A process for the preparation of zolpidem

Abstract

The application belongs to the field of pharmaceutical chemical industry, and particularly relates to a preparation method of Zolpidem. The method uses 2-bromo-N,N-dimethylacetamide as a starting material, and the starting material is activated by iodine / zinc, and then subjected to a coupling reaction with 3-bromo-6-methyl-2-(4-methylphenyl)imidazo[1,2-a]pyridine to obtain the target product. The method can avoid the use of dangerous chemical reagents, and has high product yield and purity, and is suitable for industrial production.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical chemical industry, and specifically relates to a method for preparing zolpidem. Background Technology

[0002] Zolpidem tartrate, chemically named 2-(4-methylphenyl)-N,N,6-trimethylimidazo[1,2-a]pyridine-3-acetamide tartrate, is a non-benzodiazepine Hypnotic drugs, brand name Originally developed by Synthelabo, a French company, it was first marketed in France in 1988. Clinically, it is used to treat severe sleep disorders, such as occasional and transient insomnia. In addition, it is also significantly effective for primary insomnia, depression, and insomnia caused by psychosis. It is characterized by rapid onset of action and low addictive potential. Its chemical structure is as follows:

[0003]

[0004] There are currently many reports on the synthetic process of zolpidem, including patents GB9915489, GB1076089, EP0050563, US4492695, US4382938, US20070027180A1, and literature such as 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, and Inventi. Rapid:MedChem, 2014(2):1-8 uses p-methylacetophenone or its downstream intermediates as starting materials. First, bromination is used to generate 2-bromo-4'-methylacetophenone. Then, through condensation, Mannich reaction, cyano substitution and hydrolysis, 2-(6-methyl-2-(p-methylphenyl)imidazo[1,2-a]pyridin-3-yl)acetic acid is obtained. Finally, it is reacted with a large excess of dimethylamine to obtain zolpidem.

[0005] However, this process route involves long reaction steps and cumbersome operation. Furthermore, the Mannich reaction uses genotoxic formaldehyde, the N-alkylation step uses highly toxic, low-boiling-point iodomethane, and the quaternary ammonium salt is nucleophilically substituted with highly toxic sodium cyanide to prepare the cyano intermediate 2-(6-methyl-2-(4-methylphenyl)imidazo[1,2-a]pyridin-3-yl)acetonitrile, making the entire reaction process dangerous and with low safety. In addition, the conversion of the cyano group to the amide requires prolonged passage of dry HCl gas into the reaction system under heating conditions, which is cumbersome and unsuitable for industrial production. Finally, the amidation process uses CDI (a very expensive, toxic, allergenic, and hygroscopic compound, making industrial-scale production very difficult; another issue is that the desired product obtained by this method is contaminated by CDI decomposition products, thus requiring complex purification methods to obtain zolpidem that meets the stringent pharmacopoeia requirements) and highly toxic phosphorus oxychloride or phosphorus pentachloride. The synthetic route is shown below:

[0006]

[0007] To overcome the shortcomings of the above methods, many methods for preparing heteroarylacetamides have been proposed. Generally, they differ in the methods used to introduce the acetamide side chain and the reagents used, and can be mainly divided into the following four strategies:

[0008] ①As in US patents US4794185, FR2600650, and EP251589, 6-methyl-2-(4-methylphenyl)imidazolium[1,2-a]pyridine is used as a key intermediate or starting material. It reacts with N,N-dimethyl-2,2-dimethoxy-acetamide to obtain an α-hydroxy-N,N-dimethyl-acetamide derivative. After chlorination with SOCl2, it is reduced and dechlorinated with NaBH4, Zn(BH4)2, KBH4, and LiBH4 to obtain zolpidem. The synthetic route is shown below:

[0009]

[0010] Although this synthesis method avoids the use of highly toxic sodium cyanide, it uses SOCl2, which is highly corrosive and irritating and can cause burns to humans, in 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 can cause symptoms such as sore throat, cough, shortness of breath, headache, abdominal pain, diarrhea, dizziness, conjunctival congestion, and pain). Furthermore, borohydride is highly reactive and releases hydrogen gas during the reaction, making the operation dangerous and unsuitable for use in the field of drug synthesis.

