# US 7,745,478 B2 · Perfected process for the preparation of stable nitroxide radicals > Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt - Number: US 7,745,478 B2 - Document ID: US7745478B2 - Status: Granted - Kind: B2 - Application number: 11/574,582 - Filed: 2005-08-25 - Published: 2007-12-06 - Granted: 2010-06-29 - Earliest claimed: 2004-09-17 - Assignees: Polimeri Europa S.p.A. - Inventors: Maria Caldararo; Riccardo Po; Marco Ricci - Web page: https://patentgrep.com/patent/US7745478B2 ## CPC - C07D 209/44: Iso-indoles; Hydrogenated iso-indoles - C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08) ## Abstract Process for the preparation of stable nitroxide radicals (I) starting from N-benzylphthalimide in three steps. In the first step, the N-benzylphthalimide is transformed into N-benzyl-1,1,3,3-tetralkylisoindoline by treatment with a Grignard reagent prepared in methyl-tert-butyl ether. In the second step, the N-benzyl-1,1,3,3-tetraalkylisoindoline is transformed into 1,1,3,3-tetra-alkylisoindoline by hydrogenolysis. In the third step, the 1,1,3,3-tetra-alkyl-isoindoline is transformed into the nitroxide radical by oxidation with hydrogen peroxide in the presence of a catalyst selected from acids and salts of polymolybdic or polytungstic acids. ## Claims ### Claim 1 A process for preparing a stable nitroxide radical compound of formula (I): wherein R1, R2, R3 and R4, which may be the same or different, represent alkyl or isoalkyl groups having from 1 to 8 carbon atoms, wherein said process comprises: a) preparing an N-benzyl-1,1,3,3-tetra-alkylisoindoline intermediate in a reaction mixture by reacting in the presence of an aromatic solvent an N-benzylphthalimide with a Grignard reagent formed by reacting in the presence of a methyl tertiary butyl ether solvent an alkyl halide with magnesium; (b) removing said methyl tertiary butyl ether solvent by continuously distilling during said preparing; (c) purifying said reaction mixture by oxidizing impurities present within said reaction mixture with air while stirring for a period of 3 to 5 hours to produce insolubilized oxidized impurities; (d) removing said insolubilized oxidized impurities from said reaction mixture by filtering said reaction mixture on a celite panel to obtain a purified filtrate; (e) isolating said N-benzyl-1,1,3,3-tetra-alkylisoindoline intermediate by removing said aromatic solvent from said purified filtrate; (f) forming a 1,1,3,3-tetra-alkylisoindoline by subjecting said isolated N-benzyl-1,1,3,3-tetra-alkylisoindoline intermediate to hydrogenolysis in the presence of hydrogen and a supported palladium catalyst, at room temperature and at atmospheric pressure; and (g) yielding a stable nitroxide radical of formula (I) by oxidizing said 1,1,3,3-tetra-alkylisoindoline with hydrogen peroxide in the presence of a catalyst selected from polymolybdic acids, polytungstic acids, and salts thereof, optionally incorporating an element selected from phosphorus and silicon. ### Claim 2 (depends on 1) The process according to claim 1, wherein said aromatic solvent is toluene. ### Claim 3 (depends on 1) The process according to claim 1, wherein said N-benzylphthalimide is prepared by treating a phthalimide alkaline salt with a benzyl halide. ### Claim 4 (depends on 1) The process according to claim 1, wherein said N-benzylphthalimide is prepared by reacting phthalic anhydride with benzylamine. ### Claim 5 (depends on 1) The process according to claim 1, wherein said alkyl halide is present in an excess amount of up to 10 wt. % with respect to said magnesium. ### Claim 6 (depends on 1) The process according to claim 1, wherein said magnesium is present in an excess amount of up to 10 wt. % with respect to said alkyl halide. ### Claim 7 (depends on 1) The process according to claim 1, wherein the molar ratio of said alkyl halide to said N-benzylphthalimide ranges from 4 to 10. ### Claim 8 (depends on 1) The process according to claim 1, wherein said oxidizing of said impurities present within said reaction mixture is carried out in the presence of n-hexane. ### Claim 9 (depends on 1) The process according to claim 1, wherein said isolating of said N-benzyl-1,1,3,3-tetra-alkylisoindoline intermediate by removing said aromatic solvent from said purified filtrate is carried out by drying under reduced pressure. ### Claim 10 (depends on 1) The process according to claim 1, wherein said hydrogen is provided by glacial acetic acid. ### Claim 11 (depends on 1) The process according to claim 1, wherein said supported palladium catalyst consists of a palladium catalyst on carbon. ### Claim 12 (depends on 1) The process according to claim 1, wherein the molar ratio of said isolated N-benzyl-1,1,3,3-tetra-alkylisoindoline intermediate to said supported palladium catalyst ranges from 10 to 50. ### Claim 13 (depends on 1) The process according to claim 1, wherein said oxidizing of said 1,1,3,3-tetra-alkylisoindoline with hydrogen peroxide is carried out at a temperature ranging from 0° C. to 60° C. and at atmospheric pressure. ### Claim 14 (depends on 13) The process according to claim 13, wherein said oxidizing of said 1,1,3,3-tetra-alkylisoindoline with hydrogen peroxide is carried out at a temperature ranging from 40° C. to 50° C. ### Claim 15 (depends on 1) The process according to claim 1, wherein said oxidizing of said 1,1,3,3-tetra-alkylisoindoline with hydrogen peroxide is carried out in the presence of a catalyst and a polar solvent. ### Claim 16 (depends on 15) The process according to claim 15, wherein said polar solvent is selected from water, methanol, acetonitrile, and mixtures thereof. ### Claim 17 (depends on 1) The process according to claim 1, wherein said hydrogen peroxide is a solution of hydrogen peroxide dissolved in a solvent selected from water and organic solvents. ### Claim 18 (depends on 17) The process according to claim 17, wherein said solution of hydrogen peroxide is a 30% aqueous hydrogen peroxide solution. ### Claim 19 (depends on 1) The process according to claim 1, wherein the molar ratio of said hydrogen peroxide to said 1,1,3,3-tetra-alkylisoindoline ranges from 1.5 to 20. ### Claim 20 (depends on 1) The process according to claim 1, wherein the molar ratio of said 1,1,3,3-tetra-alkylisoindoline to said catalyst ranges from 10 to 50. ### Claim 21 (depends on 1) The process according to claim 1, wherein said polymolybdic salt and said polytungstic salt are selected from ammonium salts and salts of alkali metals. ### Claim 22 (depends on 1) The process according to claim 1, wherein said catalyst is ammonium heptamolybdate. ### Claim 23 (depends on 1) The process according to claim 1, wherein said catalyst is selected from ammonium paratungstate and ammonium metatungstate. ### Claim 24 (depends on 1) The process according to claim 1, wherein said catalyst is selected from polymolybdic acids, polytungstic acids, and salts thereof, incorporating phosphorus. ### Claim 25 (depends on 1) The process according to claim 1, wherein said catalyst is selected from polymolybdic acids, polytungstic acids, and salts thereof, incorporating silicon. ### Claim 26 (depends on 1) The process according to claim 1, wherein said catalyst is selected from polymolybdic acids, polytungstic acids, and salts thereof, not incorporating an element selected from phosphorus and silicon. ### Claim 27 (depends on 26) The process according to claim 26, wherein said catalyst is selected from polymolybdic acids and salts thereof. ### Claim 28 (depends on 26) The process according to claim 26, wherein said catalyst is selected from polytungstic acids and salts thereof.