] FIELD OF THE INVENTION

[0003] The present invention relates to the formation and isolation of a compound according to Formula (I), its purification including its enantioenrichment, and its use in an improved process for the formation of antagonists of the prostaglandin E2 receptor 4 (EP4) according to Formula (V). The present invention also relates to a solid form of the compound of Formula (I), and to compounds and pharmaceutical compositions obtained by the processes disclosed herein.

[0004] BACKGROUND

[0005] Compounds of the Formula (1), or a salt thereof, are disclosed in WO 2021 / 069927 (the content of which is incorporated herein by reference in its entirety) as antagonists of the prostaglandin E2 receptor 4 (EP4)

[0006] Groups A, X and R1to R11are as defined in WO 2021 / 069927.

[0007] Prostaglandins (PG) are small-molecule (-400 Da) products produced by cyclooxygenases (COX; constitutively active COX1 and inducible COX2) and PG synthases, with a minor contribution from the isoprostane pathway, acting on arachidonic acid (AA). Prostaglandin E2(PGE2) is the main COX product in myeloid and stromal cells whose levels are determined by the balance between synthesis and 15-hydroxyprostaglandin dehydrogenase (15-PGDH)-mediated degradation. PGE2has 4 receptors (EP1-EP4) which are present on multiple cell types including macrophages, monocytes, platelets, sensory neurons, gastrointestinal tract, kidney, thymus, heart, lung, and uterus and drives a broad pharmacology mediating nociception, aspects of neuronal signalling, haematopoiesis, regulation of blood flow, renal filtration and blood pressure, regulation of mucosal integrity, vascular permeability, smooth muscle function and both pro-inflammatory (vasodilation, recruitment and activation of mast cells, macrophages and neutrophils) and immunosuppressive immune function. Functional PGE2antagonism has therapeutic potential in a wide variety of disease settings.

[0008] WO 2021 / 069927 (‘927) discloses the EP4 antagonist (R)-4-(1-(3-methyl-2-((4- (trifluoromethyl)benzyl)oxy)butanamido)cyclopropyl)benzoic acid (labelled therein as “Example 2” and herein as a compound of Formula (Vb-i)). That compound is prepared by a synthetic route involving an amide coupling reaction, and subsequent deprotection, that is summarised below (see ‘927, page 46, “Alternate Route to Example 2”).

[0009] In the synthesis of pharmaceutical compounds, minimizing impurities in both intermediate and final products is essential for enhancing efficiency, yield, and overall safety. Adhering to stringent impurity profiles is often necessary to meet regulatory requirements established by authorities such as the FDA and EMA. Achieving higher purity in intermediate compounds reduces the risk of harmful impurities being carried into the final products, thereby potentially mitigating undesirable side effects. Additionally, impurities can adversely affect the yield and effective yield of downstream compounds, which can ultimately impact cost efficiency, scalability, resource utilization, production timelines, and provide environmental benefit.

[0010] In view of the above, there is a need to provide an improved process for the production of the EP4 antagonists disclosed in WO 2021 / 069927 on a manufacturing scale, in which key intermediate compounds and final pharmaceutical products are provided in higher purity and yield. In particular, it is desirable to provide compounds exhibiting improved chromatographic purity and / or improved chiral purity (enantiomeric excess; e.e.).

[0011] SUMMARY OF INVENTION

[0012] According to a first aspect, the present invention provides a process for the purification of a compound of Formula (I), the process comprising the steps, in order, of a) providing a mixture comprising a compound of Formula (I) and a solvent; b) precipitating from the solvent the compound of Formula (I) provided in the mixture of step a) to form a precipitate; and c) isolating the precipitate from the solvent to provide the purified compound of Formula (I), wherein

[0013] R1is selected from the group consisting of H, C1-3 alkyl and C1-3 haloalkyl;

[0014] R2is selected from the group consisting of H, C1-3 alkyl and C1-3 haloalkyl, or R1and R2, together with the carbon to which they are attached, form

[0015] C3-6 cycloalkyl which is optionally substituted with one or more halo;

[0016] R3is selected from the group consisting of H, C1-3 alkyl, C1-3 haloalkyl and halo;

[0017] R4and R5are each independently selected from the group consisting of H, halo, CN, OH, SO2Me, C1-6 alkyl, C1-6 haloalkyl, C3-6 cycloalkyl and C1-6 alkoxy, wherein the C3-6 cycloalkyl and C1-6 alkoxy groups are optionally substituted with one or more halo and any one atom of the C1-6 alkyl or C3-6 cycloalkyl may be optionally replaced by a heteroatom selected from O, S and N; and

[0018] A is a protected carboxylic acid.

[0019] In view of this, the first aspect of the invention also provides a solid form comprising, or consisting of, a compound of Formula (I) wherein R1to R5and A are as defined herein.

[0020] According to a second aspect, the present invention provides a process for the formation of a compound of Formula (I) the process comprising the step of reacting a compound of Formula (II), or an alkali metal or alkaline earth metal salt thereof, with a compound of Formula (III) to form the compound of Formula (I).

[0021] This second aspect of the invention may be used to form the compound of Formula (I) that is provided in step a) of the first aspect of the invention. Therefore, group ‘A’ and R1to R5are as defined herein, including all preferences.

[0022] Compounds of Formula (I) may be used to form advanced intermediates, such as compounds of Formula (IV), prior to the formation of EP4 antagonists. Therefore, according to a third aspect, the present invention provides a process for the formation of a compound of Formula (IV) or a salt thereof, the process comprising the steps, in order, of a) providing a compound of Formula (I) in accordance with a process as defined herein; and b) reacting the compound of Formula (I) in the presence of a coupling reagent to form a compound of Formula (IV), or the salt thereof, wherein R1to R5and A are as defined herein.

[0023] Compounds of Formula (IV) may be used to form EP4 antagonists, such as compounds of Formula (V). Therefore, according to a fourth aspect, the present invention provides a process for the formation of a compound of Formula (V) or a salt thereof, the process comprising the steps, in order, of a) providing a compound of Formula (IV) in accordance with a process as defined herein, such as the first to third aspects of the invention, and in particular the third aspect of the invention; and b) deprotecting the protected carboxylic acid of group A of the compound of Formula (IV), or the salt thereof, to form the compound of Formula (V), or the salt thereof, wherein R1to R5and A are as defined herein.

[0024] As the compounds of Formula (V) are pharmaceutical compounds, they may be formulated into pharmaceutical compositions. Therefore, according to a fifth aspect, the present invention provides a process for preparing a pharmaceutical composition comprising a compound of Formula (V), or a salt thereof, and at least one pharmaceutically acceptable excipient the process comprising the steps, in order, of a) providing a compound of Formula (V) in accordance with a process as defined herein, such as the first to fourth aspects of the invention, and in particular the fourth aspect of the invention; and b) combining the compound of Formula (V), or a salt thereof, with the at least one pharmaceutically acceptable excipient, wherein R1to R5as defined herein.

[0025] BRIEF DESCRIPTION OF DRAWINGS

[0026] Figure 1 is a1H NMR spectrum of a compound of Formula (Ib-i).

[0027] Figure 2 is an X-ray powder diffraction (XRPD) pattern of a compound of Formula (Ib-i).

[0028] Figure 3 is a1H NMR spectrum of a compound of Formula (IVb-i).

[0029] DETAILED DESCRIPTION

[0030] The present invention is based upon the unexpected finding that the compound of Formula (I) may be purified by a process as defined herein to afford that compound in a higher purity, in relation to its impurity profile (e.g. unreacted starting materials from upstream processes, and by-products) and / or its enantiomeric profile. The compound of Formula (I) may be used in the synthesis of EP4 antagonists, such as those disclosed in WO 2021 / 069927. As mentioned above, a key step in the formation of the is the EP4 antagonists in WO 2021 / 069927 is the amide bond forming reaction between a compound of Formula (II) and a compound of Formula (III) forming a compound of Formula (IV). The compounds of Formula (II) and (III) may be formed by any suitable synthetic route, such as those disclosed in WO 2021 / 069927. As is typical, there may be impurities in the solution or mixture containing the compounds of Formula (II) and (III) used in the above process. During development of the amide coupling reaction, an unexpected observation was made that a mixture of a compound of Formula (II) and a compound of Formula (III) in a solvent provided a suspension at low temperatures. It was found that the suspension was a compound of Formula (I).

[0031] It was then found that the compound of Formula (I) may be purified prior to the coupling step being conducted to form a compound of Formula (IV). This purification helps to remove impurities, including an undesired enantiomer of the compound of Formula (I). It has now been found that the compound of Formula (I) may be easily prepared and produced with a very high purity and yield by a process disclosed herein. With significant impurities removed, the compound of Formula (I) can then be used to form a compound of Formula (IV), when reacted with a suitable coupling reagent. Further downstream transformations provide EP4 antagonists with an increased purity and yield when compared to those formed by the one-step coupling reaction (forming a compound of Formula (IV)) disclosed in WO 2021 / 069927.

[0032] In view of the above, in addition to the formation of a compound of Formula (I), the present invention generally relates to improved processes for forming EP4 antagonists according to Formula (V).

