Synthetic processes for pharmaceutically active compounds

Abstract

A process for making a compound of Compound 1 having the following structure: or a salt thereof, said method comprising contacting 2-fluorobenzoic acid (compound 1) with an iron catalyst and a phosphine ligand in the presence of a methylaluminum reagent and 1,2-dichloropropane.

Description

10622-W001-SECSYNTHETIC PROCESSES FOR PHARMACEUTICALLY ACTIVE COMPOUNDSCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] The present application claims benefit of priority to U.S. Provisional Application 63 / 686,361, filed August 23, 2024.FIELD

[0002] The present disclosure relates to the field of organic synthetic methodology for the preparation of compounds that are useful for the synthesis of pharmaceutically active compounds including C5aR antagonists.BACKGROUND

[0003] Complement C5a is one of the most potent proinflammatory mediators of the complement system. (The anaphylactic C5a peptide is 100 times more potent, on a molar basis, in eliciting inflammatory responses than C3a.) C5a is the activated form of C5 (190 kD, molecular weight). C5a is present in human serum at approximately 80 g / ml (Kohler, P. F. etal, J. Immunol. 99: 1211-1216 (1967)). It is composed of two polypeptide chains, a and P, with approximate molecular weights of 115 kD and 75 kD, respectively (Tack, B. F. et al, Biochemistry 18: 1490-1497 (1979)). Biosynthesized as a single-chain promolecule, C5 is enzymatically cleaved into a two-chain structure during processing and secretion. After cleavage, the two chains are held together by at least one disulphide bond as well as noncovalent interactions (Ooi, Y. M. et al., J. Immunol. 124: 2494-2498(1980)).

[0004] C5 is cleaved into the C5a and C5b fragments during activation of the complement pathways. The convertase enzymes responsible for C5 activation are multi-subunit complexes of C4b, C2a, and C3b for the classical pathway and of (C3b)2, Bb, and P for the alternative pathway (Goldlust, M. B. etal., J. Immunol. 113: 998-1007 (1974); Schreiber, R. D. et al, Proc. Natl. Acad. Sci. 75: 3948-3952 (1978)). C5 is activated by cleavage at position 74-75 (Arg-Leu) in the a-chain. After activation, the 11.2 kD, 74 amino acid peptide C5a from the amino-terminus portion of the a-chain is released. Both C5a and C3a are potent stimulators of neutrophils and monocytes (Schindler, R. etal, Blood 76: 1631-1638 (1990);Page l of 3210622-W001-SECHaeffner-Cavaillon, N. et al., J. Immunol. 138: 794-700 (1987); Cavaillon, J. M. etal., Eur.J. Immunol. 20: 253-257 (1990)).

[0005]

[0001] In addition to its anaphylatoxic properties, C5a induces chemotactic migration of neutrophils (Ward, P. A. etal., J. Immunol. 102: 93-99 (1969)), eosinophils (Kay, A. B. et al., Immunol. 24: 969-976 (1973)), basophils (Lett-Brown, M. A. etal., J. Immunol. 117: 246-252 1976)), and monocytes (Snyderman, R. etal., Proc. Soc. Exp. Biol. Med. 138: 387- 390 1971)).

[0006] The anaphylactic and chemotactic effects of C5a are believed to be mediated through its interaction with the C5a receptor. The human C5a receptor (C5aR) is a 52 kD membrane bound G protein-coupled receptor, and is expressed on neutrophils, monocytes, basophils, eosinophils, hepatocytes, lung smooth muscle and endothelial cells, and renal glomerular tissues (Van-Epps, D. E. etal., J. Immunol. 132: 2862-2867 (1984); Haviland, D. L. etal., J. Immunol. 154:1861-1869 (1995); Wetsel, R. A., Immunol. Leff. 44: 183-187 (1995);Buchner, R. R. etal., J. Immunol. 155: 308-315 (1995); Chenoweth, D. E. etal., Proc. Natl. Acad. Sci. 75: 3943-3947 (1978); Zwimer, J. et al., Mol. Immunol. 36:877-884 (1999)). The ligand -binding site of C5aR is complex and consists of at least two physically separable binding domains. One binds the C5a amino terminus (amino acids 1 -20) and disulfide-linked core (amino acids 21-61), while the second binds the C5a carboxy-terminal end (amino acids 62-74) (Wetsel, R. A., Curr. Opin. Immunol. 7: 48-53 (1995)).

[0007] Recent work has identified (2R,3S)-2-(4-(cyclopentylamino)phenyl)-l-(2-fluoro-6- methylbenzoyl)-N-(4-methyl-3-(trifluoromethyl)phenyl)piperidine-3-carboxamide,which is also known as avacopan, as useful for treating C5a mediated diseases by inhibiting the C5a receptor (C5aR). Avacopan is currently approved as a first -in-class drug that is used as an adjunctive therapy for the treatment of antineutrophilic cytoplasmic antibody (ANCA)- associated vasculitis. Processes for the synthesis of avacopan are described inWO 2010 / 075257 and WO 2016 / 053890. There is a high degree of urgency to provide patients who are in need of avacopan and other pharmaceutically active compounds, and this10622-W001-SEC requires more effective and efficient manufacturing of the drug product to meet this urgent demand.

[0008] Accordingly, there is an ongoing urgent need for new versatile and facile processes for more effective and efficient preparation of pharmaceutically active compounds such as avacopan, including intermediates thereof, to meet the ongoing and growing demand of patients who are in need.SUMMARY

[0009] The present disclosure provides an improved process for the synthesis of certain intermediate compounds that are useful for the synthesis pharmaceutically active compounds, including C5aR antagonists such as avacopan which has the following structure:

[0010] One such intermediate is Compound 1, named 2-fluoro-6-methylbenzoic acid that has the following structure:Compound 1

[0011] Compound 1 can be used for a synthetic process in making avacopan. In one example, Compound 1 can be converted into 2-fluoro-6-methylbenzoyl chloride (Compound 2) in the presence of SOCh in a suitable solvent, wherein Compound 2 is a reactant in step 3 of Route 1 described in U.S. Patent No. 9,745,268, and the final product of Route 1 is avacopan.

[0012] The following six-step synthetic process has been developed for the synthesis ofCompound 1 :10622-W001-SECCompound 1

[0013] However, even a more efficient process for the synthesis Compound 1 has been developed which reduces the number of steps from six steps to one step.

