Method for preparing compound zolpidem

A compound, zolpidem technology, applied in the field of chemical synthesis, can solve the problems of unreported zolpidem synthesis, inability to synthesize zolpidem, unsuitable for industrial production, etc., and achieve the effect of short reaction steps, low cost and atom economy

Active Publication Date: 2013-10-23
JIANGSU HANSOH PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0022] 5-methyl-2-aminopyridine and 4-methylbenzaldehyde are first condensed into imine, and then in CuCl and Cu(OTf)2 under catalysis and N,N-dimethylpropynylamide cyclization to generate the target compound; although the synthetic route is relatively simple and economical, the catalytic system is completed in a microreactor and a glove box. Under normal conditions or during enlarged operation, the yield drops sharply, so it is not suitable for industrial production
[0023] In addition, the literature Tetrahedron Letters, 2010, 51, 4605-4608, Tetrahedron Letters, 2011, 52, 5789-5793 and Synthesis, 2011, 21, 3463-3470 also A similar method has been reported, wherein the documents Tetrahedron Letters, 2010, 51, 4605-4608 and Synthesis, 2011, 21, 3463-3470 have not reported the synthesis of zolpidem, indicating that zolpidem cannot be synthesized under the conditions reported; and Although the literature Tetrahedron Letters, 2011, 52, 5789-5793 reports the synthesis of the precursor ester compound of zolpidem, it also has similar shortcomings as in Angew.Chem.Int.Ed.2010, 49, 2743-2746, And the catalyst InBr3 used is expensive, so it is not suitable for industrial production

Method used

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  • Method for preparing compound zolpidem
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  • Method for preparing compound zolpidem

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0047] Example 1 Preparation of 5-methyl-N-(4-methylbenzylidene)pyridin-2-amine

[0048] Add 395-methyl-2-aminopyridine, 260mg p-toluenesulfonic acid hydrate and 80ml anhydrous toluene into a dry 250ml two-necked bottle, stir to dissolve, add 3.4ml 4-methylbenzaldehyde, under the water separator device Stir and reflux for 12 hours; then evaporate most of the toluene, cool down to 90-80°C, transfer the reaction solution to a dry 50ml round-bottomed flask, and distill under reduced pressure to obtain 3.8g of white solid with a yield of 65.2%.

[0049] ESI-MS: [M+H] = 211.0; 1 H NMR (400MHz, CDCl3) δ9.11(s, 1H), 8.29(s, 1H), 7.86(d, J=7.9Hz, 2H), 7.53(d, J=8.0Hz, 1H), 7.26(d , J=7.8Hz, 2H), 7.22(d, J=8.0Hz, 1H), 2.40(s, 3H), 2.33(s, 3H).

Embodiment 2

[0050] Example 2 Preparation of N, N, 6-trimethyl-2-(4-methylphenyl)-imidazo[1,2-a]pyridine-3-acetamide

[0051] In a dry 25ml reaction vial, add 10mgCul, 105mg5-methyl-N-(4-methylbenzylidene)pyridin-2-amine and 97mgN, N-dimethylpropynamide successively, then add 2ml without Water toluene, reflux reaction for 36h; after the reaction is completed, cool to room temperature, dilute with 5ml of dichloromethane, then add 6-7 drops of triethylamine, stir for 10min, filter under reduced pressure under a small amount of basic alumina, and filtrate The evaporator was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate: triethylamine-1:1:0.1) to obtain the target product, 111 mg of white solid, with a yield of 72%.

[0052] 1 H NMR (400MHz, CDCl3) δ8.02(s, 1H), 7.57(d, J=7.6Hz, 2H), 7.54(s, 1H), 7.28(d, J=6.2Hz, 2H), 7.06(d , J=9.2Hz, 1H), 4.11(s, 2H), 2.94(s, 3H), 2.90(s, 3H), 2.40(s, 3H), 2.3...

Embodiment 3

[0053] Example 3 Preparation of N, N, 6-trimethyl-2-(4-methylphenyl)-imidazo[1,2-a]pyridine-3-acetamide

[0054] In a dry 25ml reaction bottle, add 108mg 5-methyl-2 aminopyridine, 19mg p-toluenesulfonic acid hydrate, 5ml anhydrous toluene to dissolve, then add 124.3μl 4-methylbenzaldehyde, reflux for 6h, cool to room temperature, then add 194 mg N, N-dimethylpropynamide and 16 mg CuSO 4 , the temperature rose to 60° C., reacted for 4 hours, and ended the reaction; the post-treatment operation method was the same as in Example 2, and 40 mg of the target product was obtained with a yield of 13%.

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Abstract

The invention belongs to the field of chemical synthesis, and relates to a method for preparing a compound zolpidem. The invention provides an effective new method for preparing zolpidem by a trimaceral serially reaction. The method for preparing the zolpidem provided by the invention has the advantages that the reaction step is short, the condition is moderate, atom economy and environmentally friendly are achieved, the yield is high, the cost is low, industrialized production is applicable, and the defects in the prior art that the synthetic route is long and the cost is high are overcome.

Description

technical field [0001] The invention belongs to the field of chemical synthesis, and in particular relates to a method for preparing a compound zolpidem. Background technique [0002] Zolpidem (Zolpidem, also known as sleeping pills, Stilnox) chemical name is N, N, 6-trimethyl-2-(4-methylphenyl)-imidazo[1,2-a]pyridine-3-ethane Amide is a non-benzodiazepine short-acting imidazopyridine sedative-hypnotic drug developed by Sanofi, France. It was first launched in 1988 and is used to treat insomnia and brain diseases. Studies have shown that Zolpidem, as a new generation of hypnotics, does not have a high affinity for the receptor GABA like traditional benzodiazepines, but it has high selectivity for the benzodiazepine receptor BZR1. The affinity is stronger than that of BZR2, and there is another special binding site, which leads to the opening of chloride ion channels, allowing chloride ions to flow into nerve cells, causing cell membrane hyperpolarization, thereby inhibiting...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D471/04
Inventor 雷新胜林国强许千千刘平
Owner JIANGSU HANSOH PHARMA CO LTD
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