[0033] According to a first aspect, the present invention therefore provides a process for the purification of a compound of Formula (I), the process comprising the steps, in order, of a) providing a mixture comprising a compound of Formula (I) and a solvent; b) precipitating from the solvent the compound of Formula (I) provided in the mixture of step a) to form a precipitate; and c) isolating the precipitate from the solvent to provide the purified compound of Formula (I), wherein

[0034] R1is selected from the group consisting of H, C1-3 alkyl and C1-3 haloalkyl; R2is selected from the group consisting of H, C1-3 alkyl and C1-3 haloalkyl, or R1and R2, together with the carbon to which they are attached, form C3-6 cycloalkyl which is optionally substituted with one or more halo;

[0035] R3is selected from the group consisting of H, C1-3 alkyl, C1-3 haloalkyl and halo;

[0036] R4and R5are each independently selected from the group consisting of H, halo, CN, OH, SO2Me, C1-6 alkyl, C1-6 haloalkyl, C3-6 cycloalkyl and C1-6 alkoxy, wherein the C3-6 cycloalkyl and C1-6 alkoxy groups are optionally substituted with one or more halo and any one atom of the C1-6 alkyl or C3-6 cycloalkyl may be optionally replaced by a heteroatom selected from O, S and N; and

[0037] A is a protected carboxylic acid.

[0038] Surprisingly, it has been found that a compound of Formula (I), i.e. the salt of the combination of compounds of Formula (II) and (III), can be purified by precipitating the compound from a solution.

[0039] The term “purification” denotes the process of removing impurities to form a substance containing a higher proportion of the desired compound. In the present case, the desired compound is a compound of Formula (I). The term “impurities” includes components in the mixture other than the desired compound or solvent (if desired in solution). Of course, the solvent may also be considered an impurity. Examples of impurities include by-products, unreacted starting materials and other unwanted materials or compounds, such as those remaining after upstream synthetic steps. If the desired compound contains chiral centres, and a single enantiomer or diastereomer is required, then the undesired enantiomer or diastereomer is also considered an impurity.

[0040] The term “purified compound of Formula (I)” denotes a compound of Formula (I) that has a higher purity than that of the compound of Formula (I) before the process of the invention is conducted, e.g. compared to that of the compound of Formula (I) provided in step a). It is preferable that the purity of the compound of Formula (I) after the process of the invention is at least 90 area%, preferably 95 area%, more preferably 98 area%, even more preferably 99 area%, most preferably 99.9 area%. The purity in “area%” is determined by HPLC in accordance with the purity determination method in the examples.

[0041] In the compounds disclosed herein, the term “C1-6 alkyl” denotes a linear or branched alkyl group having 1 to 6 carbon atoms, i.e. 1 , 2, 3, 4, 5, or 6 carbon atoms. Likewise, the term “C1-3 alkyl” denotes a linear or branched alkyl group having from 1 to 3 carbon atoms, i.e. 1 , 2, or 3 carbon atoms. For parts of the range “C1-6 alkyl” and “C1-3 alkyl” all subgroups thereof are contemplated, such as C1-5 alkyl, C1-4 alkyl, C1-3 alkyl, C1-2 alkyl, Ci alkyl, C2-6 alkyl, C2-5 alkyl, C2-4 alkyl, C2-3 alkyl, C2 alkyl, C3-6 alkyl, C3-5 alkyl, C3-4 alkyl, C3 alkyl, C4-6 alkyl, C4-5 alkyl, C4 alkyl, C5-6 alkyl, C5 alkyl, and Ce alkyl, as applicable. Examples of “C1-6 alkyl” include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, and linear or branched pentyl and hexyl.

[0042] As used herein, the term “halo” denotes a halogen atom, and unless stated otherwise (such as in the case of a “leaving group”) is preferably F, Cl, Br or I, and more preferably F or Cl.

[0043] The term “C1-6 haloalkyl” denotes an C1-6 alkyl group in which one or more of the hydrogen atoms are independently replaced with a halo atom, e.g. F, Cl, Br, or I, preferably F or Cl, more preferably F. Each halo-substituted carbon atom in C1-6 haloalkyl may be mono-, di- or, where possible, trisubstituted with an independently selected halo atom. For parts of the range “C1-6 haloalkyl” all subgroups thereof are contemplated, such as C1-5 haloalkyl, C1-4 haloalkyl, C1-3 haloalkyl, C1-2 haloalkyl, Ci haloalkyl, C2-6 haloalkyl, C2-5 haloalkyl, C2-4 haloalkyl, C2-3 haloalkyl, C2 haloalkyl, C3-6 haloalkyl, C3-5 haloalkyl, C3-4 haloalkyl, C3 haloalkyl, C4-6 haloalkyl, C4-5 haloalkyl, C4 haloalkyl, C5-6 haloalkyl, C5 haloalkyl, and Ce haloalkyl. Examples of “C1-6 haloalkyl” include mono-, di-, and tri- halomethyl wherein the halo atoms are independently F, Cl, Br, or I, such as -CH2F, -CF2H, -CF3 -CH2CI, -CCI2H, -CCI3, -CHFCI, -CF2CI, -CCI2F, mono-, di- and tri-bromomethyl, mono-, di- and tri-iodomethyl. Also included is ethyl substituted with 1 , 2, 3, 4, or 5 independently selected halo atoms; n-propyl and isopropyl substituted with 1 , 2, 3, 4, 5, 6 or 7 independently selected halo atoms; n-butyl, isobutyl, sec-butyl, and t-butyl substituted with 1 , 2, 3, 4, 5, 6, 7, 8 or 9 independently selected halo atoms; linear or branched pentyl substituted with 1 , 2, 3, 4, 5, 6, 7, 8, 9 10, or 11 independently selected halo atoms; and linear or branched hexyl substituted with 1 , 2, 3, 4, 5, 6, 7, 8, 9 10, 11 , 12 or 13 independently selected halo atoms.

[0044] In the compounds, groups R1and R2, together with the carbon to which they are attached, may form C3-6 cycloalkyl which is optionally substituted with one or more halo.

[0045] The term “C3-6 cycloalkyl” denotes an alkyl group having from 3 to 6 carbon atoms that comprises a monocyclic portion. For parts of the range “C3-6 cycloalkyl" all subgroups thereof are contemplated, such as C3-6 cycloalkyl, C3-5 cycloalkyl, C3-4 cycloalkyl, C3 cycloalkyl, C4-6 cycloalkyl, C4-5 cycloalkyl, C4 cycloalkyl, C5-6 cycloalkyl, C5 cycloalkyl, Ce cycloalkyl. Examples of these cycloalkyl groups include cyclopropyl (CyPr), cyclobutyl (CyBu), cyclopentyl (CyPe), cyclohexyl (CyHx) as well as those shown below. It is preferable that the C3-6 cycloalkyl is cyclopropyl.

[0046] The terms “optional” or “optionally” denotes that the subsequently described event or circumstance may, but need not, occur, and that the description includes instances where the event or circumstance occurs and instances in which it does not. The term “substituted” denotes that the group to which it refers has one or more hydrogen atoms substituted for a different group. For instance, “alkyl substituted with one or more halo” refers to a monovalent radical of an alkane with one or more hydrogens attached to the alkyl being replaced with halo. In view of the above, the term “optionally substituted” means that the group to which it refers may or may not be substituted, e.g. for instance, with one or more halo.

[0047] The term “C1-6 alkoxy” denotes -O-(Ci-6 alkyl) in which the C1-6 alkyl group is as defined above. Non-limiting examples of “C1-6 alkoxy” include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, t-butoxy and linear and branched-chain pentoxy and hexoxy.

[0048] Group ‘A’ is a protected carboxylic acid. Group ‘A may be any suitable protected carboxylic acid as would be understood by the person skilled in the art. A protected carboxylic acid group is a functional group within an organic molecule that has been chemically modified to shield the carboxylic acid functionality from undesired reactions during a synthetic process. The choice of a protecting group depends on the specific reaction conditions and the nature of the other functional groups in the molecule, as would be understood by the skilled person. Examples of protecting groups, and methods of protecting and deprotecting functional groups, can be found in Greene's Protective Groups in Organic Synthesis, Fifth Edition, Editor: Peter G. M. Wuts, John Wiley, 2014, (ISBN:9781118057483), incorporated herein by reference in its entirety. Preferably, group ‘A is selected from the group consisting of wherein

[0049] R6is selected from the group consisting of C1-6 alkyl and benzyl;

[0050] R7is selected from the group consisting of C1-6 alkyl; and

[0051] R8, R9and R10are each independently selected from C1-6 alkyl and phenyl.

[0052] More preferably, group ‘A is . Most preferably, group ‘A is -C(O)OMe. In a preferred feature of the invention R1and R2, together with the carbon to which they are attached, form C3-6 cycloalkyl, preferably cyclopropyl.

[0053] R3is selected from the group consisting of H, C1-3 alkyl, C1-3 haloalkyl and halo. It is preferred that R3is H.

[0054] R4and R5are each independently selected from the group consisting of H, halo, CN, OH, -S02Me, C1-6 alkyl, C1-6 haloalkyl, C3-6 cycloalkyl and C1-6 alkoxy. Here, the C3-6 cycloalkyl and C1-6 alkoxy groups may be optionally substituted with one or more halo. Further, any one atom of the C1-6 alkyl or C3-6 cycloalkyl may be optionally replaced by a heteroatom selected from O, S and N. It is preferred that R4is H. It is preferred that R5is C1-6 haloalkyl, more preferably it is -CF3. This means that a particularly favoured combination is that R4is H, and R5is C1-6 haloalkyl, e.g. -CF3.

[0055] In a particular feature of the invention, group ‘A’ is -C(O)OMe; R1and R2, together with the carbon to which they are attached, form cyclopropyl; R3is H; R4is H; and R5is -CF3.

[0056] The term “precipitate” denotes a solid material that forms and separates from a solution. Isolation of the precipitate may be achieved by any suitable method as would be understood by the skilled person. For example, isolation of the precipitate may be achieved through filtration and / or centrifugation. The precipitate may be amorphous, crystalline, or a combination thereof. By extension, the term “precipitating” if the process of forming a precipitate.