[0014] In one embodiment, this more efficient process relates to a process for making Compound 1 :Compound 1 or a salt thereof, said method comprising contacting 2-fluorobenzoic acid with an iron catalyst and a phosphine ligand in the presence of a methylaluminum reagent and 1,2- dichloropropane to provide Compound 1. 2-fluorobenzoic acid has the following structure:

[0015] Non-limiting examples of phosphine ligands that can be used in the process of this disclosure include those that are commercially available or otherwise can be made by synthetic techniques described in the art include phosphine ligands described in Rui Shang et al., Iron-Catalyzed Ortho C-H Methylation of Aromatics Bearing a Simple Carbonyl Group with Methylaluminum and Tridentate Phosphine Ligand, J. Am. Chem. Soc. 2016, 138, 10132-1013.

[0016] Rui Shang et al. describes 2,3 -dichlorobutane as the oxidant to be used for this type of reaction. In contrast to Rui Shang et al., the process of this disclosure uses 1,2- dichloropropane as an oxidant for the synthesis of Compound 1. Further, Rui Shang et al. discloses using a solvent system of 10:1 ratio of THF / DME, wherein the process of this disclosure also includes other suitable solvent systems that resulted in substantial improvements as described in the embodiments and examples of this disclosure.10622-W001-SECBRIEF DESCRIPTION OF DRAWING

[0017] FIG. 1 shows an X-ray powder diffraction (XRPD) analysis of Compound 1.DETAILED DESCRIPTIONDEFINITIONS AND ABBREVIATIONS

[0018] The term “C1-3 alkyl” refers to an alkyl group having 1 to 3 carbon atoms. All members of this range and all subgroups within that range are envisioned. For example, “C1-3 alkyl” includes methyl, ethyl, n-propyl, isopropyl.

[0019] The term “C0-3 alkyl” refers to a bond for Co or a C1-3 alkyl as defined herein.

[0020] The term “diphenylphosphaneyl” or -PPI12 refers to the following moiety:

[0021] The term “pharmaceutically acceptable” refers to a species or component that is generally safe, non-toxic, and neither biologically nor otherwise undesirable for use in a subject.

[0022] The term “pharmaceutically acceptable salt” refers to a salt of a compound that possesses the desired pharmacological activity of the parent compound and that is not biologically or otherwise undesirable for its end use. Pharmaceutically acceptable salts include, for example, acid addition salts formed with inorganic acids (e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid) or formed with organic acids (e.g., acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl) benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid). Pharmaceutically acceptable salts also include, for example, salts formed when an acidic proton present in the parent compound either is replaced by a metal ion (e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion) or associates with an organic base (e.g., ethanolamine, diethanolamine, triethanolamine, N- methylglucamine, dicyclohexylamine). Additionally, the salts of the compounds described herein, can exist in either hydrated or anhydrous form or as solvates with other solvent molecules.10622-W001-SEC

[0023] The term “pharmaceutically active compound” refers to any compound that can modulate a target (such as a C5aR antagonist) which can make such compounds potentially useful for the treatment of diseases in a patient or subject.

[0024] The term “patient” or “subject” refers to humans and other mammals. The term “mammal” as used herein includes, for example, humans, non-human primates, cattle, sheep, goats, pigs, horses, cats, dog, rabbits, rodents (e.g., rats or mice), and monkeys. Human subjects include neonates, infants, juveniles, adults, and geriatric subjects.TABLE OF ABBREVIATIONSEMBODIMENTS

[0025] Embodiment 1 of this disclosure relates to a process for making Compound 1 having the following structure:Compound 1 or a salt thereof, said method comprising contacting 2-fluorobenzoic acid with an iron catalyst and a phosphine ligand in the presence of a methylaluminum reagent and 1,2-10622-W001-SEC dichloropropane, wherein the reaction is conducted in a suitable solvent, and wherein 2- fluorobenzoic acid has the following structure:

[0026] Embodiment 2 of this disclosure relates to the process according to Embodiment 1, wherein the phosphine ligand is of the following formula:wherein R1is hydrogen or diphenylphosphaneyl;R2is H or -Co-3 alkyl-N(R3)2; and each R3is Ci -3 alkyl.In some cases, the phosphine ligand ranges from about 8 mol% to about 12 mol% or from about 9 mol% to about 11 mol% relative to 2-fluorobenzoic acid. In some cases, the phosphine ligand ranges from about 10 mol% relative to 2-fluorobenzoic acid. In some cases, the phosphine ligand ranges from about 1 mol% to about 12 mol% relative to 2-fluorobenzoic acid. In some cases, the phosphine ligand ranges from about 2.5 mol% to about 4.5 mol% relative to 2-fluorobenzoic acid. In some cases, the phosphine ligand is present in an amount that is about 3.5 mol% relative to 2-fluorobenzoic acid. In some cases, the phosphine ligand is present in an amount that is equimolar to the iron catalyst.

[0027] Embodiment 3 of this disclosure relates to the process according to Embodiment 2, wherein the phosphine ligand is of the following formula:

[0028] Embodiment 4 of this disclosure relates to the process according to Embodiment 1, wherein the phosphine ligand is one or more of the following compounds:10622-W001-SEC

[0029] Embodiment 5 of this disclosure relates to the process according to Embodiment 4, wherein the phosphine ligand is ((phenylphosphanediyl)bis(2,l- phenylene))bis(diphenylphosphane) having the following structure:

[0030] Embodiment 6 of this disclosure relates to the process according to Embodiment 4, wherein the phosphine ligand is 4-(bis(2-(diphenylphosphaneyl)phenyl)phosphaneyl)-N,N- dimethylaniline (Me2N-TP) having the following structure:

[0031] Embodiment 7 of this disclosure relates to the process according to any of the Embodiments 1-6, wherein the iron catalyst is Fe(acac)3. In some cases, Fe(acac)3 ranges from about 8 mol% to about 12 mol% or from about 9 mol% to about 11 mol% relative to 2- fluorobenzoic acid. In some cases, Fe(acac)3 ranges from about 10 mol% relative to 2- fluorobenzoic acid. In some cases, Fe(acac)3 ranges from about 1 mol% to about 12 mol% relative to 2-fluorobenzoic acid. In some cases, Fe(acac)3 ranges from about 2.5 mol% to about 4.5 mol% relative to 2-fluorobenzoic acid. In some cases, Fe(acac)3 ranges from about 3.5 mol% relative to 2-fluorobenzoic acid. In some cases, Fe(acac)3 is present in an amount that is equimolar to the phosphine ligand.