[0011] Furthermore, the above process requires the separate preparation of side-chain intermediates, resulting in a large number of steps required to prepare zolpidem and an increased 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, making it impossible to produce on an industrial scale. Moreover, it is sensitive to trace amounts of water and acid, making this route difficult to scale up for production.

[0012] US Patent US4808594A (family FR8615533, EP0267111A1) synthesized zolpidem derivatives using the same strategy, but used the highly carcinogenic sodium formaldehyde sulfoxylate in the reductive dechlorination process. This substance is extremely harmful to the lungs, liver and kidneys of humans, making the operation less safe.

[0013] Chinese patents CN1972939A (family members EP01172364, US2007213537, WO2006007289) and CN1729188A (family members WO2004058758, EP01809627, US20070213537A1), and EP01809627, describe the preparation of zolpidem by contacting a mixture of 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 dehydrating agent (carboxylic anhydride, carboxyl chloride, or magnesium sulfate, molecular sieve) with a hydrogen source (hydrogen, 1–4 atmospheres). Although this process reduces the chlorination step, it still requires a noble metal catalysis, and the reaction pressure is relatively high, making the operation quite dangerous. The synthesis route is shown below:

[0014]

[0015] Chinese patent CN1668617A (related to US20040010146 and WO20040010146) uses a hydroxyacetamide derivative as a reagent for side chain extension, but this reagent is not readily available, and the reducing agent PBr used is prone to causing burns and is irritating to the respiratory system, making it difficult to scale up during operations. The synthetic route is shown below:

[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 operations. In addition, this process uses precious metal catalysts, which need to be recycled 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 derivatives, followed by hydroxyl chlorination and reduction, and finally dimethylamine hydrolysis to obtain zolpidem. Although this method introduces the dimethylamino group through direct dimethylamine hydrolysis of the ester, eliminating the need for CDI, phosphorus oxychloride, or phosphorus pentachloride, the side chain extension reagents used are difficult to obtain. Furthermore, the reduction of the hydroxyl group requires unavailable sodium methanesulfinate or highly toxic sodium formaldehyde sulfoxylate, making it unsuitable for industrial-scale production. The synthetic route is shown below:

[0020]

[0021] ④ Chinese patent CN106946876A directly prepares 6-methyl-2-(4-methylphenyl)imidazolium[1,2-a]pyridine with 2-bromo-N,N-dimethylacetamide under photocatalytic conditions with a 5W blue LED lamp via catalysts such as fac-Ir(ppy)3, Ir(ppy)2(dtbbpy)PF6, or Ru(bpy)3Cl2·6H2O. However, this process has a long reaction time (12-18 h) and a low yield (around 65%). Furthermore, the photocatalytic method requires special equipment and is inconvenient to operate. The synthetic route is shown below:

[0022]

[0023] In summary, current methods for preparing zolpidem have many shortcomings, including poor process safety, cumbersome operation, low yield, and high production cost. Therefore, finding a reaction route suitable for the industrial production of zolpidem with mild reaction conditions, simple operation, high product yield and purity, and low production cost remains a problem that needs to be solved. Summary of the Invention

[0024] To address the problems of long routes, cumbersome operations, low yield, low purity, high technical requirements, and high production costs in existing zolpidem preparation technologies, this invention provides a novel method for synthesizing zolpidem. The zolpidem prepared by this method exhibits high purity and high yield, making it suitable for industrial production.

