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Efficient synthesis method of histamine H3 receptor antagonist pitolisant

The technology of a receptor antagonist and a synthesis method, which is applied in the field of synthesis of pharmaceutical compounds, can solve problems such as unfavorable pharmaceutical production and safe use, and achieve the effects of overcoming bottleneck problems and short reaction routes.

Active Publication Date: 2022-02-08
HENAN NORMAL UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] The currently published synthetic methods of Proprisan mainly include WO 2007006708 and CN 103435575A (synthetic route as shown above) and other literature reports, these two synthetic methods announced in the literature are all based on 3-(4-chlorophenyl) propyl methanesulfonate Ester is the key intermediate, and the preparation of 3-(4-chlorophenyl) propyl methanesulfonate needs to be raw material with banned poison methanesulfonyl chloride, and 3-(4-chlorophenyl) propyl methanesulfonate The use of methyl mesylate is very easy to introduce genotoxic impurities, which is not conducive to the production and safe use of drugs

Method used

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  • Efficient synthesis method of histamine H3 receptor antagonist pitolisant
  • Efficient synthesis method of histamine H3 receptor antagonist pitolisant
  • Efficient synthesis method of histamine H3 receptor antagonist pitolisant

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0022] Preparation of 3'-(piperidine)-propyl-4-chlorophenylpropionate (compound 3)

[0023] Add toluene (150mL), 4-chlorophenylpropionic acid (20.2g, 0.11mol), 1-piperidinepropanol (14.3g, 0.1mol) and p-toluenesulfonic acid (2g) in a 250mL three-necked flask, heat to reflux water. After the reaction was complete, the temperature was lowered to room temperature, the reaction solution was washed twice with saturated sodium carbonate (50 mL), separated, the organic phase was dried over anhydrous sodium sulfate, the desiccant was filtered off, and the mother liquor was spin-dried to obtain 26 g of the target compound 3 with a yield of 84%. . 1 H-NMR: (400MHz, CDCl 3 )δ1.43(m,2H),1.58(m,4H),1.82(m,2H),2.36(t,6H),2.61(t,2H),2.93(t,2H),4.09(t,2H) ,7.14-7.23(m,4H).

Embodiment 2

[0025] Preparation of 3'-(piperidine)-propyl-4-chlorophenylpropionate (compound 3)

[0026] Add thionyl chloride (100 mL), 4-chlorophenylpropionic acid (20.2 g, 0.11 mol) and DMF (1 mL) into a 250 mL three-necked flask, heat to reflux for 2 hours, and distill under reduced pressure to remove the remaining thionyl chloride. Anhydrous tetrahydrofuran (100 mL) and 1-piperidine propanol (14.3 g, 0.1 mol) were added to the residue, and heated to reflux until the reaction was complete. The solvent tetrahydrofuran was distilled off under reduced pressure, ethyl acetate (100 mL) was added to the residue, saturated sodium carbonate (100 mL) was added after dissolving, stirred for 10 minutes, separated, the organic phase was dried over anhydrous sodium sulfate, the desiccant was filtered off, and the mother liquor Spin-dried to obtain 25 g of the target product with a yield of 81%. 1 H-NMR: (400MHz, CDCl 3 )δ1.43(m,2H),1.58(m,4H),1.82(m,2H),2.36(t,6H),2.61(t,2H),2.93(t,2H),4.09(t,2H) ...

Embodiment 3

[0028] Preparation of 1-(3-(3-(4-chlorophenyl)-1-((trimethylsilyl)oxy)propoxy)propyl)piperidine (Compound 4)

[0029] Put DCM (50 mL) and compound 3 (3.1 g, 0.01 mol) in a three-neck flask under nitrogen protection, and cool to -78°C. Add DIBAL-H (12 mL, 1.0 M hexane dispersion) dropwise, and control the rate of addition so that the temperature of the mixed system is not higher than -70°C. After completion of the dropwise addition, control the temperature at -70°C to -78°C and stir for 30 minutes. Trimethylsilimidazole (4.2 g, 0.03 mol) was added dropwise and stirred for 1 hour. Add saturated NH dropwise 4 Aqueous Cl (30 mL) quenched the reaction. The quenched solution was naturally warmed to room temperature, filtered, and the mother liquor was separated. The aqueous phase was extracted three times with DCM (15 mL), and the organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give 3.6 g of crude compound 4. The compoun...

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Abstract

The invention discloses an efficient synthesis method of histamine H3 receptor antagonist pitolisant, which comprises the following specific steps: directly carrying out esterification reaction on 3-(4-chlorphenyl) propionic acid serving as an initial raw material and 1-piperidine propanol under the catalytic action of acid to obtain a compound 3; reducing the compound 3 into a compound 4 under the action of a reduction system, with the reduction system being a mixed system of trimethylsilylimidazole and diisobutylaluminium hydride or a mixed system of trimethylsilylimidazole and red aluminum; and reducing the compound 4 under the combined action of a mixed system of triethyl silane and trimethylsilyl trifluoromethanesulfonate to obtain the target product pitolisant. The method has the advantages of short reaction route, high production efficiency and simple and easily available raw materials.

Description

technical field [0001] The invention belongs to the technical field of synthesis of pharmaceutical compounds, and in particular relates to a high-efficiency synthesis method of a histamine H3 receptor antagonist, prolixan. Background technique [0002] Tilosan was approved by the US Food and Drug Administration (FDA) in 2019 for the treatment of excessive daytime sleepiness (EDS) in adults with narcolepsy. It is the first and only drug that has not been listed by the US Drug Enforcement Administration (DEA). Drugs dispensed by FDA for the treatment of excessive daytime sleepiness or cataplexy associated with narcolepsy. Narcolepsy is a rare, chronic, debilitating neurological disorder of unstable sleep-wake states, recognized globally as one of the rare disorders, characterized by excessive daytime sleepiness (EDS) and cataplexy , and other manifestations of REM sleep disorders. The disease affects both men and women equally, with typical symptoms appearing in adolescence ...

Claims

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Application Information

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IPC IPC(8): C07D295/088
CPCC07D295/088Y02P20/55
Inventor 杨嬅嬿杨守宁
Owner HENAN NORMAL UNIV
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