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Preparation method of levomilnacipran key intermediate

A technology of L-milnacipran and its intermediates, which is applied in the fields of medicinal chemistry and medical technology, and can solve problems such as loss and non-compliance with cost-benefit requirements

Pending Publication Date: 2020-06-26
BEIJING VENTUREPHARM BIOTECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] In the preparation method of nacipran, the racemate resolution method does not meet the cost-effectiveness requirement because half of the product is lost

Method used

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  • Preparation method of levomilnacipran key intermediate
  • Preparation method of levomilnacipran key intermediate

Examples

Experimental program
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Effect test

example 1

[0019] Add acetonitrile (150mL) to a 500mL three-neck flask at room temperature and slowly add sodium hydride (6.2g, 256.8mmol) in batches, continue to slowly add compound I (15.0g, 128.4mmol) to the system, and react at a temperature of 15°C for 1 h . Add slowly ( R )-epibromopropane (19.3g, 141.2mmol) in acetonitrile (45ml) solution, after adding, react at room temperature for 2 h. The solvent was concentrated under reduced pressure and purified by column chromatography. The obtained compound II had a purity of 98.47% and a yield of 78.77%.

example 2

[0021] Add compound II (10.0g, 57.7mmol) obtained by conventional synthesis means to a 250 mL three-necked flask, 100mL of acetonitrile, stir well to make it all dissolve, and add phthalimide potassium salt (21.4g, 115.5mmol ), PPh 3 (30.3g, 115.5mmol) and DDQ (26.2g, 115.5mmol), control the system temperature to 80°C, react for 6h, TLC monitors that the reaction is complete, stop the reaction. The reaction mixture was quenched with water (120 mL), and the organic phase was extracted with dichloromethane. The solvent was concentrated under reduced pressure and purified by column chromatography. The obtained compound III had a purity of 98.51% and a yield of 89.51%.

example 3

[0023] Add compound III (14.0g, 46.3mmol) and 140mL of acetonitrile into a 250 mL three-necked flask, stir well to dissolve them all, add concentrated sulfuric acid (9.2g, 92.6mmol), react at room temperature for 3h, TLC monitors that the raw materials have reacted completely, stop the reaction . Adjust the pH to 7-8 with 50% sodium hydroxide aqueous solution, filter with suction, collect the filter cake and purify it by column chromatography. The purity of Compound IV is 98.80%, and the yield is 75.73%.

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Abstract

Levomilnacipran has a chemical name of (1R,2S)-2-(aminomethyl)-N,N-diethyl-1-phenylcyclopropanecarboxamide, is a medicine which is researched and developed by a French PierreFabre laboratory at the earliest time and is used for treating adult severe depressive disorder. The invention relates to a method for synthesizing a key intermediate compound (I) of levomilnacipran.

Description

technical field [0001] The invention belongs to the fields of medical technology and medicinal chemistry, and in particular relates to a preparation method of a key intermediate of levomilnacipran, a drug for adult severe depressive disorder. Background technique [0002] Levomilnacipran, chemical name: (1 R ,2 S )-2-(Aminomethyl)- N , N -Diethyl-1-phenylcyclopropanecarboxamide, a drug first developed by the French PierreFabre laboratory for the treatment of major depressive disorder in adults. The drug was approved by the US Food and Drug Administration (FDA) on July 26, 2013 as a new type of SNRI drug listed in the United States, with the trade name Fetzima. The structural formula is as follows: [0003] [0004] The racemate resolution method in the preparation method of Nacipran does not meet the cost-benefit requirement because half of the product is lost. Therefore, published patents such as CN102300840(A), EP2805936(A1), IN201404226(I3), IN201403752(I3), and ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D209/49
CPCC07D209/49C07B2200/07
Inventor 齐晓溪李恩民赵国磊
Owner BEIJING VENTUREPHARM BIOTECH
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