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A method for synthesizing tapentadol hydrochloride

A technology of tapentadol hydrochloride and sodium perborate, applied in chemical instruments and methods, preparation of organic compounds, preparation of aminohydroxy compounds, etc., can solve the problems of long routes, toxic chemical reagents, complicated reaction operations, etc. The effect of high utilization rate, easy industrialization and cost reduction

Active Publication Date: 2017-05-24
HAITANG (JIANGSU) BIOTECHNOLOGY CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0037] In summary, although there are many synthetic methods of tapentadol hydrochloride reported in the literature, there are various defects that are unfavorable for industrialized production: some routes are too long, some use expensive or toxic chemical reagents, Some reaction operations are cumbersome, and some have higher requirements on reaction equipment; so that the cost of industrially preparing tapentadol hydrochloride using the prior art remains high, which cannot meet the requirements of large-scale production

Method used

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  • A method for synthesizing tapentadol hydrochloride
  • A method for synthesizing tapentadol hydrochloride
  • A method for synthesizing tapentadol hydrochloride

Examples

Experimental program
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Embodiment 1

[0084] Example 1: Synthesis of (S)-3-dimethylamino-2-methyl-1-m-methoxyphenyl-1-propanone (compound of formula III)

[0085] Dissolve 164.2g of m-methoxypropiophenone (compound of formula IV), 244.6g of dimethylamine hydrochloride, 90g of paraformaldehyde and 9.9g of 37% aqueous hydrochloric acid in 200mL of ethanol, and then add 34.5g of L -Proline, the mixed reactant was heated to reflux under the protection of nitrogen, and after 16 hours of reflux reaction, it was cooled to room temperature, and most of the solvent was evaporated under reduced pressure, and the residue was dissolved in water, and then concentrated ammonia solution was added to adjust the pH value to alkali properties, extracted 3 times with dichloromethane, combined the organic layers, washed 1 time with dilute ammonia, anhydrous Na 2 SO 4 Dried, filtered, and spin-dried to obtain a pale yellow oil: (S)-3-dimethylamino-2-methyl-1-m-methoxyphenyl-1-propanone (172.6g, molar yield 78%, HPLC purity is 98%, e...

Embodiment 2

[0086] Embodiment 2: Synthesis of (S)-3-dimethylamino-2-methyl-1-m-benzyloxyphenyl-1-propanone (compound of formula III)

[0087]Dissolve 240.3g of m-benzyloxypropiophenone (compound of formula IV), 244.6g of dimethylamine hydrochloride, 90g of paraformaldehyde and 9.9g of 37% hydrochloric acid aqueous solution in 200mL of ethanol, and then add 34.5g of L -Proline, the mixed reactant was heated to reflux under the protection of nitrogen, and after 16 hours of reflux reaction, it was cooled to room temperature, and most of the solvent was evaporated under reduced pressure, and the residue was dissolved in water, and then concentrated ammonia solution was added to adjust the pH value to alkali properties, extracted 3 times with dichloromethane, combined the organic layers, washed 1 time with dilute ammonia, anhydrous Na 2 SO 4 Dry, filter, and spin-dry to obtain light yellow oil: (S)-3-dimethylamino-2-methyl-1-m-benzyloxyphenyl-1-propanone (252g, molar yield is 85%, HPLC The p...

Embodiment 3

[0088] Example 3: Synthesis of (S)-3-dimethylamino-2-methyl-1-m-bromophenyl-1-propanone (compound of formula III)

[0089] Dissolve 213.1g of m-bromopropiophenone (compound of formula IV), 244.6g of dimethylamine hydrochloride, 90g of paraformaldehyde and 9.9g of 37% aqueous hydrochloric acid in 200mL of ethanol, and then add 34.5g of L-proline Acid; the mixed reactant was heated to reflux under the protection of nitrogen, and after 16 hours of reflux reaction, it was cooled to room temperature, and most of the solvent was evaporated under reduced pressure first, and the residue was dissolved in water, and then concentrated ammonia solution was added to adjust the pH value to alkaline, Extracted 3 times with dichloromethane, combined the organic layers, washed 1 time with dilute ammonia, anhydrous Na 2 SO 4 Dry, filter, and spin-dry to obtain light yellow oil: (S)-3-dimethylamino-2-methyl-1-m-bromophenyl-1-propanone (229.7g, molar yield is 85%, HPLC purity is 95%, ee=96%); d...

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Abstract

The invention discloses a method for synthesizing tapentadol hydrochloride. The method comprises a reaction route shown in the specification. In the reaction route, R1 is one of halogens, -OH, -OR4, -NO2, -NH2, -NR5R6, -SH and -SR7. A required chiral isomer is directly obtained through a reaction under chiral catalysis, so the method has the advantages of avoiding of problems of a large amount of wastes and environmental protection due to chiral splitting, short route, simple operation, easy industrialization, high raw material utilization rate, great improvement of the yield, cost reduction, meeting of requirements of industrial production of tapentadol hydrochloride, and significant progress.

Description

technical field [0001] The invention relates to a method for synthesizing tapentadol hydrochloride, which belongs to the technical field of medicine synthesis. Background technique [0002] The chemical name of Tapentadol Hydrochloride is (1R,2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)phenol hydrochloride, and its chemical structure is as follows : [0003] [0004] Tapentadol hydrochloride is a novel oral analgesic drug that acts on the central nervous system developed by the German company Grunenthal. It was first marketed in 2008 for the relief of moderate and severe acute pain. It has dual mechanisms of opioid μ receptor agonism and norepinephrine reuptake inhibition. [0005] According to relevant literature reports, the synthetic routes of tapentadol hydrochloride mainly contain the following types at present: [0006] Route 1 (see European patent document EP0693475): [0007] [0008] This route takes 1-(dimethylamino)-2-methyl-3-pentanone and m-bromoani...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C215/54C07C213/08C07C213/06C07C213/00
Inventor 刘振德高河勇毕鹏飞周瑾仇文军
Owner HAITANG (JIANGSU) BIOTECHNOLOGY CO LTD