Method for preparing noradrenaline reuptake dual inhibitor

A methyl and xylene technology is applied in the field of preparation of dual serotonin and norepinephrine reuptake inhibitors, and can solve the problems of increased degradation by-products, inconvenient industrial production, low yield and the like

Inactive Publication Date: 2015-04-01
SUNSHINE LAKE PHARM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0006] In the process of preparing duloxetine hydrochloride from duloxetine free base, the prior art generally adopts concentrated hydrochloric acid or hydrogen chloride ethyl acetate solution as a salt-forming reagent, and the disadvantag

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  • Method for preparing noradrenaline reuptake dual inhibitor
  • Method for preparing noradrenaline reuptake dual inhibitor
  • Method for preparing noradrenaline reuptake dual inhibitor

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specific Embodiment approach

[0045] In order to enable those skilled in the art to better understand the technical solutions of the present invention, some non-limiting examples are further disclosed below to further describe the present invention in detail.

[0046] The reagents used in the present invention can be purchased from the market or can be prepared by the methods described in the present invention.

[0047] In the present invention, mmol means millimole, h means hour, g means gram, ml means milliliter, and TBAB is tetrabutylammonium bromide.

Embodiment 1

[0048] The preparation of embodiment 1 duloxetine free base

[0049] Add xylene (100mL), DMSO (10mL), powdered KOH (11.14g), (S)-(-)-N-methyl-3-hydroxyl-3-(2 -Thienyl)propylamine (10g), TBAB (1.13g) and 1-fluoronaphthalene (10.66g), heated to about 60 ° C, HPLC monitoring of the reaction process; after the reaction was completed, the reaction solution was cooled to 25-30 ° C, added The reaction was quenched with 100 mL of water, the organic phase was separated, washed with water (100 mL×2), and the organic phase was concentrated under reduced pressure to obtain 20 g of duloxetine free base, which was directly used in the next reaction.

Embodiment 2

[0050] The preparation of embodiment 2 duloxetine free base

[0051] Add xylene (100mL), DMSO (10mL), powdered KOH (11.14g), (S)-(-)-N-methyl-3-hydroxyl-3-(2 -Thienyl)propylamine (10g), TBAB (1.13g) and 1-fluoronaphthalene (10.66g), heated to about 80 ° C, HPLC monitoring of the reaction process; after the reaction was completed, the reaction solution was cooled to 25-30 ° C, added The reaction was quenched with 100 mL of water, the organic phase was separated, washed with water (100 mL×2), and the organic phase was concentrated under reduced pressure to obtain 21.5 g of duloxetine free base, 98.26% ee.

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Abstract

The invention discloses a method for preparing a noradrenaline reuptake dual inhibitor. On one hand, the invention provides a method for preparing a compound, (+)-(S)-N-methyl-gamma-(1-naphthoxy)-2-thiophene propylamine, as shown in a formula (I) in the specification. The method comprises the step as follows: the compound as shown in a formula (II) in the specification, and (S)-(-)-N-methyl-3-hydroxy-3-(2-thienyl) propylamine and a compound 1-fluoronaphthalene as shown in a formula (III) in the specification are subjected to etherification reaction in a mixed solvent of xylene and dimethyl sulfoxide under presence of potassium hydroxide. On the other hand, the invention provides a high-yield method for obtaining high-purity duloxetine hydrochloride. The method specifically comprises the following steps: (1) dissolving a duloxetine hydrochloride crude product into a mixed solvent of acetone and water, so as to form a solution; and (2) adding acetone and crystallizing.

Description

technical field [0001] The present invention relates to the preparation method of 5-hydroxytryptamine and norepinephrine reuptake dual inhibitor, in particular to (+)-(S)-N-methyl-γ-(1-naphthyloxy)-2-thienylamine salt Method for the preparation of acid salts. Background technique [0002] Duloxetine, its structure is shown in formula (I), and its chemical name is (+)-(S)-N-methyl-γ-(1-naphthyloxy)-2-thienylamine hydrochloride, It is a dual serotonin and norepinephrine reuptake inhibitor (SNRIs), used for the treatment of various depressions, urinary incontinence and the treatment of peripheral nerve pain caused by diabetes, fibromyalgia, broad-spectrum anxiety, etc., [0003] [0004] In the synthetic process of duloxetine, the reaction of (S)-(-)-N-methyl-3-hydroxyl-3-(2-thienyl) propylamine and 1-fluoronaphthalene, i.e. the etherification reaction is duloxetine A difficult point in the process route of cetine. At present, most of the patented routes use dimethyl sulfo...

Claims

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Application Information

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IPC IPC(8): C07D333/20
CPCC07D333/20
Inventor 陈磊骆建轻贺江华王仲清
Owner SUNSHINE LAKE PHARM CO LTD
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