A process for the preparation of zolpidem

Abstract

The application belongs to the technical field of medicine synthesis, and particularly relates to a preparation method of Zolpidem. The method uses 2-(6-methyl-2-(p-tolyl) imidazo[1,2-a]pyridine-3-yl) acetaldehyde as a reaction raw material, and prepares Zolpidem through catalytic oxidation reaction with N,N-dimethylformamide. The preparation method has the advantages of safe operation, simplicity, environmental friendliness, short reaction steps, and high yield and purity of the prepared Zolpidem.

Description

TECHNICAL FIELD

[0001] The present application belongs to the technical field of medicine synthesis, and particularly relates to a preparation method of zolpidem. BACKGROUND

[0002] Zolpidem tartrate, chemical name 2-(4-methylphenyl)-N,N,6-trimethylimidazo[1,2-a]pyridine-3-acetamide tartrate, is a non-benzodiazepine hypnotic drug, and its trade name is Stilnoct. It is originally researched by Synthelabo Company of France, and was listed in France in 1988. It is clinically used for treating severe sleep disorder diseases such as occasional insomnia and temporary insomnia; in addition, the product has a significant effect on insomnia caused by primary insomnia, depression and psychosis; and has the characteristics of fast drug effect and low addiction. The chemical structural formula is as follows:

[0003]

[0004] At present, there are many reports on the synthesis process of zolpidem. For example, in the document Org. Lett., 2012, 14(17): 4580-4583, p-methyl-β-nitrostyrene is used as a starting material, and after Michael addition, acylation, ring closure and hydrolysis, the target product is obtained by condensation with dimethylamine under the action of phosphorus pentachloride. However, the starting material of this method is expensive, and the production cost is high; pyridine with strong irritation is used, which is harmful to health and environment.

[0005]

[0006] Patents GB9915489, GB1076089, EP0050563, US4492695, US4382938, US20070027180A1 and documents Arkivoc, 2009(ii) 315-320, Journal of Labelled Compounds and Radiopharmaceuticals, 1986, 23, 393-400, Journal of Labelled Compounds and Radiopharmaceuticals, 2000, 43, 385-394, Inventi Rapid: Med Chem, 2014(2): 1-8, using p-methylacetophenone or its downstream intermediates as starting material, first bromination to generate 2-bromo-4'-methylacetophenone, then condensation, Mannich reaction, cyano substitution and hydrolysis to prepare 2-(6-methyl-2-(p-methylphenyl)imidazo[1,2-a]pyridine-3-yl)acetic acid, and then reaction with a large excess of dimethylamine to prepare zolpidem.

[0007]

[0008] This process route has long reaction steps and complicated operation; at the same time, genotoxic substance formaldehyde is used in the Mannich reaction, and toxic iodomethane with low boiling point is used in the N-alkylation step, and quaternary ammonium salt is nucleophilically substituted by toxic sodium cyanide to prepare cyano intermediate 2-(6-methyl-2-(4-methylphenyl)imidazo[1,2-a]pyridine-3-yl)acetonitrile; in addition, when converting cyano to amide, dry HC1 gas needs to be introduced into the reaction system for a long time under heating conditions, which is complicated to operate; finally, CDI (CDI is a very expensive, toxic, allergenic and hygroscopic compound) is used for amidation, and the target product prepared is easily contaminated by the decomposition products of CDI, making the whole process difficult to be industrialized for large-scale production.

[0009] Patents EP1038875T1, EP1038875A2 use (condensed) glyoxylic acid monohydrate as a side chain extension, prepare the corresponding acid derivative, reduce the hydroxyl group, and finally react with dimethylamine to prepare zolpidem. However, this process uses highly corrosive and difficult to handle chemicals (such as formic acid); uses noble metal catalysts, which need to be recovered after reprocessing; and also involves filtration and vacuum distillation operations, making it difficult to implement large-scale operation.

[0010]

[0011] Patent WO0008021A2, WO0008021A3, US6407240B1 uses methyl glyoxylate or its methyl hemiacetal as a side chain extension, after preparing the corresponding ester derivative, the hydroxyl group is chlorinated and then reduced, and finally the dimethylamine is prepared by aminolysis. Although this method uses the direct aminolysis of ester to introduce dimethylamino, it can save the use of CDI, phosphorus oxychloride or phosphorus pentachloride, but the side chain extension reagent used in this method is not easy to obtain, and the reduction of the hydroxyl group uses sodium methane sulfinate or carcinogenic and toxic sodium bisulfite (sodium formaldehyde sulfoxylate / formaldehyde), which is also not suitable for industrial production.