[0057] The term “mixture” is given its normal interpretation, i.e. the combination two or more chemical substances. In the present case, the mixture in step a) comprises a compound of Formula (I) and a solvent. The mixture may contain other substances, such as impurities that are desired to be removed from the compound of Formula (I).

[0058] Any suitable solvent may be used in the processes of the invention. It is preferable that the solvent is an organic solvent. The preferred organic solvents, particularly in the first aspect of the invention, are acetone, methyl tert-butyl ether, isopropyl acetate, toluene, acetonitrile, and combinations thereof. Out of those, toluene, acetonitrile, and a combination thereof are particularly suitable, with acetonitrile being most notable.

[0059] The term “isolating” or “isolated” has it usually meaning, i.e. separating a compound from a more complex mixture. It will be understood that after isolation there may still remain part of the component from which the compound is separated. For instance, isolation of a precipitate may result in the precipitate containing a small amount, such as a trace, of the solvent from which is it isolated.

[0060] As mentioned, purification is a process of removing impurities to form a substance containing a higher proportion of the desired compound, and an impurity may be the undesired enantiomer of the compound of Formula (I). In this regard, when the desired enantiomer is provided in enantiomeric excess in the compound of Formula (I) in step a), it has been surprisingly found that the isolated compound of Formula (I) in step c) comprises a higher amount of that desired enantiomer when compared to that provided in step a). In this case, the purification comprises enantioenrichment of the compound of Formula (I). Without wishing to be bound by theory, it is believed that the process of the invention may lead to the preferential crystallisation of the enantiomer that is provided in enantiomeric excess, which leads to the enantioenrichment of the compound of Formula (I). In this case, it may be crucial that the carbon marked with a * in the compound of Formula (I) is the only chiral centre in the compound. This avoids the presence of diastereoisomers which may negatively impact the enantioenrichment process.

[0061] To achieve the enantioenrichment, the compound of Formula (I) provided in step a) should be non-racemic compound of Formula (I). This means that one of the enantiomers is present in an excess, i.e. it is in enantiomeric excess. In this case, the compound of Formula (I) isolated in step c) is the enantioenriched compound of Formula (I).

[0062] In view of the above, when the purification comprises enantioenrichment of the compound of Formula (I), the compound of Formula (I) provided in step (a) is non- racemic compound of Formula (I); and the compound of Formula (I) isolated in step (c) is the enantioenriched compound of Formula (I). In this case, the carbon marked with a * in the compound of Formula (I) is the only chiral centre in the compound.

[0063] As is known, “enantiomeric excess” (e.e.) is a measure of the chiral purity of a compound with respect to its enantiomer. Enantiomeric excess quantifies the difference in the amounts of two enantiomers in a mixture. The enantiomeric excess may be measured by HPLC, for instance chiral HPLC, and is expressed as a percentage. By extension, “enantioenrichment” is a process by which an enantiomeric excess is increased.

[0064] The term “enantioenriched compound of Formula (I)” denotes a compound of Formula (I) comprising an enantiomer that is provided in a higher enantiomeric excess than that of the same enantiomer in the compound of Formula (I) provided earlier, such as in step a).

[0065] The non-racemic compound of Formula (I) comprises at least some of both enantiomers, but not an equal amount of both enantiomers, i.e. a non-racemic compound comprises one enantiomer that is provided in an enantiomeric excess of more than 0%. Preferably, the enantiomeric excess of the desired enantiomer of the compound of Formula (I) provided in the mixture of step a) is at least about 60%, preferably at least about 70%, more preferably at least about 80%, more preferably at least about 90%, more preferably at least about 94%, more preferably at least about 95%, more preferably at least about 96%, more preferably at least about 97%, more preferably at least about 98%, most preferably at least about 99%. The enantiomeric excess of the desired enantiomer of the compound of Formula (I) isolated in step c) will be higher than provided in step a). In view of the above, and for the avoidance of any doubt, the enantiomeric excess of one enantiomer in the compound of Formula (I) isolated in step c) should be higher than the enantiomeric excess of the same enantiomer in the compound of Formula (I) provided in the mixture of step a). The present invention therefore provides a process for the enantioenrichment of a compound of Formula (I), the process comprising the steps, in order, of a) providing a mixture comprising a non-racemic compound of Formula (I) and a solvent; b) precipitating from the solvent the enantiomer of the compound of Formula (I) provided in enantiomeric excess in the mixture of step a) to form a precipitate; and c) isolating the precipitate from the solvent to provide the enantioenriched compound of Formula (I), wherein

[0066] R1is selected from the group consisting of H, C1-3 alkyl and C1-3 haloalkyl;

[0067] R2is selected from the group consisting of H, C1-3 alkyl and C1-3 haloalkyl, or R1and R2, together with the carbon to which they are attached, form C3-6 cycloalkyl which is optionally substituted with one or more halo;

[0068] R3is selected from the group consisting of H, C1-3 alkyl, C1-3 haloalkyl and halo; R4and R5are each independently selected from the group consisting of H, halo, CN, OH, SO2Me, C1-6 alkyl, C1-6 haloalkyl, C3-6 cycloalkyl and C1-6 alkoxy, wherein the C3-6 cycloalkyl and C1-6 alkoxy groups are optionally substituted with one or more halo and any one atom of the C1-6 alkyl or C3-6 cycloalkyl may be optionally replaced by a heteroatom selected from O, S and N; and

[0069] A is a protected carboxylic acid, and wherein the carbon marked with a * in the compound of Formula (I) is the only chiral centre in the compound.

[0070] In the first aspect of the invention, a mixture is provided that comprises a compound of Formula (I) and a solvent, such as those solvents listed herein. The compound of Formula (I) may be completely dissolved in the solvent, substantially dissolved in the solvent or partially dissolved in the solvent. The term “substantially dissolved" means that at least 80 weight%, such as at least 90 weight%, preferably at least 95 weight%, more preferably at least 99 weight%, of the compound of Formula (I) is dissolved in the solvent based upon the total weight of the compound of Formula (I) in the mixture. The term “partially dissolved” means less than 80 weight% but more than 0 weight% of the compound of Formula (I) is dissolved in the solvent based upon the total weight of the compound of Formula (I) in the mixture.

[0071] It is preferable that the compound of Formula (I) is substantially dissolved in the solvent, and more preferably completely dissolved.

[0072] The mixture provided in step a) may be at a first temperature of at least about 40 °C, preferably from about 40 °C to about 80 °C, more preferably from about 45 °C to about 70 °C, most preferably from about 50 °C to about 60 °C. This may help dissolve the compound of Formula (I). The temperature used may depend upon the compound of Formula (I) that is to be purified, and also the choice of solvent. The compound of Formula (I) may be substantially dissolved, preferably dissolved, once the mixture has reached the first temperature or at a timepoint thereafter. Dependent upon first temperature and agitation used, a dissolution equilibrium may take some time to be achieved. The mixture therefore may be held at the first temperature for a first period of at least about 10 minutes, preferably from about 10 minutes to about 5 hours, more preferably from about 20 minutes to about 3 hours, more preferably from about 25 minutes to about 2 hours, most preferably from about 30 minutes to about 1 hour.

[0073] When the dissolution equilibrium has been reached, the mixture may be filtered to remove any insoluble components that remain to help increase purity.

[0074] To form the precipitate in step b) the mixture may be cooled to a second temperature. The second temperature will be lower than the first temperature to help the precipitate form. The second temperature may be about 35 °C or less. This may help to start to form the precipitate. The second temperature is preferably from about -50 °C to about 35 °C, more preferably from about -50 °C to about 20 °C, more preferably from about -40 °C to about 0 °C, most preferably from about -25 °C to about -15 °C. It has been found that cooling the mixture to the second temperature further increases the recovery yield of the compound of Formula (I), particularly when the second temperature is from about -25 °C to about -15 °C.

[0075] Dependent upon second temperature and agitation used, a precipitate may take some time to form. In view of this, the mixture may be held at the second temperature for a second period of at least about 15 minutes. The second period is preferably from about 15 minutes to about 6 hours, more preferably from about 30 minutes to about 4 hours, more preferably from about 1 hour to about 2 hours. The use of the above second period may also contribute to the increased recovery yield of the compound of Formula (I).

[0076] It is believed that a higher enantiomeric excess of the desired enantiomer of the compound of Formula (I) in step a) may lead to more preferential crystallisation of the desired enantiomer in steps b) and c), providing a more significant enantioenrichment. In other words, the proportion of impurities removed from the compound of Formula (I) by the above method may be higher when the compound of Formula (I) provided in step a) has a higher enantiomeric excess.

[0077] The precipitate (which is a solid form) of a compound of Formula (I) may be amorphous, crystalline, or a combination thereof. Most preferably it is substantially crystalline, such as crystalline. A “substantially crystalline” solid may comprise amorphous compound or regions of the precipitate / solid. At least 80 weight%, for instance at least 90 weight%, preferably at least 95 weight%, more preferably at least 99 weight%, most preferably at least 99.5 weight%, of the compound of Formula (I) may be present in a crystalline form, based upon the total weight of the compound of Formula (I) in the precipitate / solid.

[0078] The precipitate may be sampled at this point to check its purity, and in particular its enantiomeric excess.

[0079] In step c), the precipitate is isolated from the solvent. This provides the purified compound of Formula (I). If non-racemic compound of Formula (I) is provided in step a) then step c) provides enantioenriched compound of Formula (I).

[0080] The isolation of the precipitate may be my any conventional means. Preferably, the isolation is by filtration.

