# US 11,078,162 B2 · Processes for preparing AG-10, its intermediates, and salts thereof > Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt - Number: US 11,078,162 B2 - Document ID: US11078162B2 - Status: Granted - Kind: B2 - Application number: 16/676,931 - Filed: 2019-11-07 - Published: 2020-08-06 - Granted: 2021-08-03 - Earliest claimed: 2017-02-17 - Assignees: Eidos Therapeutics, Inc. - Applicants: Eidos Therapeutics, Inc. - Inventors: Pooran Chand; Yogesh Kumar Gupta; Rakesh Kumar Kumawat; Mamoun Alhamadsheh; Robert Zamboni - Web page: https://patentgrep.com/patent/US11078162B2 ## CPC - C07D 231/12: with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms - A61P 13/12: of the kidneys - A61P 17/06: Antipsoriatics - C07C 309/04: containing only one sulfo group - C07C 309/30: of six-membered aromatic rings substituted by alkyl groups - C07B 2200/13: Crystalline forms, e.g. polymorphs - C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08) - A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS - C07C: ACYCLIC OR CARBOCYCLIC COMPOUNDS - C07B: GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR (preparation of carboxylic acid esters by telomerisation C07C67/47; telomerisation C08F) ## Abstract Provided herein are improved processes for the preparation of a compound of Formula IX (AG-10). Also provided herein are pharmaceutically acceptable salts of Formula I and Formula Ib as well as crystalline types of Formula IX (AG-10). The processes described herein provide improved yields and efficiency, while the pharmaceutically acceptable salts and crystalline forms provide unexpected pharmacokinetic properties. Other features and aspects of the present disclosure will be apparent to a person of skill in the art upon reading the remainder of the specification. ## Claims ### Claim 1 A method for preparing a compound of Formula IX comprising (a) contacting a compound of Formula II with a compound of Formula III a first base, and a first organic solvent to provide a compound of Formula IV wherein each R1 is independently a halogen or a sulfonate ester; (b) contacting the compound of Formula IV with hydrazine and a second organic solvent to provide a compound of Formula V (c) contacting the compound of Formula V with a sulfonating agent or halogenating agent to provide a compound of Formula VI wherein R2 is a halogen or a sulfonate ester; (d) contacting the compound of Formula VI with a compound of Formula VII a second base, and a third organic solvent to provide a compound of Formula VIII wherein R3 is selected from the group consisting of an C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, C3-8 cycloalkyl, C3-12 heterocycloalkyl, aryl, and heteroaryl, each of which is optionally substituted; and (e) contacting a compound of Formula VIII with a third base to provide a compound of Formula IX. ### Claim 2 (depends on 1) The method of claim 1, wherein each R1 is independently selected from the group consisting of chloride, bromide, tosylate, and mesylate. ### Claim 3 (depends on 2) The method of claim 2, wherein each R1 is bromide. ### Claim 4 (depends on 1) The method of claim 1, wherein the first base is an alkali metal carbonate, an alkali metal bicarbonate or a combination thereof. ### Claim 5 (depends on 4) The method of claim 4, wherein the alkali metal carbonate is selected from the group consisting of Li2CO3, Na2CO3, and K2CO3, or a combination thereof. ### Claim 6 (depends on 5) The method of claim 5, wherein the alkali metal carbonate is K2CO3. ### Claim 7 (depends on 4) The method of claim 4, wherein the alkali metal bicarbonate is selected from the group consisting of LiHCO3, NaHCO3, and KHCO3, or a combination thereof. ### Claim 8 (depends on 1) The method of claim 1, wherein the first organic solvent is a polar aprotic organic solvent. ### Claim 9 (depends on 8) The method of claim 8, wherein the polar aprotic organic solvent is selected from the group consisting of acetone, ethyl acetate, dichloromethane, tetrahydrofuran, dimethylformamide and acetonitrile. ### Claim 10 (depends on 9) The method of claim 9, wherein the polar aprotic organic solvent is acetone. ### Claim 11 (depends on 1) The method of claim 1, wherein the second organic solvent is a polar protic organic solvent. ### Claim 12 (depends on 11) The method of claim 11, wherein the polar protic organic solvent is C1-10—OH. ### Claim 13 (depends on 12) The method of claim 12, wherein the polar protic organic solvent is ethanol. ### Claim 14 (depends on 1) The method of claim 1, wherein the sulfonating agent is mesyl chloride or tosyl chloride. ### Claim 15 (depends on 1) The method of claim 1, wherein the halogenating agent is selected from the group consisting of PBr3, PCl3, PCl5, SOBr2, PBr5, and SOCl2. ### Claim 16 (depends on 15) The method of claim 15, wherein the halogenating agent is PBr3. ### Claim 17 (depends on 1) The method of claim 1, wherein R2 is selected from the group consisting of chloride, bromide, tosylate, and mesylate. ### Claim 18 (depends on 17) The method of claim 17, wherein R2 is Br. ### Claim 19 (depends on 1) The method of claim 1, wherein the second base is an alkali