Synthetic processes for pharmaceutically active compounds

Abstract

A process of preparing Compound 1: or a salt thereof, comprising reacting Compound 2: with a lithiating reagent in a suitable solvent at a suitable reaction temperature of less than -40 °C to afford Compound 3: and reacting Compound 3 with CO2 to afford a compound of Compound 1.

Description

PATENT10620-W001-SECSYNTHETIC PROCESSES FOR PHARMACEUTICALLY ACTIVE COMPOUNDS CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] The present application claims benefit of U.S. Provisional Patent Application No. 63 / 713,101 filed October 29, 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 [tg / ml (Kohler. P. F. et al., J. Immunol. 99: 1211-1216 (1967)). It is composed of two polypeptide chains, cz and 0, 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)e. Bb. and P for the alternative pathway (Goldlust, M. B. et al., 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 Oi-chain. After activation, the 11.2 kD, 74 amino acid peptide C5a from the amino-temiinus portion of the a- chain is released. Both C5a and C3a are potent stimulators of neutrophils and monocytes (Schindler, R. et al., Blood 76: 1631-1638 (1990); Haeffner-Cavaillon, N. et al., J. Immunol. 138: 794-700 (1987); Cavaillon, J. M. et al., Eur. J. Immunol. 20: 253-257 (1990)).

[0005] In addition to its anaphylatoxic properties, C5a induces chemotactic migration of neutrophils (Ward, P. A. et al., J. Immunol. 102: 93-99 (1969)), eosinophils (Kay, A. B. et al., Immunol. 24: 969-976 (1973)), basophils (Lett-Brown. M. A. et al., J. Immunol. 117: 246-252 1976)), and monocytes (Snydcrman, R. et al., Proc. Soc. Exp. Biol. Med. 138: 387-390 1971)).PATENT10620-W001-SEC

[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. et al., J. Immunol. 132: 2862-2867 (1984); Haviland, D. L. et al.. J. Immunol. 154: 1861-1869 (1995); Wetsel, R. A.. Immunol. Leff. 44: 183-187 (1995); Buchner, R. R. et al., J. Immunol. 155: 308-315 (1995); Chenoweth, D. E. et al., 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 in WO 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 this 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 arc in need.PATENT10620-W001-SECSUMMARY

[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:(avacopan).

[0010] One such intennediate 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-mcthylbcnzoyl 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.PATENT10620-W001-SEC

[0012] The following six-step synthetic process has been developed for the synthesis of Compound 1 :distillation1. NaOH (aq), tolueneCH2C12, SOC12d filter,MTBE, NaOH (aq.) water wash, dry filter, water wash, dry

[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 of preparingCompound 1 :Compound 1 or a salt thereof, comprising reacting Compound 2:Compound 2PATENT10620-W001-SEC with a lithiating reagent in a suitable solvent at a suitable reaction temperature of less than -40 °C to afford Compound 3:Compound 3 .anreacting Compound 3 with CO2 to afford a compound of Compound 1.

[0015] The process of this disclosure forms an aryl lithium intennediate (e g., Compound 3) via lithium bromide exchange which is highly advantageous since this aryl lithium intermediate is unstable and cannot be pre-formed and kept stable at room temperature. The process of this disclosure provides a scalable, end-to-end process to generate an unstable aryl lithium and react with CO2. Additional embodiments include downstream work-up and chromatography -free purification steps for the process of making Compound 1, and a process of making avacopan that utilizes the synthetic process of making Compound 1 as described in this disclosure.BRIEF DESCRIPTION OF THE DRAWINGS

[0016] FIG. 1 provides a flow diagram for a continuous flow process for making 2-fluoro-6- methylbenzoic acid (Compound 1).

[0017] FIG. 2 shows an X-ray powder diffraction (XRPD) analysis of Compound 1.DETAILED DESCRIPTIONDEFINITIONS AND ABBREVIATIONS

[0018] 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.

[0019] 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 alsoPATENT 10620-W001-SEC 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.

[0020] 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.

[0021] 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 ABBREVIATIONSPATENT10620-W001-SECEMBODIMENTS

[0022] Embodiment 1 relates to a process of preparing Compound 1 :Compound 1 or a salt thereof, comprising reacting Compound 2:Compound 2 with a lithiating reagent in a suitable solvent at a suitable reaction temperature of less than -40 °C to afford Compound 3:Compound 3 .anreacting Compound 3 with CO2 to afford a compound of Compound 1.

[0023] Embodiment 2 of this disclosure relates to the process according to Embodiment 1, wherein the process is a continuous flow process.

[0024] Embodiment 3 of this disclosure relates to the process according to Embodiment 1 or 2 , wherein the lithiating reagent is an alkyllithium. In some cases, the lithiating reagent is an n-alkyllithium.

[0025] Embodiment 4 of this disclosure relates to the process according to Embodiment 3, wherein the alk llithium is n-butyllithium or n-hexyllithium.

[0026] Embodiment 5 of this disclosure relates to the process according to Embodiment 4, wherein the alkyllithium is n-butyllithium.