[0025] The specific technical solution of the present invention is as follows:

[0026] A method for preparing zolpidem includes the following steps:

[0027] Iodine and zinc were added to a dry reaction solvent at room temperature under an inert gas atmosphere. The mixture was stirred until the iodine red color disappeared. Then, SM-1 was added, and the reaction was continued at temperature T1. After the reaction was confirmed to be complete, SM-2 and the catalyst were added at temperature T2, and the reaction was continued at temperature T2. After the reaction of SM-2 was confirmed to be complete, the product was obtained through post-processing. The reaction route is as follows:

[0028]

[0029] Preferably, the catalyst is one of Pd(PPh3)4, Pd(PPh3)2Cl2, Pd(dppf)Cl2, and Ni(PPh3)2Cl2, with Pd(dppf)Cl2 being the most preferred.

[0030] Preferably, the zinc is zinc in various physical forms, including powder, granules, and zinc shavings, with zinc powder being more preferred.

[0031] Preferably, the molar ratio of SM-1 to iodine, zinc, SM-2, and catalyst is 1:0.02-0.1:1.2-2.0:0.9-1.0:0.5%-3.0%, and more preferably 1:0.05:1.5:0.95:1.5%.

[0032] Preferably, the reaction temperature T1 is 60-100°C, particularly preferably 75-80°C; T2 is 10-30°C, even more preferably 20-25°C.

[0033] Preferably, the reaction solvent is one or a combination of dimethyl sulfoxide, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, and N,N-dimethylpropenylurea, with N,N-dimethylacetamide being particularly preferred.

[0034] Preferably, the post-processing steps are as follows: filter the reaction liquid into diatomaceous earth, quench the filtrate in dilute hydrochloric acid, wash with organic solvent, adjust the pH to 8.5-9.5, precipitate the solid, filter, and dry to obtain the target product.

[0035] Preferably, the dilute hydrochloric acid is 0.1–2 mol / L, and more preferably 1 mol / L.

[0036] Preferably, the reagent for adjusting the pH is one of sodium hydroxide, potassium hydroxide, or sodium carbonate.

[0037] Preferably, the organic solvent for washing is one or a combination of dichloromethane, chloroform, ethyl acetate, and methyl tert-butyl ether, with dichloromethane being more preferred.

[0038] Preferably, the inert gas is one or a combination of argon and nitrogen, with argon being more preferred.

[0039] The beneficial effects of this invention are:

[0040] 1. This invention provides a novel method for preparing zolpidem, which uses 2-bromo-N,N-dimethylacetamide (SM-1) as the starting material, which is activated by iodine / zinc and then reacted with 3-bromo-6-methyl-2-(4-methylphenyl)imidazolium[1,2-a]pyridine (SM-2) via a cross-coupling reaction to obtain the target product.

[0041] 2. In this invention, the zolpidem side chain is constructed using 2-bromo-N,N-dimethylacetamide reagent. Compared with the prior art, this significantly shortens the reaction steps and effectively avoids photocatalytic reactions, making the operation simpler and suitable for industrial production.

[0042] 3. The zolpidem prepared by this process has high purity and yield.

[0043] In summary, this invention provides a novel method for preparing zolpidem, which avoids the use of hazardous chemical reagents, and the synthesized product does not generate new impurities. It also boasts high yield and purity, making it suitable for industrial production. Detailed Implementation

[0044] The present invention will be further illustrated below through embodiments. It should be understood that the embodiments of the present invention are merely for illustrating the invention and not for limiting the invention. Therefore, simple improvements to the present invention under the premise of the method of the present invention are all within the scope of protection of the present invention.

[0045] The structure of the zolpidem compound obtained in this invention is confirmed as follows:

[0046] ESI-HRMS (m / z): 308.1770 [M+H] + 615.3439[2M+H] + ; 1H NMR (600MHz, DMSO-d6) δ: 8.03 (s, 1H), 7.52 (d, J = 8.04Hz, 2H), 7.47 (d, J = 9.12Hz, 1H), 7.26 (d, J = 7.86H z,2H),7.10(dd,J=9.12,1.26Hz,1H),4.14(s,2H),3.13(s,3H),2.90(s,3H),2.34(s,3H),2.30(s,3H); 13 C NMR (151MHz, DMSO-d6) δ: 167.95, 142.77, 142.43, 136.34, 131.93, 129.01, 127. 48,126.84,122.22,120.47,115.76,115.09,36.85,35.20,28.79,20.69,17.67.

