# US 10,246,423 B2 · Process for preparing statin precursor > Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt - Number: US 10,246,423 B2 - Document ID: US10246423B2 - Status: Granted - Kind: B2 - Application number: 15/545,682 - Filed: 2016-01-22 - Published: 2018-01-18 - Granted: 2019-04-02 - Earliest claimed: 2015-01-23 - Assignees: Centrient Pharmaceuticals Netherlands B.V. - Applicants: DSM Sinochem Pharmaceuticals Netherlands B.V. - Inventors: Ben De Lange; Karin Henderika Maria Bessembinder; Dennis Heemskerk - Web page: https://patentgrep.com/patent/US10246423B2 ## CPC - C07D 239/42: One nitrogen atom (nitro radicals C07D239/30) - C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08) ## Abstract The present invention relates to a process for preparing a statin precursor, which process comprises a first reaction step, wherein a hydroxy-pyrimidine-carbonitrile is reacted with an organic sulfonyl halide to form the sulfonate-pyrimidine-carbonitrile; a second reaction step, wherein the sulfonate-pyrimidine-carbonitrile is reacted with N-methylmethane sulfonamide to form a pyrimidinyl-sulfonamide; and optionally a third reaction step, wherein the pyrimidinyl-sulfonamide is reacted with a reducing agent. All steps are conducted in toluene as the main solvent. ## Claims ### Claim 1 A process for preparing the compound of formula (IV), the process comprising the steps of: (a) providing a starting mixture comprising the compound of formula (II) and toluene (b) a first reaction step, wherein the starting mixture is contacted with an organic sulfonyl halide and the resulting first reaction mixture is kept at a first temperature of below 110° C., thereby forming an intermediate mixture comprising the compound of formula (III) wherein R is an organic group having from 1 to 15 carbons; and (c) a second reaction step, wherein the intermediate mixture is contacted with N-methylmethane sulfonamide and the resulting second reaction mixture is kept at a second temperature, thereby forming a second mixture comprising the compound of formula (IV) ### Claim 2 (depends on 1) The process according to claim 1 wherein toluene is present in steps (a), (b) and (c). ### Claim 3 (depends on 1) The process according to claim 1, further comprising a reduction step, wherein the compound of formula (IV) obtained in the second reaction step is reacted with a reducing agent in toluene to form the compound of formula (I) ### Claim 4 (depends on 1) The process according to claim 1, wherein the first and second temperature are independently chosen to lie in the range of 50 to 110° C. ### Claim 5 (depends on 1) The process according to claim 1, wherein the intermediate mixture is contacted with N-methylmethane sulfonamide by adding the intermediate mixture to a sulfonamide mixture comprising N-methylmethane sulfonamide in toluene. ### Claim 6 (depends on 5) The process according to claim 5, wherein the intermediate mixture is added to the mixture comprising N-methylmethane sulfonamide over a period of at least 1 hour. ### Claim 7 (depends on 5) The process according to claim 5, wherein the mixture comprising N-methylmethane sulfonamide further comprises a base. ### Claim 8 (depends on 5) The process according to claim 5, wherein the sulfonamide mixture comprises 1-60 wt. % N-methylmethane sulfonamide, relative to the total weight of toluene in the sulfonamide mixture. ### Claim 9 (depends on 1) The process according to claim 1, wherein the organic sulfonyl halide is selected from the group consisting of methanesulfonyl chloride, ethanesulfonyl chloride, trifluoromethanesulfonyl chloride, methanesulfonyl bromide, benzenesulfonyl chloride, benzenesulfonyl bromide, p-toluenesulfonyl chloride, p-toluenesulfonyl bromide, p-toluenesulfonyl fluoride, 4-chlorobenzenesulfonyl chloride, 2-chlorobenzenesulfonyl chloride, 2-nitrobenzenesulfonyl chloride, 2-naphtalenesulfonyl chloride and 2,4,6-trimethylbenzenesulfonyl chloride. ### Claim 10 (depends on 1) The process according to claim 1, wherein the first and second reaction steps are conducted in the presence of a base selected from the group consisting of potassium carbonate, sodium carbonate, sodium hydroxide, potassium hydroxide, sodium methoxide, potassium methoxide, sodium tert-butoxide, potassium tert-butoxide, sodium tert-amyl alcohol and potassium tert-amyl alcohol. ### Claim 11 (depends on 1) The process according to claim 1, wherein R having from 1 to 15 carbons is an aromatic hydrocarbon, alkane or cycloalkane, optionally substituted with one or more of C1-C4 alkyl, halide or nitro. ### Claim 12 (depends on 1) The process according to claim 1, wherein at least 95 wt. % of the organic solvent present in the starting mixture, first reaction mixture and second reaction mixture is toluene. ### Claim 13 (depends on 1) The process according to claim 1, wherein the starting mixture is a suspension of the compound of formula (II) in toluene. ### Claim 14 (depends on 3) The process according to claim 3, wherein the reducing agent is diisobutylaluminium hydride. ### Claim 15 (depends on 14) The process according to claim 14, wherein the reduction reaction is conducted by contacting a mixture of the compound of formula (IV) in toluene with a solution of DIBALH in toluene at a temperature below 20° C. and keeping the resulting mixture at said temperature below 20° C. for an amount of time. ### Claim 16 (depends on 15) The process according to claim 15, wherein the amount of time that the resulting mixture is kept at a temperature below 20° C. is about 10-120 minutes. ### Claim 17 (depends on 1) The process according to claim 1, wherein in the starting mixture at least 90% of any solvent present is toluene. ### Claim 18 (depends on 1) The process according to claim 1, wherein in the first reaction mixture at least 90% of any solvent present is toluene. ### Claim 19 (depends on 1) The process according to claim 1, wherein in the intermediate mixture at least 90% of any solvent present is toluene. ### Claim 20 (depends on 1) The process according to claim 1, wherein in the second reaction mixture at least 90% of any solvent present is toluene.