[0081] Whilst any compound of Formula (I) may be purified, including being enantioenriched, by the process of the invention, preferred compounds of Formula (I) comprise an enantiomeric excess of a compound of Formula (l-i), preferably (la-i), more preferably (Ib-i)

[0082] wherein R1to R5and A are as defined herein. Preferably, the enantiomeric excess of the compound of Formula (l-i), (la-i) or (Ib-i) provided in step a) is at least about 70%, more preferably at least about 80%, more preferably at least about 90%, more preferably at least about 93%, more preferably at least about 94%, more preferably at least about 95%, more preferably at least about 96%, more preferably at least about 97%, more preferably at least about 98%, most preferably at least about 99%. In view of the above, the first aspect of the invention also provides a solid form comprising, or consisting of, a compound of Formula (I) wherein R1to R5and A are as defined herein. The solid form may be the precipitate formed in the process of the first aspect of the invention. The solid form may therefore consist of a compound of Formula (I). It will be understood that when the solid form consists of a compound of Formula (I) then there may be other small amounts, such as trace amounts, of impurities in the solid form.

[0083] Preferably, in the solid form, the compound of Formula (I) is a compound of Formula (la), wherein A is as defined herein.

[0084] More preferably, in the solid form, the compound of Formula (I) is a compound of Formula (lb) As discussed above, it is preferred that the compound of Formula (I) comprises an enantiomeric excess of one of the constituent compounds. Examples of compounds that are in enantiomeric excess in the solid form are a compound of Formula (l-i), preferably (la-i), more preferably (Ib-i) wherein R1to R5and A are as defined herein. Preferably, the enantiomeric excess of the compound of Formula (l-i), (la-i) or (Ib-i) in the solid form is at least about 70%, more preferably at least about 80%, more preferably at least about 90%, more preferably at least about 93%, more preferably at least about 94%, more preferably at least about 95%, more preferably at least about 96%, more preferably at least about 97%, more preferably at least about 98%, most preferably at least about 99%. As mentioned above, the solid form (e.g. the isolated precipitate) comprising, or consisting of, a compound of Formula (I) may be amorphous, crystalline, or a combination thereof. It is preferable that the solid form comprises, or consists of, a crystalline compound of Formula (I). More preferably, the solid form is substantially crystalline, such as crystalline, compound of Formula (I). As also mentioned above, “substantially crystalline” solid may comprise amorphous compound. For instance, at least 80 weight%, e.g. at least 90 weight%, preferably at least 95 weight%, more preferably at least 99 weight%, most preferably at least 99.5 weight%, of the compound of Formula (I) may be present in a crystalline form, based upon the total weight of the compound of Formula (I) in the solid form. Crystalline compound of Formula (I) is typically easier to purify, such as easier to enantioenrich. It may also be more stable, easier to handle, and is particularly suitable for use as a compound from which to form downstream pharmaceutical compounds at a manufacturing scale.

[0085] It is most preferred that the crystalline compound of Formula (I) comprises an enantiomeric excess of a compound of Formula (Ib-i) (such as an enantiomeric excess as mentioned above). That crystalline compound may exhibit an X-ray powder diffraction pattern comprising peaks at 20 of 10.3 ± 0.1 °, 17.9 ± 0.1 ° and

[0086] 20.6 ± 0.1 °. Preferably, the crystalline compound of Formula (I) exhibits an X-ray powder diffraction pattern comprising peaks at 20 of 10.3 ± 0.1 °, 17.9 ± 0.1 °, 20.6 ± 0.1 ° and 25.8 ± 0.1 °. More preferably, the crystalline compound of Formula (I) exhibits an X-ray powder diffraction pattern comprising peaks at 20 of 10.3 ± 0.1°, 13.0 ± 0.1 °, 17.9 ± 0.1 °, 20.6 ± 0.1 °, and 25.8 ± 0.1 °. More preferably, the crystalline compound of Formula (I) exhibits an X-ray powder diffraction pattern comprising peaks at 20 of 10.3 ± 0.1°, 13.0 ± 0.1°, 13.3 ± 0.1°, 15.5 ± 0.1 °, 16.1 ± 0.1 °, 17.9 ± 0.1 °, 19.2 ± 0.1 °, 19.4 ± 0.1 °, 20.6 ± 0.1 °, 21.4 ± 0.1 °, 21.9 ± 0.1 °,

[0087] 22.6 ± 0.1°, 23.0 ± 0.1°, 25.4 ± 0.1°, 25.8 ± 0.1°, 25.9 ± 0.1°, 26.4 ± 0.1°, and 26.9 ± 0.1 °.

[0088] The crystalline compound of Formula (I) may exhibit an X-ray powder diffraction pattern comprising peaks at 20 as set out in the table below and / or substantially in accordance with the X-ray powder diffraction pattern shown in Figure 2. | 20.6 ± 0.1 ° | | 29.7 ± 0.1 ° |

[0089] The X-ray powder diffraction pattern may be measured using Cu Ka radiation in accordance with the method outlined in the examples below.

[0090] According to a second aspect, the present invention provides a process for the formation of a compound of Formula (I).

[0091] The process comprises the step of reacting a compound of Formula (II), or an alkali metal or alkaline earth metal salt thereof, with a compound of Formula (III) to form the compound of Formula (I).

[0092] This second aspect of the invention may be used to form the compound of Formula (I) that is provided in step a) of the first aspect of the invention. Therefore, group ‘A and R1to R5are as defined herein, and in particular are as defined in relation to the first aspect of the invention, and preferences therein. It will be understood that the enantiomeric excess of the compound of Formula (I) provided in step a) of the first aspect of the invention is likely to be the same or similar to the enantiomeric excess of the compound of Formula (II) used in the process of the second aspect of the invention.

[0093] In the method of WO 2021 / 069927, the compound of Formula (II) is reacted with a compound of Formula (III) in the presence of a coupling reagent. The absence of the coupling reagent facilitates the formation and subsequent isolation of the compound of Formula (I) without the premature coupling reaction forming a compound of Formula (IV). Therefore, to avoid the direct formation of a compound of Formula (IV) (see below), the compound of Formula (II), or an alkali metal or alkaline earth metal salt thereof, and the compound of Formula (III) are preferably reacted in the absence of a coupling reagent.

[0094] The compound of Formula (II) may be used as its alkali metal or alkaline earth metal salt thereof. The term “alkali metal” denotes the elements lithium, sodium, potassium, rubidium, caesium and francium. Preferred alkali metals for alkali metal salts are sodium or potassium.

[0095] The term “alkali earth metal” denotes the elements beryllium, magnesium, calcium, strontium, barium and radium. Preferred alkali earth metals for alkali earth metal salts are magnesium and calcium.

[0096] When provided as their alkali metal or alkaline earth metal salt, the compounds of Formula (II) may be reacted with an acid, such as a mineral acid, e.g. HCI, and H2SO4, to form the free base of the carboxylic acid. This may be done prior to, together with, or after, the addition of the compound of Formula (III) to the reaction.

[0097] The compound of Formula (II), or an alkali metal or alkaline earth metal salt thereof, and the compound of Formula (III) should be reacted in a solvent, such as an organic solvent. Any suitable organic solvent may be used. Preferably, the organic solvent is an aprotic organic solvent. More preferably, the organic solvent is selected from the group consisting of acetone, methyl tert-butyl ether, isopropyl acetate, toluene, acetonitrile, and combinations thereof. More preferably, the organic solvent is selected from the group consisting of toluene, acetonitrile, and a combination thereof. Most preferably, the solvent is acetonitrile. As mentioned above, it has been found that compounds of Formula (I) can be purified by their precipitation and isolation. As such, the compound of Formula (II) may be provided at a lower purity and may still be used to provide an equally pure final pharmaceutical product via the formation of the compound of Formula (I) that is then purified in accordance with the present invention. The formation of the compound of Formula (I), and subsequent purification, may reduce or eliminate the need to purify the compound of Formula (II) or (III) before they are reacted to form the compound of Formula (I). This may reduce the process steps and process time to form the final pharmaceutical products.

[0098] In view of the above, the compound of Formula (II), or the alkali metal or alkaline earth metal salt thereof, and / or the compound of Formula (III), may have a chromatographic purity of less than 100%, i.e. the compound of Formula (II) and or (III) may contain impurities.

[0099] The compound of Formula (II) may comprise an enantiomeric excess of a compound of Formula (ll-i), or an alkali metal or alkaline earth metal salt thereof. It may therefore have an enantiomeric purity of less than 100%. It is preferable that the compound of Formula (II) comprises an enantiomeric excess of a compound of Formula (lla-i), or an alkali metal or alkaline earth metal salt thereof.

[0100] R4and R5are as defined herein.

[0101] When the compound of Formula (II) comprises an enantiomeric excess, for instance that of the compound of Formula (ll-i) or preferably (lla-i), that enantiomeric excess may be at least about 60%, preferably at least about 70%, more preferably at least about 80%, more preferably at least about 90%, more preferably at least about 94%, more preferably at least about 95%, more preferably at least about 96%, more preferably at least about 97%, more preferably at least about 98%, most preferably at least about 99%.

[0102] It is preferred that the compound of Formula (II) comprises an enantiomeric excess of a compound of Formula (lla-i), or an alkali metal or alkaline earth metal salt thereof. However, it is most preferred that the free acid of a compound of Formula (lla-i) is used. By free acid, we mean the neutral parent compound, i.e. not an alkali metal or alkaline earth metal salt of the compound.

[0103] For the avoidance of doubt, the compound of Formula (I) used in the first aspect of the invention may be the compound of Formula (I) formed in the second aspect of the invention.