[0032] Embodiment 8 of this disclosure relates to the process according to any of Embodiments 1-7, wherein the methylaluminum reagent is A1(CH3)3. In some cases, A1(CH3)3ranges from 1.2 to about 1.8 equivalents or from about 1.4 to about 1.6 equivalents relative to 2-fluorobenzoic acid. In some cases, the A1(CH3)3 is about 1.5 equivalents.10622-W001-SEC

[0033] Embodiment 9 of this disclosure relates to the process according to any of the Embodiments 1-8, wherein the suitable solvent is 2-MeTHF, 1,2-dimethoxy ethane (DME), toluene, a mixed solvent system of THF and toluene, a mixed solvent system of 2-MeTHF and toluene, or a mixed solvent system of 1,2-dimethoxy ethane (DME) and toluene. In some cases, a suitable solvent is 2-MeTHF, toluene, a mixed solvent system of THF and toluene, or a mixed solvent system of 1,2-dimethoxy ethane and toluene. In some cases, a suitable solvent is 2-MeTHF or a mixed solvent system of 1,2-dimethoxy ethane (DME) and toluene. In some cases, a suitable solvent is 1,2-dimethoxy ethane (DME). In some cases, a suitable solvent is toluene. In some cases, a suitable solvent does not comprise THF.

[0034] Embodiment 10 of this disclosure relates to the process according to Embodiment 9, wherein the suitable solvent is 2-MeTHF.

[0035] Embodiment 11 of this disclosure relates to the process according to Embodiment 9, wherein the suitable solvent is a mixed solvent system of 1,2-dimethoxy ethane (DME) and toluene. In some cases, a mixed solvent system comprises DME:toluene in a ratio of about 1 :1 DME:toluene to about 1 :1.2 DME:toluene by volume. In some cases, a mixed solvent system comprises DME:toluene in a ratio of about 1 :1 DME:toluene to about 1 :1.1 DME:toluene by volume.

[0036] It has been found unexpectedly that both catalyst and ligand loading can be significantly reduced from about 10 mol% to about 3.5 mol% by using 1,2-dimethoxy ethane (DME) and toluene as suitable solvent instead of using either a 10:1 ratio of THF / DME as described in Rui Shang et al. or 2-MeTHF. It was also found that using 1,2-dimethoxy ethane and toluene as a suitable solvent instead of 2-MeTHF improved the % yield of Compound 1 by more than 15%.

[0037] Embodiment 12 of this disclosure relates to the process according to Embodiment 11, wherein the phosphine ligand is ((phenylphosphanediyl)bis(2,l- phenylene))bis(diphenylphosphane) having the following structure:

[0038] Embodiment 13 of this disclosure relates to the process according to Embodiment 9, wherein the suitable solvent is toluene.

[0039] Embodiment 14 of this disclosure relates to the process according to Embodiment 9, wherein the suitable solvent is a mixed solvent system of THF and toluene or 2-MeTHF and10622-W001-SEC toluene. In some cases, a suitable solvent system is a mixed solvent system of THF and toluene. In some cases, a suitable solvent system is a mixed solvent system of 2-MeTHF and toluene.

[0040] Embodiment 15 of this disclosure relates to the process according to Embodiment 13 or 14, wherein the phosphine ligand is 4-(bis(2-(diphenylphosphaneyl)phenyl)phosphaneyl)-N,N-dimethylaniline (Me2N-TP) having the following structure:

[0041] Embodiment 16 of this disclosure relates to the process according to Embodiment 11, wherein the reaction is heated to reflux.

[0042] It has been found that the reaction purity profile is improved by running at reflux instead of 70 °C.

[0043] Embodiment 17 of this disclosure relates to the process according to Embodiment 10, wherein the methylaluminum reagent is A1(CH3)3 ranging from about 1.5 to about 2.5 equivalents relative to 2-fluorobenzoic acid.

[0044] Embodiment 18 of this disclosure relates to the process according to Embodiment 17, wherein the A1(CH3)3 ranges from about 1.8 to about 2.2 equivalents relative to 2- fluorobenzoic acid.

[0045] Embodiment 19 of this disclosure relates to the process according to Embodiment 17, wherein the A1(CH3)3 is about 2 equivalents relative to 2-fluorobenzoic acid.

[0046] Embodiment 20 of this disclosure relates to the process according to any one of Embodiments 10 or 17-19, wherein the iron catalyst is Fe(acac)3 ranging from about 8 mol% to about 12 mol%.

[0047] Embodiment 21 of this disclosure relates to the process according to Embodiment 20, wherein Fe(acac)3 ranges from about 9 mol% to about 11 mol%.

[0048] Embodiment 22 of this disclosure relates to the process according to Embodiment 20, wherein Fe(acac)3 is about 10 mol%.

[0049] Embodiment 23 of this disclosure relates to the process according to any one of Embodiments 10 or 17-22, wherein the phosphine ligand ranges from about 8 mol% to about 12 mol%.

[0050] Embodiment 24 of this disclosure relates to the process according to Embodiment 23, wherein the phosphine ligand ranges from about 9 mol% to about 11 mol%.10622-W001-SEC

[0051] Embodiment 25 of this disclosure relates to the process according to Embodiment 13, wherein the phosphine ligand is about 10 mol%.

[0052] Embodiment 26 of this disclosure relates to the process according to any one of Embodiments 10 or 17-25, wherein the 1,2-dichloropropane ranging from about 2.5 equivalents to about 3.5 equivalents relative to 2-fluorobenzoic acid.

[0053] Embodiment 27 of this disclosure relates to the process according to Embodiment 26, wherein the 1,2-dichloropropane ranges from about 2.8 equivalents to about 3.2 equivalents relative to 2-fluorobenzoic acid.

[0054] Embodiment 28 of this disclosure relates to the process according to Embodiment 26, wherein the 1,2-dichloropropane is about 3 equivalents relative to 2-fluorobenzoic acid.

[0055] Embodiment 29 of this disclosure relates to the process according to any one of Embodiments 11-16, wherein the methylaluminum reagent is Al(CHs)3 ranging from 1.2 to about 1.8 equivalents relative to 2-fluorobenzoic acid.

[0056] Embodiment 30 of this disclosure relates to the process according to Embodiment 29, wherein the Al(CHs)3 ranges from about 1.4 to about 1.6 equivalents relative to 2- fluorobenzoic acid.

[0057] Embodiment 31 of this disclosure relates to the process according to Embodiment 29, wherein the A1(CH3)3 is about 1.5 equivalents.

