# US 8,785,461 B2 · Process for preparing bosentan > Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt - Number: US 8,785,461 B2 - Document ID: US8785461B2 - Status: Granted - Kind: B2 - Application number: 12/866,373 - Filed: 2009-02-06 - Published: 2011-02-17 - Granted: 2014-07-22 - Earliest claimed: 2008-02-08 - Assignees: Generics [UK] Limited - Applicants: Abhay Gaitonde; Bindu Manojkumar; Sandeep Mekde; Vikas Padalkar; Hemant Mande - Inventors: Abhay Gaitonde; Bindu Manojkumar; Sandeep Mekde; Vikas Padalkar; Hemant Mande - Web page: https://patentgrep.com/patent/US8785461B2 ## CPC - C07D 239/52: Two oxygen atoms - A61P 9/00: Drugs for disorders of the cardiovascular system - A61P 9/04: Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure - A61P 9/10: for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis - A61P 9/12: Antihypertensives - A61P 9/14: Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers - A61P 11/00: Drugs for disorders of the respiratory system - A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 - C07D 239/69: Benzenesulfonamido-pyrimidines - C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08) - A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS ## Abstract The present invention relates to a novel intermediate useful in the preparation of bosentan and to processes for the preparation of said intermediate and bosentan. The invention further relates to compositions comprising bosentan prepared according to the processes of the invention and their use in the treatment of endothelin-receptor mediated disorders. ## Claims ### Claim 1 A process for preparing bosentan comprising: (a) reacting a dichloro compound of formula (1) with a mono-protected ethylene glycol of formula HOCH2CH2OR, wherein R is a hydroxyl protecting moiety, to afford a compound of formula (2a): (b) coupling compound (2a) with 4-tert-butyl phenyl sulfonamide; (c) removing the protecting moiety R; and (d) isolating bosentan from the mixture obtained in step (c). ### Claim 2 (depends on 1) A process according to claim 1, wherein R is selected from the group consisting of alkyl, aryl, arylalkyl, allyl, silyl, benzoate, pivalate and t-butyl. ### Claim 3 (depends on 1) A process according to claim 1, wherein in step (a) the dichloro compound of formula (1) and the mono-protected ethylene glycol are reacted in the presence of a base selected from the group consisting of sodium metal, DBU, DBN, DMAP, pyridine, lithium hydroxide and sodium hydroxide. ### Claim 4 (depends on 1) A process according to claim 1, wherein step (a) is carried out in an organic solvent selected from the group consisting of toluene, THF, xylene, DMF, DMSO, acetonitrile and dimethylacetamide. ### Claim 5 A compound having the structure as shown in formula (2a) or a salt or crystalline form thereof: wherein R is a hydroxyl protecting moiety. ### Claim 6 (depends on 5) A compound according to claim 5, wherein R is selected from the group consisting of alkyl, aryl, arylalkyl, allyl, silyl, benzoate, pivalate and tert-butyl. ### Claim 7 (depends on 5) A compound according to claim 5, wherein the salt is selected from the group consisting of a tartrate, succinate, oxalate, pimelate, adipate, acetate, suberate, salicylate, mesylate, malate, malonate, maleate, camphorsulfonate, mandelate, hydrochloride, hydrogen sulfate, sulfate, hydrobromide, besylate, benzoate, dihydrogen phosphate, glutarate, and citrate salt. ### Claim 8 A process for preparing a compound of formula (2a) comprising coupling a dichloro compound of formula (1) to a mono-protected ethylene glycol of formula HOCH2CH2OR, wherein R is a hydroxyl protecting moiety, to afford a compound of formula (2a): ### Claim 9 (depends on 8) A process according to claim 8, wherein R is selected from the group consisting of alkyl, aryl, arylalkyl, allyl, silyl, benzoate, pivalate and tert-butyl. ### Claim 10 (depends on 8) A process according to claim 8, wherein the dichloro compound of formula (1) is coupled to the mono-protected ethylene glycol in the presence of a base selected from the group consisting of sodium metal, DBU, DBN, DMAP, pyridine, lithium hydroxide and sodium hydroxide. ### Claim 11 (depends on 8) A process according to claim 8, wherein the reaction mixture is heated to between about 30-90° C. ### Claim 12 (depends on 1) The process according to claim 1, wherein in step (a) the dichloro compound of formula (1) and the mono-protected ethylene glycol are reacted in the presence of a base selected from the group consisting of alkali metal hydroxides and alkaline earth metal hydroxides. ### Claim 13 (depends on 1) The process according to claim 1, wherein the reaction mixture in step (a) is heated to between about 30-90° C. ### Claim 14 (depends on 13) The process according to claim 13, wherein the reaction mixture in step (a) is heated to between about 50-60° C. ### Claim 15 (depends on 1) The process according to claim 1, wherein the bosentan is isolated in step (d) by filtration and then dried under reduced pressure until a constant weight is achieved. ### Claim 16 (depends on 8) The process according to claim 8, wherein the dichloro compound of formula (1) is coupled to the mono-protected ethylene glycol in the presence of a base selected from the group consisting of alkali metal hydroxides and alkaline earth metal hydroxides. ### Claim 17 (depends on 8) The process according to claim 8, wherein the dichloro compound of formula (1) is coupled to the mono-protected ethylene glycol in the presence of an organic solvent selected from the group consisting of toluene, THF, xylene, DMF, DMSO, acetonitrile, and dimethylacetamide. ### Claim 18 (depends on 11) The process according to claim 11, wherein the reaction mixture is heated to between about 50-60° C.