A kind of preparation method of Zolpidem

Abstract

The present invention belongs to the field of pharmaceutical chemicals, and in particular to a method for preparing zolpidem. The present invention utilizes compound I-1 and pinacol borate to obtain an intermediate compound I-2 under the action of a catalyst; intermediate compound I-2 and 2-bromo-N,N-dimethylacetamide are reacted under the action of a catalyst to obtain zolpidem. Compared with the prior art, this method can significantly shorten the reaction steps, has low production cost, is easy to operate, and the prepared zolpidem has high purity and yield, and is suitable for industrial production.

Description

Technical Field

[0001] The invention belongs to the field of pharmaceutical chemicals, and particularly relates to a method for preparing zolpidem. Background Art

[0002] Zolpidem tartrate, chemically known as 2-(4-methylphenyl)-N,N,6-trimethylimidazo[1,2-a]pyridine-3-acetamide tartrate, is a non-benzodiazepine Hypnotic drugs, trade names Originally developed by Synthelabo, France, it was first marketed in France in 1988. It is clinically used to treat severe sleep disorders, such as occasional insomnia and transient insomnia. It also has significant efficacy for primary insomnia, depression, and insomnia caused by mental illness. It has rapid efficacy and low addictiveness. Its chemical structure is as follows:

[0003]

[0004] There are many reports on the synthesis process of zolpidem, including patents GB9915489, GB1076089, EP0050563, US4492695, US4382938, US20070027180A1 and literature 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: MedChem, 2014(2):1-8 uses p-methylacetophenone or its downstream intermediate as the starting material, first brominating to generate 2-bromo-4'-methylacetophenone, then undergoing condensation, Mannich reaction, cyano substitution and hydrolysis to obtain 2-(6-methyl-2-(p-methylphenyl)imidazo[1,2-a]pyridin-3-yl)acetic acid, and finally reacting with a large excess of dimethylamine to obtain zolpidem.

[0005] However, this process involves long reaction steps and cumbersome procedures. The Mannich reaction involves the genotoxic substance formaldehyde, and the N-alkylation step uses highly toxic, low-boiling-point methyl iodide. The quaternary ammonium salt is nucleophilically substituted with the highly toxic sodium cyanide to produce the cyano intermediate 2-(6-methyl-2-(4-methylphenyl)imidazo[1,2-a]pyridin-3-yl)acetonitrile, making the entire reaction process dangerous and unsafe. Furthermore, the conversion of the cyano group to the amide requires the prolonged passage of dry HCl gas through the reaction system under heating, a cumbersome procedure that is unsuitable for industrial production. The final amidation involves CDI (a very expensive, toxic, allergenic, and hygroscopic compound, making it difficult to manufacture on an industrial scale. Furthermore, the desired product obtained by this method is contaminated with CDI decomposition products, requiring complex purification methods to obtain zolpidem that meets the stringent pharmacopoeial requirements) and the more toxic phosphorus oxychloride or phosphorus pentachloride.

[0006]

[0007] To overcome the drawbacks of the above methods, a number of methods for preparing heteroaryl acetamides have been proposed. Generally speaking, these methods differ in the methods and reagents used to introduce the acetamide side chain, and can be categorized into the following three strategies:

[0008] ① For example, U.S. Patents US4794185, FR2600650, and EP251589 use 6-methyl-2-(4-methylphenyl)imidazo[1,2-a]pyridine as a key intermediate or starting material, which reacts with N,N-dimethyl-2,2-dimethoxy-acetamide to prepare an α-hydroxy-N,N-dimethyl-acetamide derivative, which is then chlorinated with SOCl2 and then reduced and dechlorinated with NaBH4, Zn(BH4)2, KBH4, or LiBH4 to obtain zolpidem:

[0009]

[0010] Although this synthesis method avoids the use of highly toxic sodium cyanide, it uses highly corrosive and irritating SOCl2, which can cause burns to the human body, for the chlorination reaction during the hydroxyl reduction process. At the same time, the reduction reaction uses borohydride, which is highly harmful to the human body (contact with sodium borohydride causes symptoms such as sore throat, cough, shortness of breath, headache, abdominal pain, diarrhea, dizziness, conjunctival congestion, and pain). In addition, borohydride is highly active and releases hydrogen during the reaction, which makes the operation dangerous and difficult to use in the field of drug synthesis.

[0011] In addition, the above process also requires the separate preparation of side chain intermediates, which increases the total number of steps required for the preparation of zolpidem and the production cycle, making it unsuitable for large-scale production. At the same time, the side chain N,N-dimethyl-2,2-dimethoxyacetamide can only be prepared with the assistance of special equipment and cannot be produced on an industrial scale. In addition, it is sensitive to trace amounts of water and acid, making this route difficult to scale up for production.

[0012] U.S. Patent No. 4808594A (same family as FR8615533 and EP0267111A1) uses the same strategy to synthesize zolpidem derivatives, but uses a strong carcinogen, chlorpyrifos, in the reductive dechlorination process. This substance is extremely harmful to the lungs, liver, and kidneys of the human body, making the operation less safe.