[0012]

[0013] The above processes all use low-boiling-point (7℃) and flammable dimethylamine to prepare zolpidem, which is inconvenient to operate and has low safety.

[0014] In summary, in view of the many shortcomings of the current zolpidem preparation method in terms of process safety, complicated operation, low yield, high production cost, etc., it is still a problem to be solved to find a reaction route suitable for industrial production of zolpidem with mild reaction conditions, simple operation process, high product yield and purity, and low production cost. SUMMARY

[0015] In view of the problems in the preparation process of zolpidem in the prior art, the present application provides a new preparation method of zolpidem. The method is simple, safe, mild and environmentally friendly, and the target product prepared has high purity and yield.

[0016] The application is implemented by the following technical solutions:

[0017] A preparation method of zolpidem, using 2-(6-methyl-2-(p-tolyl) imidazo[1,2-a]pyridine-3-yl) acetaldehyde, i.e. SM-1, as a reaction raw material, and N,N-dimethylformamide as a dimethylamine source, to prepare zolpidem by catalytic oxidation reaction, the reaction formula is as follows:

[0018]

[0019] A preparation method of zolpidem as shown in formula I, the specific steps are as follows:

[0020] 2-(6-methyl-2-(p-tolyl) imidazo[1,2-a]pyridine-3-yl) acetaldehyde, i.e. SM-1, N,N-dimethylformamide, tetrabutylammonium iodide (Bu4NI, TBAI), and an oxidizing agent are added to an organic solvent A, and the temperature is controlled until the reaction is completed, and then zolpidem is prepared by post-treatment.

[0021] Preferably, the oxidizing agent is selected from one of hydrogen peroxide, meta-chloroperoxybenzoic acid, cumene hydroperoxide (CHP), di-t-butyl peroxide and t-butyl hydroperoxide (TBHP), preferably di-t-butyl peroxide.

[0022] Preferably, the organic solvent A is selected from one of nitroethane, 4-methyl-2-pentanone, N-methylmorpholine, 1,1,2-trichloroethane or a combination thereof, preferably 4-methyl-2-pentanone.

[0023] Preferably, the molar ratio of SM-1 to N,N-dimethylformamide, tetrabutylammonium iodide, oxidizing agent is 1:8.0-20.0:0.1-0.3:4.0-10.0, preferably 1:14.0:0.2:6.0.

[0024] Preferably, the molar ratio of SM-1 to N,N-dimethylformamide is 1:8.0-20.0, preferably 1:14.0.

[0025] Preferably, the molar ratio of SM-1 to tetrabutylammonium iodide is 1:0.1-0.3, preferably 1:0.2.

[0026] Preferably, the molar ratio of SM-1 to oxidizing agent is 1:4.0-10.0, preferably 1:6.0.

[0027] Preferably, the reaction temperature is 85-110°C, preferably 105-110°C.

[0028] In a preferred embodiment, the post-treatment step is as follows: the reaction solution is cooled to room temperature, poured into a reducing solution A, the organic layer is separated, the aqueous layer is extracted with an organic solvent B, the organic phases are combined, dried, filtered, concentrated to dryness under reduced pressure, recrystallized, filtered, and dried to obtain zolpidem; preferably, the reducing solution A includes, but is not limited to, one of saturated sodium sulfite solution, sodium pyrosulfite solution, and sodium thiosulfate solution, preferably saturated sodium sulfite solution; preferably, the organic solvent B includes, but is not limited to, one of dichloromethane, chloroform, preferably dichloromethane; preferably, the recrystallization solvent is ethyl acetate.

[0029] In another preferred embodiment, the post-treatment step is as follows: the reaction solution is cooled to room temperature, poured into a reducing solution A, the organic solvent is evaporated under reduced pressure, the residue is extracted with an organic solvent B, the organic phases are combined, dried, filtered, concentrated to dryness under reduced pressure, recrystallized, filtered, and dried to obtain zolpidem; preferably, the reducing solution A includes, but is not limited to, one of saturated sodium sulfite solution, sodium pyrosulfite solution, and sodium thiosulfate solution, preferably saturated sodium sulfite solution; preferably, the organic solvent B includes, but is not limited to, one of dichloromethane, chloroform, preferably dichloromethane; preferably, the recrystallization solvent is ethyl acetate.