[0027] Embodiment 6 of this disclosure relates to the process according to the process of any one of Embodiments 1-5, wherein about 1.0-3.0 equivalents of the alkyllithium reagent are used relative to Compound 2. In some cases, about 1.0-1.3 equivalents of the alkyllithium reagent are used relative to Compound 2. In some cases, about 1.1-1.2 equivalents of the alkyllithium reagent are used relative toPATENT10620-W001-SECCompound 2. In some cases, about 1.2 equivalents of the alkyllithium reagent are used relative to Compound 2. In some cases, about 1.15 equivalents of the alkyllithium reagent are used relative to Compound 2.

[0028] Embodiment 7 of this disclosure relates to the process according to the process of any one of Embodiments 1-6, wherein Compound 3 is reacted with about 1.0-10.0 equivalents of CO2. In some cases, Compound 3 is reacted with about 1.0-5.0 equivalents of CO2. In some cases, Compound 3 is reacted with about 2.0-5.0 equivalents of CO2. In some cases, Compound 3 is reacted with about 1.0-3.0 equivalents of CO2. In some cases, Compound 3 is reacted with about 2.0-3.0 equivalents of CO2.

[0029] Embodiment 8 of this disclosure relates to the process according to the process of any one of Embodiments 1-5, wherein Compound 3 is reacted with CO2 at a pressure of about 1.0-10.0 atm. In some cases, Compound 3 is reacted with CO2 at a pressure of about 1.0 atm.

[0030] Embodiment 9 of this disclosure relates to the process according to any one of Embodiments 1 -8, wherein the suitable solvent is tetrahydrofuran (THF), toluene and 2-methyltetrahydrofuran, hexanes, heptane, diethyl ether, dioxane, MTBE, CPME, or acetonitrile.|00311 Embodiment 10 of this disclosure relates to the process according to Embodiment 9. wherein said suitable solvent is THF.

[0032] Embodiment 11 of this disclosure relates to the process according to any one of Embodiments 1-10, wherein the suitable reaction temperature is maintained from -40 °C to about -75 °C during the lithiation of Compound 2 and the addition of CO2 to Compound 3.

[0033] Embodiment 12 of this disclosure relates to the process according to any one of Embodiments 1-10, wherein the suitable reaction temperature is maintained from -50 °C to about -75 °C during die lithiation of Compound (2 and the addition of CO2 to Compound 3.

[0034] Embodiment 13 of this disclosure relates to the process according to any one of Embodiments 1-10, wherein the suitable reaction temperature is maintained from -65 °C to about -75 °C during the lithiation of Compound 2 and the addition of CO2 to Compound 3.

[0035] Embodiment 14 of this disclosure relates to the process according to any one of Embodiments 1-10, wherein the suitable reaction temperature is maintained at about -70 °C during the lithiation of Compound 2 and the addition of CO2 to Compound 3.

[0036] Embodiment 15 of this disclosure relates to the process according to any one of Embodiments 1-14, wherein the molarity of Compound 1 ranges from about 0.3 M to about 0.7 M.

[0037] Embodiment 16 of this disclosure relates to the process according to any one of Embodiments 1-14, wherein the molarity of Compound 1 ranges from about 0.4 M to about 0.6 M.PATENT10620-W001-SEC

[0038] Embodiment 17 of this disclosure relates to the process according to any one of Embodiments 1-14, wherein the molarity of Compound 1 is about 0.5 M.

[0039] Embodiment 18 of this disclosure relates to the process according to any one of Embodiments 1-17, wherein the molarity of Compound 2 ranges from about 0.3 M to about 0.7 M.

[0040] Embodiment 19 of this disclosure relates to the process according to any one of Embodiments 1-17, wherein the molarity of Compound 2 ranges from about 0.4 M to about 0.6 M.

[0041] Embodiment 20 of this disclosure relates to the process according to any one of Embodiments 1-17, wherein the molarity of Compound 2 is about 0.5 M.

[0042] Embodiment 21 of this disclosure relates to the process according to any one of Embodiments 1-17, wherein the concentration of Compound 2 is about 5-15 w t% in the suitable solvent. In some cases, the concentration of Compound 2 is about 8-12 wt% or 9-11 wt% in the suitable solvent. In some cases, the concentration of Compound 2 is about 10 wt% in the suitable solvent. In some cases, the suitable solvent is THF.

[0043] Embodiment 22 of this disclosure relates to the process according to any one of Embodiments 1-21, wherein the alkylhalide is n-butyllithium, and the molarity of n-butyllithium ranges from about 1.2 M to about 2.0 M.

[0044] Embodiment 23 of this disclosure relates to the process according to any one of Embodiments 1-21, wherein the molarity of n-butyllithium ranges from about 1.4 M to about 1.8 M.

[0045] Embodiment 24 of this disclosure relates to the process according to any one ofEmbodiments 1-21, wherein the molarity of n-butyllithium is about 1.6 M.

[0046] Embodiment 25 of this disclosure relates to the process according to Embodiment 1, wherein the method comprises: reacting Compound 2 as a solution in THF having a molarity that ranges from about 0.3 M to about 0.7 M or a concentration that is about 5-15 wt% in THF,Compound 2PATENT10620-W001-SEC with a lithiating reagent that is n-butyllithium having a molarity that ranges from about 1.4 M to about 1.8 M in hexanes to afford Compound 3.Compound 3 and reacting Compound 3 with about 1.0-3.0 equivalents of CO2 at 1 atm to afford CompoundCompound 1 wherein the suitable solvent for the lithiation of Compound 2 and the addition of CO2 to Compound 3 is THF; and the reaction temperature during the lithiation of Compound 2 and the addition of CO2 to Compound 3 is maintained from about -40 °C to about -80 °C for each step.

