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Novel preparation method of azasetron hydrochloride

A technology of azasetron hydrochloride and nitric acid, which is applied in the new field of preparation of azasetron hydrochloride, can solve the problems of complex post-processing, large environmental pollution, difficult refining, etc., and achieve industrial production, shorten the reaction route, and Handle simple effects

Inactive Publication Date: 2019-12-13
CHENGDU UNIV
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0010] The above-mentioned routes all adopt sulfuric acid-nitric acid mixed acid nitration in the nitration reaction, and the mixed acid nitration has great environmental pollution, which is not conducive to industrial production; in the reduction reaction, high-temperature reflux reduction is used, there are many by-products, the post-treatment is complicated, and the actual yield is low ; In the cyclization reaction, adopt methyl iodide or dimethyl sulfate as N-methylation reagent, expensive, environmental pollution is big, yield is lower, is unfavorable for suitability for suitability for industrialized production
[0011] On the other hand, when preparing azasetron hydrochloride, route one uses thionyl chloride as an acylating reagent in the reaction process, and the equipment and the environment are polluted in large quantities; in route two, the highly toxic reagent ethyl chloroformate is used ester or trimethylacetyl chloride, and requires -20°C reaction and chromatographic column separation and purification, which is not conducive to large-scale production; the reaction time of route 3 is very long and the condensing agent DCC is needed in the process, and the late DCC and by-product DCU are difficult to refine ; route four reaction conditions are mild, but directly condensed with 3-aminoquinine dihydrochloride, more by-products need column chromatography separation and purification, which is unfavorable for industrialized production

Method used

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  • Novel preparation method of azasetron hydrochloride
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  • Novel preparation method of azasetron hydrochloride

Examples

Experimental program
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Effect test

Embodiment 1

[0043] The preparation method of embodiment 1 compound III

[0044]Put 78.40g of methyl 5-chlorosalicylate into a 250mL dry three-necked bottle, add 120mL of acetic anhydride, cool to -5~0°C, add 19mL of fuming nitric acid dropwise under vigorous mechanical stirring, and react for 40min at the same temperature after dropping , poured into ice water (about 750 mL), filtered, washed with ice water and filtered to obtain a brick red solid, recrystallized from ethanol to obtain 87.82 g of light yellow powdery solid, yield 90.3%.

Embodiment 2

[0045] The preparation method of embodiment 2 compound IV

[0046] At room temperature, put 23.2g of compound III in a 250mL three-necked flask, add 100mL of ethyl acetate, stir until dissolved, then slowly add 70mL of concentrated hydrochloric acid dropwise, after the drop is complete, stir for 10min, add 35.5g of stannous chloride dihydrate in batches , Reaction at room temperature for 3.5h. Most of the solvent was removed by rotary evaporation, and the residue was poured into 200 mL of ice water, and adjusted to pH 7-8 with 2.5 mol / L sodium hydroxide solution. Extract with ethyl acetate, combine the organic phases, wash with saturated brine, dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain 18.2 g of yellow-green solid IV, with a yield of 90%.

Embodiment 3

[0047] The preparation method of embodiment 3 compound V

[0048] Put 8.9 g of compound IV in a 500 mL three-necked flask, add 210 mL of dichloromethane, stir until completely dissolved, and then add 100 mL of saturated sodium bicarbonate solution dropwise. Cool to 0°C, add 6.6 g of chloroacetyl chloride dropwise under rapid stirring, and react at the same temperature for 3 hours after dropping. The organic layer was washed with water, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a reddish-brown solid. Add 55ml of DMF and 14.5g of potassium carbonate to the concentrate, stir until dissolved, and raise the temperature to 70°C for 2h. The temperature was raised to 75°C, and 6.3 g of dimethyl carbonate was added dropwise to the reaction liquid, and reacted for 3 hours. Pour into ice water, filter, wash the filter cake with water, and dry under reduced pressure to obtain white solid V10.38g, yield 92%.

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Abstract

The invention provides a novel preparation method of azasetron hydrochloride, belonging to the technical field of medicine synthesis. According to the method, methyl 5-chlorosalicylate is used as a raw material; after acetic anhydride nitrification and stannous chloride reduction at room temperature, dimethyl carbonate is used as a methylation reagent, and an intermediate V (6-chloro-4-methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-8-carboxylic acid methyl ester) is synthesized by adopting a one-pot method; the intermediate V is hydrolyzed to obtain 6-chloro-4-methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-8-formic acid (VI); and the compound reacts with free 3-aminoquinuclidine dihydrochloride for 1 h under the catalysis of TBTU to form a salt so as to obtain I (azasetron hydrochloride). According to the method, the yield of each step is high; aftertreatment is simple; the reaction time of each step is short; conditions are mild; low-toxicity environment-friendly reagents are adopted; energy consumption is reduced; cost is saved; and industrial production is better facilitated.

Description

technical field [0001] The invention belongs to the technical field of medicine synthesis, and in particular relates to a new preparation method of azasetron hydrochloride. Background technique [0002] Azasetron Hydrochloride (Azasetron Hydrochloride) chemical name: (±)-N-[1-azabicyclo[2.2.2]oct-3-yl]-6-chloro-4-methyl-3-oxo -3,4-dihydro-2H-1,4-benzoxazine-8-carboxamide hydrochloride. The molecular formula is: C 17 h 20 ClN 3 o 3 HCl, the structural formula is: [0003] [0004] Azasetron hydrochloride is mainly used for the treatment and prevention of nausea and vomiting caused by tumor surgery and chemotherapy. It is a highly efficient, highly selective, and low-side-effect 5-HT 3 receptor inhibitors. The drug can not only effectively suppress acute nausea and vomiting, but also has a better effect on delayed nausea and vomiting. Animal experiments showed that azasetron hydrochloride had an effect on rat cerebral cortex 5-HT 3 The receptor affinity is about 41...

Claims

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Application Information

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IPC IPC(8): C07D453/02
CPCC07D453/02
Inventor 曹胜华曹宁孟健董宏波杜伟宏罗红兵唐克慧王宇驰
Owner CHENGDU UNIV
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