# US 11,299,451 B2 · Method for synthesizing 2-(1-cyclohexenyl)ethylamine > Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt - Number: US 11,299,451 B2 - Document ID: US11299451B2 - Status: Granted - Kind: B2 - Application number: 16/953,317 - Filed: 2020-11-19 - Published: 2022-01-06 - Granted: 2022-04-12 - Earliest claimed: 2020-07-01 - Assignees: Fudan University - Applicants: Fudan University - Inventors: Fener Chen; Dang Cheng; Zedu Huang; Zhining Li; Meifen Jiang; Yuan Tao - Web page: https://patentgrep.com/patent/US11299451B2 ## CPC - C07C 29/40: with compounds containing carbon-to-metal bonds - C07C 209/62: by cleaving carbon-to-nitrogen, sulfur-to-nitrogen, or phosphorus-to-nitrogen bonds, e.g. hydrolysis of amides, N-dealkylation of amines or quaternary ammonium compounds (C07C209/24 takes precedence) - C07C 17/013: by addition of halogens - C07C 17/16: of hydroxyl groups - C07C 17/358: by isomerisation - C07C 29/38: by reaction with aldehydes or ketones - C07C 2601/16: the ring being unsaturated - C07C: ACYCLIC OR CARBOCYCLIC COMPOUNDS ## Abstract A method for synthesizing 2-(1-cyclohexenyl)ethylamine. Cyclohexanone (II) is reacted with a Grignard reagent in a first organic solvent to produce 1-vinylcyclohexanol (III), which is then subjected to chlorination and rearrangement reaction with a chlorinating reagent in a second organic solvent in the presence of an organic base to synthesize (2-chloroethylmethylene)cyclolxane (IV). Then (2-chloroethylmethylene)cyclohexane (IV) and urotropine are subjected to quaternization in a third organic solvent to synthesize N-cyclohexylidene ethyl urotropine hydrochloride (V). Finally, the N-cyclohexylidene ethyl urotropine hydrochloride (V) undergoes hydrolysis and rearrangement reaction in a solvent in the presence of an inorganic mineral acid to synthesize 2-(1-cyclohexenyl)ethylamine (I). ## Claims ### Claim 1 A method for synthesizing 2-(1-cyclohexenyl)ethylamine of formula (I): the method comprising: (1) reacting cyclohexanone (II) with a Grignard reagent in a first organic solvent to produce 1-vinylcyclohexanol (III); (2) subjecting 1-vinylcyclohexanol (III) to chlorination and rearrangement reaction with a chlorinating reagent in a second organic solvent in the presence of an organic base to synthesize (2-chloroethylmethylene)cyclohexane (IV); (3) subjecting (2-chloroethylmethylene)cyclohexane (IV) and urotropine to quaternization in a third organic solvent to synthesize N-cyclohexylidene ethyl urotropine hydrochloride (V); and (4) subjecting the N-cyclohexylidene ethyl urotropine hydrochloride (V) to hydrolysis and rearrangement in a solvent in the presence of an inorganic mineral acid to produce 2-(1-cyclohexenyl)ethylamine (I); as shown in the following scheme: ### Claim 2 (depends on 1) The method of claim 1, wherein in step (1), the Grignard reagent is vinylmagnesium bromide, vinylmagnesium chloride or vinylmagnesium iodide; the first organic solvent is tetrahydrofuran or an alkyl ether; a molar ratio of the cyclohexanone (II) to the Grignard reagent is 1:1-3; and the reaction is performed at −10° C.-40° C. ### Claim 3 (depends on 1) The method of claim 1, wherein in step (2), the organic base is a C1-C5 alkylamine or a pyridine compound; the chlorinating reagent is thionyl chloride, phosphorus oxychloride, phosphorus trichloride, phosphorus pentachloride or acetyl chloride; the second organic solvent is tetrahydrofuran, dichloromethane, 1,4-dioxane, alkyl ethers, toluene, or a combination thereof; a molar ratio of the 1-vinylcyclohexanol (III) to the organic base is 1:0.05-3.0; a molar ratio of the 1-vinylcyclohexanol (III) to the chlorinating reagent is 1:1.1-3.5; and the chlorination and rearrangement reaction is performed at −10° C.-25° C. ### Claim 4 (depends on 1) The method of claim 1, wherein in step (3), a molar ratio of the (2-chloroethylmethylene)cyclohexane (IV) to urotropine is 1:1.0-3.0; the third organic solvent is tetrahydrofuran, dichloromethane, 1,4-dioxane, or a combination thereof; and the quaternization is performed at 30° C.-80° C. ### Claim 5 (depends on 1) The method of claim 1, wherein in step (4), the inorganic mineral acid is hydrochloric acid, sulfuric acid or nitric acid; the solvent is water or a mixture of water and a low molecular weight alcohol; and the hydrolysis and rearrangement reaction is performed at 40° C.-100° C. ### Claim 6 (depends on 1) The method of claim 1, wherein in step (1), the Grignard reagent is vinylmagnesium bromide, vinylmagnesium chloride or vinylmagnesium iodide; the first organic solvent is tetrahydrofuran or an alkyl ether; a molar ratio of the cyclohexanone (II) to the Grignard reagent is 1:1-3; the reaction is performed at −10° C.