[0104] According to a third aspect, the present invention provides a process for the formation of a compound of Formula (IV) or a salt thereof, the process comprising the steps, in order, of a) providing a compound of Formula (I) in accordance with a process as defined herein; and b) reacting the compound of Formula (I) in the presence of a coupling reagent to form a compound of Formula (IV), or the salt thereof, wherein R1to R5and A are as defined herein. In step a), it is preferrable that the compound of Formula (I) is provided in accordance with a process as defined in the first aspect of the invention, including a process as defined in the first and second aspects of the invention.

[0105] As it is preferred that the compound of Formula (I) comprises an enantiomeric excess of a compound of Formula (l-i), preferably (la-i), more preferably (Ib-i), in the third aspect of the invention it is preferred that the compound of Formula (IV) is a compound of Formula (IV-i), (IVa-i), and (IVb-i), respectively. R1to R5and A are as defined herein.

[0106] The enantiomeric excess of the compound of Formula (IV-i), (IVa-i) and (IVb-i) (or the salt of each thereof) should be similar to that of the corresponding compound of Formula (I) that is used in its formation. This may be, for example, at least about 70%, more preferably at least about 80%, more preferably at least about 90%, more preferably at least about 93%, more preferably at least about 94%, more preferably at least about 95%, more preferably at least about 96%, more preferably at least about 97%, more preferably at least about 98%, most preferably at least about 99%. A “coupling reagent” is a compound or agent used to facilitate the formation of a chemical bond between two molecules. In the present case, the couple reagent facilitates the formation of an amide bond between a carboxylic acid and an amine. Any suitable coupling reagent may be used, such as those disclosed in WO 2021 / 069927. The coupling reagent may be selected from the group consisting of 1 -Ethyl-3- (3-dimethylaminopropyl)carbodiimide (EDCI), EDCI.HCI, (1-Cyano- 2-ethoxy-2-oxoethylidenaminooxy)dimethylamino-morpholino-carbenium hexafluorophosphate (COMU), Ethyl cyano (hydroxyimino)acetate (Oxyma Pure), Dicyclohexylcarbodiimide (DCC), Diisopropylcarbodiimide (DIC), Benzotriazol-1- yloxy-tris(dimethylamino)-phosphonium hexafluorophosphate (BOP), Benzotriazol-1 -yloxy-tripyrrolidino-phos-phonium hexafluorophosphate (PyBOP), Bromo-tripyrrolidino-phosphonium hexa-fluorophosphate (PyBrOP), 7-Aza- benzotriazol-1 -yloxy-tripyrrolidino-phosphonium hexafluorophosphate (PyAOP), Ethyl cyano(hydroxyimino)acetato-O2)-tri-(1-pyrrolidinyl)-phosphonium hexafluorophosphate (PyOxim), 3-(Diethoxy-phosphoryloxy)-1 ,2,3-benzo[d] triazin-4(3H)-one (DEPBT), 2-(1 H-Benzotriazol-1-yl)-N,N,N’,N’- tetramethylaminium tetrafluoroborate / hexafluorophosphate (HBTU), 2-(7-Aza-1 H- benzotriazol-1-yl)-N,N,N’,N’-tetramethylaminium hexafluorophosphate (HATU), Tetramethylfluoroformamidinium hexafluorophosphate (TFFH), 2-(6-Chloro-1 H- benzotriazol-1-yl)-N,N,N’,N’-tetramethylaminium hexafluorophosphate (HCTU), N-[(5-Chloro-1 H-benzotriazol-1-yl)-dimethylamino-morpholino]-uronium hexafluorophosphate N-oxide (HDMC), 2-(1-0xy-pyridin-2-yl)-1 , 1 ,3,3- tetramethyl-isothiouronium tetrafluoroborate (TOTT), Propylphosphonic anhydride (T3P), and combinations thereof. More preferably, the coupling reagent is selected from the group consisting of EDCI, EDCI.HCI, COMU and a combination thereof.

[0107] Other features of the reaction of the compound of Formula (I) in the presence of a coupling reagent to form a compound of Formula (IV) may be those as defined in WO 2021 / 069927.

[0108] According to a fourth aspect, the present invention provides a process for the formation of a compound of Formula (V) or a salt thereof, the process comprising the steps, in order, of a) providing a compound of Formula (IV) in accordance with a process as defined herein, such as the first to third aspects of the invention, and in particular the third aspect of the invention; and b) deprotecting the protected carboxylic acid of group A of the compound of Formula (IV), or the salt thereof, to form the compound of Formula (V), or the salt thereof, wherein R1to R5and A are as defined above.

[0109] As it is preferred that the compound of Formula (I) comprises an enantiomeric excess of a compound of Formula (l-i), preferably (la-i), more preferably (Ib-i), in the fourth aspect of the invention it is preferred that the compound of Formula (IV) is a compound of Formula (IV-i), (IVa-i), and (IVb-i), respectively, and then the compound of Formula (V) is preferably a compound of Formula (V-i), such as (Va- i).

[0110] The enantiomeric excess of the compound of Formula (V-i), and (Va-i) (or the salt of each thereof) should be similar to that of the corresponding compound used in its formation. This may be, for example, at least about 70%, more preferably at least about 80%, more preferably at least about 90%, more preferably at least about 93%, more preferably at least about 94%, more preferably at least about 95%, more preferably at least about 96%, more preferably at least about 97%, more preferably at least about 98%, most preferably at least about 99%.

[0111] As mentioned above, it is preferred that A is selected from the group consisting of

[0112] The skilled person would be aware of the variety of ways in which those groups may be converted into a carboxylic acid, i.e. -C(O)OH. This may be by acid or base hydrolysis, particularly when A is -C(O)OR6.

[0113] According to a fifth aspect, the present invention provides a process for preparing a pharmaceutical composition comprising a compound of Formula (V), or a salt thereof, and at least one pharmaceutically acceptable excipient the process comprising the steps, in order, of a) providing a compound of Formula (V) in accordance with a process as defined herein, such as the first to fourth aspects of the invention, and in particular the fourth aspect of the invention; and b) combining the compound of Formula (V), or a salt thereof, with the at least one pharmaceutically acceptable excipient, wherein R1to R5as defined above. The preferences for the compound of Formula (V) in the fourth aspect of the invention, e.g. it having an enantiomeric excess of a compound of Formula (V-i), preferably (Va-i) apply equally to the compound of Formula (V) in the fifth aspect of the invention. Again, the enantiomeric excess of the compound of Formula (V- i), and (Va-i) (or the salt of each thereof) in the fifth aspect of the invention should be similar to that of the corresponding compound used in its formation. This may be, for example, at least about 70%, more preferably at least about 80%, more preferably at least about 90%, more preferably at least about 93%, more preferably at least about 94%, more preferably at least about 95%, more preferably at least about 96%, more preferably at least about 97%, more preferably at least about 98%, most preferably at least about 99%.

[0114] The compound of Formula (V) may preferably be in its non-salt form. The compound of Formula (V) may preferably be present as a free acid.

[0115] In the above, e.g. the fourth and fifth aspects of the invention, the “salt” of a compound of Formula (V) may be any suitable salt. Preferably, that salt is a pharmaceutically acceptable salt.

[0116] Salts or pharmaceutically acceptable salts of the compound of Formula (V) include acid addition salts and base addition salts. Such salts may be formed by conventional means, for example by reaction of a free acid or a free base form of the compound with one or more equivalents of an appropriate acid or base, optionally in a solvent, or in a medium in which the salt is insoluble, followed by removal of said solvent, or said medium, using standard techniques (e.g. in vacuo, by freeze-drying or by filtration). Salts may also be prepared by exchanging a counter-ion of the compound in the form of a salt with another counter-ion, for example using a suitable ion exchange resin.

[0117] Examples of pharmaceutically acceptable salts include acid addition salts derived from mineral acids and organic acids, and salts derived from metals such as sodium, magnesium, potassium and calcium. Examples of acid addition salts include acid addition salts formed with acetic, 2,2- dichloroacetic, adipic, alginic, aryl sulfonic acids (e.g. benzenesulfonic, naphthalene-2-sulfonic, naphthalene-1 ,5-disulfonic and p-toluenesulfonic), ascorbic (e.g. L-ascorbic), L-aspartic, benzoic, 4-acetamidobenzoic, butanoic, (+) camphoric, camphor-sulfonic, (+)-(1S)-camphor-10-sulfonic, capric, caproic, caprylic, cinnamic, citric, cyclamic, dodecylsulfuric, ethane-1 ,2-disulfonic, ethanesulfonic, 2-hydroxyethanesulfonic, formic, fumaric, galactaric, gentisic, glucoheptonic, gluconic (e.g. D-gluconic), glucuronic (e.g. D-glucuronic), glutamic (e.g. L-glutamic), a-oxoglutaric, glycolic, hippuric, hydrobromic, hydrochloric, hydriodic, isethionic, lactic (e.g. (+)-L-lactic and (±)-DL-lactic), lactobionic, maleic, malic (e.g. (-)-L-malic), malonic, (±)-DL-mandelic, metaphosphoric, methanesulfonic, 1-hydroxy-2-naphthoic, nicotinic, nitric, oleic, orotic, oxalic, palmitic, pamoic, phosphoric, propionic, L-pyroglutamic, salicylic, 4-amino- salicylic, sebacic, stearic, succinic, sulfuric, tannic, tartaric (e.g.(+)-L-tartaric), thiocyanic, undecylenic and valeric acids.