[0013] Chinese patents CN1972939A (similar to EP01172364, US2007213537, and WO2006007289), CN1729188A (similar to WO2004058758, EP01809627, and US20070213537A1), and EP01809627 prepare zolpidem by contacting a mixture of a heteroaryl α-hydroxyacetamide, a strong acid (sulfuric acid, perchloric acid, or a mixture thereof), a halide (LiBr, NaBr, KBr, MgBr2, CaBr2, or NH4Br), a catalyst (platinum, palladium, ruthenium, osmium, iridium, or rhodium catalyst), and a water scavenger (carboxylic anhydride, carboxylic acid chloride, magnesium sulfate, or molecular sieves) with a hydrogen source (hydrogen at 1 to 4 atmospheres). Although this process eliminates the need for a chlorination step, it still requires the reaction to be carried out under noble metal catalysis, resulting in high reaction pressure and dangerous operation.

[0014]

[0015] Chinese patent CN1668617A (similar to US20040010146 and WO20040010146) uses glycolamide derivatives as reagents for side chain extension. However, these reagents are difficult to obtain, and the reducing agent PBr3 used is prone to burns and is irritating to the respiratory system, making it difficult to perform during scale-up operations.

[0016]

[0017] ② Patents EP1038875T1 and EP1038875A2 use glyoxylic acid monohydrate as a side chain extension to prepare the corresponding acid derivative, then 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), and also involves filtration and vacuum distillation. Furthermore, the process uses a precious metal catalyst that needs to be recovered after reprocessing, making it difficult to implement on a large scale:

[0018]

[0019] ③ Patents WO0008021A2, WO0008021A3, and US6407240B1 use methyl glyoxylate or its methyl hemiacetal as a side chain extension to prepare the corresponding ester derivative, followed by chlorination of the hydroxyl group and subsequent reduction, and finally dimethylamine hydrolysis to produce zolpidem. Although this method introduces the dimethylamino group by direct dimethylamine hydrolysis of the ester, eliminating the need for CDI, phosphorus oxychloride, or phosphorus pentachloride, the side chain extension reagents used in this method are difficult to obtain, and the reduction of the hydroxyl group requires sodium methanesulfonate, which is difficult to obtain, or the highly toxic bleaching agent, making it unsuitable for industrial scale-up production.

[0020]

[0021] In summary, the current preparation methods of zolpidem have many shortcomings in terms of process safety, cumbersome operation, low yield, and high production cost. Therefore, research and search for a reaction route suitable for industrial production of zolpidem with mild reaction conditions, simple operation process, high product yield, high purity, and low production cost is still a problem that needs to be solved. Summary of the Invention

[0022] The present invention addresses the problems of existing zolpidem preparation technologies, such as long routes, complicated operations, low yield, low purity, high technical requirements, and high production costs. The present invention provides a novel zolpidem synthesis method. The zolpidem prepared by this method has high purity and yield, and is suitable for industrial production.

[0023] The specific technical solutions of the present invention are as follows:

[0024] A method for preparing Zolpidem comprises the following steps:

[0025] Compound I-1 reacts with diboronic acid pinacol in the presence of a catalyst to obtain intermediate compound I-2; compound I-2 reacts with 2-bromo-N,N-dimethylacetamide in the presence of a catalyst to obtain zolpidem I;

[0026] The reaction synthesis route is as follows:

[0027]

[0028] Preferably, the above steps are further described in detail in the following sections:

[0029] Preparation of compound I-2:

[0030] The preparation method of compound I-2 comprises the following steps: under inert gas protection, at room temperature, adding compound I-1, boric acid pinacol, a base, and a catalyst to a reaction solvent, controlling the temperature until the reaction is completed, and obtaining a reaction solution containing product I-2.

[0031] Preferably, the catalyst is selected from one of Pd(PPh3)4, Pd(PPh3)2Cl2, and Pd(dppf)Cl2, with Pd(dppf)Cl2 being particularly preferred.

[0032] Preferably, the base is selected from one of K2CO3, Na2CO3, K3PO4, Na3PO4, NaOAc, and KOAc, with KOAc being particularly preferred.

[0033] Preferably, the molar ratio of the compound I-1 to the boric acid pinacol, the base, and the catalyst is 1:1.1-1.4:1.2-1.8:0.03-0.08, particularly preferably 1:1.2:1.5:0.05.

[0034] Preferably, the reaction solvent is selected from dimethyl sulfoxide, N,N-dimethylformamide, 1,4-dioxane, and N,N-dimethylacetamide, with dimethyl sulfoxide being particularly preferred.

[0035] Preparation of Compound I:

[0036] The preparation method of compound I comprises the following steps: under inert gas protection, continuously adding alkali, purified water and compound SM-3, i.e., 2-bromo-N,N-dimethylacetamide, to the reaction solution containing product I-2, controlling the temperature until the reaction is completed, and post-processing the reaction to obtain zolpidem.