[0030] Advantages of the present application:

[0031] The present application provides a new preparation method of Zolpidem, taking 2-(6-methyl-2-(p-tolyl) imidazo[1,2-a]pyridine-3-yl) acetaldehyde as a starting material and N,N-dimethylformamide as a dimethylamine source to prepare Zolpidem. Compared with the prior art, in the present application, the use of dimethylamine reagent with low boiling point (7℃) and flammable can be effectively avoided by using cheap N,N-dimethylformamide as a dimethylamine source; the catalyst and oxidant used in the present application do not contain transition metals, are green and pollution-free, and are cheap and easy to obtain; at the same time, the preparation method described in the present application significantly shortens the reaction steps, and the operation is safer and simpler; the Zolpidem prepared by the process described in the present application has high purity and yield, and is suitable for industrial production. DETAILED DESCRIPTION

[0032] The present application will be further described below by examples, and it should be understood that: the examples of the present application are only used to illustrate the present application, and are not a limitation of the present application, so that the simple improvement of the present application under the premise of the method of the present application belongs to the scope of the present application.

[0033] The purity of Zolpidem is determined by HPLC, and the chromatographic conditions are as follows:

[0034] Chromatographic column: YMC Triart-C 18 column (4.6mmx250mm, 5um) or a chromatographic column with equivalent performance;

[0035] Mobile phase: mobile phase A: sodium sulfate aqueous solution (take anhydrous sodium sulfate 2.84g and trifluoroacetic acid 1ml, dissolve and dilute to 1000ml with water), mobile phase B: acetonitrile, gradient elution;

[0036] Column temperature: 35℃;

[0037] Detection wavelength: 248nm;

[0038] Flow rate: 1.0ml / min;

[0039] Injection volume: 20ul;

[0040] Among them, the retention time of Zolpidem is about 18.7min.

[0041] The elution gradient is shown in Table 1:

[0042] Table 1 Elution gradient table

[0043]

[0044] In the following examples, various processes and methods not specifically described are conventional methods well known in the art.

[0045] Example 1

[0046] The 2-(6-methyl-2-(p-tolyl)imidazo[l,2-a]pyridin-3-yl)acetaldehyde (SM-1, 26.43 g, 0.1 mol), N,N-dimethylformamide (109.64 g, 1.5 mol), tetrabutylammonium iodide (7.39 g, 0.02 mol), dicumyl peroxide (162.22 g, 0.6 mol) were added into 4-methyl-2-pentanone (110 ml) at room temperature, and the reaction was carried out at 105-110°C. After the reaction was completed, the reaction solution was poured into saturated sodium sulfite solution (500 ml), and the organic phase was separated. The aqueous phase was extracted with dichloromethane (200 ml x 2), and the combined organic phase was dried, filtered, and concentrated to dryness under reduced pressure. The residue was recrystallized with ethyl acetate as a solvent, filtered, and the filter cake was washed with pre-cooled ethyl acetate, and dried to obtain zolpidem, with a yield of 94.2% and a purity of 99.5%.

[0047] Example 2

[0048] The 2-(6-methyl-2-(p-tolyl)imidazo[l,2-a]pyridin-3-yl)acetaldehyde (SM-1, 26.43 g, 0.1 mol), N,N-dimethylformamide (109.64 g, 1.5 mol), tetrabutylammonium iodide (7.39 g, 0.02 mol), dicumyl peroxide (162.22 g, 0.6 mol) were added into 4-methyl-2-pentanone (110 ml) at room temperature, and the reaction was carried out at 105-110°C. After the reaction was completed, the reaction solution was poured into saturated sodium sulfite solution (500 ml), and the organic phase was separated. The aqueous phase was extracted with dichloromethane (200 ml x 2), and the combined organic phase was dried, filtered, and concentrated to dryness under reduced pressure. The residue was recrystallized with ethyl acetate as a solvent, filtered, and the filter cake was washed with pre-cooled ethyl acetate, and dried to obtain zolpidem, with a yield of 94.2% and a purity of 99.5%.