[0047] Embodiment 26 of this disclosure relates to the process according to Embodiment 25, wherein the reaction temperature during the lithiation of Compound 2 and the addition of CO2 to Compound 3 is maintained from about -50 °C to about -70 °C or from about -65 °C to about -75 °C for each step. In some cases, the reaction temperature is maintained from about -50 °C to about -70 °C. In some cases, the reaction temperature is maintained from about -65 °C to about -75 °C.

[0048] Embodiment 27 of this disclosure relates to the process according to Embodiment 25 or 26, wherein the solution of Compound 2 in THF has a concentration that is about 10 wt% in THF, the n-butyllithium lithiating reagent has a molarity that is about 1.6 M; andCompound 3 is reacted with about 2.0-3.0 equivalents of CO2.PATENT10620-W001-SEC

[0049] Embodiment 28 of this disclosure relates to the process according to any one of Embodiments 1-27, wherein the lithiation of Compound 2 and the addition of CO2 to Compound 3 are carried out in a suitable continuous reactor.

[0050] Embodiment 29 of this disclosure relates to the process according to any one of Embodiments 1-27, wherein the lithiation of Compound 2 and the addition of CO2 to Compound 3 are carried out separately and sequentially using two consecutive flow reactors.

[0051] Embodiment 30 of this disclosure relates to the process according to Embodiment 29, wherein the flow reactor is selected from a plug flow reactor, a chemtrix reactor, and a coming reactor.

[0052] Embodiment 31 of this disclosure relates to the process according to Embodiment 29 or 30, wherein the volume of each individual reactor ranges from 2 mL to 200 mL. In some cases, the volume of each individual reactor ranges from 2 mL to 10 mL or 2 mL to 5 mL. In some cases, the volume of each individual reactor is 2 mL or 5 mL. In some cases, the volume of each individual reactor is 5 mL.

[0053] Embodiment 32 of this disclosure relates to the process according to Embodiment 31, wherein the volume of each individual reactor is 2 mL.

[0054] Embodiment 33 of this disclosure relates to the process according to any one of Embodiments 29-32. wherein:Compound 2 is provided in a first feed tank; n-butyllithium is provided in a second feed tank;CO2 is provided in a third feed tank;Compound 2 and n-butyllithium each flow into a first mixer to form a first mixture; the first mixture flows into a first plug flow reactor to form Compound 3;Compound 3 and CO2 each flow into a second mixer to fonn a second mixture; and the second mixture flows into a second plug flow reactor to form Compound 1.

[0055] Embodiment 34 of this disclosure relates to the process according to Embodiment 33, wherein the first mixer, the first plug flow reactor, the second mixture, and the second first plug flow reactor are each maintained at a temperature ranging from about -50 °C to about -75 °C.

[0056] Embodiment 35 of this disclosure relates to the process according to any one of Embodiments 33 or 34, wherein: a first pump is employed to create a flowrate for Compound 2; a second pump is employed to create a flowrate for n-butyllithium; and a third pump is employed to create a flowrate for CO2.PATENT10620-W001-SEC

[0057] Embodiment 36 of this disclosure relates to the process according to any one of Embodiments 33-35, wherein: the flowrate of Compound 1 from the first feed tank into the first mixer ranges from about f .5 to about 875 mL / min: the flowrate of n-butyllithium from the second feed tank into the first mixer ranges from about 1.0 to about 290 mL / min; and the flowrate of CCL from the third feed tank into the second mixer ranges from about 80 to about 30000 mL / min.

[0058] Embodiment 37 of this disclosure relates to the process according to any one of Embodiments 33-35, wherein: the flowrate of Compound 1 from the first feed tank into the first mixer ranges about1.8 to about 2.2 mL / min; the flowrate of n-butyllithium from the second feed tank into the first mixer ranges from about 2.2 to about 2.6 mL / min; and the flowrate of CO2 from the third feed tank into the second mixer ranges from about 80 to about 450 mmol / min.

[0059] Embodiment 38 of this disclosure relates to the process according to any one of Embodiments 33-35, wherein the flowrates of the three pumps are as described in Table 1 herein, wherein the flowrate of Compound 1 from the first feed tank into the first mixer is about 122.8 g / min; the flowrate of n-butyllithium from the second feed tank into the first mixer is about29.6 g / min; and the flowrate of CO2 from the third feed tank into the second mixer is about3.5-4.5 L / min.

[0060] Embodiment 39 of this disclosure relates to the process according to any one of Embodiments 1-38, wherein the product Compound 1 is collected and quenched in an aqueous acid. In some cases, the aqueous acid is aqueous hydrochloric acid.

[0061] Embodiment 40 of this disclosure relates to the process according to any one of Embodiments 30-39, wherein Compound 1 from the second plug flow reactor is collected and quenched in an aqueous acid. In some cases, the aqueous acid is aqueous hydrochloric acid.

