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Preparation method of zaleplon

A technology of zaleplon and synthetic route, applied in the direction of organic chemistry, can solve the problem of high yield, achieve the effect of short route, reduce synthesis cost, and avoid the production of isomers

Active Publication Date: 2021-04-30
XINXIANG MEDICAL UNIV +1
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  • Abstract
  • Description
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  • Application Information

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Problems solved by technology

[0011] In 2020, Chinese patent CN107973800 reported the use of N-ethyl-N-(3-(pyrazolo[1,5-a]pyrimidin-7-yl)phenyl)acetamide and trimethylsilylacetonitrile in the presence of acridine Carry out light reaction in the reaction solvent of salt catalyst, directly realize cyanation reaction and prepare zaleplon, although this preparation route is short, and yield is high, but the raw material N-ethyl-N-(3-(pyrazolo [1,5-a]pyrimidin-7-yl)phenyl)acetamide requires multi-step pre-preparation

Method used

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  • Preparation method of zaleplon
  • Preparation method of zaleplon
  • Preparation method of zaleplon

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0025] Preparation of compound 3

[0026]

[0027] Add m-nitrobenzaldehyde 1 (75.5mg, 0.5mmol), 3-amino-4-cyanopyrazole 2 (54mg, 0.5mmol), triethylamine (101mg, 1mmol), ammonium iodide in a 35mL sealed tube (72.5mg, 0.5mmol), di-tert-butyl peroxide (219mg, 1.5mmol) and toluene (2mL), then placed in an oil bath at 130°C and stirred for 10h. Add 50mL of water to quench the reaction, extract with ethyl acetate (50mL×3), and then the organic phase is treated with 10% Na 2 S 2 o 3 The solution was washed successively with saturated brine, and dried over anhydrous sodium sulfate. It was filtered, spin-dried, and separated by silica gel column (petroleum ether / ethyl acetate=3 / 1, v / v) to obtain compound 3 (114 mg, 86%) as a yellow solid product. The characterization data of this compound are as follows: 1 H NMR (400MHz, DMSO-d 6 ): δ (ppm) 8.97 (d, J = 1.6Hz, 1H), 8.95 (d, J = 4.8Hz, 1H), 8.88 (s, 1H), 8.48 (dd, J = 8.0, 2.0Hz, 2H) ,7.92(t,J=8.0Hz,1H),7.72(d,J=4.4Hz,1H); 13...

Embodiment 2

[0029] Preparation of Compound 4

[0030]

[0031] Iron powder (184.8 mg, 3.3 mmol) and glacial acetic acid (20 mL) were put into a three-necked flask, stirred and heated to reflux, acidified for 10 min, and a solution of compound 3 (265 mg, 1 mmol) in glacial acetic acid (25 mL) was added dropwise. After the dropwise addition, continue to reflux for 4h. The reaction was quenched by adding 50 mL of water, extracted with ethyl acetate (50 mL×3), and then the organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. Filtered, spin-dried, and dried to give compound 4 (230 mg, 83%) as a white solid. The characterization data of this compound are as follows: 1 HNMR (400MHz, DMSO-d 6 ):δ(ppm)10.25(s,1H),8.89(d,J=4.4Hz,1H),8.86(s,1H),8.32(t,J=1.8Hz,1H),7.85–7.81(m, 1H), 7.70–7.67(m, 1H), 7.54(t, J=8.0Hz, 1H), 7.50(d, J=4.8Hz, 1H), 2.08(s, 3H); 13 C NMR (100MHz, DMSO-d 6 ):δ(ppm)168.7,153.8,151.1,147.5,147.3,139.4,129.9,129.1,124.3,122.0,119.9,113...

Embodiment 3

[0033] Preparation of compound 5

[0034]

[0035]Sodium hydride (58mg, 2.4mmol) and anhydrous DMF (2mL) were put into a three-necked flask filled with nitrogen, stirred in an ice-water bath, a DMF (6mL) solution of compound 4 (110.8mg, 0.4mmol) was added dropwise, and After the addition was completed, reacted for 5 minutes, added bromoethane (436 mg, 4 mmol) dropwise, and continued to stir in an ice-water bath for 30 minutes. It was extracted with ethyl acetate (50 mL×3), and the organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. Filtered, spin-dried, and dried to give compound 5 (103.7 mg, 85%) as a white solid. The characterization data of this compound are as follows: 1 H NMR (400MHz, DMSO-d 6 ): δ (ppm) 8.92 (d, J = 4.4Hz, 1H), 8.87 (d, J = 0.4Hz, 1H), 8.09 (d, J = 7.6Hz, 1H), 8.04 (s, 1H), 7.71 (t, J=7.8Hz, 1H), 7.67(d, J=4.4Hz, 1H), 7.61(d, J=7.2Hz, 1H), 3.70(q, J=6.8Hz, 2H), 1.81(s ,3H),1.03(t,J=6.8Hz,3H); 13 C NMR (100MHz, ...

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Abstract

The invention discloses a preparation method of zaleplon, and belongs to the technical field of medicinal chemistry. According to the method, m-nitrobenzaldehyde and triethylamine which are simple and cheap are adopted as raw materials, and a core skeleton of zaleplon is efficiently and highly selectively constructed through a one-pot cascade reaction without transition metal catalysis, so that the generation of isomers is avoided, the generation of byproducts is reduced, the yield of a target product is increased, and the synthesis cost is reduced; and simple nitro reduction modification is performed to prepare zaleplon. The whole route is short, reaction conditions are mild, operation is easy and convenient, and the method is suitable for industrial production.

Description

technical field [0001] The invention belongs to the technical field of medicinal chemistry, and in particular relates to a preparation method of zaleplon. Background technique [0002] Zaleplon (Zaleplon), the chemical name is N-[3-(3-cyanopyrazolo[1,5-a]pyrimidin-7-yl)phenyl]-N-ethylacetamide, which is the United States A novel pyrazolopyrimidine sedative-hypnotics developed by Wyeth-Ayerst. In March 1999, the European Union approved zaleplon for the treatment of insomnia, and in August 1999, the US FDA approved zaleplon for adult insomnia. First launched in Denmark and Sweden in July 1999. Zaleplon, as a third-generation non-benzodiazepine sedative-hypnotics that has been used in clinical practice, is a complete agonist of benzodiazepine ω1 receptors, with short half-life, good curative effect, few side effects, and no spirit It is mainly used for the short-term treatment of adult insomnia. It can make insomnia patients fall asleep quickly, shorten the time to fall asle...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D487/04
CPCC07D487/04
Inventor 高庆贺韩新亚徐永涛段迎超吕洁丽房立真张妍严菊芬李莹莹
Owner XINXIANG MEDICAL UNIV
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