metal carbonate, an alkali metal bicarbonate or a combination thereof. ### Claim 20 (depends on 18) The method of claim 18, wherein the alkali metal carbonate is selected from the group consisting of Li2CO3, Na2CO3, and K2CO3, or a combination thereof. ### Claim 21 (depends on 20) The method of claim 20, wherein the alkali metal carbonate is K2CO3. ### Claim 22 (depends on 18) The method of claim 18, wherein the alkali metal bicarbonate is selected from the group consisting of LiHCO3, NaHCO3, and KHCO3, or a combination thereof. ### Claim 23 (depends on 1) The method of claim 1, wherein the third organic solvent is a polar aprotic organic solvent. ### Claim 24 (depends on 23) The method of claim 23, wherein polar organic solvent is selected from the group consisting of acetone, ethyl acetate, dichloromethane, tetrahydrofuran, dimethylformamide, dimethylsulfoxide and acetonitrile. ### Claim 25 (depends on 24) The method of claim 24, wherein polar organic solvent is dimethylformamide. ### Claim 26 (depends on 24) The method of claim 24, wherein polar organic solvent is dimethylsulfoxide. ### Claim 27 (depends on 1) The method of claim 1, wherein R3 is C1-8 alkyl. ### Claim 28 (depends on 27) The method of claim 27, wherein R3 is methyl. ### Claim 29 (depends on 1) The method of claim 1, wherein the third base is a metal hydroxide. ### Claim 30 (depends on 29) The method of claim 29, wherein the metal hydroxide is an alkali metal hydroxide. ### Claim 31 (depends on 30) The method of claim 30, wherein the alkali metal hydroxide is a selected from the group consisting of LiOH, NaOH, KOH, RbOH, and CsOH. ### Claim 32 (depends on 31) The method of claim 31, wherein the alkali metal hydroxide is LiOH. ### Claim 33 (depends on 31) The method of claim 31, wherein the alkali metal hydroxide is NaOH. ### Claim 34 (depends on 1) The method of claim 1, wherein the first base is a hydrated base. ### Claim 35 A method for preparing a compound of Formula Ia comprising (e) contacting a compound of Formula VIII with a solvent and a base to provide a solid, wherein R3 is selected from the group consisting of an C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, C3-8 cycloalkyl, C3-12 heterocycloalkyl, aryl, and heteroaryl, each of which is optionally substituted; (f) removing the solvent to provide a residue; (g) dissolving the residue in water to form a solution; (h) acidifying the solution with HCl to form a compound of Formula Ia. ### Claim 36 (depends on 35) The method of claim 35, further comprising (i) filtering the solution to provide isolated Formula Ia. ### Claim 37 (depends on 35) The method of claim 35, wherein the solvent in step (f) is removed via filtration. ### Claim 38 (depends on 35) The method of claim 35, wherein the solvent is polar protic organic solvent. ### Claim 39 (depends on 35) The method of claim 35, wherein the solvent is C1-8—OH. ### Claim 40 (depends on 35) The method of claim 35, wherein the solvent is methanol. ### Claim 41 (depends on 35) The method of claim 35, wherein the base is an alkali metal hydroxide. ### Claim 42 (depends on 41) The method of claim 41, wherein the alkali metal hydroxide is a selected from the group consisting of LiOH, NaOH, KOH, RbOH, and CsOH. ### Claim 43 (depends on 35) The method of claim 35, wherein the pH of the solution after step (h) is less than about 2. ### Claim 44 (depends on 35) The method of claim 35, wherein the pH of the solution after step (h) is less about 1.4-1.6. ### Claim 45 A method for preparing a compound of Formula Ia comprising (e) contacting a compound of Formula VIII with a solvent and a base to provide an intermediate, wherein R3 is selected from the group consisting of an C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, C3-8 cycloalkyl, C3-12 heterocycloalkyl, aryl, and heteroaryl, each of which is optionally substituted; (f) contacting the intermediate with water; (g) removing the solvent to provide a concentrated aqueous component; (h) acidifying the concentrated aqueous component with HCl to form a compound of Formula Ia. ### Claim 46 (depends on 45) The method of claim 45, further comprising (i) filtering the concentrated aqueous component to provide isolated Formula Ia. ### Claim 47 (depends on 45) The method of claim 45, wherein the solvent in step (g) is removed using reduced pressure. ### Claim 48 (depends on 45) The method of claim 45, wherein the solvent is polar protic organic solvent. ### Claim 49 (depends on 45) The method of claim 45, wherein the solvent is C1-8—OH. ### Claim 50 (depends on 45) The method of claim 45, wherein the solvent is methanol. ### Claim 51 (depends on 45) The method of claim 45, wherein the base is an alkali metal hydroxide. ### Claim 52 (depends on 51) The method of claim 51, wherein the alkali metal hydroxide is a selected from the group consisting of LiOH, NaOH, KOH, RbOH, and CsOH. ### Claim 53 (depends on 45) The method of claim 45, wherein the pH of the concentrated aqueous component after step (h) is less than about 2. ### Claim 54 (depends on 45) The method of claim 45, wherein the pH of the concentrated aqueous component after step (h) is less about 1.4-1.6.