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Synthesis method of tapentadol

A synthesis method and tapentadol technology, applied in the field of drug synthesis, can solve the problems of long reaction route steps, high toxicity and high production requirements, and achieve the effects of fewer synthesis steps, easy operation and cost reduction.

Active Publication Date: 2013-02-20
HEFEI NEWSTAR PHARMA & CHEM
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The reaction process uses relatively expensive chemical reagents as the reaction reagent. In the process of reducing the cyano group to amine, borane dimethyl sulfide, which is more harmful to the environment, has been used as the reducing agent. Combustion needs to be carried out under absolutely anhydrous and oxygen-free conditions. In addition, this product is highly toxic and requires high production requirements. At the same time, the reaction route has long steps

Method used

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  • Synthesis method of tapentadol
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  • Synthesis method of tapentadol

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0061] Example 1 Preparation of 1-(dimethylamino)-2-methylpentan-3-ol (compound III)

[0062] 1.5L methanol, 1-dimethylamino-2-methyl-3-pentanone (143.23g, 1mol, compound II) were added to the reaction flask, stirred and passed into N 2 , when the system is down to about 0°C, add 60g (1.52mol) 96% sodium borohydride in batches, continue the insulation reaction for 8 hours after the addition (TLC monitoring in the reaction process), distill the solvent under reduced pressure, pour the reactant Pour into water, adjust the pH to neutral, extract with ethyl acetate, dry over anhydrous magnesium sulfate, and concentrate under reduced pressure to obtain 124 g of colorless oil, yield: 85.4%, purity (GC): 96.2%.

[0063] Molecular formula: C 8 h 19 NO; molecular weight: 145.24; MS (m / z): 146.15 (M + +H).

Embodiment 2

[0064] Example 2 Preparation of 3-bromo-N, N, 2-trimethylpentan-1-amine (compound IV-A)

[0065] Add 1-(dimethylamino)-2-methylpentan-3-ol (145.3g, 1mol, compound III) and 2L of dichloromethane into the reaction flask, and when the temperature is cooled to about 0°C in an ice bath, dropwise 270.7(1mol)PBr 3 , the addition was completed in about 2 hours, and the stirring reaction was continued for 1 minute after the addition, and the degree of the reaction was monitored by TLC. After the reaction was completed, the reactant was poured into water, extracted with dichloromethane, and the organic layer was washed with aqueous sodium bicarbonate and saturated salt Washed with water, then washed with water, dried over anhydrous magnesium sulfate, concentrated under reduced pressure to obtain 172g of yellow oil, yield: 82.6%, purity (GC): 97.6%.

[0066] Molecular formula: C 8 h 18BrN; molecular weight: 208.14; MS (m / z): 208.1 (M + ).

Embodiment 3

[0067] Example 3 Preparation of 3-(3-methoxyphenyl)-N,N-2-trimethylpentan-1-amine (compound VI)

[0068] Under the protection of nitrogen, bis(cyclooctyl 1,5-diene)nickel (1.37g, 0.005mol), 4,7-diphenyl-1,10-phenanthroline (CAS: 1945-77-3, 8.44g, 0.01mol), sec-butanol (CAS: 78-92-2, 200mL) were put into the reaction flask, stirred for 15 minutes, anhydrous potassium tert-butoxide (15.7g, 0.14mol), 3-methoxy phenylboronic acid (12.2g, 0.08mol, CAS: 5720-06-9) and 3-bromo-N,N,2-trimethylpentan-1-amine (20.8g, 0.1mol, compound IV-A), Slowly heated to 60°C, kept stirring and reacted overnight, TLC monitored the extent of the reaction, stopped the reaction after the reaction was complete, cooled to room temperature, slowly added the reaction solution into saturated saline, extracted with ethyl acetate, dried over anhydrous magnesium sulfate, filtered, The filtrate was concentrated to dryness under reduced pressure and separated on a silica gel column to obtain 12.1g of light yello...

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Abstract

The invention discloses a synthesis method of tapentadol. The method includes taking 1-dimethylamino-2-methyl-3-pentanone as a starting material, obtaining 3-bromine-N,N-2-trimethylpentyl-1-amine after reduction and halogenation reactions, then performing a coupling reaction with a metal reagent under the catalysis of transition metal to obtain 3-(3-methoxyphenyl)-N,N-2-trimethylpentyl-1-amine, and obtaining the tapentadol after demethylation and resolution. The synthesis method has the advantages that the raw materials are low in cost and easy to obtain, the steps are few, the operation is simple, and the cost can be effectively reduced; highly purified tapentadol can be obtained through the method, and the liquid phase purity and ee value of hydrochloric acid tapentadol obtained after salification can reach above 99%; and the method can be applied to the medical field.

Description

technical field [0001] The invention belongs to the field of drug synthesis, and in particular relates to a synthesis method of tapentadol. Background technique [0002] 3-[(1R,2R)-3-(dimethylamino)-1-ethyl-2-methylpropyl]phenol (structure shown in formula (I)), also known as tapentadol, It is a new type of central analgesic drug developed by Johnson & Johnson Company of the United States, which has dual action modes of mu opioid receptor (MOR) agonism and norepinephrine (Norepinephrine, NE) reabsorption inhibition (Tzschentke TM, et al ., J.Pharm.Exper.Therap., 2007, 323, 265), often used as medicine in the form of hydrochloride. On January 23, 2008, the U.S. FDA accepted the new drug listing application for tapentadol hydrochloride immediate-release tablets, which was approved by the U.S. FDA on November 21, 2008. It is clinically used to relieve moderate to severe acute pain in the central nervous system of adults. treat. [0003] [0004] Tapentadol belongs to 1-ph...

Claims

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Application Information

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IPC IPC(8): C07C215/54C07C213/00
Inventor 徐自奥赵永海李德刚李晓祥
Owner HEFEI NEWSTAR PHARMA & CHEM
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