[0047] This invention uses HPLC to determine the purity of zolpidem, and the chromatographic conditions are as follows:

[0048] Column: YMC Triart-C 18 Column (4.6 mm × 250 mm, 5 μm) or equivalent chromatographic column;

[0049] Mobile phase: Mobile phase A: Sodium sulfate aqueous solution (dissolve 2.84 g of anhydrous sodium sulfate and 1 ml of trifluoroacetic acid in water and dilute to 1000 ml), Mobile phase B: Acetonitrile, gradient elution;

[0050] Column temperature: 35℃;

[0051] Detection wavelength: 248nm;

[0052] Flow rate: 1.0 ml / min;

[0053] Injection volume: 20 μl;

[0054] The retention time of zolpidem is approximately 18.7 minutes.

[0055] The elution gradient is shown in Table 1:

[0056] Table 1 Elution gradient table

[0057]

[0058] In the following embodiments, the various processes and methods not described in detail are conventional methods known in the art.

[0059] Example 1

[0060] Under argon protection at room temperature, iodine (1.27 g, 0.005 mol) and zinc powder (9.81 g, 0.15 mol) were added to dry N,N-dimethylacetamide (300 ml). The mixture was stirred at room temperature until the iodine red color disappeared. Then, 2-bromo-N,N-dimethylacetamide (SM-1, 16.60 g, 0.10 mol) was added, and the reaction was continued at 75–80 °C. After the reaction of SM-1 was complete as detected by TLC, 3-bromo-6-methyl-2-(4-methylphenyl)imidazolium[1,2-a]pyridine (SM-1) was added at 20–25 °C. SM-2 (28.61 g, 0.095 mol) and Pd(dppf)Cl2 (1.10 g, 0.0015 mol) were added and the reaction was continued at a controlled temperature of 20-25℃. After the reaction of SM-2 was detected to be complete, the reaction solution was filtered through diatomaceous earth. The filtrate was quenched in 1 mol / L dilute hydrochloric acid (3 L), washed with dichloromethane (1000 ml × 3), and the pH was adjusted to 8.5-9.5 with sodium hydroxide. The precipitated solid was filtered and dried to obtain the target product zolpidem, with a yield of 95.9% (based on SM-2) and an HPLC purity of 99.83%.

[0061] Example 2

[0062] Under argon protection at room temperature, iodine (1.27 g, 0.005 mol) and zinc granules (9.81 g, 0.15 mol) were added to dry N,N-dimethylacetamide (300 ml). The mixture was stirred at room temperature until the iodine red color disappeared. Then, 2-bromo-N,N-dimethylacetamide (SM-1, 16.60 g, 0.10 mol) was added, and the reaction was continued at 75–80 °C. After the reaction of SM-1 was complete as detected by TLC, 3-bromo-6-methyl-2-(4-methylphenyl)imidazolium[1,2-a]pyridine was added at 25–30 °C. SM-2 (27.11 g, 0.090 mol) and Pd(PPh3)4 (1.73 g, 0.0015 mol) were reacted at a controlled temperature of 25–30 °C. After the reaction of SM-2 was detected to be complete, the reaction solution was filtered through diatomaceous earth. The filtrate was quenched in 1 mol / L dilute hydrochloric acid (3 L), washed with dichloromethane (1000 ml × 3), and the pH was adjusted to 8.5–9.5 with sodium hydroxide. The precipitated solid was filtered and dried to obtain the target product zolpidem, with a yield of 97.2% (based on SM-2) and an HPLC purity of 98.72%.

