A kind of preparation method of r-(-)-atomoxetine hydrochloride

A technology of atomoxetine hydrochloride and mandelic acid salt, which is applied in the field of medicine, can solve the problems of human skin permeability, dizziness symptoms, unpleasant smell, and difficult sources.

Active Publication Date: 2020-05-15
SHANDONG UNIV
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Problems solved by technology

[0024] Chinese patent CN201210329697.8 uses (E)-3-(N-methylamino)-1-phenyl-2-propen-1-one as a raw material, and undergoes reduction and etherification reaction with 2-halogenated toluene to form Tomo However, the starting material 1-phenylpropargyl ketone is searched and found that there is no commercially available product, the source is not easy to obtain, and there is a certain difficulty in industrialization; at the same time, Pd-C / H 2 , Pd(OH)2-C / H 2 、Raney Ni / H 2 As a catalyst for hydrogen high-pressure reduction of unsaturated double bonds, there is a high risk of safe operation
[0028] U.S.Pat.No.7317127B2 uses the aprotic polar solvent dimethyl sulfoxide as the solvent for the etherification reaction, but DMSO has certain toxicity, is permeable to human skin, and irritating to the eyes, and the reaction requires a long time and high temperature (145-147°C) reaction, DMSO in the reactor will decompose above 120°C, producing toxic gas, dizziness symptoms, and very bad smell

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  • A kind of preparation method of r-(-)-atomoxetine hydrochloride
  • A kind of preparation method of r-(-)-atomoxetine hydrochloride
  • A kind of preparation method of r-(-)-atomoxetine hydrochloride

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preparation example Construction

[0073] In an embodiment of the present invention, the preparation method of the R-(-)-atomoxetine hydrochloride comprises the following steps:

[0074] (1) Slowly add compound 1, that is, 1-phenyl-2-propenyl-1-ketone (alcohol solution of methylamine and 1-phenyl-2-propenyl-1-ketone) dropwise in the alcohol solution of methylamine The molar ratio is 1.0-1.5:1, such as 1.2:1, 1.3:1 or 1.4:1), and the temperature is controlled at 20-40°C (such as 25°C or 30°C) to stir the reaction, and the sample is detected until there is no 1 - When phenyl-2-propenyl-1-one remains, add sodium borohydride in batches and control the temperature of the system at -5-5°C (the temperature can be -1-1°C, 0-2°C or -2-0 ℃), the molar ratio of 1-phenyl-2-propenyl-1-one to the total amount of sodium borohydride is 1:1.0-1.2 (the molar ratio can be 1:1.0, 1:1.05, 1:1.08, 1 : 1.2), after the stirring reaction finishes, add purified water, hydrochloric acid, stir, add toluene to extract 2 to several times, ...

Embodiment 1

[0088] Add 1.36 kg of 33% methylamine ethanol solution into the reaction kettle, slowly add 1.58 kg of 1-phenyl-2-propenyl-1-one dropwise under stirring, and stir the reaction at a temperature of 25°C, and take samples to detect when there are no residues of raw and auxiliary materials , add 0.48kg of sodium borohydride in batches, control the temperature of the system at -1~1°C, add 10L of purified water and 2L of 2N hydrochloric acid after the stirring reaction is completed, stir for 30min, add 10L of toluene for extraction twice, combine the organic phases, and add 20L of purified water Wash with water to obtain 3-methylamino-1-phenyl-1-propanol toluene solution for use.

[0089]At room temperature, add 4.4 kg of triethylene glycol dimethyl ether to the reaction kettle containing the 3-methylamino-1-phenyl-1-propanol toluene solution, add 2.39 kg of KOH into the reaction kettle, stir and heat up to When the temperature of the system reaches 120°C, reflux for water separatio...

Embodiment 2

[0094] Add 1.36 kg of 33% methylamine ethanol solution into the reaction kettle, slowly add 1.58 kg of 1-phenyl-2-propenyl-1-one dropwise under stirring, and stir the reaction at a temperature of 25°C, and take samples to detect when there are no residues of raw and auxiliary materials , add 0.49kg of sodium borohydride in batches, control the temperature of the system at 0-2°C, add 10L of purified water and 2L of 2N hydrochloric acid after the stirring reaction is completed, stir for 30min, add 15L of toluene for extraction twice, combine the organic phases, wash with 20L of purified water , to get 3-methylamino-1-phenyl-1-propanol toluene solution, set aside.

[0095] At room temperature, add 6.6 kg of triethylene glycol dimethyl ether to the reaction kettle equipped with 3-methylamino-1-phenyl-1-propanol toluene solution, add 2.39 kg of KOH into the reaction kettle, stir and heat up to When the temperature of the system reaches 125°C, reflux for water separation for 1 hour,...

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Abstract

The invention provides an R-(-)-atomoxetine hydrochloride preparation method, which comprises: preparing 3-methylamino-1-phenyl-1-propanol by using 1-phenyl-2-propenyl-1-one as a starting raw material, carrying out etherification on the 3-methylamino-1-phenyl-1-propanol and o-halo toluene in an inorganic alkali environment, splitting with L-(+)-mandelic acid to obtain R-(-)-tomoxetine-S-(+)-mandelate, refining the R-(-)-tomoxetine-S-(+)-mandelate, and carrying out hydrochloride forming to obtain the R-(-)-atomoxetine hydrochloride. According to the present invention, the method eliminates theoxalate refining step so as to reduce the reaction step, has advantages of cheap and easily available raw materials, less side reactions, low toxicity of the reaction solvent, high yield, high purity,low cost and the like, and is suitable for industrial production.

Description

technical field [0001] The invention relates to the field of medicine, in particular to a preparation method of R-(-)-atomoxetine hydrochloride. Background technique [0002] The information disclosed in this background section is only intended to increase the understanding of the general background of the present invention, and is not necessarily taken as an acknowledgment or any form of suggestion that the information constitutes the prior art already known to those skilled in the art. [0003] Children's attention deficit hyperactivity disorder (Attention Deficit Hyperactivity Disorder, ADHD) is called ADHD in my country, which is a common type of psychological disorder in childhood. Excessive and impulsive, often with learning difficulties, conduct disorders, and maladjustment. Most of the symptoms started before the age of 7, and continued to affect the children's cognition, emotion, behavior, quality of life and social function. At the same time, most of them had other...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C217/48C07C213/06C07C59/50C07C51/41C07C51/43C07C213/08C07C213/10C07C215/30C07C213/00
CPCC07B2200/07C07C51/412C07C51/43C07C59/50C07C213/00C07C213/06C07C213/08C07C213/10C07C215/30C07C217/48
Inventor 李树英翟光喜何淑旺张英郭伟
Owner SHANDONG UNIV
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