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Synthetic method of tomoxetine

A technology of atomoxetine and compounds, which is applied in the field of synthesis of drugs for the treatment of attention deficit hyperactivity disorder (ADHD), can solve problems such as increased production costs, difficulty in control, and unsatisfactory yields, and achieves the reduction of by-products, The effect of mild reaction conditions and simple steps

Active Publication Date: 2014-03-26
BEIJING WINSUNNY PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The tert-butoxide used in the above reaction steps is unstable and difficult to control, and the solvent 1,3-dimethyl-2-imidazolidinone used is expensive, which increases the production cost and the yield is not satisfactory, so it is not suitable for large-scale industrialization Production

Method used

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  • Synthetic method of tomoxetine
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  • Synthetic method of tomoxetine

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0042] 10g of compound I and 20g of ethanol solution containing 33% methylamine were dissolved in 60mL of ethanol for reaction. TLC determined that the reaction was complete, adding an appropriate amount of water, extracting with dichloromethane, drying over anhydrous magnesium sulfate, and concentrating to obtain 10.52g of oily compound II. Yield 85%.

[0043] 10g of compound II and 9.4g of sodium borohydride were dissolved in 50mL of tetrahydrofuran for reaction. TLC determined that the reaction was complete. Water was added and extracted with ethyl acetate. The organic phases were combined, dried and concentrated to obtain 7.94g of colorless oily compound III with a yield of 78.5%. .

[0044] Dissolve 7g of compound III and 0.7g of 10% Pd / C in 35mL of ethanol, pass through hydrogen to react, TLC determines that the reaction is complete, filter off the catalyst, concentrate to obtain an oil, and recrystallize with petroleum ether to obtain 6.25g of compound Ⅳ, the yield 88....

Embodiment 2

[0047] Dissolve 10g of compound I and 22g of ethanol solution containing 33% methylamine in 80mL of isopropanol for reaction. TLC determines that the reaction is complete. Add appropriate amount of water, extract with ethyl acetate, dry with anhydrous calcium chloride, and concentrate to obtain 10.42g of oil Compound II, yield 84.2%.

[0048] 9.5 g of compound II and 9.5 g of potassium borohydride were dissolved in 50 mL of ethanol for reaction. TLC determined that the reaction was complete, adding water, extracting with ethyl acetate, combining the organic phases, drying and concentrating to obtain 7.5 g of colorless oily compound III with a yield of 78 %.

[0049] 7g of compound III and 0.5g of Raney Ni were dissolved in 40mL of ethanol and reacted with hydrogen gas. TLC determined that the reaction was complete. The catalyst was filtered off, concentrated to obtain an oil, and recrystallized with petroleum ether to obtain 6.2g of compound IV with a yield of 87.4%.

[0050]...

Embodiment 3

[0052]8 g of compound I and 23 g of ethanol solution containing 33% methylamine were dissolved in 50 mL of methanol for reaction. TLC determined that the reaction was complete, adding an appropriate amount of water, extracting with dichloromethane, drying over anhydrous magnesium sulfate, and concentrating to obtain 8.32 g of oily compound II. Yield 84%.

[0053] 7.5g of compound II and 8.8g of lithium aluminum hydride were dissolved in 60mL of methanol and reacted. TLC determined that the reaction was complete. Water was added and extracted with ethyl acetate. The organic phases were combined, dried and concentrated to obtain 5.9g of colorless oily compound III with a yield of 77.7% %.

[0054] 5g of compound III and 0.4g of 8% Pd(OH)2 / C were dissolved in 30mL of tetrahydrofuran and reacted. TLC determined that the reaction was complete. The catalyst was filtered off, concentrated to obtain an oil, and recrystallized with petroleum ether to obtain 4.43g of compound IV. The r...

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Abstract

The invention relates to a synthetic method of tomoxetine. The tomoxetine is generated by taking (E)-3-(N-methyl amino)-1-phenyl-2-propylene-1-ketone as the material through reduction and 2-benzyl halide etherification reaction. The synthetic method disclosed by the invention is simple in step, easy to operate, less in byproducts, better in yield, lower in cost and suitable for large-scale industrial production.

Description

field of invention [0001] The invention relates to a synthesis method of a drug for treating attention deficit hyperactivity disorder (ADHD), in particular to a synthesis method of atomoxetine. Background technique [0002] ADHD is a group of syndromes characterized by marked difficulty concentrating, short attention span, hyperactivity, or impulsiveness compared with children of the same age. Attention-deficit hyperactivity disorder is the most common mental and behavioral disorder in children. The academic and occupational achievements of patients are far behind normal children, causing serious burdens to families and society. The incidence of this disease among school-age children in my country is about 5%, about 15 to 19 million children. [0003] The chemical name of atomoxetine is (R)-N-methyl-3-(2-methylphenoxy)-3-phenylpropylamine, and the specific structure is: [0004] [0005] Atomoxetine, developed by Eli Lilly and Company, is a selective norepinephrine reup...

Claims

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Application Information

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IPC IPC(8): C07C217/48C07C213/06C07C225/16C07C221/00
Inventor 林国良郑南桥张利华王帅彭小玲耿玉先
Owner BEIJING WINSUNNY PHARMA CO LTD
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