[0058] Embodiment 32 of this disclosure relates to the process according to any one of Embodiments 11 or 29-31, wherein the iron catalyst is Fe(acac)3 ranging from about 1 mol% to about 12 mol%.

[0059] Embodiment 33 of this disclosure relates to the process according to Embodiment 32, wherein Fe(acac)3 ranges from about 2.5 mol% to about 4.5 mol%.

[0060] Embodiment 34 of this disclosure relates to the process according to Embodiment 32, wherein Fe(acac)3 is about 3.5 mol%.

[0061] Embodiment 35 of this disclosure relates to the process according to any one of Embodiments 11 or 29-34, wherein the phosphine ligand ranges from about 1 mol% to about 12 mol%.

[0062] Embodiment 36 of this disclosure relates to the process according to Embodiment 35, wherein the phosphine ligand ranges from about 2.5 mol% to about 4.5 mol%.

[0063] Embodiment 37 of this disclosure relates to the process according to Embodiment 36, wherein the phosphine ligand is about 3.5 mol%.

[0064] Embodiment 38 of this disclosure relates to the process according to any one of Embodiments 11 or 29-37, wherein dichloropropane ranges from about 1.2 equivalents to about 1.8 equivalents relative to 2-fluorobenzoic acid.10622-W001-SEC

[0065] Embodiment 39 of this disclosure relates to the process according to Embodiment 38, wherein 1,2-dichloropropane ranges from about 1.4 equivalents to about 1.6 equivalents relative to 2-fluorobenzoic acid.

[0066] Embodiment 40 of this disclosure relates to the process according to Embodiment 38, wherein the 1,2-dichloropropane is about 1.5 equivalents relative to 2-fluorobenzoic acid.

[0067] Embodiment 41 of this disclosure relates to the process according to any one of Embodiments 11 or 29-40, wherein the ratio of 1,2-dimethoxy ethane to toluene ranges from 1 : 1 to about 1 : 1.2 by volume.

[0068] Embodiment 42 of this disclosure relates to the process according to Embodiment 41, wherein the ratio of 1,2-dimethoxy ethane to toluene is about 1 :1.1 by volume.

[0069] Embodiment 43 of this disclosure relates to the process according to any one of Embodiments 11 and 29-42, wherein Compound 1 is purified using a process that includes performing an inverse quench.

[0070] Embodiment 44 of this disclosure relates to the process according to Embodiment 43, wherein the inverse quench is performed using aqueous L-tartaric acid, aqueous citric acid, hydrochloric acid, or sodium dihydrogen phosphate.

[0071] Embodiment 45 of this disclosure relates to the process according to Embodiment 44, wherein the inverse quench is performed using aqueous L-tartaric acid.

[0072] Embodiment 46 of this disclosure relates to the process according to Embodiment 45, wherein the aqueous L-tartaric acid ranges from about 10 wt% to about 25 wt%.

[0073] Embodiment 47 of this disclosure relates to the process according to Embodiment 46, wherein the aqueous L-tartaric acid is about 15 wt%.

[0074] Embodiment 48 of this disclosure relates to the process according to any one of Embodiments 43-47, wherein Compound 1 is further purified by recrystallization. In some cases, the recrystallization solvent is toluene. In some cases, Compound 1 is further purified by cooling crystallization. In some cases, a solution of Compound 1 in toluene is heated (e.g., to about 60-110 °C such as about 65-75 °C or about 70 °C) and then cooled (e.g., to 0 °C or lower such as about 0 °C to -20 °C or about -10 °C). In some cases, a solution of Compound 1 in toluene is heated to about 65-75 °C and then cooled to about 0 °C to -20 °C. In some cases, a solution of Compound 1 in toluene is heated to about 70 °C and then cooled to about -10 °C.10622-W001-SEC

[0075] Embodiment 49 of this disclosure relates to a process of making a compound ofCompound 2Compound 2 comprising contacting Compound 1 with SOCh in a suitable solvent, wherein Compound 1 is made by the process according to any one of Embodiments 1-48.

[0076] Embodiment 49(a) of this disclosure relates to the process according to Embodiment 45, wherein the reaction temperature ranges from 50 °C - 80 °C.

[0077] Embodiment 49(b) of this disclosure relates to the process according to Embodiment 45, wherein the reaction temperature ranges from 60 °C - 70 °C.

[0078] Embodiment 49(c) of this disclosure relates to the process according to any one of Embodiments 49, 49(a) or 49(b), wherein the suitable solvent is toluene.

[0079] Embodiment 49(d) of this disclosure relates to the process according to Embodiment49(c), wherein the toluene is azeotropically dry.

[0080] Embodiment 50 of this disclosure relates to a process of making avacopan having the following formula:or a pharmaceutically acceptable salt thereof, comprising:(a) contacting a compound having the formula (i-3):under conditions sufficient to form a compound of formula (i-4):10622-W001-SEC(b) contacting the compound of formula (i-4) with an aniline having the formula:to provide avacopan, wherein Compound 2 is made by the process according to any one of Embodiments 49, 49(a), 49(b), 49(c) or 49(d). In some cases, the compound of Formula (i-3) is provided as a salt. In some cases, the compound of Formula (i-3) is provided as a L-DTTA salt ((-)-< ,< ’-di-p-toluoyl-L-tartaric acid salt). In some cases, the compound of Formula (i-3) is provided as a bis L-DTTA salt,(Formula (i-3) x 2 L-DTTA).

[0081] Embodiment 51 of this disclosure relates a process for making Compound 1 having the following structure:Compound 1 or a salt thereof, said method comprising: contacting 2-fluorobenzoic acid,with about 2.5 mol% to about 4.5 mol% of an iron catalyst that is Fe(acac)s and about 2.5 mol% to about 4.5 mol% of a phosphine ligand having a structure that is10622-W001-SECin the presence of 1,2-dichloropropane and about 1.4 to about 1.6 equivalents of a methylaluminum reagent that is Al(CHs)3 to form Compound 1, and wherein the reaction is conducted in a mixed solvent system of 1,2 -dimethoxy ethane (DME) and toluene.

[0082] Embodiment 52 of this disclosure relates to the process of Embodiment 51, wherein Fe(acac)3 and the phosphine ligand are present in equimolar amounts. In some cases, each of Fe(acac)3 and the phosphine ligand is present at about 3.5 mol%.

