Method for synthesizing 2-(1-cyclohexenyl)ethylamine

Patent metadata

Field	Value
Publication number	US-2022002224-A1
Application number	US-202016953317-A
Country	US
Kind code	A1
Filing date	Nov 19, 2020
Priority date	Jul 1, 2020
Publication date	Jan 6, 2022
Grant date	—

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).

First claim

What is claimed is:

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:

2 . 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.

3 . The method of claim 1 , wherein in step (2),
the organic base is a C 1 -C 5 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.

4 . 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.

5 . 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.

6 . 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 C 1 -C 5 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.

7 . 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.

8 . 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.;

9 . 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.;

10 . 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.

11 . 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.

12 . 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.;

13 . 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.;

14 . 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.

15 . 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 thir

Assignees

• Univ Fudan

Inventors

• Chen Fener
• Cheng Dang
• Huang Zedu
• Li Zhining
• Jiang Meifen
• Tao Yuan

Classifications

• C07C29/40 Primary

  with compounds containing carbon-to-metal bonds · CPC title

• C07C17/358

  by isomerisation · CPC title

• C07C17/16

  of hydroxyl groups · CPC title

• C07C2601/16

  the ring being unsaturated · CPC title

• C07C209/62 Primary

  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) · CPC title