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Preparation method of vortioxetine

A technology of vortioxetine hydrobromide and molar ratio, applied in organic chemistry and other directions, can solve the problems of many impurities, high purification pressure, low yield and the like, and achieve high yield, low purification pressure and high reaction selectivity. Effect

Active Publication Date: 2015-05-27
ZHONGSHAN WANHAN PHARM CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0024] The purpose of the present invention is to provide a method for preparing vortioxetine hydrobromide with simple process and high reaction selectivity for the problems of many impurities, high purification pressure and low yield in the prior art scheme

Method used

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  • Preparation method of vortioxetine
  • Preparation method of vortioxetine
  • Preparation method of vortioxetine

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0044] The 100mL four-necked bottle is equipped with an electromagnetic stirrer, a condenser tube and a thermometer. Add 2,4‐dimethyliodobenzene (2.32g, 10mmol, 1.0eq), o-bromothiophenol (1.90g, 10mmol, 1.0eq) and 25mL of tetrahydrofuran, and replace with nitrogen three times. Put in Pd(dba) 2 (0.58g, 1mmol, 0.1eq), BINAP (0.93g, 1.5mmol, 0.15eq) and 1-Boc-piperazine (1.86g, 10mmol, 1.0eq), nitrogen replacement 3 times. Finally, 18‐C‐6 (7.40g, 28mmol, 2.8eq) and sodium tert-butoxide (2.69g, 28mmol, 2.8eq) were added, stirred at 30°C for 24 hours, and HPLC showed that the selectivity was 98.6%.

[0045] Throw in 0.1 g of activated carbon, and stir for 2 hours. The filtrate was precipitated to dryness, 40 mL of toluene was added, and stirred for 0.5 hours. After filtration, 48% hydrobromic acid (2.53g, 15mmol, 1.5eq) was added dropwise to the filtrate, and stirred for 0.5 hours. Filter, filter cake with toluene 10mL × 2 Rinse. Vortioxetine hydrobromide is obtained. Vacuum...

Embodiment 2

[0047] The 100mL four-necked bottle is equipped with an electromagnetic stirrer, a condenser tube and a thermometer. Add 2,4‐dimethylthiophenol (1.38g, 10mmol, 1.0eq), o-bromothiophenol (2.83g, 10mmol, 1.0eq) and 25mL of tetrahydrofuran, and replace with nitrogen three times. Put into Pd 2 (dba) 3 (0.46g, 0.5mmol, 0.05eq), DPEphos (0.27g, 0.5mmol, 0.05eq) and 1-Boc-piperazine (1.86g, 10mmol, 1.0eq), nitrogen replacement 3 times. Finally, 18‐C‐6 (7.40g, 28mmol, 2.8eq) and potassium tert-butoxide (3.37g, 30mmol, 3.0eq) were added, stirred at 40°C for 36 hours, and HPLC showed that the selectivity was 98.2%.

[0048] Throw in 0.1 g of activated carbon, and stir for 2 hours. The filtrate was precipitated to dryness, 40 mL of toluene was added, and stirred for 0.5 hours. After filtration, 48% hydrobromic acid (2.53g, 15mmol, 1.5eq) was added dropwise to the filtrate, and stirred for 0.5 hours. Filter, filter cake with toluene 10mL × 2 Rinse. Vortioxetine hydrobromide is obta...

Embodiment 3

[0050] The 100mL four-necked bottle is equipped with an electromagnetic stirrer, a condenser tube and a thermometer. Add 2,4-dimethyliodobenzene (2.32g, 10mmol, 1.0eq), o-bromothiophenol (1.90g, 10mmol, 1.0eq) and 35mL tetrahydrofuran, and replace with nitrogen three times. Put in Pd(dba) 2 (2.9g, 5mmol, 0.5eq), BINAP (3.11g, 5mmol, 0.5eq) and 1-Boc-piperazine (1.86g, 10mmol, 1.0eq), nitrogen replacement 3 times. Finally, 18‐C‐6 (11.90g, 45mmol, 4.5eq) and sodium tert-butoxide (2.69g, 28mmol, 2.8eq) were added and stirred at 25°C for 20 hours. HPLC showed that the selectivity was 98.8%.

[0051]Throw in 0.1 g of activated carbon, and stir for 2 hours. The filtrate was precipitated to dryness, 50 mL of toluene was added, and stirred for 0.5 hours. After filtration, 48% hydrobromic acid (2.53g, 15mmol, 1.5eq) was added dropwise to the filtrate, and stirred for 0.5 hours. Filter, filter cake with toluene 10mL × 2 Rinse. Vortioxetine hydrobromide is obtained. Vacuum drying ...

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Abstract

The invention relates to a preparation method of vortioxetine. The preparation method of vortioxetine comprises the following steps: enabling 2,4-dimethyl-iodobenzene, o-bromothiophenol and 1-Boc-piperazine to react at the temperature of 25-40 DEG C in the presence of the catalysis of an appropriate amount of palladium catalyst, ligand, alkali and phase transfer catalyst to prepare a compound II and de-protecting the compound II by hydrobromic acid solution to obtain vortioxetine which shown in a formula I, or enabling 2,4-dimethylbenzenethiol, 1-bromo-2-iodobenzene and 1-Boc-piperazine to react at the temperature of 25-40 DEG C in the presence of the catalysis of an appropriate amount of palladium catalyst, alkali and phase transfer catalyst to prepare a compound II and de-protecting the compound II by the hydrobromic acid solution to obtain vortioxetine which is shown in a formula I. According to the preparation method, the preparation process is simple, the reaction selectivity is high, few impurities exist, the purification pressure is low and the yield is high.

Description

technical field [0001] The invention belongs to the field of organic synthesis, and in particular relates to a preparation method of vortioxetine bulk drug and intermediate. Background technique [0002] Vortioxetine (see Figure 1) is a drug jointly developed by Lundbeck of Denmark and Takeda Pharmaceutical of Japan for the treatment of major depressive disorder (MDD). This drug is 5‐HT 3 , 5‐HT 7 and 5‐HT 1D Receptor Antagonist, 5‐HT 1A Agonist, 5‐HT 1B Receptor partial agonist, 5‐HT transporter inhibitor. The drug increases levels of the neurotransmitters serotonin, norepinephrine, dopamine, acetylcholine, and histamine in specific parts of the brain. Clinical trials have shown that the drug is safe and effective for major depressive disorder. The FDA approved the drug in September 2013. The Chinese translation name is usually "vortioxetine", and the structural formula is as follows: [0003] [0004] The synthesis method of vortioxetine is mainly found in the ...

Claims

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Application Information

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IPC IPC(8): C07D295/096
CPCC07D295/096
Inventor 杜志博王鹤然张婧嫄
Owner ZHONGSHAN WANHAN PHARM CO LTD
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