[0063] Example 3

[0064] Under argon protection at room temperature, iodine (1.27 g, 0.005 mol) and zinc filings (9.81 g, 0.15 mol) were added to 300 ml of dry N,N-dimethylacetamide. The mixture was stirred at room temperature until the iodine red color disappeared. Then, 2-bromo-N,N-dimethylacetamide (SM-1, 16.60 g, 0.10 mol) was added, and the reaction was continued at 85–90 °C. After the reaction of SM-1 was complete as detected by TLC, 3-bromo-6-methyl-2-(4-methylphenyl)imidazolium[1,2-a]pyridine (SM-1) was added at 20–25 °C. The reaction mixture (SM-2, 25.60 g, 0.085 mol) and Pd(dppf)Cl2 (1.10 g, 0.0015 mol) were continued at a controlled temperature of 20–25 °C. After the reaction was completed, the reaction solution was filtered through diatomaceous earth. The filtrate was quenched in 1 mol / L dilute hydrochloric acid (3 L), washed with dichloromethane (1000 ml × 3), and the pH was adjusted to 8.5–9.5 with sodium hydroxide. The precipitated solid was filtered and dried to obtain the target product zolpidem, with a yield of 97.9% (based on SM-2) and an HPLC purity of 97.85%.

[0065] Example 4

[0066] Under argon protection at room temperature, iodine (1.27 g, 0.005 mol) and zinc powder (9.81 g, 0.15 mol) were added to 300 ml of dry dimethyl sulfoxide. The mixture was stirred at room temperature until the iodine red color disappeared. Then, 2-bromo-N,N-dimethylacetamide (SM-1, 16.60 g, 0.10 mol) was added, and the reaction was continued at 75–80 °C. After the reaction of SM-1 was complete as detected by TLC, 3-bromo-6-methyl-2-(4-methylphenyl)imidazolium[1,2-a]pyridine (SM-2) was added at 25–30 °C. 30.12 g (0.1 mol) and Pd(PPh3)2Cl2 (1.05 g, 0.0015 mol) were added and the reaction was continued at a controlled temperature of 25-30℃. After the reaction of SM-2 was detected to be complete, the reaction solution was filtered through diatomaceous earth. The filtrate was quenched in 1 mol / L dilute hydrochloric acid (3 L), washed with dichloromethane (1000 ml × 3), and the pH was adjusted to 8.5-9.5 with sodium hydroxide. The precipitated solid was filtered and dried to obtain the target product zolpidem, with a yield of 92.1% (based on SM-2) and an HPLC purity of 99.71%.

[0067] Example 5

[0068] Under argon protection at room temperature, iodine (0.51 g, 0.002 mol) and zinc powder (9.81 g, 0.15 mol) were added to dry N,N-dimethylformamide (300 ml). The mixture was stirred at room temperature until the iodine red color disappeared. Then, 2-bromo-N,N-dimethylacetamide (SM-1, 16.60 g, 0.10 mol) was added, and the reaction was continued at 80–85 °C. After the reaction of SM-1 was complete as detected by TLC, 3-bromo-6-methyl-2-(4-methylphenyl)imidazolium[1,2-a]pyridine (SM-1) was added at 25–30 °C. The reaction mixture (SM-2, 28.61 g, 0.095 mol) and Pd(dppf)Cl2 (1.10 g, 0.0015 mol) was continued at a controlled temperature of 25–30 °C. After the reaction was completed, the reaction solution was filtered through diatomaceous earth. The filtrate was quenched in 1 mol / L dilute hydrochloric acid (3 L), washed with dichloromethane (1000 ml × 3), and the pH was adjusted to 8.5–9.5 with sodium hydroxide. The precipitated solid was filtered and dried to obtain the target product zolpidem, with a yield of 93.4% (based on SM-2) and an HPLC purity of 99.73%.