[0083] Embodiment 53 of this disclosure relates to the process of Embodiment 51 or 52, wherein 1,2-dichloropropane in an amount that is about 1.2 equivalents to about 1.8 equivalents relative to 2-fluorobenzoic acid.

[0084] Embodiment 54 of this disclosure relates to the process of any one of Embodiments 51-53, wherein the ratio of 1,2-dimethoxy ethane (DME) to toluene ranges from 1 :1 to about 1 :1.2 by volume.

[0085] Embodiment 55 of this disclosure relates to the process of any one of Embodiments 51-54, wherein 1,2-dichloropropane and A1(CH3)3 are present in equimolar amounts. In some cases, each of 1,2-dichloropropane and A1(CH3)3 is present in an amount that is about 1.5 equivalents relative to 2-fluorobenzoic acid.

[0086] Embodiment 56 of this disclosure relates to the process of any one of Embodiments 51-55, wherein the reaction is conducted at reflux (e.g., at about 100 °C).

[0087] Embodiment 57 of this disclosure relates a process for making Compound 1 having the following structure:Compound 1 or a salt thereof, said method comprising: contacting 2-fluorobenzoic acid,10622-W001-SECwith about 8 mol% to about 12 mol% of an iron catalyst that is Fe(acac)s and about 8 mol% to about 12 mol% of a phosphine ligand having a structure that isin the presence of 1,2-dichloropropane and about 2.5 equivalents to about 3.5 equivalents of a methylaluminum reagent that is Al(CHs)3 to form Compound 1, and wherein the reaction is conducted in a solvent system comprising 2-methyl THF.

[0088] Embodiment 58 of this disclosure relates to the process of Embodiment 57, wherein Fe(acac)s and the phosphine ligand are present in equimolar amounts. In some cases, each of Fe(acac)3 and the phosphine ligand is present in an amount ranging from about 9 mol% to about 11 mol%. In some cases, each of Fe(acac)3 and the phosphine ligand is present in an amount that is about 10 mol%.

[0089] Embodiment 59 of this disclosure relates to the process of Embodiment 57 or 58, wherein 1,2-dichloropropane in an amount that is about 2.8 equivalents to about 3.2 equivalents relative to 2-fluorobenzoic acid. In some cases, the process comprises 1,2- dichloropropane in an amount that is about 3.0 equivalents relative to 2-fluorobenzoic acid.

[0090] Embodiment 60 of this disclosure relates to the process of any one of Embodiments 57-59, wherein A1(CH3)3 is present in an amount ranging from about 1.5 to about 2.5 equivalents relative to 2-fluorobenzoic acid. In some cases, A1(CH3)3 is present in an amount ranging from about 1.8 to about 2.2 equivalents relative to 2-fluorobenzoic acid. In some cases, In some cases, A1(CH3)3 is present in an amount that is about 2 equivalents relative to 2-fluorobenzoic acid.

[0091] Embodiment 61 of this disclosure relates to the process of any one of Embodiments 57-60, wherein the reaction is conducted at about 70 °C.

[0092] Embodiment 62 of this disclosure relates to the process of any one of Embodiments 51-61, wherein the solvent system does not comprise THF.10622-W001-SEC

[0093] Embodiment 63 of this disclosure relates to the process according to any one of Embodiments 1-48 and 51-62, wherein Compound 1 is obtained in greater than about 95% purity. In some cases, Compound 1 is obtained in greater than about 96% purity. In some cases, Compound 1 is obtained in greater than about 97% purity. In some cases, Compound 1 is obtained in greater than about 98% purity. In some cases, Compound 1 is obtained in greater than about 99% purity. In some cases, Compound 1 is obtained in greater than about 99.5% purity. In some cases, purity is determined by HPLC.

[0094] Embodiment 64 of this disclosure relates to the process according to any one of Embodiments 1-48 and 51-63, wherein Compound 1 is obtained in an amount that is at least about 1 gram. In some cases, Compound 1 is obtained in an amount that is at least about 5 grams. In some cases, Compound 1 is obtained in an amount that is at least about 50 grams.In some cases, Compound 1 is obtained in an amount that is at least about 1-1,000 grams. In some cases, Compound 1 is obtained in an amount that is at least about 5-500 grams. In some cases, Compound 1 is obtained in an amount that is at least about 5-100 grams. In some cases, Compound 1 is obtained in an amount that is at least about 50-1000 grams. In some cases, Compound 1 is obtained in an amount that is at least about 50-500 grams. In some cases, Compound 1 is obtained in an amount that is at least about 50-250 grams.

[0095] Embodiment 65 of this disclosure relates to the process according to any one of Embodiments 51-64, wherein Compound 1 is purified using a process that includes performing an inverse quench.

[0096] Embodiment 66 of this disclosure relates to the process according to Embodiment 65, wherein the inverse quench is performed using aqueous L-tartaric acid, aqueous citric acid, hydrochloric acid, or sodium dihydrogen phosphate.

[0097] Embodiment 67 of this disclosure relates to the process according to Embodiment 66, wherein the inverse quench is performed using aqueous L-tartaric acid.

[0098] Embodiment 68 of this disclosure relates to the process according to Embodiment 67, wherein the aqueous L-tartaric acid ranges from about 10 wt% to about 25 wt%.

[0099] Embodiment 69 of this disclosure relates to the process according to Embodiment 68, wherein the aqueous L-tartaric acid is about 15 wt%.

[0100] Embodiment 70 of this disclosure relates to the process according to any one of Embodiments 51-69, wherein Compound 1 is further purified by recrystallization. In some cases, the recrystallization solvent is toluene. In some cases, Compound 1 is further purified by cooling crystallization. In some cases, a solution of Compound 1 in toluene is heated (e.g., to about 60-110 °C such as about 65-75 °C or about 70 °C) and then cooled (e.g., to 0 °C or lower such as about 0 °C to -20 °C or about -10 °C). In some cases, a solution of10622-W001-SECCompound 1 in toluene is heated to about 65-75 °C and then cooled to about 0 °C to -20 °C. In some cases, a solution of Compound 1 in toluene is heated to about 70 °C and then cooled to about -10 °C.

[0101] Embodiment 71 of this disclosure relates to a process of making a compound of Compound 2Compound 2 comprising contacting Compound 1 with SOCh in a suitable solvent, wherein Compound 1 is made by the process according to any one of Embodiments 51-63.

[0102] Embodiment 72(a) of this disclosure relates to the process according to Embodiment63, wherein the reaction temperature ranges from 50 °C - 80 °C.

