A process for the synthesis of zolpidem

Abstract

The application provides a low-cost, mild reaction condition, safe and environmentally friendly method for synthesizing zolpidem tartrate and derivatives thereof. The method uses 6-methyl-2-(4-methylphenyl) imidazo[1,2-a]pyridine and N,N-dimethyl halogenated acetamide as raw materials to prepare zolpidem in one step, which is simple in operation, short in period, solves the problems of long reaction step, low yield, high cost, production safety hazards and great harm in the existing method for synthesizing N,N,6-trimethyl-2-(4-methylphenyl) imidazo[1,2-a]pyridine-3-acetamide.

Description

TECHNICAL FIELD

[0001] The present application relates to a method for synthesizing zolpidem tartrate and its derivatives, belonging to the field of pharmaceutical synthesis chemistry. BACKGROUND

[0002] Zolpidem is a typical non-benzodiazepine

[0003] The structural formula is as follows:

[0004]

[0005] Zolpidem is a typical non-benzodiazepine hypnotic drug with the characteristics of fast onset, obvious effect and small adverse reactions. The drug is developed by Synthelabo Company of France and is widely used as a hypnotic drug in various parts of the world. In China, many pharmaceutical factories have put this product on the market, and the market sales are good, and the recognition is high.

[0006] At present, the preparation of zolpidem mainly has the following methods:

[0007] (1) Patent documents US4382938, US2007027180 and EP0050563 utilize p-methyl phenylacetone bromide and p-aminopyridine to cyclize under alkaline conditions to obtain 6-methyl-2-(4-methylphenyl)-imidazo[1,2-a]pyridine, then Mannich reaction with formaldehyde-dimethylamine to obtain N,N,6-trimethyl-2-(4-methylphenyl)-imidazo[1,2-a]pyridine-3-methylamine, ammonium saltization with iodomethane, substitution reaction with sodium cyanide to obtain 6-methyl-2-(4-methylphenyl)-imidazo[1,2-a]pyridine-3-acetonitrile, and then hydrolysis under alkaline conditions, carbonyl dimidazole ketone activation, and dimethylamine amidation to prepare zolpidem, with a total yield of 19%. The specific route of the synthesis is as follows:

[0008]

[0009] The preparation method has long reaction steps, complicated operation, large amount of wastewater, and uses toxic cyanide, which is poor in safety operation and high in cost, and is not suitable for industrial production.

[0010] (2) Patent document US4492695 directly uses 6-methyl-2-(4-methylphenyl)- imidazo[l,2-a]pyridine and oxalyl chloride-DMF to carry out formylation reaction to obtain 6-methyl-2-(4-methylphenyl)-3-formyl-imidazo[l,2-a]pyridine, sodium borohydride is used to reduce the aldehyde group, pyridine is used to salt, sodium cyanide is used to substitute to obtain 6-methyl-2-(4-methylphenyl)-imidazo[l,2-a]pyridine-3-acetonitrile, then hydrolysis under alkaline conditions, activation of carbonyl dimidazole ketone, and amidation of dimethylamine to prepare zolpidem, and the specific route of the synthesis is as follows:

[0011]

[0012] This preparation method also has the problems of long reaction steps, complicated operation, large amount of wastewater, and use of sodium cyanide, in addition, the operation period is long, and the production efficiency is low.

[0013] (3) Patent documents US4794185 and US6407240 use 6-methyl-2-(4-methylphenyl)- imidazo[l,2-a]pyridine and N,N-dimethyl glyoxylamide to carry out condensation to obtain N,N,6-trimethyl-2-(4-methylphenyl)-3-(2-hydroxy)dimethylaminocarbonylmethyl imidazo[l,2-a]pyridine, then thionyl chloride is used for substitution reaction to obtain N,N,6-trimethyl-2-(4-methylphenyl)-3-(2-chloro)dimethylaminocarbonylmethyl imidazo[l,2-a]pyridine, and then sodium borohydride is used for dechlorination to prepare zolpidem, and the specific route of the synthesis is as follows:

[0014]

[0015] This preparation method has the problems of expensive raw materials, large amount of wastewater, and being not conducive to industrial production.

