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A method for preparing n-methylazepine-4-one hydrochloride

A technology of methylazepam and hydrochloride, which is applied in the field of medicinal chemistry, can solve the problems of limited industrial use, difficult storage, and high price, and achieve the effects of mild reaction conditions, cheap raw materials, and easy operation

Active Publication Date: 2022-03-15
JIANGSU LINGYUN PHARMA
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  • Abstract
  • Description
  • Claims
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AI Technical Summary

Problems solved by technology

[0007] (1) Use N-methylpiperidin-4-one as raw material, react with diazomethane at low temperature to generate N-methylhexahydroazepine-4-one, and then form a salt with hydrogen chloride to obtain its hydrochloride, during the reaction The use of diazomethane, a dangerous explosive and toxic raw material, is not suitable for industrial production. Later, it was reported that N-nitroso-N-methylurethane was used to prepare diazomethane in situ, although to a certain extent The explosiveness of the reaction is reduced, but the dangerous substance diazomethane is still produced in the reaction, and N-nitroso-N-methylurethane itself is a 2B carcinogen, and the price is high, so industrial production This method should not be used in
[0008] (2) The method that industrial synthesis N-methylazepine-4-one hydrochloride mainly adopts at present is to take N-methyl-2-pyrrolidone (NMP) as starting raw material, heating and reflux ring-opening in hydrochloric acid obtains 4 -Methylaminobutyric acid hydrochloride, esterify the carboxyl group and then react with methyl acrylate to obtain a diester compound, and cyclize the diester compound under the condition of potassium tert-butoxide to obtain N-methylazepine-4-one , and finally use hydrochloric acid to form a salt to obtain N-methylazepine-4-one hydrochloride, but methyl acrylate is used in the synthesis process of this method, and methyl acrylate is in the list of carcinogens published by the International Agency for Research on Cancer of the World Health Organization carcinogens, and methyl acrylate is prone to polymerization above 10°C and is not easy to store, which brings certain restrictions to the industrial use of this method

Method used

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  • A method for preparing n-methylazepine-4-one hydrochloride

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Experimental program
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Effect test

Embodiment 1

[0041] Embodiment 1: synthetic reaction route is as follows:

[0042]

[0043] (1) Dissolve 4-oxime cyclohexanone (38.1g, 0.300mol) in 200mL of trifluoroacetic acid, trifluoroacetic acid is not only used as a catalyst to catalyze the Beckmann rearrangement, but also as a solvent, and the reaction solution is heated to 77°C, After refluxing for 1 hour, the trifluoroacetic acid was spin-dried and recrystallized from ethyl acetate to obtain 35.5 g of azepane-2,5-dione with a yield of 93%.

[0044](2) Add azepane-2,5-dione (31.8g, 0.250mol) to toluene 200mL, p-toluenesulfonic acid (2.2g, 0.013mol), ethylene glycol (23.3g, 0.375mol), Heat to 120°C, reflux for 2 hours to remove water, wash the solution successively with saturated sodium carbonate aqueous solution and saturated brine, dry and filter with anhydrous sodium sulfate, add red aluminum (416.6mL, 3.6mol / L toluene solution, 1.500mol), after the reaction solution was stirred at room temperature for 5 hours, 250mL of 5N aq...

Embodiment 2

[0046] Embodiment 2: synthetic reaction route is as follows:

[0047]

[0048] As described in Example 1, the difference is that the reagent used for Beckmann rearrangement in step (1) is p-toluenesulfonyl chloride, and the solvent is acetone. Dissolve 4-oxime cyclohexanone (38.1g, 0.300mol) in 500mL of acetone, add 180mL of 4N sodium hydroxide solution, then slowly add p-toluenesulfonyl chloride solution (102.9g, 0.540mol, dissolved in 500mL acetone), the reaction solution was stirred at room temperature for 3 hours, the acetone was evaporated, extracted with dichloromethane 3×200mL, dried over anhydrous sodium sulfate, filtered and spin-dried, and recrystallized with ethyl acetate to obtain 36.6g nitrogen Heteracycloheptane-2,5-dione, the yield is 96%.

Embodiment 3

[0049] Embodiment 3: synthetic reaction route is as follows:

[0050]

[0051] As described in Example 1, the difference is that the reagent used for Beckmann rearrangement in step (1) is concentrated sulfuric acid, and 4-oxime cyclohexanone (38.1 g, 0.300 mol) is slowly added to 100 mL under ice bath conditions Concentrated sulfuric acid, after adding, add this mixture into 100mL concentrated sulfuric acid which has been preheated to 120°C, react for 10 minutes, cool it with an ice bath, then add it dropwise into concentrated ammonia water, and use concentrated ammonia water After adjusting the pH to 6, extract with dichloromethane 3×200mL, dry and filter with anhydrous sodium sulfate, spin dry, and recrystallize from ethyl acetate to obtain 32.4 azepane-2,5-dione with a yield of 85% .

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Abstract

The invention discloses a method for preparing N-methylazepam-4-one hydrochloride. The method uses 4-oxime cyclohexanone as a raw material to obtain azepane-2,5-dione under Beckmann rearrangement conditions, and then condenses with ethylene glycol to generate a ketal, reduces the amide through red aluminum, and forms Kylation, and ethylene glycol is removed under hydrochloric acid conditions to finally obtain N-methylazepine-4-one hydrochloride. The present invention provides a safe, reliable and efficient synthetic route, with cheap raw materials and mild reaction conditions, without the use of explosive diazomethane and methyl acrylate, an easily polymerizable and highly carcinogenic chemical reagent. Suitable for industrial mass production.

Description

technical field [0001] The invention relates to the field of medicinal chemistry, in particular to a preparation method of N-methylazepine-4-one hydrochloride, a synthetic intermediate of a long-acting antiallergic drug Azelastine hydrochloride. Background technique [0002] Azelastine hydrochloride is an oral long-acting antiallergic drug with a unique structure. It has strong antihistamine pharmacological activity and is the most active of all antihistamine drugs. It also has comprehensive anti-inflammatory mediators The role of , developed by Asta-Werke AG of Germany and Eisai of Japan, its chemical name is 4-(4-chlorobenzyl)-2-(hexahydro-1-methyl-1H-azepine-4-yl )-1-(2H)-phthalazine hydrochloride. CAS number: 153408-27-6, molecular formula: C 22 h 25 Cl 2 N 3 O, whose structure is: [0003] [0004] In the current route for the synthesis of azelastine hydrochloride, an important intermediate is N-methylazepine-4-one hydrochloride. The present invention relates t...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D223/08
CPCC07D223/08
Inventor 凌青云蒋忠良杨杰
Owner JIANGSU LINGYUN PHARMA
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