# US 7,608,725 B2 · Processes for nitration of N-substituted imidazoles > Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt - Number: US 7,608,725 B2 - Document ID: US7608725B2 - Status: Granted - Kind: B2 - Application number: 11/746,727 - Filed: 2007-05-10 - Published: 2008-02-21 - Granted: 2009-10-27 - Earliest claimed: 2006-05-11 - Assignees: The Richard Stockton College of New Jersey - Inventors: Shanthi Rajaraman; Umar Yaqub - Web page: https://patentgrep.com/patent/US7608725B2 ## CPC - C07D 233/91: Nitro radicals - C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08) ## Abstract The present invention relates to a process for making 2-nitroimidazoles that involves the selective nitration of N-substituted imidazoles. ## Claims ### Claim 1 A process for making an N-substituted-2-nitroimidazole or a pharmaceutically-acceptable salt thereof, the process comprising: a. reacting an N-substituted imidazole of formula I: wherein: R is halogen, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, alkoxy, alkenoxy, alkynoxy, alkylalkoxy, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, arylalkyl, alkylaryl, heteroaryl, heterocycloalkyl, heterocycloalkenyl, heterocycloalkynyl, or C(O)OR2, where R2 is C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, alkoxy, alkenoxy, alkynoxy, alkylalkoxy, cycloalkyl, cycloalkenyl, cycloalkynyl; wherein: each C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, alkoxy, alkylalkoxy, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, arylalkyl, alkylaryl, heteroaryl, heterocycloalkyl, heterocycloalkenyl or heterocycloalkynyl is, independently, optionally substituted by one or more halogen, hydroxy, alkoxy or phenyl groups, with the proviso that C1 is not substituted with three phenyl groups, with a base to produce a mixture; and b. reacting the mixture with at least one nitrating agent, with the proviso that the nitrating agent is not a non-acidic alkyl nitrate. ### Claim 2 (depends on 1) The process according to claim 1, wherein the base is in the presence of a solvent. ### Claim 3 (depends on 2) The process according to claim 2, wherein the solvent comprises tetrahydrofuran, tetrahydropyran, dimethylformamide, diethyl ether or hexane. ### Claim 4 (depends on 3) The process according to claim 3, wherein the solvent comprises tetrahydrofuran. ### Claim 5 (depends on 3) The process according to claim 3, wherein the solvent comprises tetrahydropyran. ### Claim 6 (depends on 5) The process according to claim 5, wherein the base comprises a base with a pKa value of at least about 40, a phosphazene base, sodium amide, potassium hexamethyldisilazane, lithium tetramethylpiperidide, diisopropyl ethylamine, butyl lithium, or R5Li, where R5 is at least a C4-alkyl. ### Claim 7 (depends on 6) The process according to claim 6, wherein the base comprises butyl lithium. ### Claim 8 (depends on 7) The process according to claim 7, wherein the butyl lithium comprises n-butyl lithium, t-butyl lithium or s-butyl lithium. ### Claim 9 (depends on 8) The process according to claim 8, wherein the butyl lithium comprises n-butyl lithium. ### Claim 10 (depends on 1) The process according to claim 1, wherein the nitrating agent comprises an inorganic nitrate, nitronium tetrafluoroborate or cerric ammonium nitrate. ### Claim 11 (depends on 10) The process according to claim 10, wherein the inorganic nitrate comprises ammonium nitrate, barium nitrate, calcium nitrate, lead nitrate, lithium nitrate, magnesium nitrate, potassium nitrate, silver nitrate, sodium nitrate or strontium nitrate. ### Claim 12 (depends on 10) The process according to claim 10, wherein the inorganic nitrate is in the presence of a carboxylic acid anhydride. ### Claim 13 (depends on 12) The process according to claim 12, wherein the carboxylic acid anhydride has a formula of (R3CO)2O or R3R4(CO)2O, wherein: R3 and R4 are each, independently, H, halogen, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, cycloalkyl, aryl, or arylalkyl, wherein: each C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, cycloalkyl, aryl, or arylalkyl is, independently, optionally substituted by one or more halogen, hydroxyl or alkoxy; or R3 and R4 taken together form an aryl, a cycloalkyl or cycloakenyl. ### Claim 14 (depends on 13) The process according to claim 13, wherein R3 and R4 are each, independently, C1-C10 alkyl optionally substituted by one or more halogen, hydroxyl or alkoxy. ### Claim 15 (depends on 14) The process according to claim 14, wherein R3 and R4 are each C1 alkyl optionally substituted by one or more halogen, hydroxyl or alkoxy. ### Claim 16 (depends on 15) The process according to claim 15, wherein the carboxylic acid anhydride comprises acetic anhydride, difluoroacetic anhydride, trifluoroacetic anhydride, dichloroacetic anhydride, or trichloroacetic anhydride. ### Claim 17 (depends on 16) The process according to claim 16, wherein the carboxylic acid anhydride comprises trifluoroacetic anhydride or trichloroacetic anhydride. ### Claim 18 (depends on 17) The process according to claim 17, wherein the carboxylic acid anhydride comprises trifluoroacetic anhydride. ### Claim 19 (depends on 13) The process according to claim 13, wherein R3 and R4 taken together form a cycloalkyl, cycloakenyl or an aryl. ### Claim 20 (depends on 14) The process according to claim 14, wherein R3 and R4 are each, independently, cycloalkyl optionally substituted with one or more halogen, hydroxyl or alkoxy. ### Claim 21 (depends on 13) The process according to claim 13, wherein R3 and R4 are each, independently, aryl optionally substituted with one or more halogen, hydroxyl or alkoxy. ### Claim 22 (depends on 1) The process according to claim 1, wherein the N-substituted-2-nitroimidazole made has a yield of at least about 60%.