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Process for the preparation of 2-phenyl-imidazo [1, 2-a] pyridine-3-acetamides

a technology of pyridine and phenylimidazo, which is applied in the field of process for the preparation of 2phenylimidazo 1, 2a pyridine3acetamide, can solve the problems of toxic reagents, industrially unsuitable procedures, and restrictions on the industrial application of this synthetic approach

Inactive Publication Date: 2002-02-14
DINAMITE DIPHARMA ABBREVIATED DIPHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The use of methyl iodide (highly toxic, low-boiling alkylating agent) in the alkylation step and the nucleophilic substitution of the quaternary ammonium salt with sodium cyanide (which is per se a dangerous starting product) restricts the industrial application of this synthetic approach.
This procedure, although being direct and requiring only two steps, is critical due to formation of methylmercaptan (toxic gas) from the reduction reaction, to the use of nickel-Raney (cancerogenic) and to the poor yield.
In conclusion, all known synthesis of Zolpidem use either reagents commercially available with difficulty, toxic reagents, or industrially unsuitable procedures due to low yields and / or products with poor purity which should undergo repeated purification procedures.

Method used

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  • Process for the preparation of 2-phenyl-imidazo [1, 2-a] pyridine-3-acetamides
  • Process for the preparation of 2-phenyl-imidazo [1, 2-a] pyridine-3-acetamides
  • Process for the preparation of 2-phenyl-imidazo [1, 2-a] pyridine-3-acetamides

Examples

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Effect test

example 2

[0064] Preparation of Ethyl 2-(4-methylphenyl)-6-methylimidazo[1,2-a]-pyri-dine-3-glyoxalate

[0065] A suspension of potassium monoethyl oxalate (84.3 g; 0.54 mols) in methylene chloride (395 mL) is added dropwise with phosphorous oxychloride (82.8 g; 0.54 mols) keeping the temperature at about 30.degree. C. After 4-6 hours, 2-(4-methylphenyl)-6-methylimidazo[1,2-a]--pyridine (100.0 g; 0.45 mols) is added, keeping the temperature below 35.degree. C. The resulting suspension is added dropwise with triethylamine (50.5 g; 0.50 mols) keeping the mixture at the reflux temperature. After one hour under these conditions, the reaction mixture is cooled to 5.div.10.degree. C. and poured into a suspension of sodium carbonate (95 g; 0.89 mols) in water (500 mL) keeping the temperature below 35.degree. C. The phases are separated and the upper aqueous phase is reextracted with methylene chloride (45 mL). The combined organic phases are washed with water (45 mL) and concentrated to a residue under...

example 3

[0067] Preparation of 2-(4-methylphenyl)-6-methylimidazo[1,2-a]-pyridine-3--acetic acid

[0068] A solution of potassium hydroxide (90% titre; 30.3 g; 0.48 mols) in water (225 mL) and ethanol (65 mL) is added with ethyl 2-(4-methylphenyl)-6-methylimidazo[1,2-a]-pyridine-3-glyoxalate (141.5 g; 0.44 mols). The suspension is refluxed to obtain a yellow--orange solution, which is concentrated to reach a temperature of 98-100.degree. C. and added with hydrazine (51.7% titre, 27.5 g; 0.44 mols). The solution is refluxed for 14 hours, then cooled to about 60.degree. C., added with potassium hydroxide (90% titre, 54.9 g; 0.88 mols), then distilled under atmospheric pressure to reach the inner temperature of 122.div.124.degree. C., keeping the resulting suspension under reflux until nitrogen evolution ceases. The mixture is cooled to about 100.degree. C., diluted with water (500 mL), cooled at room temperature and filtered through Celite. The resulting clear solution is dropped in about one hou...

example 4

[0070] Preparation of N,N,6-trimethyl-2-4(methylphenyl) -imidazo[1,2-a]pyridine-3-acetamide

[0071] A suspension of 2-(4-methylphenyl)-6-methylimidazo[1,2-a]-pyridine--3-acetic acid (59.2 g; 0.21 mols) in methylene chloride (820 mL) is added dropwise with oxalyl chloride (29.9 g; 0.23 mols) adjusting the addition according to the gas evolution and keeping the temperature under 35.degree. C. The resulting suspension is added with 2-(4-methylphenyl)-6-methylimidazo[1,2-a]-pyridine-3-acetic acid (59.2 g; 0.21 mols) and oxalyl chloride (29.9 g; 0.23 mols) is added dropwise with same procedure as in the previous step. The suspension is refluxed for 30 minutes, then cooled to 10.div.15.degree. C. and added with N,N-dimethylamine hydrochloride (98% titre, 41 g, 0.49 mols). Keeping the temperature below 15.degree. C., triethylamine (167 g, 1.65 mols) is added dropwise. After one hour at room temperature, water is added (200 mL), the phases are separated and the lower organic phase is washed w...

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Abstract

A process for the preparation of 2-phenyl-imidazo[1,2-a]pyridine-3 -acetamides comprises the reaction of a 2-phenyl-imidazo[1,2-a]pyridine with an oxalic ester reactive derivative, followed by reduction of the carbonyl group and reaction with an amine.

Description

[0001] The present invention relates to a process for the preparation of 2-phenyl-imidazo[1,2-a]pyridine-3-acetamides.[0002] More particularly, the invention relates to a process for the preparation of Zolpidem (N,N-dimethyl-6-methyl-2-(4-methylphenyl)imidazo[-1,2-a]pyridine-3-acetamide hemitartrate), a pharmaceutical compound with hypnotic-sedative activity at present widely used in clinic, disclosed in EP 50.563.[0003] Zolpidem has the following structural formula: 1TECHNOLOGICAL BACKGROUND[0004] Zolpidem is the parent compound of a chemical class with hypnotic activity which has recently arisen interest: 2-phenyl-imidazo[1,2-a]pyrid-ine-3-acetamides, having the following general formula: 2[0005] wherein X, Y, R.sup.1 and R.sup.2 are substituents widely documented in a number of patents and articles published in the last two decades, concerning the preparation of a great deal of derivatives as well as the hypnotic-sedative properties thereof.[0006] The known processes for the prep...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K31/4188A61K31/437A61P25/00C07D471/04
CPCC07D471/04A61P25/00
Inventor CASTALDI, GRAZIANO
Owner DINAMITE DIPHARMA ABBREVIATED DIPHARMA