[0037] Preferably, the catalyst is selected from one of Pd(PPh3)4, Pd(PPh3)2Cl2, and Pd(dppf)Cl2, with Pd(PPh3)2Cl2 being particularly preferred.

[0038] Preferably, the base is selected from one of K2CO3, Na2CO3, K3PO4, Na3PO4, NaOAc, and KOAc, with K3PO4 being particularly preferred.

[0039] Preferably, the molar ratio of the continuously added base, 2-bromo-N,N-dimethylacetamide and compound I-1 is 0.8-1.5:1.2-1.5:1, particularly preferably 1.2:1.3:1.

[0040] In a preferred embodiment, the post-treatment step is to control the temperature until the reaction is completed, filter, add the filtrate to purified water, extract with an extractant, combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate to dryness under reduced pressure to obtain Zolpidem I; preferably, the extractant is selected from one of dichloromethane, chloroform, ethyl acetate, and methyl tert-butyl ether, particularly preferably ethyl acetate.

[0041] In the present invention, the inert gas in the preparation method of compounds I-2 and I is usually nitrogen or argon, with argon being particularly preferred; the reaction temperature is 80-110°C, with 95-100°C being particularly preferred.

[0042] Beneficial effects of the present invention:

[0043] 1. The present invention provides a novel method for preparing zolpidem, wherein the zolpidem prepared by the process has high purity and yield;

[0044] 2. The present invention uses 2-bromo-N,N-dimethylacetamide as a reagent to construct the zolpidem side chain, which can significantly shorten the reaction steps compared to the existing technology, is easy to operate, and is suitable for industrial production;

[0045] In summary, the present invention provides a new method for preparing zolpidem, which can avoid the use of hazardous chemical reagents, and the synthesized intermediates will not produce new impurities, and has high yield and purity, and is suitable for industrial production. DETAILED DESCRIPTION

[0046] The present invention is further illustrated by the following examples. It should be understood that the examples of the present invention are merely illustrative of the present invention and are not intended to limit the present invention. Therefore, simple modifications to the present invention based on the method of the present invention fall within the scope of the present invention.

[0047] Simple improvements to the present invention all fall within the scope of protection claimed by the present invention.

[0048] The structural confirmation data of the intermediate compound I-1 obtained in the present invention are as follows:

[0049] ESI-HRMS (m / z): 301.0342 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ8.30 (s, 1H), 7.56 (d, J = 7.4Hz, 2H), 7.51 (d, J = 7.6Hz, 1H),7.25(d,J=7.6Hz,1H),7.16(d,J=7.4Hz,2H),2.435(s,3H),2.36(s,3H); 13C NMR (101MHz, DMSO-d6) δ154.12,138.30,137.52,134.10,129.73,129.55,128.35,123.350,119.12,118.03,94.32,21.10,15.48.

[0050] The structural confirmation data of the intermediate compound I-2 obtained in the present invention are as follows:

[0051] ESI-HRMS (m / z): 349.2082 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ8.06 (s, 1H), 7.60 ~ 7.54 (d, J = 7.4Hz, 2H), 7.50 ~ 7.45 (d,J=6.8Hz,1H),7.21~7.10(m,3H),2.44(s,3H),2.37(s,3H),1.30(s,12H); 13 C NMR (101MHz, DMSO-d6) δ145.66,140.12,136.77,134.42,129.90,129.54,128.23,128.03,123.50,122.04,119.02,86.45,24.71,21.12,15.45.

[0052] The structure of the Zolpidem compound obtained in the present invention is confirmed as follows:

[0053] mp.: 195.2~196.1℃; ESI-HRMS(m / z): 308.1756[M+H] + ; 1 H NMR (400MHz, CD3OD-d4) δ9.52 (s, 1H), 7.62~7.85 (m, 2H), 7.38 (d, J = 7.4Hz, 2H), 7.32 (d, J=7.4Hz,2H),4.47(d,J=5.4Hz,2H),2.80(s,3H),2.48(s,3H),2.41(s,3H),2.36(s,3H); 13 C NMR(101MHz,CD3OD-d4)δ176.73,140.55,138.15,137.99,133.35,129.89,1 29.57,129.33,126.69,124.78,119.91,119.00,36.93,36.73,21.13,15.47.

[0054] The present invention adopts HPLC to measure the purity of Zolpidem, and the chromatographic conditions are as follows:

[0055] Chromatographic column: YMC Triart-C 18 Column (4.6 mm × 250 mm, 5 μm) or chromatographic column of equivalent performance;

[0056] Mobile phase: Mobile phase A: sodium sulfate aqueous solution (take 2.84g of anhydrous sodium sulfate and 1ml of trifluoroacetic acid, dissolve in water and dilute to 1000ml), mobile phase B: acetonitrile, gradient elution;

[0057] Column temperature: 35°C;

[0058] Detection wavelength: 248nm;

[0059] Flow rate: 1.0 ml / min;

[0060] Injection volume: 20 μl;

[0061] Among them, the retention time of zolpidem is about 18.7 minutes.