[0069] Example 6

[0070] Under argon protection at room temperature, iodine (2.54 g, 0.01 mol) and zinc powder (9.81 g, 0.15 mol) were added to dry N,N-dimethylacetamide (300 ml). The mixture was stirred at room temperature until the iodine red color disappeared. Then, 2-bromo-N,N-dimethylacetamide (SM-1, 16.60 g, 0.10 mol) was added, and the reaction was continued at 65–70 °C. After the reaction of SM-1 was complete as detected by TLC, 3-bromo-6-methyl-2-(4-methylphenyl)imidazolium[1,2-a]pyridine (SM-1) was added at 20–25 °C. The reaction mixture (28.61 g, 0.095 mol) and Ni(PPh3)2Cl2 (0.98 g, 0.0015 mol) was continued at a controlled temperature of 20–25 °C. After the reaction of SM-2 was detected to be complete, the reaction solution was filtered through diatomaceous earth. The filtrate was quenched in 1 mol / L dilute hydrochloric acid (3 L), washed with chloroform (1000 ml × 3), and the pH was adjusted to 8.5–9.5 with sodium hydroxide. The precipitated solid was filtered and dried to obtain the target product zolpidem, with a yield of 94.5% (based on SM-2) and an HPLC purity of 99.70%.

[0071] Example 7

[0072] Under argon protection at room temperature, iodine (1.27 g, 0.005 mol) and zinc powder (7.85 g, 0.12 mol) were added to dry N-methylpyrrolidone (300 ml). The mixture was stirred at room temperature until the iodine red color disappeared. Then, 2-bromo-N,N-dimethylacetamide (SM-1, 16.60 g, 0.10 mol) was added, and the reaction was continued at 75–80 °C. After the reaction of SM-1 was complete as detected by TLC, 3-bromo-6-methyl-2-(4-methylphenyl)imidazolium[1,2-a]pyridine (SM-1) was added at 25–30 °C. 28.61 g (0.095 mol) and Pd(dppf)Cl2 (1.10 g, 0.0015 mol) were added and the reaction was continued at a controlled temperature of 25-30℃. After the reaction of SM-2 was detected to be complete, the reaction solution was filtered through diatomaceous earth. The filtrate was quenched in 1 mol / L dilute hydrochloric acid (3 L), washed with dichloromethane (1000 ml × 3), and the pH was adjusted to 8.5-9.5 with sodium hydroxide. The precipitated solid was filtered and dried to obtain the target product zolpidem, with a yield of 92.5% (based on SM-2) and an HPLC purity of 99.76%.

[0073] Example 8

[0074] Under argon protection at room temperature, iodine (1.27 g, 0.005 mol) and zinc powder (13.08 g, 0.20 mol) were added to dry N,N-dimethylacetamide (300 ml). The mixture was stirred at room temperature until the iodine red color disappeared. Then, 2-bromo-N,N-dimethylacetamide (SM-1, 16.60 g, 0.10 mol) was added, and the reaction was continued at 90–95 °C. After the reaction of SM-1 was complete as detected by TLC, 3-bromo-6-methyl-2-(4-methylphenyl)imidazolium[1,2-a]pyridine (S) was added at 10–15 °C. M-2 (28.61 g, 0.095 mol) and Pd(dppf)Cl2 (1.10 g, 0.0015 mol) were reacted at a controlled temperature of 10–15 °C. After the reaction of SM-2 was detected to be complete, the reaction solution was filtered through diatomaceous earth. The filtrate was quenched in 1 mol / L dilute hydrochloric acid (3 L), washed with ethyl acetate (1000 ml × 3), and the pH was adjusted to 8.5–9.5 with sodium hydroxide. The precipitated solid was filtered and dried to obtain the target product zolpidem, with a yield of 94.8% (based on SM-2) and an HPLC purity of 99.79%.

[0075] Example 9

[0076] Under nitrogen protection at room temperature, iodine (1.27 g, 0.005 mol) and zinc powder (9.81 g, 0.15 mol) were added to dry N,N-dimethylacetamide (300 ml). The mixture was stirred at room temperature until the iodine red color disappeared. Then, 2-bromo-N,N-dimethylacetamide (SM-1, 16.60 g, 0.10 mol) was added, and the reaction was continued at 75–80 °C. After the reaction of SM-1 was complete as detected by TLC, 3-bromo-6-methyl-2-(4-methylphenyl)imidazolium[1,2-a]pyridine (SM-1) was added at 25–30 °C. 28.61 g (0.095 mol) and Pd(dppf)Cl2 (0.37 g, 0.0005 mol) were added and the reaction was continued at a controlled temperature of 25-30℃. After the reaction of SM-2 was detected to be complete, the reaction solution was filtered through diatomaceous earth. The filtrate was quenched in 1 mol / L dilute hydrochloric acid (3 L), washed with methyl tert-butyl ether (1000 ml × 3), and the pH was adjusted to 8.5-9.5 with sodium hydroxide. The precipitated solid was filtered and dried to obtain the target product zolpidem, with a yield of 93.5% (based on SM-2) and an HPLC purity of 99.75%.