[0118] The “pharmaceutically acceptable excipient” may be any suitable pharmaceutically acceptable excipient. These include carriers (e.g. a solid, liquid or semi-solid carrier), adjuvants, diluents (e.g solid diluents such as fillers or bulking agents; and liquid diluents such as solvents and co-solvents), granulating agents, binders, flow aids, coating agents, release-controlling agents (e.g. release retarding or delaying polymers or waxes), binding agents, disintegrants, buffering agents, lubricants, preservatives, anti-fungal and antibacterial agents, antioxidants, buffering agents, tonicity-adjusting agents, thickening agents, flavouring agents, sweeteners, pigments, plasticizers, taste masking agents, stabilisers or any other excipients conventionally used in pharmaceutical compositions.

[0119] The term “pharmaceutically acceptable” as used herein means compounds, materials, compositions, and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of a subject (e.g. a human subject) without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio. Each excipient must also be “acceptable” in the sense of being compatible with the other ingredients of the formulation.

[0120] Pharmaceutical compositions containing compounds of the formula (1) can be formulated in accordance with known techniques, see for example, Remington’s Pharmaceutical Sciences, Mack Publishing Company, Easton, PA, USA. The pharmaceutical compositions can be in any form suitable for oral, parenteral, topical, intranasal, intrabronchial, sublingual, ophthalmic, otic, rectal, intra-vaginal, or transdermal administration.

[0121] Pharmaceutical dosage forms suitable for oral administration include tablets (coated or uncoated), capsules (hard or soft shell), caplets, pills, lozenges, syrups, solutions, powders, granules, elixirs and suspensions, sublingual tablets, wafers or patches such as buccal patches.

[0122] Tablet compositions can contain a unit dosage of active compound together with an inert diluent or carrier such as a sugar or sugar alcohol, e.g. lactose, sucrose, sorbitol or mannitol; and / or a non-sugar derived diluent such as sodium carbonate, calcium phosphate, calcium carbonate, or a cellulose or derivative thereof such as microcrystalline cellulose (MCC), methyl cellulose, ethyl cellulose, hydroxypropyl methyl cellulose, and starches such as com starch. Tablets may also contain such standard ingredients as binding and granulating agents such as polyvinylpyrrolidone, disintegrants (e.g. swellable crosslinked polymers such as crosslinked carboxymethylcellulose), lubricating agents (e.g. stearates), preservatives (e.g. parabens), antioxidants (e.g. BHT), buffering agents (for example phosphate or citrate buffers), and effervescent agents such as citrate / bicarbonate mixtures. Such excipients are well known and do not need to be discussed in detail here.

[0123] Tablets may be designed to release the drug either upon contact with stomach fluids (immediate release tablets) or to release in a controlled manner (controlled release tablets) over a prolonged period of time or with a specific region of the Gl tract. The pharmaceutical compositions typically comprise from approximately 1 % (w / w) to approximately 95%, preferably% (w / w) active ingredient and from 99% (w / w) to 5% (w / w) of a pharmaceutically acceptable excipient (for example as defined above) or combination of such excipients. Preferably, the compositions comprise from approximately 20% (w / w) to approximately 90% (w / w) active ingredient and from 80% (w / w) to 10% of a pharmaceutically excipient or combination of excipients. The pharmaceutical compositions comprise from approximately 1% to approximately 95%, preferably from approximately 20% to approximately 90%, active ingredient. Pharmaceutical compositions according to the invention may be, for example, in unit dose form, such as in the form of ampoules, vials, suppositories, pre-filled syringes, dragees, powders, tablets or capsules.

[0124] Tablets and capsules may contain, for example, 0-20% disintegrants, 0-5% lubricants, 0-5% flow aids and / or 0-99% (w / w) fillers / or bulking agents (depending on drug dose). They may also contain 0-10% (w / w) polymer binders, 0-5% (w / w) antioxidants, 0-5% (w / w) pigments. Slow release tablets would in addition typically contain 0-99% (w / w) release-controlling (e.g. delaying) polymers (depending on dose). The film coats of the tablet or capsule typically contain 0-10% (w / w) polymers, 0-3% (w / w) pigments, and / or 0-2% (w / w) plasticizers.

[0125] Parenteral formulations typically contain 0-20% (w / w) buffers, 0-50% (w / w) cosolvents, and / or 0-99% (w / w) Water for Injection (WFI) (depending on dose and if freeze dried). Formulations for intramuscular depots may also contain 0-99% (w / w) oils.

[0126] The pharmaceutical formulations may be presented to a patient in “patient packs” containing an entire course of treatment in a single package, usually a blister pack.

[0127] The compounds of the Formula (V) will generally be presented in unit dosage form and, as such, will typically contain sufficient compound to provide a desired level of biological activity. For example, a formulation may contain from 1 nanogram to 2 grams of active ingredient, e.g. from 1 nanogram to 2 milligrams of active ingredient. Within these ranges, particular sub-ranges of compound are 0.1 milligrams to 2 grams of active ingredient (more usually from 10 milligrams to 1 gram, e.g. 50 milligrams to 500 milligrams), or 1 microgram to 20 milligrams (for example 1 microgram to 10 milligrams, e.g. 0.1 milligrams to 2 milligrams of active ingredient).

[0128] For oral compositions, a unit dosage form may contain from 1 milligram to 2 grams, more typically 10 milligrams to 1 gram, for example 50 milligrams to 1 gram, e.g. 100 milligrams to 1 gram, of active compound.

[0129] The active compound will be administered to a patient in need thereof (for example a human or animal patient) in an amount sufficient to achieve the desired therapeutic effect (effective amount). The precise amounts of compound administered may be determined by a supervising physician in accordance with standard procedures.

[0130] It has been found that the purity and yield of compound downstream from the compound of Formula (I), e.g. compounds of Formulas (IV) and (V), are increased when the compound of Formula (I) is purified in accordance with the first aspect of the invention. Without wishing to be bound by theory, this is believed to be a direct consequence of the increased purity of the compound of Formula (I).

[0131] Further, when using an enantioenriched compound of Formula (I) for the formation of a compound of Formula (IV), the process affords compounds of Formulae (IV) and (V) with higher chiral purity than that of the compound of Formula (II) used to prepare the compound of Formula (I). Increasing the chiral purity of the advanced pharmaceutical intermediate (i.e. a compound of Formula (I)) enables the formation of a pharmaceutical with a higher chiral purity, thereby enhancing its yield, efficacy, and safety.

[0132] For the avoidance of doubt, in all aspects of the invention it is preferred that the compounds of Formula (I) comprise an enantiomeric excess of a compound of

[0133] Formula (l-i), preferably (la-i), more preferably (Ib-i). The enantiomeric excess is preferably at least about 70%, more preferably at least about 80%, more preferably at least about 90%, more preferably at least about 93%, more preferably at least about 94%, more preferably at least about 95%, more preferably at least about 96%, more preferably at least about 97%, more preferably at least about 98%, most preferably at least about 99%.

[0134] There is also provided a compound of Formula (I) obtained or obtainable by a process as defined herein. There is also provided a compound of Formula (IV) obtained or obtainable by a process as defined herein. There is also provided a compound of Formula (V) obtained or obtainable by a process as defined herein. There is also provided a pharmaceutical composition comprising a compound of Formula (V) and at least one pharmaceutically acceptable excipient, wherein the compound of Formula (V) is obtained or obtainable by a process as defined herein. There is also provided a pharmaceutical composition obtained or obtainable by a process as defined herein.

[0135] Chemical terms are all used in their conventional sense (e.g. as defined in the IUPAC Gold Book), unless indicated otherwise.

[0136] Compounds of the invention may be disclosed by the name or chemical structure. If a discrepancy exists between the name of a compound and its associated chemical structure, then the chemical structure prevails.

[0137] While the specific embodiments described herein illustrate the invention, it is understood that the invention is not limited to those embodiments. Rather, the spirit of the invention encompasses various modifications, adaptations, and alternatives that may be apparent to those skilled in the art. The underlying principles of the invention aim to provide an improved synthetic process for the formation of compounds of Formula (V) and associated pharmaceutical compositions thereby enhancing access to such EP4 receptor antagonists. It is the intention of the inventors that the claims of this patent be interpreted in a manner that captures the full scope of the invention's spirit and intended functionality. EXAMPLES

[0138] The invention will now be illustrated, but not limited, by reference to the following examples.

[0139] Instruments and methodologies

[0140] Purity

[0141] Purity determination was by UV (215 nm) using HPLC equipped with a Waters XSelect CSH C18 150 mm x 4.6 mm x 3.5 pm column. Column temperature 40 °C. Flow rate 1.0 mL / min. Detector was an Agilent 1260 PDA. Injection volume 1 pL. Mobile phase A was 2% w / w TFA in acetonitrile. Mobile phase B was 1 % w / w TFA in 19:1 acetonitrile:water. Gradient was 100% v / v mobile phase A to 100% v / v mobile phase B over 15.0 minutes.

[0142] Purity was calculated using area% using the equation

[0143] Areaproduct HPLC area of product peak in chromatograph

[0144] Areatotal total area of all peaks in chromatograph

[0145] Enantiomeric excess

[0146] Enantiomeric excess determination was by UV (215 nm) using HPLC equipped with a Phenomenex Lux Amylose-2 250 mm x 4.6 mm x 3 pm column. Column temperature 40 °C. Detector was an Agilent 1100 VWD. Flow rate 1.0 mL / min. Mobile phase 1 :98.9:0.1 v / v of ethanol:n-heptane:trifluoroacetic acid. Injection volume 10 pL. UV detection at 248 nm. The sample solution is prepared at a concentration of 1.0 mg / mL in 15 / 85 ethanol / n-heptane. Expected retention time of the compound of Formula (lla-i) (tR) is 12.95 mins, with the expected retention time of the undesired enantiomer (tR) is 10.62 mins. The relative retention times are 1.00 and 0.82, respectively.