[0062] The elution gradient is shown in Table 1:

[0063] Table 1 Elution gradient

[0064]

[0065] In the following embodiments, various processes and methods not described in detail are conventional methods well known in the art.

[0066] Synthesis of intermediate Ⅰ-1:

[0067] Example 1

[0068] At room temperature, 6-methyl-2-(4-methylphenyl)imidazo[1,2-a]pyridine (SM-1, 44.46 g, 0.2 mol) and trifluoroacetic acid (1.14 g, 0.01 mol) were added to dichloromethane (350 ml) and stirred. NBS (42.72 g, 0.24 mol) was added to the reaction solvent at a temperature of 0-5°C and the reaction was carried out at a temperature of 10-15°C. After the reaction was completed, the reaction was detected and filtered. The filtrate was washed with 10% aqueous sodium sulfite solution (200 ml × 2) and purified water (200 ml × 2), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to dryness under reduced pressure to obtain 3-bromo-6-methyl-2-(4-methylphenyl)imidazo[1,2-a]pyridine (Ⅰ-1) with a yield of 94.6% and a purity of 99.95%.

[0069] Synthesis of Compound I:

[0070] Example 2

[0071] Under argon protection and room temperature, compound I-1 (30.12 g, 0.10 mol), boric acid pinacol (17.28 g, 0.12 mol), potassium acetate (14.72 g, 0.15 mol), and Pd (dppf) Cl2 (3.66 g, 5.0 mmol) were added to dimethyl sulfoxide (250 ml) and the temperature was controlled at 95 to 100 ° C. After the reaction was completed, a reaction solution containing compound I-2 was obtained; under inert gas protection, potassium acetate ( A solution of 2-bromo-N,N-dimethylacetamide (11.77 g, 0.12 mol) in water (40 ml) and 2-bromo-N,N-dimethylacetamide (21.58 g, 0.13 mol) was stirred and mixed, and the temperature was controlled at 95-100°C. After the reaction was detected to be complete, the mixture was filtered through diatomaceous earth. The filtrate was added to purified water (800 ml), extracted with ethyl acetate (250 ml × 3), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure to obtain zolpidem (I) with a yield of 90.2% and a purity of 99.93%.

[0072] Example 3

[0073] Under argon protection and room temperature, compound I-1 (30.12 g, 0.10 mol), boric acid pinacol (15.84 g, 0.11 mol), potassium carbonate (20.73 g, 0.15 mol), Pd (PPh3) 4 (5.78 g, 5.0 mmol) were added to dimethyl sulfoxide (250 ml), and the temperature was controlled at 100-105 ° C. After the reaction was completed, a reaction solution containing compound I-2 was obtained; under inert gas protection, potassium acetate ( A solution of 2-bromo-N,N-dimethylacetamide (11.77 g, 0.12 mol) in water (40 ml) and 2-bromo-N,N-dimethylacetamide (21.58 g, 0.13 mol) was stirred and mixed, and the temperature was controlled at 95-100°C. After the reaction was detected to be complete, the mixture was filtered through diatomaceous earth. The filtrate was added to purified water (800 ml), extracted with dichloromethane (250 ml × 3), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure to obtain zolpidem (I) with a yield of 83.5% and a purity of 99.67%.

[0074] Example 4

[0075] Under argon protection at room temperature, compound I-1 (30.12 g, 0.10 mol), boric acid pinacol (14.40 g, 0.1 mol), sodium carbonate (12.90 g, 0.15 mol), Pd (PPh 3) 2Cl 2 (3.51 g, 5.0 mmol) were added to N, N-dimethylformamide (250 ml), and the temperature was controlled at 75-80 ° C. After the reaction was completed, a reaction solution containing compound I-2 was obtained; under inert gas protection, the reaction solution was continued to be added A solution of potassium acetate (11.77 g, 0.12 mol) in water (40 ml) and 2-bromo-N,N-dimethylacetamide (21.58 g, 0.13 mol) were stirred and mixed, and the temperature was controlled at 95-100°C. After the reaction was detected to be complete, the mixture was filtered through diatomaceous earth. The filtrate was added to purified water (800 ml) and extracted with chloroform (250 ml × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure to obtain zolpidem (I) with a yield of 78.9% and a purity of 99.11%.

[0076] Example 5

[0077] Under argon protection at room temperature, compound I-1 (30.12 g, 0.10 mol), boric acid pinacol (20.15 g, 0.14 mol), potassium phosphate (31.84 g, 0.15 mol), Pd (PPh3) 2Cl2 (3.51 g, 5.0 mmol) were added to N, N-dimethylacetamide (250 ml), and the temperature was controlled at 110-115 ° C. and refluxed to obtain a reaction solution containing compound I-2 after the reaction was completed. Under inert gas protection, the reaction solution was continued to be added. A solution of potassium acetate (11.77 g, 0.12 mol) in water (40 ml) and 2-bromo-N,N-dimethylacetamide (21.58 g, 0.13 mol) were added, stirred and mixed, and the temperature was controlled at 95-100° C. After the reaction was detected to be complete, the mixture was filtered through diatomaceous earth. The filtrate was added to purified water (800 ml), extracted with ethyl acetate (250 ml×3), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure to obtain zolpidem (I) with a yield of 85.4% and a purity of 99.79%.

