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Preparation method of tapentadol hydrochloride and compounds for preparation of tapentadol hydrochloride

A tapentadol and compound technology, applied in the field of drug synthesis, can solve the problems of shortened route, cumbersome operation, and easily corroded equipment.

Active Publication Date: 2013-06-19
NHWA PHARMA CORPORATION
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0012] Compared with EP0693475, the above-mentioned route is obviously shortened and is more suitable for industrial production, but there are still deficiencies in the patent WO2008012047. The compound of formula I obtains (2S, 3R)-1-(dimethylamino)-3-(3 -Methoxyphenyl)-2-methyl-3-pentanol, further (2S,3S)-1-(dimethylamino)-3-(3-methoxyphenyl)-2-methyl- 3-Pentanol is dehydrated under the catalysis of acid, acid anhydride or ion exchange resin with immobilized acid, and the catalytic dehydration produces (R)-3-(3-methoxyphenyl)-N,N,2-trimethylpentane -3-en-1-amine will have 3-(3-methoxyphenyl)-N,N,2-trimethylpent-2-en-1-amine as a by-product, which will be introduced after reduction The by-products with the opposite configuration cannot be removed by a simple method, which is not conducive to obtaining tapentadol with high optical purity, and the format reaction conditions are harsh, there are many steps, and the operation is cumbersome, which is not conducive to industrial production
This method still uses methyl as the protecting group, and volatile concentrated hydrochloric acid is used during demethylation, which is easy to corrode equipment and is harmful to the environment

Method used

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  • Preparation method of tapentadol hydrochloride and compounds for preparation of tapentadol hydrochloride
  • Preparation method of tapentadol hydrochloride and compounds for preparation of tapentadol hydrochloride
  • Preparation method of tapentadol hydrochloride and compounds for preparation of tapentadol hydrochloride

Examples

Experimental program
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Effect test

Embodiment 1

[0087] Synthesis of 3-allyloxypropiophenone (preparation of formula I compound)

[0088]

[0089] Add the compound 3-hydroxypropiophenone (300.1g), potassium carbonate (450.0g), sodium iodide (40.0g) into 2L of acetone, add 3-chloropropene (208.0g) dropwise under stirring at room temperature, and the addition is complete Afterwards, the reaction mixture was warmed up to reflux temperature and stirred at reflux for 36h. After the reaction, the reaction mixture was cooled to 25° C., and potassium carbonate was removed by suction filtration. After concentrating the acetone under reduced pressure, 1.2 L of ethyl acetate was added to dissolve the oil and 0.5 L of water was added for washing. After washing with water, the organic phase was dried with magnesium sulfate, and the organic phase was concentrated under reduced pressure to obtain oily 3-allyloxypropiophenone (370.8 g), with a yield of 97.6%. 1 HNMR (400MHz, DMSO-d 6 )δ: 7.52 (d, J=8.0Hz, 1H, ArH), 7.49 (s, 1H, ArH), 7...

Embodiment 2

[0091] The preparation of the synthetic formula I compound of 3-allyloxy propiophenone, reaction formula is the same as embodiment 1.

[0092] Add the compound 3-hydroxypropiophenone (30.1g), sodium carbonate (51.0g), sodium bromide (3.5g) into 150ml ethanol, add 3-chloropropene (18.0g) dropwise under stirring at room temperature, and the addition is complete After post-stirring for 1 h, the reaction mixture was warmed to 40 °C and stirred at reflux for 30 h. After the reaction was finished, the reaction mixture was cooled to 25° C., and sodium carbonate was removed by suction filtration. After concentrating the ethanol under reduced pressure, 120 ml of ethyl acetate was added to dissolve the oil and 50 ml of water was added for washing. After washing with water, the organic phase was dried with magnesium sulfate, and the organic phase was concentrated under reduced pressure to obtain oily 3-allyloxypropiophenone (34.8 g), with a yield of 91.3%.

[0093] 1 HNMR (400MHz, DMSO...

Embodiment 3

[0095] The preparation of the synthetic formula I compound of 3-allyloxy propiophenone, reaction formula is the same as embodiment 1.

[0096] The compound 3-hydroxypropiophenone (25.3g), sodium bicarbonate (38.0g), potassium bromide (2.5g) was added to 100ml of toluene, and 3-chloropropene (18.0g) was added dropwise under stirring at room temperature. After stirring for 1 h after completion, the reaction mixture was warmed up to 110° C. and stirred at reflux for 28 h. After the reaction was finished, the reaction mixture was cooled to 25° C., and sodium bicarbonate was removed by suction filtration. After concentrating the toluene under reduced pressure, 120 ml of ethyl acetate was added to dissolve the oil and 50 ml of water was added for washing. After washing with water, the organic phase was dried with magnesium sulfate, and the organic phase was concentrated under reduced pressure to obtain oily 3-allyloxypropiophenone (24.8 g), with a yield of 77.4%.

[0097] 1 HNMR (...

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Abstract

The invention discloses a preparation method of tapentadol hydrochloride and compounds for preparation of the tapentadol hydrochloride. The preparation method comprises steps using compound hydrochlorides in a formula V as raw materials for preparation of the tapentadol hydrochloride, and is characterized in that the preparation method of the compound hydrochlorides in the formula V comprises the following steps that (1) in solvent, compound hydrochlorides in a formula IV react under existence of hydrogenolysis reagents and catalytic agents, and then the compound hydrochlorides in the formula V are collected from reaction products. According to the process, chiral column separation is not needed, a removal condition of protecting group allyl is mild, yield is high, and industrialization production is benefited. An equation is as follows.

Description

technical field [0001] The invention belongs to the technical field of drug synthesis, and provides a synthesis process of tapentadol and a compound used for preparing tapentadol. Background technique [0002] Tapentadol (Tapentadol), chemical name 3-[(1R,2R)-3-(dimethylamino)-1-ethyl-2-methylpropyl]phenol monohydrochloride, is produced by Gruenenthal, Germany The central nervous system analgesic created by the company has dual effects of opioid μ receptor agonism and norepinephrine reabsorption inhibition. In November 2008, the US FDA approved its immediate-release tablet for marketing, and it is clinically used to relieve central nervous system pain in adults. to severe acute pain. This compound has the following structure: [0003] [0004] According to literature reports, the synthetic routes mainly contain the following: [0005] 1. The patent EP0693475 firstly reported the synthesis of tapentadol. Using 1-(dimethylamino)-2-methyl-3-pentanone and m-bromoanisole as...

Claims

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Application Information

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IPC IPC(8): C07C215/54C07C215/58C07C213/08C07C217/72C07C225/16C07C221/00C07C49/84C07C45/71
CPCC07C213/00C07B2200/07C07C45/64C07C49/84C07C213/06C07C213/08C07C217/72C07C221/00Y02P20/55C07C225/16C07C215/54C07C215/62
Inventor 杨相平李超张桂森彭卫娟
Owner NHWA PHARMA CORPORATION
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