[0016] (4) Patent document CN103360387A and document Angew. Chem. Int. Ed. 2010, 49, 2743-2746 use 5-methyl-2-aminopyridine to condense with p-methylbenzaldehyde to generate imine, then ring closure is carried out with N,N-dimethyl propargylamide under the catalysis of CuCl and Cu(OTf)2 or other copper catalysts to generate zolpidem, and the specific reaction route is as follows:

[0017]

[0018] Although this preparation method has short reaction steps, the raw materials and catalysts used are expensive, the yield is unstable (13% to 80%), and the product is difficult to purify, which is not conducive to industrial operation.

[0019] Therefore, the present application provides an effective method for safely and environmentally preparing N,N,6-trimethyl-2-(4-methylphenyl)imidazo[1,2-a]pyridine-3-acetamide in one step in view of the good social benefits of zolpidem and the reaction yield, industrial production conditions and environmental protection policy of preparing N,N,6-trimethyl-2-(4-methylphenyl)imidazo[1,2-a]pyridine-3-acetamide. SUMMARY

[0020] The present application aims to solve the defects of long reaction steps, low yield, high cost, production safety hazards and great harm in the prior art method for synthesizing N,N,6-trimethyl-2-(4-methylphenyl)imidazo[1,2-a]pyridine-3-acetamide, and provides an effective method for preparing N,N,6-trimethyl-2-(4-methylphenyl)imidazo[1,2-a]pyridine-3-acetamide in one step with low cost, mild reaction conditions, safety and environmental protection.

[0021] To achieve the above-mentioned purpose, the method for preparing N,N,6-trimethyl-2-(4-methylphenyl)imidazo[1,2-a]pyridine-3-acetamide is as follows:

[0022] 6-methyl-2-(4-methylphenyl)imidazo[1,2-a]pyridine and N,N-dimethylacetamide are placed in light under the action of iodine salt and base to obtain N,N,6-trimethyl-2-(4-methylphenyl)imidazo[1,2-a]pyridine-3-acetamide, and the reaction formula is as follows:

[0023]

[0024] Preferably, the iodine salt is one or more of potassium iodide, sodium iodide, ammonium iodide and tetrabutylammonium iodide.

[0025] Preferably, the base is one or more of DBU, TMEDA, DIPEA, DABCO and TEA.

[0026] Preferably, the N,N-dimethyl halogenated acetamide is one or more of N,N-dimethyl chloroacetamide, N,N-dimethyl bromoacetamide and N,N-dimethyl iodoacetamide.

[0027] Preferably, the solvent of the reaction is one or more of water, acetonitrile, methanol, ethanol, dichloromethane, dichloroethane, tetrahydrofuran, ethyl acetate, toluene, dioxane, acetone, N,N-dimethylformamide, N,N-dimethylacetamide, C5-C7 straight-chain alkanes or cycloalkanes, ethylene glycol diethyl ether, formaldehyde dimethyl ether, diethyl ether and methyl tert-butyl ether.

[0028] Preferably, the molar ratio of the iodine salt to 6-methyl-2-(4-methylphenyl)imidazo[1,2-a]pyridine is 0.5-2.0, and the molar ratio of the N,N-dimethylhaloacetamide to the 6-methyl-2-(4-methylphenyl)imidazo[1,2-a]pyridine is 0.5-2.0.

[0029] Preferably, the reaction temperature is 0-60℃.

[0030] Preferably, the reaction time is 12-72h.

[0031] Preferably, the light source is one or more of a white light lamp, a blue light lamp, and an ultraviolet lamp.

[0032] Technical features and beneficial effects of the present application:

[0033] 1. The present application provides a new and simple method for synthesizing zolpidem, which uses 6-methyl-2-(4-methylphenyl)imidazo[1,2-a]pyridine and N,N-dimethylhaloacetamide as raw materials to prepare zolpidem in one step.

[0034] 2. The process flow of the method of the present application is short, and zolpidem can be prepared in one step, which is simple to operate and has a short operation period. The reaction conditions of the present application are mild, safe, and environmentally friendly. The raw materials used in the present application are inexpensive and easy to obtain, and the entire preparation process has a low cost. DETAILED DESCRIPTION

[0035] The following examples will help to understand the present application, but the content of the present application is not limited thereto.