[0062] Embodiment 41 of this disclosure relates to the process according to any one of Embodiments 1-40, wherein the production flow rate is from about 300 mL / hr to about 72000 mL / hr.PATENT10620-W001-SEC

[0063] Embodiment 42 of this disclosure relates to the process according to any one of Embodiments 1-40, wherein the production flow rate is about 70000 mL / hr.

[0064] Embodiment 43 of this disclosure relates to the process according to any to any one of Embodiments 1-42, wherein Compound 1 is purified by crystallization. In some cases, Compound 1 is purified by cry stallization from a solvent system comprising toluene and heptane. In some cases, crystallization provides a crystalline solid form of Compound 1 that has an X-ray powder diffraction pattern comprising one or more peaks at 14.472. 23.989, 24.890, 27.255, and 38.391 ±0.2° 20. In some cases, the cry stalline solid form of Compound 1 obtained following cr stallization has an X-ray powder diffraction pattern comprising peaks at 14.472, 23.989. 24.890, 27.255, and 38.391 ±0.2° 20. In some cases, the solid form of Compound 1 obtained following crystallization has an X-ray powder diffraction pattern substantially similar to FIG. 2. In some cases, Compound 1 has an X-ray powder diffraction pattern according to FIG. 2.

[0065] Embodiment 44 of this disclosure relates to the process according to any to any one of Embodiments 1-43, wherein Compound 1 is obtained in at least about 70% yield. In some cases, Compound 1 is obtained in at least about 75% yield. In some cases, Compound 1 is obtained in at least about 80% yield. In some cases, Compound 1 is obtained in at least about 70-80% or at least about 75-80% yield. In some cases, Compound 1 is obtained in about 70-100% yield. In some cases, Compound 1 is obtained in about 75-100% yield. In some cases, Compound 1 is obtained in about 80- 100% yield. In some cases. Compound 1 is obtained in about 70-90% yield. In some cases, Compound 1 is obtained in about 75-90% yield. In some cases. Compound 1 is obtained in about 80- 90% yield.

[0066] Embodiment 45 of this disclosure relates to the process according to any to any one of Embodiments 1-44, wherein Compound 1 is obtained in at least about 90% purity. In some cases, Compound 1 is obtained in at least about 90%, 91%. 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% purity, hr some cases, Compound 1 is obtained in at least about 95% purity. In some cases, Compound 1 is obtained in at least about 96% purity. In some cases. Compound 1 is obtained in at least about 97% purity. In some cases, Compound 1 is obtained in at least about 98% purity. In some cases, Compound 1 is obtained in at least about 99% purity. In some cases, Compound 1 is obtained in at least about 99% purity. In some cases, Compound 1 is obtained in at least about 99.1% purity. In some cases, Compound 1 is obtained in at least about 99.2% purity. In some cases, Compound 1 is obtained in at least about 99.3% purity. In some cases. Compound 1 is obtained in at least about 99.4% purity. In some cases. Compound 1 is obtained in at least about 99.6% purity. In some cases, Compound 1 is obtained in at least about 99.6% purity. In some cases, Compound 1 is obtained in at least about 99.7% purity. In some cases, Compound 1 is obtained in at least about 99.8% purity. In some cases. Compound 1 is obtained in at least about 99.9% purity. In some cases, purity is determined by HPLCPATENT10620-W001-SEC

[0067] Embodiment 46 of this disclosure relates to a process according to a process of making a compound of Compound 4Compound 4 / comprising contacting Compound 1 having the following formula:Compound 1 with SOCk in a suitable solvent, wherein Compound 1 is made by the process according to any one of Embodiments 1-45.

[0068] Embodiment 47 of this disclosure relates to a process of making avacopan having the following formula:(avacopan), or a pharmaceutically acceptable salt thereof, comprising:(a) contacting a compound having the formula (i-3):with Compound 4:under conditions sufficient to form a compound of formula (i-4):PATENT10620-W001-SEC(i-4); and(b) contacting the compound of formula (i-4) with an aniline having the formula:to provide avacopan. wherein Compound 4 is made by the process according to Embodiment 46. Additional details of the synthetic process of Embodiment 46 are described within Route 1 of U.S. Patent No. 9,745,268.OTHER EMBODIMENTS

[0069] Provided herein as Embodiment A.1 is a process of preparing Compound 1 :Compound 1 or a salt thereof, comprising reacting Compound 2:Compound 2 with a lithiating reagent in a suitable solvent at a suitable reaction temperature of less than -40 °C to afford Compound 3 :Compound 3 .andPATENT10620-W001-SEC reacting Compound 3 with CO2 to afford a compound of Compound 1.

[0070] Provided herein as Embodiment A.2 is the process according to Embodiment A.l, wherein the process is a continuous flow process.

[0071] Provided herein as Embodiment A.3 is the process according to Embodiment A.1 or Embodiment A.2, wherein the lithiating reagent is an alkyllithium.

[0072] Provided herein as Embodiment A.4 is the process according to Embodiment A.3, wherein the alkyllithium is n-butyllithium or n-hexyllithium.

[0073] Provided herein as Embodiment A.5 is the process according to Embodiment A.4, wherein the alkyllithium is n-butyllithium.

[0074] Provided herein as Embodiment A.6 is the process according to any one of Embodiments A.1-A.5, wherein the suitable solvent is tetrahydrofuran, toluene and 2-methyltetrahydrofuran, hexanes, heptane, diethyl ether, dioxane, MTBE, CPME, or acetonitrile.