[0147] Enantiomeric excess (e.e.) of the compounds of Formulae (I) to (V) is quantified on a %area basis calculated as: where R and S are the % of the peak area due to the (R) and (S) enantiomers, respectively.

[0148] A mixture with 100% enantiomeric excess is completely composed of one enantiomer, while a 0% e.e. indicates a racemic mixture, where the two enantiomers are present in equal amounts.

[0149] Chiral purity

[0150] Chiral purity is defined herein as the proportion of a desired enantiomer in a mixture containing two enantiomers. Chiral purity is measured according to the same HPLC method as enantiomeric excess to determine the amounts of the enantiomers on an %area basis. For example, the chiral purity for the desired enantiomer (which may be (R) or (S)) may be calculated as: chiral purity where D is the % of the peak area due to the desired enantiomer, and R and S are the % of the peak area due to the (R) and (S) enantiomers, respectively.

[0151] If the enantiomeric excess of a sample is known, it is possible to determine the chiral purity according to the formula below, and vice versa:

[0152] 100 + e. e. chiral purity =

[0153] 2 Nuclear Magnetic Resonance (NMR)

[0154] 1H NMR spectra may be collected on a Bruker400 MHz instrument equipped with an auto-sampler and controlled by a DRX400 console. Samples were prepared in DMSO-cfe solvent, unless otherwise stated. Automated experiments were acquired using ICON-NMR configuration within Topspin software, using standard Bruker-loaded experiments (1H). Off-line analysis was performed using ACD Spectrus Processor.

[0155] X-ray Powder Diffraction (XRPD)

[0156] XRPD spectra

[0157] XRPD diffractograms were captured on a BrukerAXS D8 Advance diffractometer using Cu Ka radiation (40 kV, 40 mA) and a 0-20 goniometer fitted with a Ge monochromator. The wavelength of the X-ray radiation used to measure the XRPD pattern may be 1.5418 A. The incident beam passes through a 2.0 mm divergence slit followed by a 0.2 mm anti-scatter slit and knife edge. The diffracted beam passes through an 8.0 mm receiving slit with 2.5° Sol ler slits followed by the Lynxeye Detector. The software used for data collection and analysis was Diffrac Plus XRD Commander and Diffrac Plus EVA respectively.

[0158] Samples were run under ambient conditions as flat plate specimens using powder as received. The sample was prepared on a polished, zero-background (510) silicon wafer by gently pressing onto the flat surface or packed into a cut cavity. The sample was rotated in its own plane.

[0159] The details of the data collection method are:

[0160] • Angular range: 2 to 42° 20

[0161] Step size: 0.05° 20

[0162] Collection time: 0.5 s / step (total collection time: 6.40 min) Appearance

[0163] A sample of the compounds formed is examined for physical form and colour. A qualitative statement about the visual appearance of the drug substance is made. The acceptance criteria was set as white to off-white powder.

[0164] Example 1 - Formation of a compound of Formula (Ib-i)

[0165] (lla-i)

[0166] A solution of a compound of Formula (lla-i) (16.8 kg, 60.8 mol, 1.00 eq.) in acetonitrile (total solution was 95 kg) was added to a reactor. The solution was stirred. The temperature was adjusted to about 55 °C. Compound of Formula (Illa) (1.00 eq.) in acetonitrile (about 6.2 kg) was added slowly, with stirring, to maintain a temperature at about 55 °C. The reaction mixture was stirred for about 45 minutes after which the temperature was adjusted to -20 °C during which time crystallisation occurred. Once at that temperature, the mixture was stirred for about one hour. The solids were filtered and washed with acetonitrile and then dried under vacuum. At a temperature of about 20 to 25 °C. This afforded the title compound (24.279 kg). Chromatic purity was 98.9 area%, and volatiles (by TGA- DSC) were <0.1 w / w%.

[0167] The1H NMR spectrum of the compound of Formula (Ib-i) was as provided in Figure 1 . Analysis of the spectrum shows that that ratio of the compound of Formula (lla-i) to the compound of Formula (Illa) is 1 :1 This indicates that the salt of these two compounds (according to Formula (Ib-i)) had formed in a ratio of 1 :1. The compound of Formula (II) used in this example was prepared via the method described in WO2021 / 069927.

[0168] The crystalline compound of Formula (Ib-i) was analysed via X-ray powder diffraction (XRPD) affording the XRPD pattern as shown in Figure 2.

[0169] Example 2 - Improved purity of a compound of Formula (Ib-i)

[0170] Part 1 : purity impact of Compound of Formula (lla-i)

[0171] Compound of Formula (lla-i) (two different batches 15 g, 0.08 mol, 1.0 eq) was reacted with compound of Formula (Illa) in acetonitrile to form the compound of Formula (Ib-i), and the solids were isolated, in accordance with the process in Example 1. The HPLC purity and chiral purity were examined for the compound of Formula (lla-i) before the reaction took place (initial HPLC / chiral purity) and after the formation of the compound of Formula (Ib-i) (final HPLC / chiral purity). The results are in the table below.

[0172] These results show that both the HPLC purity and chiral purity are significantly improved by the process of the invention.

[0173] Part 2: purity impact of Compound of Formula (Illa)

[0174] The method of Example 1 was repeated with compounds of Formula (Illa) having different purities. The compound of Formula (III) was provided in different purities ranging from 86.7 area% to 98.3 area%, whereas the same batch of the compound of Formula (lla-i) was used for each experiment. The HPLC purity was examined for the compound of Formula (Illa) before the reaction took place (initial HPLC) and after the formation of the compound of Formula (Ib-i) (final HPLC / chiral purity). The results are in the table below.

[0175] These results show that both the HPLC purity is significantly improved by the process of the invention.

[0176] Example 3 - Formation of a compound of Formula (IVb-i)

[0177] Compound of Formula (Ib-i) (24.27 kg, 1.00 eq) was added to a reactor, together with acetonitrile (82.0 kg). 1-Methy imidazole (6.37 kg. 1.50 eq.) was then added. The mixture was stirred at about 20 °C and the temperature was then adjusted to about 0 °C. 1-Ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDCI.HCI, 14.98 kg, 1.50 eq.) was added portion-wise. 1 -Cyano-2-ethoxy-2- oxoethylidenaminooxy)dimethylamino-morpholino-carbenium hexafluorophosphate (COMU) (1.216 g; 0.05 eq.) was then added. Conversion was determined by HPLC. Upon completion of the reaction, water (121 kg) was added and the mixture was cooled to 0 °C. The solid that formed was filtered and washed with a 1 :1 mixture of wateracetonitrile and then water, and then dried in at a temperature of 20 to 25 °C affording the compound of Formula (IVb-i) (97.3% conversion). This was re-slurried in water to increase removal of COMU giving the compound of Formula (IVb-i) after drying as before as a powder (15.9 kg, 67%). Chromatographic purity: 99.5 area-%).

[0178] The1H NMR spectrum for the compound of Formula (IVb-i) was as shown in Figure 3. Performing this reaction starting from the compound of Formula (Ib-i) instead of the individual building reagents (compounds of Formulae (lla-i) and (Illa)) considerably improved conversion, yield and purity (both chromatographic and chiral purity) compared to the literature method, even though additional water washes were required in this particular case (which are not normally required).

[0179] Example 4 - Formation of a compound of Formula (Va-i)

[0180] Compound of Formula (IVb-i) (15.9 kg, 1 .00 eq.) was added to a reactor, together with isopropanol (444 L). The mixture was stirred at about 25 °C until the compound of Formula (IVb-i) was dissolved and then the mixture was then microfiltered. The temperature of the mixture was adjusted to about 50 °C and the solvent amount was reduced to about 10vol% (about 44 L). The temperature was adjusted to about 20 °C. NaOH in water (33%, total 6.57 kg, 1 .50 eq.) was added and lines were flushed with additional water. The reaction was heated at about 60 °C for at least 4 hours. Conversion was monitored by HPLC. Upon completion, the temperature was adjusted to 65 °C and the pH of the mixture was adjusted to below 3.5 using aqueous citric acid. The temperature was adjusted to about 80 °C at which point water (193 kg) was added, slowly. The temperature was the adjusted to 20 °C and the solid formed was filtered and washed with water several times. The solid was dried under vacuum at a temperature of about 25 °C affording the compound of Formula (Va-i) (14.1 kg, conversion > 99.9% by HPLC, HPLC purity > 99.9 area%, chiral purity > 99.9%).

Claims

46CLAIMS1 . A process for the purification of a compound of Formula (I), the process comprising the steps, in order, of a) providing a mixture comprising a compound of Formula (I) and a solvent; b) precipitating from the solvent the compound of Formula (I) provided in the mixture of step a) to form a precipitate; and c) isolating the precipitate from the solvent to provide the purified compound of Formula (I),whereinR1is selected from the group consisting of H, C1-3 alkyl and C1-3 haloalkyl;R2is selected from the group consisting of H, C1-3 alkyl and C1-3 haloalkyl, or R1and R2, together with the carbon to which they are attached, form C3-6 cycloalkyl which is optionally substituted with one or more halo;R3is selected from the group consisting of H, C1-3 alkyl, C1-3 haloalkyl and halo;R4and R5are each independently selected from the group consisting of H, halo, CN, OH, -SO2Me, C1-6 alkyl, C1-6 haloalkyl, C3-6 cycloalkyl and C1-6 alkoxy, wherein the C3-6 cycloalkyl and C1-6 alkoxy groups are optionally substituted with47 one or more halo and any one atom of the C1-6 alkyl or C3-6 cycloalkyl may be optionally replaced by a heteroatom selected from O, S and N; andA is a protected carboxylic acid.