[0078] Example 6

[0079] Under argon protection at room temperature, compound I-1 (30.12 g, 0.10 mol), boric acid pinacol (24.47 g, 0.17 mol), sodium phosphate (57.01 g, 0.15 mol), Pd (dppf) Cl2 (3.66 g, 5.0 mmol) were added to 1,4-dioxane (250 ml), and the temperature was controlled at 80-85 ° C. reflux reaction was carried out. After the reaction was completed, a reaction solution containing compound I-2 was obtained; under inert gas protection, acetic acid was continued to be added to the reaction solution. A solution of potassium (11.77 g, 0.12 mol) in water (40 ml) and 2-bromo-N,N-dimethylacetamide (21.58 g, 0.13 mol) were stirred and mixed, and the temperature was controlled at 90-95°C. After the reaction was detected to be complete, the mixture was filtered through diatomaceous earth. The filtrate was added to purified water (800 ml), extracted with methyl tert-butyl ether (250 ml × 3), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure to obtain zolpidem (I) with a yield of 78.5% and a purity of 98.99%.

[0080] Example 7

[0081] Under argon protection at room temperature, compound I-1 (30.12 g, 0.10 mol), boric acid pinacol (17.28 g, 0.12 mol), potassium acetate (11.78 g, 0.12 mol), Pd (dppf) Cl2 (3.66 g, 5.0 mmol) were added to N, N-dimethylformamide (250 ml), and the temperature was controlled at 105-110 ° C. After the reaction was completed, a reaction solution containing compound I-2 was obtained; under inert gas protection, the reaction solution was continued to be added A solution of potassium acetate (11.77 g, 0.12 mol) in water (40 ml) and 2-bromo-N,N-dimethylacetamide (21.58 g, 0.13 mol) were stirred and mixed, and the temperature was controlled at 95-100°C. After the reaction was detected to be complete, the mixture was filtered through diatomaceous earth. The filtrate was added to purified water (800 ml) and extracted with dichloromethane (250 ml × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure to obtain zolpidem (I) with a yield of 83.5% and a purity of 99.90%.

[0082] Example 8

[0083] Under argon protection and room temperature, compound I-1 (30.12 g, 0.10 mol), boric acid pinacol (17.28 g, 0.12 mol), potassium acetate (9.81 g, 0.10 mol), Pd (dppf) Cl2 (3.66 g, 5.0 mmol) were added to N, N-dimethylacetamide (250 ml), and the temperature was controlled at 100-105 ° C. After the reaction was completed, a reaction solution containing compound I-2 was obtained; under inert gas protection, the reaction solution was continued to be added A solution of potassium acetate (11.77 g, 0.12 mol) in water (40 ml) and 2-bromo-N,N-dimethylacetamide (21.58 g, 0.13 mol) were stirred and mixed, and the temperature was controlled at 95-100°C. After the reaction was detected to be complete, the mixture was filtered through diatomaceous earth. The filtrate was added to purified water (800 ml) and extracted with chloroform (250 ml × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure to obtain zolpidem (I) with a yield of 78.4% and a purity of 99.15%.

[0084] Example 9

[0085] Under argon protection at room temperature, compound I-1 (30.12 g, 0.10 mol), boric acid pinacol (17.28 g, 0.12 mol), potassium acetate (17.67 g, 0.18 mol), Pd (dppf) Cl2 (3.66 g, 5.0 mmol) were added to 1,4-dioxane (250 ml), and the temperature was controlled at 75-80 ° C. and refluxed to obtain a reaction solution containing compound I-2 after the reaction was completed. Acetate was added to the reaction solution under inert gas protection. A solution of potassium hydroxide (11.77 g, 0.12 mol) in water (40 ml) and 2-bromo-N,N-dimethylacetamide (21.58 g, 0.13 mol) were stirred and mixed, and the temperature was controlled at 90-95°C. After the reaction was detected to be complete, the mixture was filtered through diatomaceous earth. The filtrate was added to purified water (800 ml), extracted with ethyl acetate (250 ml × 3), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure to obtain zolpidem (I) with a yield of 85.1% and a purity of 99.74%.