[0103] Embodiment 72(b) of this disclosure relates to the process according to Embodiment63, wherein the reaction temperature ranges from 60 °C - 70 °C.

[0104] Embodiment 72(c) of this disclosure relates to the process according to any one of Embodiments 72, 72(a) or 72(b), wherein the suitable solvent is toluene.

[0105] Embodiment 72(d) of this disclosure relates to the process according to Embodiment 72(c), wherein the toluene is azeotropically dry.

[0106] Embodiment 73 of this disclosure relates to a process of making avacopan having the following formula:or a pharmaceutically acceptable salt thereof, comprising:(a) contacting a compound having the formula (i-3):10622-W001-SEC with Compoundunder conditions sufficient to form a compound of formula (i-4):(b) contacting the compound of formula (i-4) with an aniline having the formula:to provide avacopan, wherein Compound 2 is made by the process according to any one of Embodiments 72, 72(a), 72(b), 72(c) or 72(d). In some cases, the compound of Formula (i-3) is provided as a pharmaceutically acceptable salt. In some cases, the compound of Formula (i-3) is provided as a L-DTTA salt ((-)-0,0 ’-di-p-toluoyl-L-tartaric acid salt). In some cases, the compound of Formula (i-3) is provided as a bis L-DTTA salt,(Formula (i-3) x 2 L-DTTA).

[0107] Additional details of the synthetic process of Embodiments 50 and 73 is described within Route 1 of U.S. Patent No. 9,745,268.

[0108] Embodiment 74 of this disclosure relates to a crystalline solid form of Compound 1,wherein Compound 1 is obtained according to the method of Embodiment 48 or 70.

[0109] Embodiment 75 of this disclosure relates to a crystalline solid form of Compound 1, wherein Compound 1 has an X-ray powder diffraction pattern comprising one or more peaks10622-W001-SEC at 14.472, 23.989, 24.890, 27.255, and 38.391 ±0.2° 29. In some cases, Compound 1 has an X-ray powder diffraction pattern comprising peaks at 14.472, 23.989, 24.890, 27.255, and 38.391 ±0.2° 29. In some cases, Compound 1 is obtained according to the method of Embodiment 48 or 62.

[0110] Embodiment 76 of this disclosure relates to a crystalline solid form of Compound 1 of Embodiment 74 or 75, wherein Compound 1 has an X-ray powder diffraction pattern substantially similar to FIG. 1. In some cases, Compound 1 has an X-ray powder diffraction pattern according to FIG. 1.EXAMPLES[oni] The compounds of the disclosure may be prepared using methods disclosed herein and routine modifications thereof which will be apparent given the disclosure herein and methods well known in the art. Conventional and well-known synthetic methods may be used in addition to the teachings herein. The synthesis of compounds described herein, may be accomplished as described in the following examples. If available, reagents may be purchased commercially, e.g. from Sigma Aldrich or other chemical suppliers. Unless otherwise noted, the starting materials for the following reactions may be obtained from commercial sources.

[0112] Purification methods for the compounds described herein are known in the art and include, for example, crystallization, recrystallization, chromatography (for example, liquid, gas phase, and supercritical fluid), extraction, distillation, trituration, and reverse phase HPLC.

[0113] The following examples are given for the purpose of illustrating various embodiments of the disclosure and are not meant to limit the present disclosure in any fashion. One skilled in the art will appreciate readily that the present disclosure is well-adapted to carry out the objects and obtain the ends and advantages mentioned, as well as those objects, ends, and advantages inherent herein. Changes therein and other uses which are encompassed within the spirit of the disclosure as defined by the scope of the claims will occur to those skilled in the art.10622-W001-SECEXAMPLE 13. NaOH2-Fluorobenzoic acid 4. MTBE wash Compound 15. HCI6. MTBE extraction7. Solvent swap to PhMe8. Charge Heptane9. Crystallize from 70 °C to -10 °CReaction Conditions

[0114] 2-fluorobenzoic acid (1.0 eq.), Fe(acac)3 (0.035eq.) and Me2N-TP (0.035 eq.) were suspended in 2-methyltetrahydrofuran (2-MeTHF, 5.0 L / kg). 1,2-dichloropropane (1.5 eq.) was added, and the mixture was degassed by sparging with nitrogen for NLT 30 min. The internal temperature was increased to 60-75 °C, and trimethylaluminum solution in toluene (1.5 eq.) was added at a rate to ensure the reaction temperature within 60-75 °C. Upon completion of trimethylaluminum charge, the reaction mixture was heated to 75 °C and stirred for 3-6 hours. Reaction completion was assessed with an HPLC IPC.Workup Conditions after Reaction1. The reaction mixture was cooled to 20 °C and quenched by transferring the reaction solution to a separate reactor containing 15 wt% L-tartaric acid in water (10-12 L / kg), adding at such a rate to maintain internal temperature less than 35 °C.2. The mixture was stirred for 15-30 min, then the layers were separated.3. The organic layer was extracted with aqueous 1 M NaOH solution (10 L / kg).4. The basic aqueous layer was washed with MTBE (5 L / kg) and is subsequently acidified to pH <3 by the addition of aqueous 6 M HC1.5. The acidified aqueous layer was then extracted with MTBE (10 L / kg), and the aqueous layer is discarded.6. Solution assay of the final organic layer was assessed with an HPLC, and the assay of IM1 is used to determine distillation and crystallization volumes.7. The solvent was then exchanged to toluene through put-and-take distillations (endpoint: 3L / kg).8. The solution was heated to 70 °C and heptane (3kg / L) was slowly added to the mixture to make sure a clear solution was obtained.9. Subsequently, the mixture was initially cooled to 50-60 °C over 30 min, then further cooled to -15 — 5 °C over 5.5-8.5 h.10622-W001-SEC10. The mixture was then stirred for Ih, filtered, and washed with pre-cooled toluene (2L / kg) to provide Compound 1.EXAMPLE 2

[0115] Synthesis of 2-fluoro-6-methylbenzoic acid (Compound 1)1. AIMe3, Fe(acac)2, ligand 1, DME, 70 °C2. 15 wt% L-tartaric acid (inverse quench)3. Extract with 1 M NaOH4. Wash with MTBE5. Acidify with 6M HCI Compound 16. Extract with MTBE7. Solvent swap to PhMe8. Crystallize from 70 °C to -10 °C