[0075] Provided herein as Embodiment A.7 is the process according to Embodiment A.6, wherein said suitable solvent is THF.

[0076] Provided herein as Embodiment A.8 is the process according to any one of Embodiments A.1-A.7, wherein the suitable reaction temperature is maintained from -40 °C to about -75 °C during the lithiation of Compound 2 and the addition of CO2 to Compound 3.

[0077] Provided herein as Embodiment A.9 is the process according to any one of Embodiments A.1-A.7, wherein the suitable reaction temperature is maintained from -50 °C to about -75 °C during the lithiation of Compound 2 and the addition of CO2 to Compound 3.

[0078] Provided herein as Embodiment A.10 is the process according to any one of Embodiments A.1-A.7, wherein the suitable reaction temperature is maintained from -65 °C to about -75 °C during the lithiation of Compound 2 and the addition of CO2 to Compound 3.

[0079] Provided herein as Embodiment A.11 is the process according to any one of Embodiments A.l -A.7, wherein the suitable reaction temperature is maintained at about -70 °C during the lithiation of Compound 2 and the addition of CO2 to Compound 3.

[0080] Provided herein as Embodiment A.12 is the process according to any one of Embodiments A.1 -A.11 , w herein the molarity of Compound 1 ranges from about 0.3 M to about 0.7 M.

[0081] Provided herein as Embodiment A.13 is the process according to any one of Embodiments A.1-A.11. wherein the molarity of Compound 1 ranges from about 0.4 M to about 0.6 M.

[0082] Provided herein as Embodiment A.14 is the process according to any one of Embodiments A.l-A.ll, wherein the molarity of Compound 1 is about 0.5 M.PATENT10620-W001-SEC

[0083] Provided herein as Embodiment A.15 is the process according to any one of Embodiments A.1-A.14, wherein the alkylhalide is n-butyllithium, and the molarity of n-butyllithium ranges from about 1.2 M to about 2.0 M.

[0084] Provided herein as Embodiment A.16 is the process according to any one of Embodiments A.1-A.14, wherein the molarity of n-butyllithium ranges from about 1.4 M to about 1.8 M.

[0085] Provided herein as Embodiment A.17 is the process according to any one of Embodiments A.1-A.14, wherein the molarity of n-butyllithium is about 1.6 M.

[0086] Provided herein as Embodiment A.18 is the process according to any one of Embodiments A.1-A.17. wherein the lithiation of Compound 2 and the addition of CO2 to Compound 3 are carried out in a suitable continuous reactor.

[0087] Provided herein as Embodiment A.19 is the process according to any one of Embodiments A.1-A.17, wherein the lithiation of Compound 2 and the addition of CO2 to Compound 3 are carried out separately and sequentially using two consecutive flow reactors.

[0088] Provided herein as Embodiment A.20 is the process according to Embodiment A.19, wherein the flow' reactor is selected from a plug flow' reactor, a chemtrix reactor, and a corning reactor.

[0089] Provided herein as Embodiment A.21 is the process according to Embodiment A.19 or A.20, w herein the volume of each individual reactor ranges from 2 mL to 200 mL.

[0090] Provided herein as Embodiment A.22 is the process according to Embodiment A.21. wherein the volume of each individual reactor is 2 mL.

[0091] Provided herein as Embodiment A.23 is the process according to any one of Embodiments A.19-A.22, wherein:Compound 2 is provided in a first feed tank; n-butyllithium is provided in a second feed tank;CO2 is provided in a third feed tank;Compound 2 and n-butyllithium each flow into a first mixer to form a first mixture; the first mixture flow s into a first plug flow reactor to form Compound 3;Compound 3 and CO2 each flow into a second mixer to form a second mixture; and the second mixture flows into a second plug flow reactor to form Compound 1.

[0092] Provided herein as Embodiment A.24 is the process according to Embodiment A.23, wherein the first mixer, the first plug flow reactor, the second mixture, and the second first plug flow reactor are each maintained at a temperature ranging from about -50 °C to about -75 °C.PATENT10620-W001-SEC

[0093] Provided herein as Embodiment A.25 is the process according to any one of Embodiments A.23-A.24, wherein: a first pump is employed to create a flowrate for Compound 2; a second pump is employed to create a flowrate for n-butyllithium; and a third pump is employed to create a flowrate for CO2.

[0094] Provided herein as Embodiment A.26 is the process according to any one of Embodiments A.23-A.25, wherein: the flowrate of Compound 1 from the first feed tank into the first mixer ranges from about 1.5 to about 875 mL / min; the flowrate of n-butyllithium from the second feed tank into the first mixer ranges from about 1.0 to about 290 mL / min; and the flowrate of CO; from the third feed tank into the second mixer ranges from about 80 to about 30000 mL / min.

[0095] Provided herein as Embodiment A.27 is the process according to any one of Embodiments A.23-A.25, wherein: the flowrate of Compound 1 from the first feed tank into the first mixer ranges about 1.8 to about 2.2 mL / min; the flowrate of n-butyllithium from the second feed tank into the first mixer ranges from about 2.2 to about 2.6 mL / min; and the flowrate of CO2 from the third feed tank into the second mixer ranges from about 80 to about 450 mmol / min.

