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Method for preparing tapentadol intermediate

A technology of intermediates and catalysts, applied in the field of drug synthesis, can solve the problem of large release, and achieve the effects of high purity, simple post-processing, and convenient feeding

Inactive Publication Date: 2011-10-05
CHINA PHARM UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The above-mentioned process has the following disadvantages: on the one hand, a large amount of thionyl chloride is used, and a large amount of acid waste gas is released during the reaction process and post-treatment process; A large amount of waste residue will be produced when tin hydride is used, and there are certain fire and health risks

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  • Method for preparing tapentadol intermediate
  • Method for preparing tapentadol intermediate
  • Method for preparing tapentadol intermediate

Examples

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Embodiment 1

[0019] Synthesis of (2S,3R)-[3-chloro-3-(3-methoxyphenyl)]-N,N,2-trimethylpentylamine hydrochloride (IV)

[0020] Weigh (2S, 3R)-1-(dimethylamino)-3-(3-methoxyphenyl)-2-methylpentan-3-ol III 10.0g (39.8mmol) in a 100ml eggplant-shaped bottle , add 40ml of dichloromethane, add phosphorus pentachloride 9.8g (47.8mmol) in batches under stirring, heat up and reflux for 2h, cool, add 10% sodium hydroxide aqueous solution to adjust the pH to 9-10, filter, and the filtrate is dichloromethane Methane was extracted three times (40ml×3), and the dichloromethane layer was dried over anhydrous magnesium sulfate. After filtration, the filtrate was spin-dried to obtain 8.2 g of yellow oily substance IV, which was dissolved by adding 10 ml of 2-butanone and passing through dry hydrogen chloride gas, cooling to precipitate a white solid VI (6.6 g, 54.2%), melting point 148-149°C. 1 H-NMR (300MHz, CDCL 3 ), δ (ppm): 0.67 (3H, t, J=6.8Hz, CH 3 ), 0.89 (3H, d, J=6.2Hz, CH 3 ), 2.28~2.33 (2H,...

Embodiment 2

[0022] Synthesis of (2R,3R)-3-(3-methoxyphenyl)-N,N,2-trimethylpentylamine hydrochloride (I)

[0023] Weigh IV (6.6g, 21.5mmol) into a 100ml eggplant-shaped bottle, add methanol 50ml, 10% Pd / C (0.6g, 6.1mmol), react with hydrogen at 40-45°C for 6h under normal pressure, filter, evaporate Remove the solvent, add 40ml of ethyl acetate to the residue, adjust the pH to 9-10 by adding 10% ammonia solution, extract with ethyl acetate (30ml×3), combine the organic phases, and dry over anhydrous magnesium sulfate. Filter and evaporate to dryness to obtain 5.9 g of pale yellow oily substance V. After dissolving in ethyl acetate, pass through dry hydrogen chloride gas to form hydrochloride. Filter to obtain white solid I (4.9 g, 84%), melting point 162-164 ° C, 1 H-NMR (300MHz, CDCL 3 ), δ (ppm): 0.70 (3H, t, CH 3 ), 1.01 (3H, d, CH 3 ), 1.57~1.61 (1H, m, CH), 1.75~1.83 (1H, m, 1 / 2CH 2 ), 1.87~1.92 (1H, m, 1 / 2CH 2 ), 2.13~2.17 (2H, m, CH 2 ), 2.29 (6H, s, N (CH 3 ) 2 ), 2.25~2...

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Abstract

The invention relates to the field of drug synthesis, in particular to a method for preparing an analgesic tapentadol intermediate (2R,3R)-3-(3-methoxyl phenyl)-N,N,2-trimethyl amylamine hydrochloride. The method is characterized by comprising the following steps of: chlorinating optically active (2S,3R)-1-dimethylamino-3-(3-methoxyl phenyl)-2-methyl amyl-3-ol and phosphorus pentachloride and salifying with hydrogen chloride to obtain hydrochloride, and then carrying out stereoselective hydrogenolysis in the presence of a catalyst, and salifying with the hydrogen chloride to obtain the analgesic tapentadol intermediate. The method provided by the invention has the advantages of cleanness, safety, convenience for after treatment and lower production cost. Compared with a method in a literature, the method has reaction time shortened by nearly 80 hours.

Description

technical field [0001] The invention relates to the field of drug synthesis, in particular to analgesic tapentadol intermediate (2R, 3R)-3-(3-methoxyphenyl)-N,N,2-trimethylpentylamine hydrochloride method of preparation. Background technique [0002] Tapentadol is a synthetic analgesic that acts on the central nervous system, and its inhibitory activity on human μ-opioid receptors is 18 times weaker than that of morphine, while its analgesic activity is only 2 to 3 times weaker than morphine in animal models . Tapentadol is a novel oral central analgesic drug with dual mechanisms of μ-receptor agonism and NA reuptake inhibition, and inactive metabolites. Due to the dual analgesic mechanism, tapentadol has broad-spectrum and high-efficiency analgesic activity for dull and sharp pains, and despite its low affinity to μ-receptors, it is more tolerable than morphine due to its partly non-opioid analgesic mechanism. Good, with low dependence and few side effects (especially ga...

Claims

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Application Information

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IPC IPC(8): C07C217/62C07C213/08
Inventor 徐云根张迪杭太俊宋巧徐梓宸
Owner CHINA PHARM UNIV
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