[0077] Example 10

[0078] Under argon protection at room temperature, iodine (1.27 g, 0.005 mol) and zinc powder (9.81 g, 0.15 mol) were added to dry N,N-dimethylpropenylurea (300 ml). The mixture was stirred at room temperature until the iodine red color disappeared. Then, 2-bromo-N,N-dimethylacetamide (SM-1, 16.60 g, 0.10 mol) was added, and the reaction was continued at 75–80 °C. After the reaction of SM-1 was complete as detected by TLC, 3-bromo-6-methyl-2-(4-methylphenyl)imidazolium[1,2-a]pyridine (S) was added at 20–25 °C. M-2 (28.61 g, 0.095 mol) and Pd(dppf)Cl2 (2.20 g, 0.003 mol) were reacted at a controlled temperature of 20–25 °C. After the reaction of SM-2 was detected to be complete, the reaction solution was filtered through diatomaceous earth. The filtrate was quenched in 1 mol / L dilute hydrochloric acid (3 L), washed with dichloromethane (1000 ml × 3), and the pH was adjusted to 8.5–9.5 with sodium hydroxide. The precipitated solid was filtered and dried to obtain the target product zolpidem, with a yield of 95.2% (based on SM-2) and an HPLC purity of 99.70%.

Claims

1. A method for preparing zolpidem, characterized in that, Specifically, the following steps are included: Iodine and zinc were added to a dry reaction solvent at room temperature under an inert gas atmosphere. The mixture was stirred until the iodine red color disappeared. Then, SM-1 was added, and the reaction was continued at temperature T1. After the reaction was confirmed to be complete, SM-2 and a catalyst were added at temperature T2, and the reaction was continued at temperature T2. After the reaction of SM-2 was confirmed to be complete, the target product was obtained through post-processing. The reaction route is as follows: ； The catalyst is one of Pd(PPh3)4, Pd(PPh3)2Cl2, Pd(dppf)Cl2, and Ni(PPh3)2Cl2; The reaction temperature T1 is 60–100°C; The reaction temperature T2 is 10–30°C; The reaction solvent is dimethyl sulfoxide. N , N -Dimethylformamide, N , N -Dimethylacetamide, N -Methylpyrrolidone, N,N - One or a combination of dimethylpropenylurea.

2. The preparation method according to claim 1, characterized in that, The catalyst is Pd(dppf)Cl2.

3. The preparation method according to claim 1, characterized in that, The molar ratio of SM-1 to iodine, zinc, SM-2, and catalyst is 1:0.02-0.1:1.2-2.0:0.9-1.0:0.5%-3.0%.

4. The preparation method according to claim 1, characterized in that, The reaction temperature T1 is 75-80℃.

5. The preparation method according to claim 1, characterized in that, The reaction temperature T2 is 20-25℃.

6. The preparation method according to claim 1, characterized in that, The post-processing steps are as follows: filter the reaction liquid into diatomaceous earth, quench the filtrate in dilute hydrochloric acid, wash with organic solvent, adjust the pH to 8.5-9.5, precipitate the solid, filter, and dry to obtain the target product.

7. The preparation method according to claim 6, characterized in that, The organic solvent is one or a combination of dichloromethane, chloroform, ethyl acetate, and methyl tert-butyl ether.

8. The preparation method according to claim 6, characterized in that, The organic solvent is dichloromethane.

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