Method for synthesizing tramadol hydrochloride

A technology for the synthesis of tramadol hydrochloride and its synthesis method, which is applied in the field of synthesis of tramadol hydrochloride, which can solve the problems of flammability, anesthesia, explosion, etc., and achieve shortened reaction time, high reaction yield, and easy separation The effect of purification

Active Publication Date: 2008-09-17
DUODUO PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

Due to the low boiling point of ether, it is extremely flammable and explosive, and has an anesthetic effect, which is dangerous and not suitable for industrial production; because tetrahydrofuran is miscible with water, another solvent such as toluene must be added to extract the produ

Method used

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  • Method for synthesizing tramadol hydrochloride
  • Method for synthesizing tramadol hydrochloride
  • Method for synthesizing tramadol hydrochloride

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0033] The amount ratio of the feed material is 2-dimethylaminomethylcyclohexanone: m-methoxybromobenzene: metal magnesium is 1.0: 1.0: 1.0, and the dropwise reaction method is to add 2-dimethylaminomethyl The 2-MeTHF solution of cyclohexanone (III) is dropped into the Grignard reagent solution, and the solvent is 2-MeTHF.

[0034] Add magnesium bar (2.4g, 0.1mol) and 2-MeTHF (8.6g, 10mL) in reaction bottle, N 2 Under protection, an appropriate amount of 1,2-dibromoethane was added to initiate the reaction, m-methoxybromobenzene (18.6g, 0.1mol) in 2-MeTHF solution (30.15g, 35mL) was slowly added dropwise, and the reaction was stirred at 80°C After 2 hours, the Grignard reagent (II) was prepared. After cooling to 0°C, a solution of 2-dimethylaminomethylcyclohexanone (15.5 g, 0.1 mol) in 2-MeTHF (23.25 g, 27 mL) was slowly dropped into the above reaction flask, and the reaction was kept for 4 hours after dropping. with saturated NH 4 The reaction was quenched with Cl, and the...

Embodiment 2

[0036] The amount ratio of the feed material is 2-dimethylaminomethylcyclohexanone: m-methoxybromobenzene: metal magnesium is 1.0: 1.5: 1.6, and the dropwise reaction method is to add 2-dimethylaminomethyl The 2-MeTHF solution of cyclohexanone (III) is dropped into the Grignard reagent solution, and the solvent is 2-MeTHF.

[0037] Add magnesium bar (3.84g, 0.16mol) and 2-MeTHF (8.6g, 10mL) in reaction flask, N 2 Under protection, an appropriate amount of 1,2-dibromoethane was added to initiate the reaction, m-methoxybromobenzene (27.9g, 0.15mol) in 2-MeTHF solution (30.15g, 35mL) was slowly added dropwise, and the reaction was stirred at 80°C After 2 hours, the Grignard reagent (II) was prepared. After cooling to 0°C, a solution of 2-dimethylaminomethylcyclohexanone (15.5 g, 0.1 mol) in 2-MeTHF (23.25 g, 27 mL) was slowly dropped into the above reaction flask, and the reaction was kept for 4 hours after dropping. with saturated NH 4Cl quenched the reaction, recovered 2-MeT...

Embodiment 3

[0039] The amount ratio of the feed material is 2-dimethylaminomethylcyclohexanone: m-methoxy bromobenzene: metal magnesium is 1.0: 1.2: 1.2, and the dropwise reaction method is to add 2-dimethylaminomethyl The 2-MeTHF solution of cyclohexanone (III) is dropped into the Grignard reagent solution, and the solvent is 2-MeTHF.

[0040] In the reaction flask, add magnesium bar (2.88g, 0.12mol), 2-MeTHF (8.6g, 10mL), N 2 Under protection, add an appropriate amount of iodine to initiate the reaction, slowly add m-methoxybromobenzene (22.32g, 0.12mol) in 2-MeTHF solution (30.15g, 35mL) dropwise, and stir the reaction at 80°C for 2 hours to obtain Grignard Reagent (II). 2-Dimethylaminomethylcyclohexanone (15.51 g, 0.1 mol) in 2-MeTHF (23.25 g, 27 mL) was slowly dropped into the above-mentioned reaction flask at 0° C., and the reaction was incubated for 4 hours after the dropping. with saturated NH 4 The reaction was quenched with Cl, and the separated 2-MeTHF layer was washed with ...

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Abstract

The invention discloses a synthesis method of tramadol hydrochloride. The synthesis method comprises the steps as follow: Grignard reagent that is m-methoxy phenyl magnesium bromide is manufactured in 2-methyltetrahydrofuran that is green solvent, then the Grignard reagent reacts with 2-dimethylamino methyl cyclohexanone to obtain crude products which are salified in hydrochloric alcoholic solution, so as to manufacture the tramadol hydrochloride. Compared with the traditional technology, the synthesis method has the advantages that the 2-methyltetrahydrofuran that is green solvent is adopted in the Grignard reaction, the reaction yield rate is higher, products are easy to separate and purify, the solvent consumption is less and easy to be recycled and reused, the environmental pollution is small, and the synthesis method is suitable for industrialized production.

Description

(1) Technical field [0001] The invention relates to a synthesis method of tramadol hydrochloride, which belongs to the field of medicine and chemical industry. (2) Background technology [0002] Tramadol Hydrochloride (Tramadol Hydrochloride, I), chemical name is (±)-(E)-2-(dimethylamino)methyl-1-(3-methoxyphenyl)cyclohexanol hydrochloride, Researched and developed by Gruenenthal Company in Germany, it has been widely used clinically since it was launched in Germany in 1977. Tramadol hydrochloride is a non-morphine central analgesic and a partial opioid receptor agonist. The analgesic efficacy is equivalent to that of pethidine, which is 1 / 10 to 1 / 6 of that of morphine. [0003] [0004] The document synthesis method of tramadol hydrochloride mainly is: prepare Grignard reagent---m-methoxyphenylmagnesium bromide in ether or tetrahydrofuran (THF), react with 2-dimethylaminomethylcyclohexanone again, the obtained The intermediate product is obtained by salting in an alco...

Claims

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Application Information

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IPC IPC(8): C07C217/74C07C213/00A61P25/04
Inventor 钟为慧吴窈窕苏为科
Owner DUODUO PHARMA
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