# US 8,569,508 B2 · Synthetic method for montelukast sodium intermediate > Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt - Number: US 8,569,508 B2 - Document ID: US8569508B2 - Status: Granted - Kind: B2 - Application number: 13/393,488 - Filed: 2010-08-24 - Published: 2012-06-28 - Granted: 2013-10-29 - Earliest claimed: 2009-09-02 - Assignees: Shandong New Time Pharmaceutical Co., Ltd. - Applicants: Zhiquan Zhao; Haixin Wang; Zengxue Wang - Inventors: Zhiquan Zhao; Haixin Wang; Zengxue Wang - Web page: https://patentgrep.com/patent/US8569508B2 ## CPC - C07D 215/18: Halogen atoms or nitro radicals - C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08) ## Abstract A synthesis method for preparing Montelukast sodium intermediate 2-(2-(3-(2-(7-chloro-2-quinolyl)vinyl)phenyl-3-oxopropyl)phenyl) propanol is provided. In this method, the target compound is prepared by condensing the starting materials 7-chloroquinaldine and 3-cyanobenzaldehyde, and then reacting the resultant product with 2-(2-ortho-(2-haloethyl)-phenylpropyl)tetrahydropyrane ether. The present invention can easily obtain start materials and is applicable for mass production. ## Claims ### Claim 1 A synthesis method for preparing Montelukast sodium intermediate, 2-(2-(3-(2-(7-chloro-2-quinolyl)vinyl)phenyl-3-oxopropyl)phenyl) propanol, as shown in the following formula 1, said method comprising the following steps of: (f) Reacting the compound of formula 9 with the compound of formula 4 under the existence of metal magnesium and an inert solvent, to generate the target product of formula 1, 2-(2-(3-(2-(7-chloro-2-quinolyl)vinyl)phenyl-3-oxopropyl)phenyl) propanol, through the following reaction: ### Claim 2 (depends on 1) The method according to claim 1, wherein the compound of formula 4 is synthesized by the following steps: (a) Condensing the compound of formula 2 with the compound of formula 3 under the existence of acetic anhydride and sodium acetate to generate the compound of formula 4, through the following reaction: ### Claim 3 (depends on 1) The method according to claim 1, wherein the compound of formula 9 is synthesized by the following steps: (b) Reacting the compound of formula 5 in an inert solvent with methylmagnesium halide, to generate the compound of formula 6, through the following reaction: (c) Reacting the compound of formula 6 under the existence of a catalyst with dihydrodihydropyran to generate the compound of formula 7 with protection of hydroxyl, through the following reaction: (d) Reacting the compound of formula 7 with formaldehyde or paraformaldehyde under the existence of a catalyst to generate the compound of formula 8, through the following reaction: (e) Reacting the compound of formula 8 with a halogenating reagent to generate the compound of formula 9, through the following reaction: ### Claim 4 (depends on 3) The method according to claim 3, wherein the reaction solvent in step (a) is one or more selected from the group consisting of dimethyl sulfoxide, acetic anhydride, dimethyl fomamide, dimethyl acetylamide and hexamethyl phosphoramide. ### Claim 5 (depends on 4) The method according to claim 4, wherein the reaction temperature in step (a) is 120° C.-140° C. ### Claim 6 (depends on 5) The method according to claim 5, wherein the methylmagnesium halide in step (b) is methylmagnesium chloride or methylmagnesium bromide. ### Claim 7 (depends on 6) The method according to claim 6, wherein the molar ratio among reactants in step (b) is methylmagnesium halide:the compound of formula 5=1:1.0-1.5. ### Claim 8 (depends on 7) The method according to claim 7, wherein the inert solvent in step (b) is one or more selected from the group consisting of benzene, tetrahydrofuran, 2-methyl-tetrahydrofuran, diethyl ether, isopropyl ether and ethylene glycol dimethyl ether. ### Claim 9 (depends on 8) The method according to claim 8, wherein the reaction temperature in step (b) is 20° C.-30° C. ### Claim 10 (depends on 9) The method according to claim 9, wherein the catalyst in step (c) is one or more selected from the group consisting of triphenylphosphine hydrobromide, tri-tertbutylphosphine hydrobromide, hydrochloric acid, hydrobromic acid, phosphorus oxychloride, p-toluenesulfonic acid and boron trifluoride-diethyl ether. ### Claim 11 (depends on 10) The method according to claim 10, wherein the catalyst in step (c) is triphenylphosphine hydrobromide. ### Claim 12 (depends on 11) The method according to claim 11, wherein the reaction solvent in step (c) is one or more selected from the group consisting of dichloromethane, chloroform, carbon tetrachloride, tetrahydrofuran, diethyl ether, dioxane, dimethyl fomamide and ethyl acetate. ### Claim 13 (depends on 12) The method according to claim 12, wherein the molar ratio among the reactants in step (c) is the compound of formula 6:dihydropyran:catalyst=1:2-6:0.1-1. ### Claim 14 (depends on 13) The method according to claim 13, wherein the reaction solvent in step (d) is one or more selected from the group consisting of dimethyl sulfoxide, dimethyl fomamide, dimethyl acetylamide and water. ### Claim 15 (depends on 14) The method according to claim 14, wherein the catalyst in step (d) is one selected from the group consisting of alkali metal hydroxide, alkali metal carbonate and organic quaternary ammonium hydroxide. ### Claim 16 (depends on 15) The method according to claim 15, wherein the molar ratio among reactants in step (d) is the compound of formula 7:catalyst:formaldehyde=1:0.001-0.1:1-4. ### Claim 17 (depends on 16) The method according to claim 16, wherein the reaction temperature in step (d) is 20° C.-100° C., while the reaction time is 1.5-24 hours. ### Claim 18 (depends on 17) The method according to claim 17, wherein the reaction solvent in step (e) is one or more selected from the group consisting of benzene, diethyl ether, dichloromethane, chloroform, carbon tetrachloride, dioxane and hexamethyl phosphoramide. ### Claim 19 (depends on 18) The method according to claim 18, wherein the halogenating reagent in step (e) is one or more selected from the group consisting of thionyl chloride, hydrochloric acid-zinc chloride, phosphorus pentachloride, phosphorus oxychloride, bromine hydride and phosphorus tribromide; while the reaction temperature is −5° C.-10° C. ### Claim 20 (depends on 19) The method according to claim 19, wherein the reaction in step (f) is carried out by adding dropwise, and during the adding dropwise the reaction temperature is controlled at 0° C.-5° C., while the molar ratio of reactants is the compound of formula 9:metal magnesium:the compound of formula 4=1:1.2-2.5:0.8-1.