[0116] 2-fluorobenzoic acid (60.00 g, 0.428 mol, 1.0 equiv.), Fe(acac)3 (5.30 g, 0.0150 mol, 0.035 equiv.), and ((phenylphosphanediyl)bis(2,l-phenylene))bis(diphenylphosphane) as the triphosphine ligand 1 (9.46 g, 0.0150 mol, 0.035 equiv.) were suspended in 1,2- dimethoxy ethane (300 mL, 5.0 L / kg). 1,2-dichloropropane (62.7 mL, 0.642 mol, 1.50 equiv.) was added, and the mixture was degassed by sparging with nitrogen forNLT 15 minutes. The internal temperature was controlled to 20 °C, and trimethylaluminum solution in PhMe (321.2 mL, 0.642 mol, 1.50 equiv.) was added at a rate to ensure the reaction temperature does not exceed 35 °C. Upon completion of trimethylaluminum charge, the temperature of the reaction mixture was adjusted to reflux (-100 °C) and stirred for 18 hours. Reaction completion was assessed with an HPLC IPC (acceptance limit: RSM < 2.0 A%). Additional reaction time and / or a kicker charge of Fe(acac)3 and triphosphine ligand (0.010 equiv. ea.) was added if the conversion IPC did not initially meet the action limit. The reaction mixture was cooled to 20 °C and was quenched by transferring the reaction solution to a separate reactor containing 15 wt% L-tartaric acid in water (720 mL, 12 L / kg), added at such a rate to maintain internal temperature less than 35 °C. The layers were separated, and the organic layer was extracted with aqueous 1 M NaOH solution (600 mL, 10 L / kg). The aqueous layer was washed with MTBE (300 mL, 5 L / kg), and was subsequently acidified to pH <3 by the addition of aqueous 6M HCI (95 mL). The acidified aqueous layer was then extracted with MTBE (600 mL, 10 L / kg), and the aqueous layer was discarded. Solution assay of the final10622-W001-SEC organic layer was assessed with an HPLC, and the assay of Compound 1 was used to determine distillation and crystallization volumes. The solvent was then distilled under vacuum (350-400 Torr) at a jacket temperature of 55 °C until 350 mL (6 L / kg) remain. Toluene (350 mL, 6.0 L / kg) was added, and the solvent was distilled under vacuum (100-350 Torr) at a jacket temperature of 55 °C until 350 mL remained. An additional portion of toluene (350 mL, 6 L / kg) was charged, and the solvent was distilled under vacuum (100-200 Torr) at a jacket temperature of 70 °C until 350 mL remained (6.0 L / kg). The solution was heated to an internal temperature of 70 °C to obtain a clear solution. Subsequently, the mixture was initially cooled to 50 °C to 60 °C then further cooled to -15 °C to -5 °C over 5.5 - 8.5 hours. The mixture was then stirred for 1 hour, filtered, and washed with toluene (116 mL, 2 L / kg) to provide Compound 1 (50.46 g, 99.44 A%, 100 wt%). An additional recrystallization was performed from toluene (5.8 L / kg) using the same crystallization conditions if additional purity upgrade was required.

[0117] iH NMR (400 MHz, CDCh) 6 12.48 - 11.97 (br. S, 1 H), 7.40 - 7.31 (m, 1H), 7.09 - 6.94 (m, 2H), 2.54 (S, 3H)

[0118] 13C NMR (101 MHz, CDCh) 171.7, 160.8 (d, 7=253.6 Hz) 140.0 (d, 7=1.3 Hz) 132.3 (d, 7=9.5 Hz) 126.4 (d, 7=3.0 Hz) 119.8 (d, 7=13.9 Hz) 113.6 (d, 7=22.1 Hz) 20.4 (d, 7=2.2 Hz)

[0119] All NMR spectral data (XH,13C) were collected at 300 K (27 °C) on a Bruker Avance III 400 equipped with a 5 mm BBFO z-gradient probe. All observed protons are reported as parts-per-million (ppm) using the residual solvent peak (CHCI3) of the NMR solvent as reference.

[0120] 2-MeTHF is also a useful solvent for this transformation, with a 60% isolated yield of Compound 1 following recrystallization and >99 % purity using 10 mol% Fe(acac)3,10 mol% ((phenylphosphanediyl)bis(2,l-phenylene))bis(diphenylphosphane), and DCP as the oxidant.

[0121] In Example 2, both catalyst and ligand loading has been substantially reduced from about 10 mol% to about 3.5 mol% by using 1,2-dimethoxy ethane and toluene instead of a 10:1 ratio of THF / DME as described in Rui Shang et al. Further, using 1,2-dimethoxy ethane and toluene instead of 2-MeTHF improved the % yield of Compound 1 of more than 15%.

[0122] To counter emulsification and precipitation of salts during the HC1 quench which significantly impacted stirring, it was discovered that performing an inverse quench of the reaction mixture into about 15 wt% aqueous L-tartaric acid avoids emulsification and alleviate aluminum precipitation, leading to a smoother quenching process.10622-W001-SEC

[0123] In Example 2, a chromatography -free work-up and isolation process using crystallization and recrystallization was developed to allow for large scale manufacturing.

[0124] All charges in this example are relative to 2 -fluorobenzoic acid. Studies testing the purge of the starting 2 -fluorobenzoic acid in the crystallization were conducted and it was found the purge factor to be 75%, giving the ability to further upgrade purity through a recrystallization of the isolated solids.

[0125] Although the foregoing disclosure has been described in some detail by way of illustration and example for purposes of clarity of understanding, one of skill in the art will appreciate that certain changes and modifications may be practiced within the scope of the appended claims. Where a conflict exists between the instant application and a reference provided herein, the instant application shall dominate.

Claims

10622-W001-SECWHAT IS CLAIMED IS:

1. A process for making a compound of Compound 1 having the following structure:Compound 1 or a salt thereof, said method comprising contacting 2-fluorobenzoic acid,with an iron catalyst and a phosphine ligand in the presence of a methylaluminum reagent and 1,2-dichloropropane, wherein the reaction is conducted in a suitable solvent.

2. The process according to claim 1, wherein the phosphine ligand is of the following formula:wherein R1is hydrogen or diphenylphosphaneyl;R2is H or -Co-3 alkyl-N(R3)2; and each R3independently is C1-3 alkyl.