[0096] Provided herein as Embodiment A.28 is the process according to any one of Embodiments A.25-A.27, wherein Compound 1 from the second plug flow reactor is collected and quenched in an aqueous acid.

[0097] Provided herein as Embodiment A.29 is the process according to any one of Embodiments A.1-A.28, wherein the production flow rate is from about 300 mL / hr to about 72000 mL / hr.

[0098] Provided herein as Embodiment AJO is the process according to any one of Embodiments A.1-A.28, wherein the production flow rate is about 70000 mL / hr.

[0099] Provided herein as Embodiment A.31 is the process according to any to any one of Embodiments A.1 -A.30, wherein the Compound 1 is purified by crystallization.PATENT10620-W001-SEC

[0100] Provided herein as Embodiment A.32 is a process of making a compound of Compound 4Compound 4 comprising contacting Compound lhaving the following formula:Compound 1 with SOCh in a suitable solvent, wherein Compound 1 is made by the process according to any one of Embodiments A.1 - A.31.

[0101] Provided herein as Embodiment A.33 is 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 Compound 4: (XFunder conditions sufficient to form a compound of formula(i-4):PATENT10620-W001-SEC(b) contacting the compound of formula (i-4) with an aniline having the formula:to provide avacopan. wherein Compound 4 is made by the process according to Embodiment A.32.EXAMPLES

[0102] The compounds of the disclosure may be prepared using methods (also referred to as processes) 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.

[0103] 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.]00104] 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.Flow Diagram for Continuous Flow Process for Making Compound 1 :

[0105] An exemplary flow diagram for making Compound 1 is provided in FIG. 1.PATENT10620-W001-SEC

[0106] A solution of 2-bromo-3 -fluorotoluene (Ar-Br), also referred to as Compound 2, in THF is provided in one or more Ar-Br / THF feed tanks (see Fig. 1), wherein the one or more Ar-Br / THF feed tanks are connected to Pump 1 (see FIG. 1).

[0107] A solution of n-BuLi is provided in one or more n-BuLi feed tanks (Fig. 1), wherein the one or more second containers are connected to Pump 2 (FIG. 1).

[0108] Pump 1 is connected between the (1) one or more the Ar-Br / THF feed tanks and Mixer 1 (FIG. 1). Pump 1 controls the flow of the Ar-Br / THF to the Mixer 1.

[0109] Pump 2 is connected between the (1) one or more n-BuLi feed tanks and (2) Mixer 1 (FIG. 1). Pump 2 controls the flow of the n-BuLi n-hexane to Mixer 1.

[0110] Precooling (FIG. 1) occurs between Pumps 1 and 2 and Mixer 1.

[0111] CO2 gas: A carbon dioxide cylinder (CO2 gas in FIG. 1) is comiected to Mixer 2 and controlled by a volume flow meter (Fig. 1).

[0112] A IM solution of HC1 in a IM HC1 feed tank (IM HCL Aq. in FIG. 1) is provided.

[0113] Pump 3 (Fig. 1) is connected between (1) the IM HC1 feed tank and (2) the CSTR that controls the flow of IM HC1 into the CSTR.

[0114] A stage 1 plug flow reactor (PFR1 stage 1 in FIG. 1) is provided wherein the contents of Mixer 1 flows into PFR1, and the reaction product of PFR1 and CO2 gas both flow into Mixer 2.

[0115] A stage 2 plug flow reactor (PFR2 stage 2 in FIG. 1) is provided wherein the contents of Mixer 2 flow into PFR2, and the reaction product of PFR2 flows into the CSTR. Sampling of the reaction mixture can be obtained between the PFR2 and the CSTR (FIG. 1). The stainless steel of PFR1 and the stainless steel of PFR2 is maintained at a temperature from about -75 to about -65 °C, and the jacket of the CSTR is cooled to a temperature ranging from about 0 to about 20 °C.

[0116] The temperature jacket of both PFR1 and PFR2 is maintained at a temperature ranging from about -75 to about -65 °C. the CSTR quenching mixture is maintained at a temperature ranging from about 0 to about 20 °C (Fig. 1 depicts the temperature ranges).PATENT10620-W001-SECEXAMPLE 14 Solvent swap to PhMeAr-Br 5. Charge heptane IM15. Crystallize from 70 °C to -7 °C (C0340807)Chemical Formula: C HgBrF Chemical Formula: CgHyFOj Molecular Weight: 189.03 Molecular Weight: 154.14A, Flow reaction set-up procedure:

[0117] An exemplary equipment flow chart is shown in FIG. 1.1. Compound 2 / THF Solution: A total of 71.2 kg THF was added to two 80 L Ar-Br / THF solution feed tanks. 8Kg 2-bromo-3-fluorotoluene (Compound 2) was added to the two Compound 2 / THF solution feed tanks to form a 10 wt% Ar-Br solution. The Compound 2 / THF solution was stirred for about 10 to about 30 minutes. Pump 1 was connected betw een (1) the Compound 2 / THF feed tanks and (2) Mixer 1 to control the flow of the Compound 2 / THF solution into Mixer 1.2. n-BuLi n-hcxanc Solution: A 1.6M n-BuLi n-hcxanc solution in a n-BuLi feed tank was provided. Pump 2 was connected betw een the 1.6M n-BuLi n-hexane feed tank and (2) Mixer 1 to control the flow of the n-BuLi n-hexane solution to Mixer 1.3. CO? gas: A high-purity carbon dioxide cylinder was connected to Mixer 2.4. A IM solution of HO in a IM HCI feed tank was provided by adding purified water (60 kg) with 36% hydrochloric acid (6.4 kg), stirring for 10~30min at 15-30 °C, and discharging the IM solution of HCI into the IM HCI feed tank. Purified w ater (10 kg) and sodium chloride (40 kg) was then added together and stirred for about 10 to 30 minutes until dissolved, and then w as discharged into the IM HCI feed tank. Pump 3 was connected between (1) the IM HCI feed tank and (2) the CSTR.5. A stage 1 plug flow’ reactor (PFR1) was provided wherein the contents of Mixer 1 w ould flow into PFR1, and the reaction product of PFR1 and CO2 gas would both flow into Mixer 2.6. A second plug flow reactor (PFR2) was provided w herein the contents of Mixer 2 would flow' into PFR2, and the reaction product of PFR2 would flow' into the CSTR. Sampling of the reaction product was obtained between the PFR2 and the CSTR. The stainless steel of PFR1 and die stainless steel of PFR2 was maintained at a temperature from about -75 to aboutPATENT 10620-W001-SEC-65 °C, and the jacket of the CSTR was cooled to a temperature ranging from about 0 to about 20 °C.7. The temperature jacket of both PFR1 and PFR2 was maintained at a temperature ranging from about -75 to about -65°C, the temperature of the CSTR quenching mixture was maintained at a temperature ranging from about 0 to about 20 °C.B, Flow reaction procedure for the synthesis of 2-fluoro-6-methylbenzoic acid (Compound 1):(1) Pump 1 and Pump 2 were started and the 2-bromo-3 -fluoro toluene (Compound 2) solution and n-butyllithium / n -hexane solutions were both pre-cooled and then entered Mixer 1 and then PFR1 to undergo a lithiation reaction to form Compound 3. The retention time was about 10 seconds.(2) Compound 3 from PFR1 and carbon dioxide (controlled by a volume flowmeter) were both introduced into MIXER 2 the contents of which then entered PFR2. Compound 3 then underwent a carboxylation reaction to form crude Compound 1. The retention time was about 2 seconds.(3) The reaction mixture entered CSTR, and at the same time, Pump 3 was started to pump in IM hydrochloric acid aqueous solution for quenching.

[0118] The flow rate of Pumps 1-3 was based on those listed in Table 1 and were also adjusted according to the actual situation.Table 1: Conditions and flow rates for the process

[0119] Workup procedure:1. At a temperature ranging from about 15 to about 30 °C, the crude Compound Iwas stirred for about 10 to about 15 minutes and allowed to settle and then separate for about 0.5 to about 1 hour.2. Sodium chloride solution was introduced and the mixture was stirred for about 10 to about30 minutes at a temperature ranging from about 15 to about 30"C and then allowed to settle and separate for about 0.5to about 1 hour.PATENT10620-W001-SEC3. The mixture was concentrated at a temperature of less than 50 °C, the reference jacket temperature of <60 °C, reference P<-0.08 MPa until 2.5 to 3.5V left, and then 3V toluene was added and concentrated to 2.5 to 3.5 V, and then this step was repeated twice.4. The mixture was heated to a temperature ranging from about 65 to about 75 °C and stirred for 0.5 to about 1 horn until the mixture is dissolved. If there was still solid insoluble in the mixture, the temperature of the mixture was increased to about 75 °C. stir until the mixture was dissolved.5. At 65 to about 75 °C, n-heptane was added at a rate of about 10 to about 20 kg / hour. After the addition was complete, the mixture was stirred for about 10 to about 15 minutes. If a small amount of solid precipitated out. the mixture was heated up to about 75 °C and stirred until the mixture dissolved.5. The mixture was cooled to temperature ranging from about - 10 to about 0 °C at a cooling rate of about 5 to about 10 °C / hour. At about -10 to about 0 °C, the mixture was stirred and maintained for about 2 to about 4 hours.6. The mixture was fdtered with Nutsche filter (2000 mesh filter cloths). After filtering, the filter cake was rinsed tw ice with n-heptane.7. The solid was sweeped with nitrogen and dried about for 12 hours. The solid was sampled for solvent residual every 4 to 8 hours and turned over every 4 to 8 hours until KF<1000ppm, THF residual < 500ppm, n -heptane residual<2800ppm, n-hexane residual <200ppm, and toluene residual < 620ppm.8. 5.47 kg of compound 1 was obtained at about 83% yield with 99.9% purity . HPLC assayanalysis: 99 wt% Compound 1.

[0120] 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

PATENT10620-W001-SECWHAT IS CLAIMED IS:

1. A process of preparing Compound 1 :Compound 1 or a salt thereof, comprising reacting Compound 2:Compound 2 with a lithiating reagent in a suitable solvent at a suitable reaction temperature of less than -40 °C to afford Compound 3:Compound 3andreacting Compound 3 with CO; to afford a compound of Compound 1.

