Method for preparing meptazinol and analogs thereof

A compound and low-level technology, applied in the direction of organic chemistry, etc., can solve the problems of difficult to achieve large-scale production of meptanol, time-consuming post-processing, slow quenching operation, etc., achieve synthesis conditions and process optimization, easy feeding, and easy to overcome fire effect

Active Publication Date: 2012-01-18
CHINA RESOURCES DOUBLE CRANE PHARMA COMPANY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, exposure of Lithium Aluminum Hydride to the air, especially humid air, is easy to cause combustion, and the feeding operation during production will inevitably make Lithium Aluminum Hydride come into contact with the air, which brings great safety hazards to production operations.
Secondly, the post-treatment of lithium aluminum hydride reduction reaction is time-consuming, and the quenching operation must be carried out very slowly to ensure safety.
These disadvantages of Lithium Aluminum Hydride make it difficult to scale up the production of Mebutamol

Method used

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  • Method for preparing meptazinol and analogs thereof
  • Method for preparing meptazinol and analogs thereof
  • Method for preparing meptazinol and analogs thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 2

[0046] Example 2 Preparation of 1-methyl-3-ethyl-3-(3-hydroxyphenyl)-hexahydro-1H-azepine (mebutamol) by red aluminum method

[0047] Add 20.0g (0.081mol) 1-methyl-3-ethyl-3-(3-hydroxyphenyl)-hexahydro-1H-azepine-2-one and 400ml methyl For tert-butyl ether, pass nitrogen under stirring and cool down to 10°C with an ice-water bath, add 116.9g (0.405mol, d=1.036) red aluminum dropwise, heat up after dropping, and react at the reflux temperature of methyl tert-butyl ether for 9 After one hour, the reaction solution was cooled to 10°C, and 60.7ml of saturated ammonium chloride solution was slowly added dropwise, and the drop was completed in 10 minutes. The reaction solution was a suspension with a large number of small white particles, and the powder could settle quickly after standing. Filtrate, add 300 ml of methyl tert-butyl ether to the filter cake, stir and wash, filter, combine the filtrates, and distill off the solvent under reduced pressure to obtain 17.8 g of a light yel...

Embodiment 3

[0048] Example 3 Preparation of 1-methyl-3-ethyl-3-(3-hydroxyphenyl)-hexahydro-1H-azepine (mebutamol) by red aluminum method

[0049] Add 20.0g (0.081mol) 1-methyl-3-ethyl-3-(3-hydroxyphenyl)-hexahydro-1H-azepine-2-one and 400ml methyl For tert-butyl ether, pass nitrogen under stirring and cool down to 10°C with an ice-water bath, add 46.7g (0.162mol, d=1.036) red aluminum dropwise, heat up after dropping, and react at the reflux temperature of methyl tert-butyl ether for 30 After one hour, the reaction solution was cooled to 10° C., and 24.3 ml of a saturated ammonium chloride solution was slowly added dropwise, and the dropwise was completed in 10 minutes. Filter, add 300ml of methyl tert-butyl ether to the filter cake, stir and wash, filter, combine the filtrates, evaporate the solvent under reduced pressure to obtain a light yellow crude product, HPLC content: 84.1% of meprotamol, unreacted 1-methyl- 3-Ethyl-3-(3-hydroxyphenyl)-hexahydro-1H-azepin-2-one 15.3%. The crude ...

Embodiment 4 3

[0051] Example 4 Preparation of 1-methyl-3-ethyl-3-(3-hydroxyphenyl)-hexahydro-1H-azepine (mebutamol) by boron trifluoride ether-sodium borohydride method

[0052] Under ice-cooling, add 400ml tetrahydrofuran containing 9.5g (0.243mol) sodium borohydride into a three-necked flask, add 46.0g (0.324mol) boron trifluoride etherate complex with stirring, and stir for 1 hour. Carefully add 20.0g (0.081mol) of 1-methyl-3-ethyl-3-(3-hydroxyphenyl)-hexahydro-1H-azepin-2-one, stir and heat, at the reflux temperature of tetrahydrofuran React for 2 hours. The reaction solution was cooled and neutralized with saturated sodium bicarbonate. The solvent was removed under reduced pressure, the residue was dissolved in 300ml of ethanol, 5N hydrochloric acid was added, and heated to reflux for 1 hour. After the reaction solution was cooled, the solvent was removed under reduced pressure, the residue was neutralized with saturated sodium bicarbonate to pH=7-8, the aqueous phase was extracted w...

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Abstract

The invention relates to a method for preparing meptazinol and analogs thereof, in particular to a method for preparing a compound shown in the general formula (1) from a compound shown in the general formula (2). Reducing agents are selected from one kind of or several kinds of materials in dihydro (2-methoxyethoxy) sodium aluminate (vitride solution), sodium borohydride, boron triflouride-aether, boron triflouride aether-sodium borohydride, boron triflouride and borane-methyl sulfide and is preferably the vitride solution. The reducing agents used in the method are stable in the air, in addition, the material addition is easy, and the quenching process can be completed in a shorter time, so the operation requirement is low, and the defect that the fire catching and the explosion are easy to occur in the traditional tetrahydro aluminum lithium reduction method is overcome.

Description

technical field [0001] The present invention relates to the preparation method of mebutanol and its analogs, in particular to the reduction of 1-alkyl-3-alkyl-3-substituted phenyl-hexahydro-1H-azepine-2-one compounds It is a method for 1-alkyl-3-alkyl-3-substituted phenyl-hexahydro-1H-azepine compounds, which overcomes the flammable and explosive problems of the traditional lithium tetrahydrohydride reduction method in production. defect. Background technique [0002] 1-methyl-3-ethyl-3-(3-hydroxyphenyl)-hexahydro-1H-azepine is commonly known as Meptazinol, and its hydrochloride is used clinically. It was established in 1986 It was listed in the UK for the first time, with trade names of Meptid (Wyeth.UK) and Meptid (Ger) and Meptidol (Aust). It was recorded in the British Pharmacopoeia in 1998. It is a powerful analgesic used to treat moderate and severe pain. The reported patents are basically unavoidable to undergo the reaction process of reducing the amide carbonyl gro...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D223/04
Inventor 江超周宜遂戴畅戎娜李梦琳
Owner CHINA RESOURCES DOUBLE CRANE PHARMA COMPANY
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