2. The process according to claim 1 , wherein the purification comprises enantioenrichment of the compound of Formula (I), and wherein the compound of Formula (I) provided in step (a) is non-racemic compound of Formula (I); and the compound of Formula (I) isolated in step (c) is the enantioenriched compound of Formula (I),and wherein the carbon marked with a * in the compound of Formula (I) is the only chiral centre in the compound.

3. The process according to claim 1 or claim 2, wherein the solvent is an organic solvent, preferably selected from the group consisting of acetone, methyl tert-butyl ether, isopropyl acetate, toluene, acetonitrile, and combinations thereof, more preferably toluene, acetonitrile, and a combination thereof, most preferably the solvent is acetonitrile.

4. The process according to any preceding claim, wherein step a) comprises providing the mixture comprising the compound of Formula (I) and the solvent at a first temperature of at least about 40 °C, preferably from about 40 °C48 to about 80 °C, more preferably from about 45 °C to about 70 °C, most preferably from about 50 °C to about 60 °C, and optionally maintaining the mixture at that first temperature for a first period of at least about 10 minutes, preferably from about 10 minutes to about 5 hours, preferably from about 20 minutes to about 3 hours, more preferably from about 25 minutes to about 2 hours, most preferably from about 30 minutes to about 1 hour.

5. The process according to claim 4, wherein step b) comprises cooling the mixture comprising the compound of Formula (I) and the solvent to a second temperature of about 35 °C or less, preferably from about -50 °C to about 35 °C, more preferably from about -50 °C to about 20 °C, even more preferably from about -40 °C to about 0 °C, most preferably from about -25 °C to about -15 °C, to form the precipitate, and optionally maintaining that second temperature for a second period of at least about 15 minutes, preferably from about 15 minutes to about 6 hours, more preferably from about 30 minutes to about 4 hours, most preferably from about 1 hour to about 2 hours.

6. The process according to any preceding claim, wherein the compound of Formula (I) in step a) comprises an enantiomeric excess of a compound of Formula (l-i), preferably (la-i), more preferably (Ib-i)wherein R1to R5and A are as defined in any one of claims 1 to 5, preferably wherein the enantiomeric excess of the compound of Formula (l-i), (la- i) or (Ib-i) is at least about 70%, preferably at least about 80%, more preferably at least about 90%, more preferably at least about 93%, more preferably at least about 95%, more preferably at least about 96%, more preferably at least about 97%, more preferably at least about 98%, most preferably at least about 99%.

7. A process for the formation of a compound of Formula (I)the process comprising the step of reacting a compound of Formula (II), or an alkali metal or alkaline earth metal salt thereof, with a compound of Formula (III) to form the compound of Formula (I),whereinR1is selected from the group consisting of H, C1-3 alkyl and C1-3 haloalkyl;R2is selected from the group consisting of H, C1-3 alkyl and C1-3 haloalkyl, or R1and R2, together with the carbon to which they are attached, form C3-6 cycloalkyl which is optionally substituted with one or more halo;R3is selected from the group consisting of H, C1-3 alkyl, C1-3 haloalkyl and halo;R4and R5are each independently selected from the group consisting of H, halo, CN, OH, SO2Me, C1-6 alkyl, C1-6 haloalkyl, C3-6 cycloalkyl and C1-6 alkoxy, wherein the C3-6 cycloalkyl and C1-6 alkoxy groups are optionally substituted with one or more halo and any one atom of the C1-6 alkyl or C3-6 cycloalkyl may be optionally replaced by a heteroatom selected from O, S and N; andA is a protected carboxylic acid.

8. The process according to claim 7, wherein the compound of Formula (II), or an alkali metal or alkaline earth metal salt thereof, and the compound of Formula (III) are reacted in the absence of a coupling reagent.

9. The processing according to claim 7 or claim 8, wherein the compound of Formula (II), or an alkali metal or alkaline earth metal salt thereof, and the compound of Formula (III) or an alkali metal or alkaline earth metal salt thereof are reacted in an organic solvent, preferably wherein the organic solvent is anaprotic organic solvent, more preferably wherein the organic solvent is selected from the group consisting of acetone, methyl tert-butyl ether, isopropyl acetate, toluene, acetonitrile, and combinations thereof, more preferably toluene, acetonitrile, and a combination thereof, most preferably the organic solvent is acetonitrile.

10. The process according to any one of claims 7 to 9, wherein the compound of Formula (II) comprises an enantiomeric excess of a compound of Formula (ll-i) or an alkali metal or alkaline earth metal salt thereof, preferably Formula (lla-i) or an alkali metal or alkaline earth metal salt thereof,(lla-i), wherein R4and R5are as defined in any one of claims 1 to 9, preferably wherein the enantiomeric excess of the compound of Formula (ll-i) or (lla-i) is at least about 60%, preferably at least about 70%, more preferably at least about 80%, more preferably at least about 90%, more preferably at least about 94%, more preferably at least about 95%, more preferably at least about 96%, more preferably at least about 97%, more preferably at least about 98%, most preferably at least about 99%.11 . The process according to any one of claims 1 to 6, wherein the compound of Formula (I) in step a) is formed by the process as defined in any one of claims 7 to 10.

12. The process according to any one of the preceding claims, whereinA is selected from the group consisting of52whereinR6is selected from the group consisting of C1-6 alkyl and benzyl;R7is selected from the group consisting of C1-6 alkyl; andR8, R9and R10are each independently selected from C1-6 alkyl and phenyl.

13. The process according to any one of the preceding claims, whereinR1and R2, together with the carbon to which they are attached, form C3-6 cycloalkyl, preferably cyclopropyl; andR3is H, preferably whereinR4is H; andR5is C1-6 haloalkyl, preferably -CF3.

14. The process according to any one of the preceding claims, whereinA is -C(0)0Me;R1and R2, together with the carbon to which they are attached, form cyclopropyl;R3is H;R4is H; and53R5is -CF3.

15. A process for the formation of a compound of Formula (IV)or a salt thereof, the process comprising the steps, in order, of a) providing a compound of Formula (I) in accordance with a process as defined in any preceding claim; and b) reacting the compound of Formula (I) in the presence of a coupling reagent to form a compound of Formula (IV), or the salt thereof, wherein R1to R5and A are as defined in any one of claims 1 to 14.

16. A process for the formation of a compound of Formula (V)or a salt thereof, the process comprising the steps, in order, of a) providing a compound of Formula (IV) in accordance with a process as defined in claim 15; and b) deprotecting the protected carboxylic acid of group A of the compound of Formula (IV), or the salt thereof, to form the compound of Formula (V), or the salt thereof, wherein R1to R5and A are as defined in any one of claims 1 to 15.5417. A process for preparing a pharmaceutical composition comprising a compound of Formula (V), or a salt thereof, and at least one pharmaceutically acceptable excipientthe process comprising the steps, in order, of a) providing a compound of Formula (V) in accordance with a process as defined in claim 16; and b) combining the compound of Formula (V), or a salt thereof, with the at least one pharmaceutically acceptable excipient, wherein R1to R5as defined in any one of claims 1 to 16.

18. A solid form comprising, or consisting of, a compound of Formula (I)wherein R1to R5and A are as defined in any one of claims 1 to 17, preferably wherein the compound of Formula (I) is a compound ofFormula (la)wherein A is as defined in any one of claims 1 to 17, more preferably wherein the compound of Formula (I) is a compound of Formula (lb)19. The solid form according to claim 18, wherein the compound of Formula (I) comprises an enantiomeric excess of a compound of Formula (l-i), preferably (la-i), more preferably (Ib-i)56 wherein R1to R5and A are as defined in any one of claims 1 to 18, preferably wherein the enantiomeric excess of the compound of Formula (l-i), (la- i) or (Ib-i) is at least about 70%, preferably at least about 80%, more preferably at least about 90%, more preferably at least about 93%, more preferably at least about 95%, more preferably at least about 96%, more preferably at least about 97%, more preferably at least about 98%, most preferably at least about 99%.

20. The solid form according to claim 18 or claim 19, wherein the solid form comprises, or consists of, a crystalline compound of Formula (I).

21. The solid form according to claim 20, wherein the crystalline compound of Formula (I) comprises an enantiomeric excess of a compound of Formula (Ib- i), preferably wherein the enantiomeric excess of the compound of Formula (Ib-i) is at least about 70%, preferably at least about 80%, more preferably at least about 90%, more preferably at least about 93%, more preferably at least about 95%, more preferably at least about 96%, more preferably at least about 97%, more preferably at least about 98%, most preferably at least about 99%.

22. The solid form according to claim 21 , having an X-ray powder diffraction pattern comprising peaks at 20 of 10.3 ± 0.1°, 17.9 ± 0.1° and 20.6 ± 0.1°, preferably peaks at 10.3 ±0.1°, 17.9 ± 0.1°, 20.6 ±0.1° and 25.8 ±0.1°, more preferably peaks at 10.3 ± 0.1°, 13.0 ± 0.1°, 17.9 ± 0.1°, 20.6 ± 0.1°, and 25.8 ± 0.1°, more preferably peaks at 10.3 ±0.1°, 13.0 ±0.1°, 13.3 ±0.1°, 15.5 ±0.1°, 16.1 ±0.1°, 17.9±0.1°, 19.2±0.1°, 19.4±0.1°, 20.6 ± 0.1°, 21.4 ± 0.1°, 21.9 ± 0.1°, 22.6 ± 0.1°, 23.0 ± 0.1°, 25.4 ± 0.1°, 25.8 ±0.1°, 25.9 ±0.1°, 26.4 ±0.1°, and 26.9 ±0.1°, and most preferably peaks at 20 as set out in the table below and / or substantially in accordance with the X-ray powder diffraction pattern shown in Figure 2.

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