# US 9,518,021 B2 · Process for the preparation of histamine H3 receptor modulators > Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt - Number: US 9,518,021 B2 - Document ID: US9518021B2 - Status: Granted - Kind: B2 - Application number: 14/261,713 - Filed: 2014-04-25 - Published: 2014-11-20 - Granted: 2016-12-13 - Earliest claimed: 2009-03-18 - Assignees: Janssen Pharmaceutica NV - Applicants: Janssen Pharmaceutica NV - Inventors: Diego Broggini; Vit Lellek; Susanne Lochner; Neelakandha S. Mani; Adrian Maurer; Daniel J. Pippel; Lana K. Young - Web page: https://patentgrep.com/patent/US9518021B2 ## CPC - C07D 213/82: in position 3 - C07D 405/12: linked by a chain containing hetero atoms as chain links - C07B 2200/13: Crystalline forms, e.g. polymorphs - C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08) - C07B: GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR (preparation of carboxylic acid esters by telomerisation C07C67/47; telomerisation C08F) ## Abstract The present invention is directed to novel processes for the preparation of histamine H3 receptor modulators, in the treatment of for example, cognitive disorders, sleep disorders and/or psychiatric disorders. ## Claims ### Claim 1 A process for the preparation of compound (I-C) or a pharmaceutically acceptable salt or a pharmaceutically active metabolite thereof; comprising reacting compound (V-S) with compound (VIII-S), neat or in an organic solvent; to yield the corresponding compound (IX-S); reacting compound (IX-S) with a reducing agent; neat, in water or in an organic solvent; to yield the corresponding compound (XI-S); reacting compound (XI-S) with compound (VI-S), wherein LG1 is a first leaving group and LG2 is a second leaving group; in an organic solvent; alternatively, reacting compound (XI-S) with compound (VI-S), wherein LG1 is a first leaving group and LG2 is a second leaving group; in the presence of a base; in a mixture of water and an organic solvent; to yield the corresponding compound (X-S); reacting compound (X-S) with compound (XIII-C); in the presence of a second inorganic base; in an organic solvent; to yield the corresponding compound (I-C). ### Claim 2 (depends on 1) A process as in claim 1, wherein compound (VIII-S) is present in an amount in the range of from about 1.0 to about 1.5 molar equivalents. ### Claim 3 (depends on 2) A process as in claim 2, wherein compound (VIII-S) is present in an amount of about 1.05 molar equivalents. ### Claim 4 (depends on 1) A process as in claim 1, wherein compound (V-S) is reacted with compound (VIII-S) in an organic solvent and wherein the organic solvent is toluene. ### Claim 5 (depends on 1) A process as in claim 1, wherein compound (V-S) is reacted with compound (VIII-S) at a temperature of about reflux temperature. ### Claim 6 (depends on 1) A process as in claim 1, wherein compound (IX-S) is reacted with the reducing agent in the presence of an acid. ### Claim 7 (depends on 6) A process as in claim 6, wherein the acid is hydrochloric acid and is present in an amount in the range of from about 3.0 to about 5.0 molar equivalents. ### Claim 8 (depends on 1) A process as in claim 1, wherein the reducing agent is added as a solution in water, stabilized with sodium hydroxide in an amount of about 0.1 molar equivalents. ### Claim 9 (depends on 1) A process as in claim 1, wherein the reducing agent is sodium borohydride. ### Claim 10 (depends on 9) A process as in claim 9, wherein the sodium borohydride is present in an amount in the range of from about 0.5 to about 1.5 molar equivalents. ### Claim 11 (depends on 1) A process as in claim 1, wherein compound (IX-S) is reacted with the reducing agent at a temperature in the range of from about −10° C. to about 0° C. ### Claim 12 (depends on 1) A process as in claim 1, wherein compound (VI-S) LG1 and LG2 are each chloro. ### Claim 13 (depends on 1) A process as in claim 1, wherein compound (VI-S) is present in an amount in the range of from about 1.0 to about 1.5 molar equivalents. ### Claim 14 (depends on 13) A process as in claim 13, wherein compound (VI-S) is present in an amount of about 1.05 molar equivalents. ### Claim 15 (depends on 1) A process as in claim 1, wherein compound (XI-S) is reacted with compound (VI-S) in an organic solvent selected from the group consisting of methyl t-butyl ether, toluene and 2-methyl-THF. ### Claim 16 (depends on 1) A process as in claim 1, wherein compound (XI-S) is reacted with compound (VI-S) at a temperature in the range of from about 0° C. to about 35° C. ### Claim 17 (depends on 1) A process as in claim 1, wherein compound (XI-S) is reacted with compound (VI-S) in the presence of a base; wherein the base is sodium hydroxide; and wherein the sodium hydroxide is present in an amount in the range of from about 1.05 to about 1.2 molar equivalents. ### Claim 18 (depends on 1) A process as in claim 1, wherein compound (VI-S) in MTBE is reacted with compound (XI-S) in water, in the presence of 30% NaOH, at a temperature in the range of from about 10° C. to about 15° C. ### Claim 19 (depends on 1) A process as in claim 1, wherein compound (XIII-C) is present in an amount in the range of from about 1.1 to about 1.5 molar equivalents. ### Claim 20 (depends on 1) A process as in claim 1, wherein the second inorganic base is potassium hydroxide. ### Claim 21 (depends on 20) A process as in claim 20, wherein the potassium hydroxide is present in an amount in the range of from about 2.0 to about 4.0 molar equivalents. ### Claim 22 (depends on 1) A process as in claim 1, wherein compound (X-S) is reacted with compound (XIII-C) at about reflux temperature. ### Claim 23 (depends on 1) A process as in claim 1, wherein LG2 is chloro and wherein compound (X-S) is prepared as its corresponding HCl salt. ### Claim 24 (depends on 23) A process as in claim 23, wherein compound (X-S) as its corresponding HCl salt is reacted with a first inorganic base prior to reacting with compound (XIII-C). ### Claim 25 (depends on 24) A process as in claim 24, wherein the first inorganic base is sodium carbonate. ### Claim 26 (depends on 25) A process as in claim 25, wherein the sodium carbonate is present in an amount sufficient to liberate compound (X-S) as a free base. ### Claim 27 (depends on 25) A process as in claim 25, wherein the sodium carbonate is present in an amount of about 1.5 molar equivalents. ### Claim 28 A crystalline form of a HCl salt of compound (I-C) comprising the following powder X-ray diffraction peaks: POSITION [°2θ] d-spacing [Å] 8.13 10.87 14.76 6.00 15.66 5.66 16.28 5.44 17.71 5.01 18.06 4.91 19.20 4.62 19.62 4.52 21.88 4.06 23.35 3.81 24.40 3.65 24.67 3.61 26.36 3.38 29.46 3.03 31.60 2.83.