[0086] Example 10

[0087] Under argon protection at room temperature, compound I-1 (30.12 g, 0.10 mol), boric acid pinacol (17.28 g, 0.12 mol), potassium acetate (20.61 g, 0.21 mol), and Pd (dppf) Cl2 (3.66 g, 5.0 mmol) were added to dimethyl sulfoxide (250 ml), and the temperature was controlled at 110-105 ° C. and refluxed to obtain a reaction solution containing compound I-2 after the reaction was completed. Potassium acetate was continued to be added to the reaction solution under inert gas protection. A solution of 2-bromo-N,N-dimethylacetamide (11.77 g, 0.12 mol) in water (40 ml) and 2-bromo-N,N-dimethylacetamide (21.58 g, 0.13 mol) were stirred and mixed, and the temperature was controlled at 95-100° C. After the reaction was detected to be complete, the mixture was filtered through diatomaceous earth. The filtrate was added to purified water (800 ml), and extracted with methyl tert-butyl ether (250 ml×3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure to obtain Zolpidem (I) with a yield of 78.8% and a purity of 98.98%.

[0088] Example 11

[0089] Under argon protection at room temperature, compound I-1 (30.12 g, 0.10 mol), boric acid pinacol (17.28 g, 0.12 mol), sodium acetate (12.31 g, 0.15 mol), and Pd (dppf) Cl2 (2.20 g, 3.0 mmol) were added to dimethyl sulfoxide (250 ml), and the temperature was controlled at 100-105 ° C. After the reaction was completed, a reaction solution containing compound I-2 was obtained; potassium acetate was continued to be added to the reaction solution under inert gas protection. A solution of 2-bromo-N,N-dimethylacetamide (11.77 g, 0.12 mol) in water (40 ml) and 2-bromo-N,N-dimethylacetamide (21.58 g, 0.13 mol) were stirred and mixed, and the temperature was controlled at 95-100° C. After the reaction was detected to be complete, the mixture was filtered through diatomaceous earth. The filtrate was added to purified water (800 ml), extracted with dichloromethane (250 ml×3), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure to obtain zolpidem (I) with a yield of 86.2% and a purity of 99.59%.

[0090] Example 12

[0091] Under argon protection at room temperature, compound I-1 (30.12 g, 0.10 mol), boric acid pinacol (17.28 g, 0.12 mol), potassium carbonate (20.73 g, 0.15 mol), Pd (dppf) Cl2 (0.73 g, 1.0 mmol) were added to dimethyl sulfoxide (250 ml), and the temperature was controlled at 75-80 ° C. After the reaction was completed, a reaction solution containing compound I-2 was obtained; potassium acetate was continued to be added to the reaction solution under inert gas protection. A solution of 2-bromo-N,N-dimethylacetamide (11.77 g, 0.12 mol) in water (40 ml) and 2-bromo-N,N-dimethylacetamide (21.58 g, 0.13 mol) were stirred and mixed, and the temperature was controlled at 95-100° C. After the reaction was detected to be complete, the mixture was filtered through diatomaceous earth. The filtrate was added to purified water (800 ml), extracted with chloroform (250 ml×3), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure to obtain Zolpidem (I) with a yield of 80.4% and a purity of 98.93%.

[0092] Example 13

[0093] Under argon protection at room temperature, compound I-1 (30.12 g, 0.10 mol), boric acid pinacol (17.28 g, 0.12 mol), sodium carbonate (12.60 g, 0.15 mol), Pd (dppf) Cl2 (5.85 g, 8.0 mmol) were added to dimethyl sulfoxide (250 ml), and the temperature was controlled at 95-100 ° C. After the reaction was completed, a reaction solution containing compound I-2 was obtained; potassium acetate was continued to be added to the reaction solution under inert gas protection. A solution of 2-bromo-N,N-dimethylacetamide (11.77 g, 0.12 mol) in water (40 ml) and 2-bromo-N,N-dimethylacetamide (21.58 g, 0.13 mol) were stirred and mixed, and the temperature was controlled at 95-100° C. After the reaction was detected to be complete, the mixture was filtered through diatomaceous earth. The filtrate was added to purified water (800 ml), and extracted with ethyl acetate (250 ml×3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure to obtain zolpidem (I) with a yield of 85.6% and a purity of 99.72%.

[0094] Example 14

[0095] Under argon protection and room temperature, compound I-1 (30.12 g, 0.10 mol), boric acid pinacol (17.28 g, 0.12 mol), potassium acetate (15.90 g, 0.15 mol), and Pd (dppf) Cl2 (7.33 g, 10 mmol) were added to dimethyl sulfoxide (250 ml) and the temperature was controlled at 110 to 105 ° C. After the reaction was completed, a reaction solution containing compound I-2 was obtained; under inert gas protection, potassium acetate ( A solution of 2-bromo-N,N-dimethylacetamide (11.77 g, 0.12 mol) in water (40 ml) and 2-bromo-N,N-dimethylacetamide (21.58 g, 0.13 mol) was stirred and mixed, and the temperature was controlled at 95-100°C. After the reaction was detected to be complete, the mixture was filtered through diatomaceous earth. The filtrate was added to purified water (800 ml), extracted with methyl tert-butyl ether (250 ml × 3), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure to obtain zolpidem (I) with a yield of 79.4% and a purity of 99.48%.