[0049] Example 3

[0050] The 2-(6-methyl-2-(p-tolyl)imidazo[l,2-a]pyridin-3-yl)acetaldehyde (26.45 g, 0.1 mol), N,N-dimethylformamide (146.19 g, 2.0 mol), tetrabutylammonium iodide (7.39 g, 0.02 mol), cumene hydroperoxide (CHP, 91.31 g, 0.6 mol) were added into 4-methyl-2-pentanone (100 ml) at room temperature, and the reaction was carried out at 85-90 °C. After the reaction was completed, the reaction solution was poured into saturated sodium sulfite solution (500 ml), and the organic phase was separated. The aqueous phase was extracted with chloroform (200 ml x 2), and the combined organic phase was dried, filtered, and concentrated under reduced pressure to dryness. The residue was recrystallized with ethyl acetate as a solvent, filtered, and the filter cake was washed with pre-cooled ethyl acetate. The obtained zolpidem was dried to give a yield of 92.9% and a purity of 98.7%.

[0051] Example 4

[0052] The 2-(6-methyl-2-(p-tolyl)imidazo[l,2-a]pyridin-3-yl)acetaldehyde (26.41 g, 0.1 mol), N,N-dimethylformamide (109.64 g, 1.5 mol), tetrabutylammonium iodide (3.69 g, 0.01 mol), and m-chloroperbenzoic acid (103.54 g, 0.6 mol) were added into N-methylmorpholine (110 ml) at room temperature, and the reaction was carried out at 105-110 °C. After the reaction was completed, the reaction solution was poured into saturated sodium metabisulfite solution (500 ml), and the organic solvent was removed under reduced pressure. The residue was extracted with dichloromethane (200 ml x 3), and the combined organic phase was dried, filtered, and concentrated under reduced pressure to dryness. The residue was recrystallized with ethyl acetate as a solvent, filtered, and the filter cake was washed with pre-cooled ethyl acetate. The obtained zolpidem was dried to give a yield of 92.1% and a purity of 99.3%.

[0053] Example 5

[0054] The 2-(6-methyl-2-(p-tolyl)imidazo[l,2-a]pyridin-3-yl)acetaldehyde (26.45 g, 0.1 mol), N,N-dimethylformamide (109.64 g, 1.5 mol), tetrabutylammonium iodide (11.08 g, 0.03 mol), and tert-butyl hydroperoxide (TBHP, 54.07 g, 0.6 mol) were added into nitroethane (110 ml) at room temperature, and the reaction was carried out at 85-90 °C. After the reaction was completed, the reaction solution was poured into saturated sodium thiosulfate solution (500 ml), and the organic phase was separated. The aqueous phase was extracted with dichloromethane (200 ml x 2), and the combined organic phase was dried, filtered, and concentrated under reduced pressure to dryness. The residue was recrystallized with ethyl acetate as a solvent, filtered, and the filter cake was washed with pre-cooled ethyl acetate. The obtained zolpidem was dried to give a yield of 93.4% and a purity of 99.0%.

[0055] Example 6

[0056] The 2-(6-methyl-2-(p-tolyl)imidazo[l,2-a]pyridin-3-yl)acetaldehyde (26.42 g, 0.1 mol), N,N-dimethylformamide (109.64 g, 1.5 mol), tetrabutylammonium iodide (7.39 g, 0.02 mol), and hydrogen peroxide (ω = 30%, 113.37 g, 1.0 mol) were added to 4-methyl-2-pentanone (110 ml) at room temperature. The reaction was controlled at 95-100 °C. After the reaction was completed, the reaction solution was poured into saturated sodium sulfite solution (600 ml). The organic phase was separated, and the aqueous phase was extracted with dichloromethane (200 ml x 2). The organic phases were combined, dried, filtered, and the filtrate was concentrated to dryness under reduced pressure. The residue was recrystallized from ethyl acetate as a solvent. The filter cake was washed with pre-cooled ethyl acetate, dried, and zolpidem was obtained in a yield of 93.5% and a purity of 99.1%.