3. The process according to claim 2, wherein the phosphine ligand is of the following formula:10622-W001-SEC4. The process according to claim 1, wherein the phosphine ligand isThe process according to claim 4, wherein the phosphine ligand is((phenylphosphanediyl)bis(2, 1 -phenylene))bis(diphenylphosphane) having the6. The process according to claim 4, wherein the phosphine ligand is 4-(bis(2- (diphenylphosphaneyl)phenyl)phosphaneyl)-N,N -dimethylaniline having the7. The process according to any of claims 1-6, wherein the iron catalyst is Fe(acac)s.

8. The process according to any of the claims 1-7, wherein the methylaluminum reagent is A1(CH3)3.

9. The process according to any of claims 1-8, wherein the suitable solvent is 2-MeTHF, toluene, a mixed solvent system of THF and toluene, or a mixed solvent system of 1,2-dimethoxy ethane and toluene.

10. The process according to claim 9, wherein the suitable solvent is 2-MeTHF.

11. The process according to claim 9, wherein the suitable solvent is a mixed solvent system of 1,2-dimethoxy ethane and toluene.10622-W001-SEC12. The process according to claim 10 or 11, wherein the phosphine ligand is ((phenylphosphanediyl)bis(2, 1 -phenylene))bis(diphenylphosphane) having the following structure:.

13. The process according to claim 9, wherein the suitable solvent is toluene.

14. The process according to claim 9, wherein the suitable solvent is a mixed solvent system of THF and toluene.

15. The process according to claim 13 or 14, wherein the phosphine ligand is 4-(bis(2- (diphenylphosphaneyl)phenyl)phosphaneyl)-N,N -dimethylaniline (Me2N-TP) having the following structure:

16. The process according to claim 11, wherein the reaction is heated to reflux.

17. The process according to claim 10, wherein the methylaluminum reagent is A1(CH3)3 ranging from 1.5 to about 2.5 equivalents relative to 2-fluorobenzoic acid.

18. The process according to claim 17, wherein the A1(CH3)3 ranges from about 1.8 to about 2.2 equivalents relative to 2-fluorobenzoic acid.

19. The process according to claim 17, wherein the A1(CH3)3 is about 2 equivalents relative to 2-fluorobenzoic acid.

20. The process according to any one of claims 10 or 17-19, wherein the iron catalyst is Fe(acac)3 ranging from about 8 mol% to about 12 mol%.

21. The process according to claim 20, wherein Fe(acac)3 ranges from about 9 mol% to about 11 mol%.

22. The process according to claim 20, wherein Fe(acac)3 is about 10 mol%.10622-W001-SEC23. The process according to any one of claims 10 or 17-22, wherein the phosphine ligand ranges from about 8 mol% to about 12 mol%.

24. The process according to claim 23, wherein the phosphine ligand ranges from about 9 mol% to about 11 mol%.

25. The process according to claim 23, wherein the phosphine ligand is about 10 mol%.

26. The process according to any one of claims 10 or 17-25, wherein the 1,2- dichloropropane ranging from about 2.5 equivalents to about 3.5 equivalents relative to 2-fluorobenzoic acid.

27. The process according to claim 26, wherein the 1,2-dichloropropane ranges from about 2.8 equivalents to about 3.2 equivalents relative to 2-fluorobenzoic acid.

28. The process according to claim 26, wherein the 1,2-dichloropropane is about 3 equivalents relative to 2-fluorobenzoic acid.

29. The process according to any one of claims 11-16, wherein the methylaluminum reagent is Al(CHs)3 ranging from about 1.2 to about 1.8 equivalents relative to 2- fluorobenzoic acid.

30. The process according to claim 29, wherein the Al(CHs)3 ranges from about 1.4 to about 1.6 equivalents relative to 2-fluorobenzoic acid.

31. The process according to claim 29, wherein the A1(CH3)3 is about 1.5 equivalents relative to 2-fluorobenzoic acid.

32. The process according to any one of claims 11 or 29-31, wherein the iron catalyst is Fe(acac)3 ranging from about 1 mol% to about 12 mol%.

33. The process according to claim 32, wherein Fe(acac)3 ranges from about 2.5 mol% to about 4.5 mol%.

34. The process according to claim 32, wherein Fe(acac)3 is about 3.5 mol%.

35. The process according to any one of claims 11 or 29-34, wherein the phosphine ligand ranges from about 1 mol% to about 12 mol%.10622-W001-SEC36. The process according to claim 35, wherein the phosphine ligand ranges from about 2.5 mol% to about 4.5 mol%.

37. The process according to claim 35 or 36, wherein the phosphine ligand is about 3.5 mol%.

38. The process according to any one of claims 11 or 28-37, wherein dichloropropane ranges from about 1.2 equivalents to about 1.8 equivalents relative to 2-fluorobenzoic acid.

39. The process according to claim 38, wherein 1,2-dichloropropane ranges from about 1.4 equivalents to about 1.6 equivalents relative to 2-fluorobenzoic acid.

40. The process according to claim 38, wherein the 1,2-dichloropropane is about 1.5 equivalents relative to 2-fluorobenzoic acid.

41. The process according to any one of claims 11 or 29-40, wherein the ratio of 1,2- dimethoxy ethane to toluene ranges from about 1 :1 to about 1 :1.2 by volume.

42. The process according to claim 41, wherein the ratio of 1,2-dimethoxy ethane to toluene is about 1 :1.1 by volume.

43. The process according to any one of claims 11 or 29-42, wherein Compound 1 is purified using a process that includes performing an inverse quench.

44. The process according to claim 43, wherein the inverse quench is performed using aqueous L-tartaric acid, aqueous citric acid, hydrochloric acid, or sodium dihydrogen phosphate.

45. The process according to claim 44, wherein the inverse quench is performed using aqueous L-tartaric acid.

46. The process according to claim 45, wherein the aqueous L-tartaric acid ranges from about 10 wt% to about 25 wt%.

47. The process according to claim 45, wherein the aqueous L-tartaric acid is about 15 wt%.

48. The process according to any one of claims 1-47, wherein the process further comprises a recrystallization of Compound 1.10622-W001-SEC49. A process of making a compound that is Compound 2Compound 2 comprising contacting Compound 1,Compound 1 with SOCh in a suitable solvent, wherein Compound 1 is made by a process according to any one of claims 1-48.

50. A process of making avacopan having the following formula:or a pharmaceutically acceptable salt thereof, comprising:(a) contacting a compound having the formula (i-3):with Compoundunder conditions sufficient to form a compound of formula (i-4):10622-W001-SEC(b) contacting the compound of formula (i-4) with an aniline having the formula:to provide avacopan, wherein Compound 2 is made by the process according to claim 49.

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