[0096] Example 15

[0097] Under argon protection and room temperature, compound I-1 (30.12 g, 0.10 mol), boric acid pinacol (17.28 g, 0.12 mol), potassium acetate (14.72 g, 0.15 mol), Pd (dppf) Cl2 (3.66 g, 5.0 mmol) were added to dimethyl sulfoxide (250 ml), and the temperature was controlled at 95-100 ° C. After the reaction was completed, a reaction solution containing compound I-2 was obtained; under inert gas protection, acetic acid was continued to be added to the reaction solution. A solution of potassium (7.85 g, 0.08 mol) in water (40 ml) and 2-bromo-N,N-dimethylacetamide (21.58 g, 0.08 mol) were stirred and mixed, and the temperature was controlled at 80-85°C. After the reaction was detected to be complete, the mixture was filtered through diatomaceous earth. The filtrate was added to purified water (800 ml), extracted with dichloromethane (250 ml × 3), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure to obtain zolpidem (I) with a yield of 81.7% and a purity of 99.33%.

[0098] Example 16

[0099] Under argon protection at room temperature, compound I-1 (30.12 g, 0.10 mol), pinacol borate (17.28 g, 0.12 mol), potassium acetate (14.72 g, 0.15 mol), and Pd(dppf)Cl2 (3.66 g, 5.0 mmol) were added to toluene (250 ml) and the temperature was controlled at 95-100 ° C. After the reaction was completed, a reaction solution containing compound I-2 was obtained; potassium acetate was continued to be added to the reaction solution under inert gas protection. A solution of 2-bromo-N,N-dimethylacetamide (5.89 g, 0.06 mol) in water (40 ml) and 2-bromo-N,N-dimethylacetamide (21.58 g, 0.13 mol) were stirred and mixed, and the temperature was controlled at 85-90° C. After the reaction was detected to be complete, the mixture was filtered through diatomaceous earth. The filtrate was added to purified water (800 ml), and extracted with chloroform (250 ml×3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure to obtain zolpidem (I) with a yield of 75.5% and a purity of 99.07%.

[0100] Example 17

[0101] Under argon protection at room temperature, compound I-1 (30.12 g, 0.10 mol), boric acid pinacol (17.28 g, 0.12 mol), potassium acetate (14.72 g, 0.15 mol), Pd (dppf) Cl2 (3.66 g, 5.0 mmol) were added to N, N-dimethylformamide (250 ml), and the temperature was controlled at 95-100 ° C. After the reaction was completed, a reaction solution containing compound I-2 was obtained; under inert gas protection, acetic acid was continued to be added to the reaction solution. A solution of potassium hydroxide (14.72 g, 0.15 mol) in water (40 ml) and 2-bromo-N,N-dimethylacetamide (21.58 g, 0.13 mol) were stirred and mixed, and the temperature was controlled at 100-105°C. After the reaction was detected to be complete, the mixture was filtered through diatomaceous earth. The filtrate was added to purified water (800 ml), extracted with ethyl acetate (250 ml × 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure to obtain zolpidem (I) with a yield of 83.4% and a purity of 99.49%.

[0102] Example 18

[0103] Under argon protection and room temperature, compound I-1 (30.12 g, 0.10 mol), boric acid pinacol (17.28 g, 0.12 mol), potassium acetate (14.72 g, 0.15 mol), and Pd (dppf) Cl2 (3.66 g, 5.0 mmol) were added to dimethyl sulfoxide (250 ml) and the temperature was controlled at 95 to 100 ° C. After the reaction was completed, a reaction solution containing compound I-2 was obtained; under inert gas protection, potassium acetate (1 A solution of 2-bromo-N,N-dimethylacetamide (6.68 g, 0.17 mol) in water (40 ml) and 2-bromo-N,N-dimethylacetamide (21.58 g, 0.13 mol) was stirred and mixed, and the temperature was controlled at 105-110°C. After the reaction was detected to be complete, the mixture was filtered through diatomaceous earth. The filtrate was added to purified water (800 ml), extracted with methyl tert-butyl ether (250 ml × 3), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure to obtain zolpidem (I) with a yield of 81.8% and a purity of 99.35%.

[0104] Example 19

[0105] Under argon protection at room temperature, compound I-1 (30.12 g, 0.10 mol), pinacol borate (17.28 g, 0.12 mol), potassium acetate (14.72 g, 0.15 mol), and Pd(dppf)Cl2 (3.66 g, 5.0 mmol) were added to toluene (250 ml) and the temperature was controlled at 95-100 ° C. After the reaction was completed, a reaction solution containing compound I-2 was obtained; potassium acetate was continued to be added to the reaction solution under inert gas protection. A solution of 1,4-dimethyl-2-nitropropene (11.77 g, 0.12 mol) in water (40 ml) and 2-bromo-N,N-dimethylacetamide (16.6 g, 0.1 mol) were stirred and mixed, and the temperature was controlled at 90-95° C. After the reaction was detected to be complete, the mixture was filtered through diatomaceous earth. The filtrate was added to purified water (800 ml), and extracted with dichloromethane (250 ml×3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure to obtain zolpidem (I) with a yield of 77.9% and a purity of 99.41%.