[0057] Example 7

[0058] The 2-(6-methyl-2-(p-tolyl)imidazo[l,2-a]pyridin-3-yl)acetaldehyde (26.42 g, 0.1 mol), N,N-dimethylformamide (109.64 g, 1.5 mol), tetrabutylammonium iodide (7.39 g, 0.02 mol), and hydrogen peroxide (ω = 30%, 113.37 g, 1.0 mol) were added to 4-methyl-2-pentanone (110 ml) at room temperature. The reaction was controlled at 95-100 °C. After the reaction was completed, the reaction solution was poured into saturated sodium sulfite solution (600 ml). The organic phase was separated, and the aqueous phase was extracted with dichloromethane (200 ml x 2). The organic phases were combined, dried, filtered, and the filtrate was concentrated to dryness under reduced pressure. The residue was recrystallized from ethyl acetate as a solvent. The filter cake was washed with pre-cooled ethyl acetate, dried, and zolpidem was obtained in a yield of 93.5% and a purity of 99.1%.

[0059] Example 8

[0060] The 2-(6-methyl-2-(p-tolyl)imidazo[l,2-a]pyridin-3-yl)acetaldehyde (26.42 g, 0.1 mol), N,N-dimethylformamide (182.73 g, 2.5 mol), tetrabutylammonium iodide (18.47 g, 0.05 mol), dicumyl peroxide (324.44 g, 1.2 mol) were added into 4-methyl-2-pentanone (220 ml) at room temperature, and the reaction was carried out at 105-110 °C. After the reaction was completed, the reaction solution was poured into saturated sodium sulfite solution (600 ml), and the organic phase was separated. The aqueous phase was extracted with dichloromethane (200 ml x 3), and the combined organic phase was dried, filtered, and concentrated to dryness under reduced pressure. The residue was recrystallized with ethyl acetate as the solvent, filtered, and the filter cake was washed with pre-cooled ethyl acetate and dried to obtain zolpidem with a yield of 89.2% and a purity of 98.1%.

[0061] Example 9

[0062] The 2-(6-methyl-2-(p-tolyl)imidazo[l,2-a]pyridin-3-yl)acetaldehyde (26.42 g, 0.1 mol), N,N-dimethylformamide (182.73 g, 2.5 mol), tetrabutylammonium iodide (18.47 g, 0.05 mol), dicumyl peroxide (324.44 g, 1.2 mol) were added into 4-methyl-2-pentanone (220 ml) at room temperature, and the reaction was carried out at 105-110 °C. After the reaction was completed, the reaction solution was poured into saturated sodium sulfite solution (600 ml), and the organic phase was separated. The aqueous phase was extracted with dichloromethane (200 ml x 3), and the combined organic phase was dried, filtered, and concentrated to dryness under reduced pressure. The residue was recrystallized with ethyl acetate as the solvent, filtered, and the filter cake was washed with pre-cooled ethyl acetate and dried to obtain zolpidem with a yield of 89.2% and a purity of 98.1%.

Claims

1. A process for the preparation of Zolpidem characterized in that, Zolpidem is prepared by catalytic oxidation reaction with SM-1 as a reaction raw material and N,N-dimethylformamide as a dimethylamine source, and a reaction formula is as follows: ， The catalyst is selected from tetrabutylammonium iodide; the oxidant is selected from one of hydrogen peroxide, meta-chloro-peroxybenzoic acid, cumene hydroperoxide and dicumyl peroxide; The specific steps are as follows: SM-1, N,N-dimethylformamide, tetrabutylammonium iodide and an oxidant are added into an organic solvent A, temperature is controlled until the reaction is completed, and zolpidem is prepared by post-treatment; the organic solvent A is selected from one or a combination of nitroethane, 4-methyl-2-pentanone, N-methylmorpholine and 1,1,2-trichloroethane; the reaction temperature is 85-110 DEG C.

2. The production method according to claim 1, characterized by, The feeding molar ratio of SM-1 to N,N-dimethylformamide is 1:8.0-20.

0.

3. The production method according to claim 1, characterized by, The feeding molar ratio of SM-1 to tetrabutylammonium iodide is 1:0.1-0.

3.

4. The method of claim 1, wherein, The feeding molar ratio of SM-1 to the oxidant is 1:4.0-10.

0. The feeding molar ratio of SM-1 to tetrabutylammonium iodide is 1:0.1-0.

3. The feeding molar ratio of SM-1 to the oxidant is 1:4.0-10.0.

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