2. The process according to claim 1, wherein the process is a continuous How process.

3. The process according to claim 1 or 2, wherein the lithiating reagent is an alkyllithium.

4. The process according to claim 3, wherein the alkyllithium is n-butj llithium or n-hexyllithium.

5. The process according to claim 4, wherein the alkyllithium is n-butyllithium.

6. The process according to any one of claims 1-5, wherein the suitable solvent is tetrahydrofuran, toluene and 2-methyltetrahydrofuran, hexanes, heptane, diethyl ether, dioxane, MTBE, CPME, or acetonitrile.

7. The process according to claim 6, wherein said suitable solvent is THF.PATENT10620-W001-SEC8. The process according to any one of claims 1-7, wherein the suitable reaction temperature is maintained from -40 °C to about -75 °C during the lithiation of Compound 2 and the addition of CO2 to Compound 3.

9. The process according to any one of claims 1-7. wherein the suitable reaction temperature is maintained from -50 °C to about -75 °C during the lithiation of Compound (2 and the addition of CO2 to Compound 3.

10. The process according to any one of claims 1-7, wherein the suitable reaction temperature is maintained from -65 °C to about -75 °C during the lithiation of Compound 2 and the addition of CO2 to Compound 3.

11. The process according to any one of claims 1-7, wherein the suitable reaction temperature is maintained at about -70 °C during the lithiation of Compound 2 and the addition of CO2 to Compound 3.

12. The process according to any one of claims 1-11, wherein the molarity of Compound 1 ranges from about 0.3 M to about 0.7 M.

13. The process according to any one of claims 1-11, wherein the molarity of Compound 1 ranges from about 0.4 M to about 0.6 M.

14. The process according to any one of claims 1-11, wherein the molarity of Compound 1 is about 0.5 M.

15. The process according to any one of claims 1-14, wherein the alky lhalidc is n-butyllithium, and the molarity of n-butyllithium ranges from about 1.2 M to about 2.0 M.

16. The process according to any one of claims 1-14. wherein the molarity of n-butyllithium ranges from about 1.4 M to about 1.8 M.

17. The process according to any one of claims 1-14, wherein the molarity of n-butyllithium is about 1.6 M.

18. The process according to any one of claims 1-17. wherein the lithiation of Compound 2 and the addition of CO2 to Compound 3 are carried out in a suitable continuous reactor.

19. The process according to any one of claims 1-17, wherein the lithiation of Compound 2 and the addition of CO2 to Compound 3 are carried out separately and sequentially using two consecutive flow reactors.PATENT 10620-W001-SEC20. The process according to claim 19, wherein the flow reactor is selected from a plug flow reactor, a chemtrix reactor, and a coming reactor.

21. The process according to claim 19 or 20. wherein the volume of each individual reactor ranges from 2 mL to 200 mL.

22. The process according to claim 21, wherein the volume of each individual reactor is 2 mL.

23. The process according to any one of claims 19-22. wherein:Compound 2 is provided in a first feed tank; n-buty llithium is provided in a second feed tank;CO; is provided in a third feed tank;Compound 2 and n-buty llithium each flow into a first mixer to form a first mixture; the first mixture flows into a first plug flow reactor to form Compound 3;Compound 3 and CO; each flow into a second mixer to form a second mixture; and the second mixture flows into a second plug flow reactor to form Compound 1.

24. The process according to claim 23, wherein the first mixer, the first plug flow reactor, the second mixture, and the second first plug flow reactor are each maintained at a temperature ranging from about -50 °C to about -75 °C.

25. The process according to any one of claims 23-24. wherein: a first pump is employed to create a flowrate for Compound 2; a second pump is employed to create a flowrate for n-buty llithium; and a third pump is employed to create a flowrate for CO;.

26. The process according to any one of claims 23-25, wherein: the flowrate of Compound 1 from the first feed tank into the first mixer ranges from about 1.5 to about 875 mL / min; the flowrate of n-buty llithium from the second feed tank into the first mixer ranges from about 1.0 to about 290 mL / min; and the flowrate of CO; from the third feed tank into the second mixer ranges from about 80 to about 30000 mL / min.

27. The process according to any one of claims 23-25. wherein: the flowrate of Compound 1 from the first feed tank into the first mixer ranges about 1.8 to about 2.2 mL / min; the flowrate of n-buty llithium from the second feed tank into the first mixer ranges from about 2.2 to about 2.6 mL / min; andPATENT10620-W001-SEC the flowrate of CO2 from the third feed tank into the second mixer ranges from about 80 to about 450 mmol / min.

28. The process according to any one of claims 25-27, wherein Compound 1 from the second plug flow reactor is collected and quenched in an aqueous acid.

29. The process according to any one of claims 1-28, wherein the production flow rate is from about 300 mL / hr to about 72000 mL / hr.

30. The process according to any one of claims 1-28, wherein the production flow rate is about 70000 mL / hr.

31. The process according to any to any one of claims 1-30, wherein the Compound 1 is purified by crystallization.

32. A process of making a compound of Compound 4Compound 4 comprising contacting Compound lhaving the following formula:Compound 1 with SOCh in a suitable solvent, wherein Compound 1 is made by the process according to any one of claims 1-31.

33. A process of making avacopan having the following formula:PATENT10620-W001-SEC or a pharmaceutically acceptable salt thereof, comprising:(a) contacting a compound having the formula (i-3):with Compound 4:under 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 4 is made by the process according to Claim 32.

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