[0036] Example 1: Synthesis of zolpidem

[0037] The substrate 6-methyl-2-(4-methylphenyl)imidazo[1,2-a]pyridine (111 mg, 0.5 mmol), N,N-dimethyl bromoacetamide (166 mg, 1 mmol), sodium iodide (150 mg, 1 mmol), DIPEA (129 mg, 1 mmol), and solvent 2 ml of methanol were added to a 25 ml sealed tube. Then the sealed tube was placed under blue light irradiation, and the reaction was carried out at room temperature for 36 h. After the reaction was completed, the reaction liquid was rotary evaporated under reduced pressure, and then separated by silica gel column chromatography (petroleum ether / ethyl acetate = 2:1 as eluent) to obtain 123 mg of white solid, with a yield of 80%.

[0038] Example 2: Synthesis of zolpidem

[0039] The substrate 6-methyl-2-(4-methylphenyl)imidazo[l,2-a]pyridine (111 mg, 0.5 mmol), N,N-dimethylacetamide (166 mg, 1 mmol), potassium iodide (166 mg, 1 mmol), DIPEA (129 mg, 1 mmol) and solvent 2 ml dichloromethane were added into a 25 ml sealed tube. Then the sealed tube was placed under blue light irradiation and the reaction was allowed to proceed at room temperature for 36 h. After the reaction was completed, the reaction solution was rotary evaporated under reduced pressure and separated by silica gel column chromatography (petroleum ether / ethyl acetate = 2: 1 as eluent) to obtain 120 mg of white solid with a yield of 78%.

[0040] Example 3: Synthesis of Zolpidem

[0041] The substrate 6-methyl-2-(4-methylphenyl)imidazo[l,2-a]pyridine (111 mg, 0.5 mmol), N,N-dimethylacetamide (166 mg, 1 mmol), potassium iodide (166 mg, 1 mmol), DIPEA (129 mg, 1 mmol) and solvent 2 ml dichloromethane were added into a 25 ml sealed tube. Then the sealed tube was placed under blue light irradiation and the reaction was allowed to proceed at room temperature for 36 h. After the reaction was completed, the reaction solution was rotary evaporated under reduced pressure and separated by silica gel column chromatography (petroleum ether / ethyl acetate = 2: 1 as eluent) to obtain 120 mg of white solid with a yield of 78%.

[0042] 1H NMR (400 MHz, CDC13) δ 7.99 (s, 1H), 7.53 (t, J = 8.0 Hz, 3H), 7.26 (d, J = 8.0 Hz, 2H), 7.04 (d, J = 9.2 Hz, 1H), 4.08 (s, 2H), 2.94 (s, 3H), 2.88 (s, 3H), 2.40 (s, 3H), 2.34 (s, 3H).

[0043] 13C{1H} NMR (100 MHz, CDC13) δ 168.3, 144.1, 143.8, 137.4, 131.8, 129.3, 128.4, 127.4, 122.2, 121.7, 116.5, 113.6, 37.5, 35.8, 30.2, 21.2, 18.4.

[0044] HRMS m / z: [M]+calcd for C19H21N3O 307.1685, found 307.1681.

Claims

1. A method of synthesis of N,N,6-trimethyl-2-(4-methylphenyl)imidazo[l,2- a]pyridine-3-acetamide, characterized by: The synthesis method comprises the following steps: under the action of an iodine salt and a base, 6-methyl-2-(4-methylphenyl)imidazo[1,2-a]pyridine is reacted with N,N-dimethyl bromoacetamide under the irradiation of a blue light lamp, the reaction solvent is selected from one of methanol, acetonitrile or dichloromethane, the reaction temperature is room temperature, and the reaction time is 36 h, so as to obtain N,N,6-trimethyl-2-(4-methylphenyl)imidazo[1,2-a]pyridine-3-acetamide, and the reaction formula is as follows: ； The iodine salt is one or both of potassium iodide and sodium iodide; and the base is DIPEA.

2. A process for the synthesis of N,N,6-trimethyl-2-(4-methylphenyl)imidazo[l,2- a]pyridine-3 acetamide as claimed in claim 1, characterized in that: The molar feeding ratio of the iodine salt to 6-methyl-2-(4-methylphenyl)imidazo[1,2-a]pyridine is 0.5-2.0, and the molar feeding ratio of the N,N-dimethyl bromoacetamide to the 6-methyl-2-(4-methylphenyl)imidazo[1,2-a]pyridine is 0.5-2.0.

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