-40° C.; in step (2), the organic base is a C1-C5 alkylamine or a pyridine compound; the chlorinating reagent is thionyl chloride, phosphorus oxychloride, phosphorus trichloride, phosphorus pentachloride or acetyl chloride; the second organic solvent is tetrahydrofuran, dichloromethane, 1,4-dioxane, alkyl ethers, toluene, or a combination thereof; a molar ratio of the 1-vinylcyclohexanol (III) to the organic base is 1:0.05-3.0; a molar ratio of the 1-vinylcyclohexanol (III) to the chlorinating reagent is 1:1.1-3.5; the chlorination and rearrangement reaction is performed at −10° C.-25° C.; in step (3), a molar ratio of the (2-chloroethylmethylene)cyclohexane (IV) to urotropine is 1:1.0-3.0; the third organic solvent is tetrahydrofuran, dichloromethane, 1,4-dioxane, or a combination thereof; the quaternization is performed at 30° C.-80° C.; and in step (4), the inorganic mineral acid is hydrochloric acid, sulfuric acid or nitric acid; the solvent is water or a mixture of water and a low molecular weight alcohol; and the hydrolysis and rearrangement reaction is performed at 40° C.-100° C. ### Claim 7 (depends on 2) The method of claim 2, wherein in step (1), the Grignard reagent is vinylmagnesium bromide or vinylmagnesium chloride; the first organic solvent is tetrahydrofuran or isopropyl ether; the molar ratio of the cyclohexanone (II) to the Grignard reagent is 1:1.2-1.6; and the reaction is performed at −5° C.-20° C. ### Claim 8 (depends on 3) The method of claim 3, wherein in step (2), the organic base is triethylamine or pyridine; the chlorinating reagent is thionyl chloride or phosphorus oxychloride; the second organic solvent is tetrahydrofuran or dichloromethane; the molar ratio of the 1-vinylcyclohexanol (III) to the organic base is 1:1.3-2.2; the molar ratio of the 1-vinylcyclohexanol (III) to the chlorinating reagent is 1:1.2-1.8; and the chlorination and rearrangement reaction is performed at 0° C.-15° C. ### Claim 9 (depends on 4) The method of claim 4, wherein in step (3), the molar ratio of the (2-chloroethylmethylene)cyclohexane (IV) to urotropine is 1:1.02-1.1; the third organic solvent is dichloromethane; and the quaternization is performed at 40° C.-60° C. ### Claim 10 (depends on 5) The method of claim 5, wherein in step (4), the inorganic mineral acid is hydrochloric acid; the solvent is a mixture of water and ethanol; and the hydrolysis and rearrangement reaction is performed at 60° C.-80° C. ### Claim 11 (depends on 6) The method of claim 6, wherein in step (1), the Grignard reagent is vinylmagnesium bromide or vinylmagnesium chloride; the first organic solvent is tetrahydrofuran or isopropyl ether; the molar ratio of the cyclohexanone (II) to the Grignard reagent is 1:1.2-1.6; and the reaction is performed at −5° C.-20° C. ### Claim 12 (depends on 6) The method of claim 6, wherein in step (2), the organic base is triethylamine or pyridine; the chlorinating reagent is thionyl chloride or phosphorus oxychloride; the second organic solvent is tetrahydrofuran or dichloromethane; the molar ratio of the 1-vinylcyclohexanol (III) to the organic base is 1:1.3-2.2; the molar ratio of the 1-vinylcyclohexanol (III) to the chlorinating reagent is 1:1.2-1.8; and the chlorination and rearrangement reaction is performed at 0° C.-15° C. ### Claim 13 (depends on 6) The method of claim 6, wherein in step (3), the molar ratio of the (2-chloroethylmethylene)cyclohexane (IV) to urotropine is 1:1.02-1.1; the third organic solvent is dichloromethane; and the quaternization is performed at 40° C.-60° C. ### Claim 14 (depends on 6) The method of claim 6, wherein in step (4), the inorganic mineral acid is hydrochloric acid; the solvent is a mixture of water and ethanol; and the hydrolysis and rearrangement reaction is performed at 60° C.-80° C. ### Claim 15 (depends on 6) The method of claim 6, wherein in step (1), the Grignard reagent is vinylmagnesium bromide or vinylmagnesium chloride; the first organic solvent is tetrahydrofuran or isopropyl ether; the molar ratio of the cyclohexanone (II) to the Grignard reagent is 1:1.2-1.6; and the reaction is performed at −5° C.-20° C.; in step (2), the organic base is triethylamine or pyridine; the chlorinating reagent is thionyl chloride or phosphorus oxychloride; the second organic solvent is tetrahydrofuran or dichloromethane; the molar ratio of the 1-vinylcyclohexanol (III) to the organic base is 1:1.3-2.2; the molar ratio of the 1-vinylcyclohexanol (III) to the chlorinating reagent is 1:1.2-1.8; and the chlorination and rearrangement reaction is performed at 0° C.-15° C.; in step (3), the molar ratio of the (2-chloroethylmethylene)cyclohexane (IV) to urotropine is 1:1.02-1.1; the third organic solvent is dichloromethane; and the quaternization is performed at 40° C.-60° C.; and in step (4), the inorganic mineral acid is hydrochloric acid; the solvent is a mixture of water and ethanol; and the hydrolysis and rearrangement reaction is performed at 60° C.-80° C.