[0106] Example 20

[0107] Under argon protection at room temperature, compound I-1 (30.12 g, 0.10 mol), boric acid pinacol (17.28 g, 0.12 mol), potassium acetate (14.72 g, 0.15 mol), Pd (dppf) Cl2 (3.66 g, 5.0 mmol) were added to N, N-dimethylformamide (250 ml), and the temperature was controlled at 95-100 ° C. After the reaction was completed, a reaction solution containing compound I-2 was obtained; under inert gas protection, the reaction solution was continued to be added. A solution of potassium acetate (11.77 g, 0.12 mol) in water (40 ml) and 2-bromo-N,N-dimethylacetamide (19.92 g, 0.12 mol) were added, stirred and mixed, and the temperature was controlled at 85-90°C. After the reaction was detected to be complete, the mixture was filtered through diatomaceous earth. The filtrate was added to purified water (800 ml), extracted with chloroform (250 ml × 3), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure to obtain zolpidem (I) with a yield of 81.3% and a purity of 99.68%.

[0108] Example 21

[0109] Under argon protection at room temperature, compound I-1 (30.12 g, 0.10 mol), pinacol borate (17.28 g, 0.12 mol), potassium acetate (14.72 g, 0.15 mol), and Pd(dppf)Cl2 (3.66 g, 5.0 mmol) were added to dimethyl sulfoxide (250 ml) and the temperature was controlled at 95-100 ° C. After the reaction was completed, a reaction solution containing compound I-2 was obtained; potassium acetate was continued to be added to the reaction solution under inert gas protection. A solution of 1,4-dimethyl-2-nitropropene (11.77 g, 0.12 mol) in water (40 ml) and 2-bromo-N,N-dimethylacetamide (24.9 g, 0.15 mol) were stirred and mixed, and the temperature was controlled at 95-100° C. After the reaction was detected to be complete, the mixture was filtered through diatomaceous earth. The filtrate was added to purified water (800 ml), and extracted with ethyl acetate (250 ml×3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure to obtain zolpidem (I) with a yield of 83.9% and a purity of 99.81%.

[0110] Example 22

[0111] Under argon protection at room temperature, compound I-1 (30.12 g, 0.10 mol), boric acid pinacol (17.28 g, 0.12 mol), potassium acetate (14.72 g, 0.15 mol), Pd (dppf) Cl2 (3.66 g, 5.0 mmol) were added to toluene (250 ml), and the temperature was controlled at 95-100 ° C. After the reaction was completed, a reaction solution containing compound I-2 was obtained; under inert gas protection, potassium acetate (1 A solution of 2-bromo-N,N-dimethylacetamide (1.77 g, 0.12 mol) in water (40 ml) and 2-bromo-N,N-dimethylacetamide (28.22 g, 0.17 mol) was stirred and mixed, and the temperature was controlled at 90-95°C. After the reaction was detected to be complete, the mixture was filtered through diatomaceous earth. The filtrate was added to purified water (800 ml), extracted with methyl tert-butyl ether (250 ml × 3), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure to obtain zolpidem (I) with a yield of 79.7% and a purity of 99.65%.

Claims

1. A method for preparing zolpidem, characterized in that: The preparation method comprises the following steps: (1) Under inert gas protection, at room temperature, compound I-1, compound SM-2, a base, and a catalyst are added to a reaction solvent, and the temperature is controlled until the reaction is complete to obtain a reaction solution containing compound I-2; (2) Under inert gas protection, alkali, purified water and compound SM-3 are added to the reaction solution containing compound I-2, and after stirring and mixing, the temperature is controlled until the reaction is completed. The reaction is post-treated to obtain zolpidem. The reaction synthesis route is as follows: 。 2. The preparation method according to claim 1, characterized in that The reaction solvent in step (1) is selected from dimethyl sulfoxide, N , N -Dimethylformamide, 1,4-dioxane, N , N -A type of dimethylacetamide.

3. The preparation method according to claim 1, characterized in that The temperature control in step (1) and step (2) is 80-110°C.

4. The preparation method according to claim 1, characterized in that The molar ratio of compound I-1, compound SM-2, base and catalyst in step (1) is 1:1.1-1.4:1.2-1.8:0.03-0.

08.

5. The preparation method according to claim 1, characterized in that The catalyst in step (1) is selected from One of Pd(PPh3)4, Pd(PPh3)2Cl2, and Pd(dppf)Cl2.

6. The preparation method according to claim 1, characterized in that The base in step (1) and step (2) is selected from one of K2CO3, Na2CO3, K3PO4, Na3PO4, NaOAc, and KOAc.

7. The preparation method according to claim 1, characterized in that The molar ratio of the base, compound SM-3 and compound I-1 added continuously in step (2) is 0.8~1.5:1.2~1.5:1.

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