A preparation method of zolpidem and its key intermediates

Abstract

The present invention belongs to the technical field of drug synthesis, and provides a method for preparing zolpidem and its key intermediates, wherein SM is used as a raw material, and trimethylsilyl chloride and alkali metal iodide are used to reduce α-hydroxyl to obtain compound I under the protection of inert gas. The α-hydroxyl reduction method of the present invention can effectively avoid the use of SOCl2, noble metal catalysts, sodium methanesulfinate or bleaching powder in the prior art, reduce production costs, improve operational safety, and is suitable for industrial production.

Description

Technical Field

[0001] The invention belongs to the technical field of drug synthesis, and specifically relates to a preparation method of zolpidem and a key intermediate thereof. 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 in France, it was first marketed in France in 1988. It is clinically used to treat serious sleep disorders, such as occasional insomnia and temporary insomnia. In addition, this product also has significant therapeutic effects on primary insomnia, depression, and insomnia caused by mental illness. It has the characteristics of fast efficacy and low addiction. Its chemical structure is as follows:

[0003]

[0004] At present, there are many reports on the synthesis process of zolpidem, such as CN106946876A, CN106749237A, CN103360387A, CN101336242A (same family as WO2007064444), CN106866661A and literature on the green synthesis process of zolpidem tartrate, "Chinese Journal of Medicinal Chemistry", 2018, 28(1), 39-42, the synthesis of zolpidem tartrate, "China Pharmaceutical Industry", 2014, 23(5), 16-17, a new synthesis process of zolpidem tartrate, "China Pharmaceutical Industry", 2014, 23(5), 16-17. Journal of Pharmaceutical Industry, 2017, 48(12), 1726-1730, Angew.Chem.Int.Ed., 2010, 49, 2743-2746, Chem.Sci., 2013, 4, 764-769, Eur.J.Org.Chem., 2019, 4034-4042, Heterocycl.Commun., 2017; aop, 445-448, J.Med.Chem., 1997, 40, 3109-3118, Journal of Pharmacy and Pharmacology, 2018, 79 (9), 1164-1173, Org. Lett., 2012, 14 (17), 4580-4583, Organic Preparations and Procedures International: The New Journal for Organic Synthesis, 43: 2, 260-264, Der Pharma Chemica,2012,4(6):2466-2469, J.Org.Chem.,2017,5391-5397, Organic Letters,2017,19,9,2226-2229, IN288884, WO2009007995A1, 2003MU01081, 2004CH00125, 2007MU00 160. 2009CH00904, 2013MU02428 (same family as WO2015011722A2), DE10121638A1, EP1311509B1, EP1395586B1, EP1917263B1, EP1172364B1, PL196300B1, US4492695A, US6562975B1, US2002183522A1, US2006084806A1, US20040087794A1, US20050054669A1, US200900799A1, WO0214306A1, WO02090356A2, WO2004087703A1, WO2005010002A1, WO2010122576A1, and WO2015011722A2 all report methods for preparing zolpidem and related intermediates.

[0005] In addition, 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: Med Chem, 2014 (2): 1-8, 6-methyl-2-(4-methylphenyl) imidazole [1,2-a] pyridine is used as a key intermediate or starting material, and N, N-dimethylaminomethylene is introduced at the 2-position by Mannich reaction, and then reacted with iodomethane to form a quaternary ammonium salt, and then reacted with sodium cyanide to introduce a cyano group, hydrolyzed to obtain a carboxylic acid, and finally reacted with dimethylamine to obtain zolpidem. The relevant reaction route is as follows:

[0006]

[0007] However, the process route has long reaction steps and cumbersome operation. At the same time, the genotoxic substance formaldehyde is used in the Mannich reaction for reaction, and the highly toxic and low-boiling-point iodomethane is used in the N-alkylation step. The quaternary ammonium salt is nucleophilically replaced by the 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 operation process dangerous and less safe. In addition, when converting the cyano group to an amide, it is necessary to pass dry HCl gas into the reaction system for a long time under heating conditions, which is cumbersome and not conducive to industrial production. Finally, CDI (CDI is a very expensive, toxic, allergenic and hygroscopic compound, so it is very difficult to use for industrial-scale production. Another reason is that the desired target product obtained by this method is contaminated by the decomposition products of CDI, so Zolpidem that meets the strict requirements of the pharmacopoeia can only be obtained with the help of a complex purification method) and phosphorus oxychloride or phosphorus pentachloride with relatively high toxicity are used for the reaction.

[0008] In order to eliminate the defects in the above methods, many methods for preparing heteroaryl acetamides have been proposed. Generally speaking, they differ in the methods and reagents used to introduce acetamide side chains, which can be divided into the following three strategies:

[0009] ① For example, patents US4794185, FR2600650, and EP251589 use 6-methyl-2-(4-methylphenyl)imidazole [1,2-a] pyridine as a key intermediate or starting material, react with N,N-dimethyl-2,2-dimethoxy-acetamide to obtain α-hydroxy-N,N-dimethyl-acetamide derivatives, which are then chlorinated with SOCl2 and then reduced and dechlorinated with NaBH4, Zn(BH4)2, KBH4, and LiBH4 to obtain zolpidem. The relevant reaction routes are as follows:

[0010]

[0011] 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, borohydride, which is highly harmful to the human body, is used in the reduction reaction (contact with sodium borohydride will cause 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. It is dangerous to operate and difficult to use in the field of drug synthesis.

[0012] Literature Study on the Synthesis Process of Zolpidem Tartrate, Tianjin Pharmacy, 2002, 14(l), 69-70 also adopts the above strategy to prepare Zolpidem, but uses precious metal Pd / C catalysis in the reduction and dechlorination process, which has high requirements on production equipment and high production cost.

[0013] Patent US2011189794A1 also uses precious metal Pd / C to catalyze the synthesis of zolpidem derivatives. The relevant reaction route is as follows:

[0014]

[0015] Patent US4808594A (same family FR8615533, EP0267111A1) adopts the same strategy to synthesize zolpidem derivatives, but uses a strong carcinogen, chlorpyrifos, in the reduction and dechlorination process. This substance is extremely harmful to the lungs, liver and kidneys of the human body, making the operation less safe.

[0016] Patents CN1972939A (same family EP01172364, US2007213537, WO2006007289) and CN1729188A (same family WO2004058758, EP01809627, US20070213537A1), EP01809627, a mixture of heteroaryl α-hydroxyacetamide, strong acid (sulfuric acid, perchloric acid or a mixture thereof), halide (LiBr, NaBr, KBr, MgBr2, CaBr2 or NH4Br), catalyst (platinum, palladium, ruthenium, osmium, iridium, or rhodium catalyst) and dehydrating agent (carboxylic anhydride, carboxylic acid chloride or magnesium sulfate, molecular sieve) is contacted with a hydrogen source (hydrogen, 1 to 4 atmospheres) to prepare zolpidem. Although this process reduces the chlorination process, it still needs to be reacted under the catalysis of precious metals, and the reaction pressure is relatively high, and the operation is relatively dangerous. The relevant reaction routes are as follows:

[0017]

[0018] Patent CN1668617A (same family US20040010146, WO20040010146) uses glycolamide derivatives as reagents to extend the side chain, but the reagents are not easy to obtain, and the reducing reagent PBr used is easy to cause burns and irritate the respiratory system, so it is difficult to carry out during the scale-up operation. The relevant reaction route is as follows:

[0019]

[0020] ② Patents SI, EP1038875T1 and EP1038875A2 use (contracted) glyoxylic acid monohydrate as a side chain extension to prepare the corresponding acid derivatives, 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, the process also uses precious metal catalysts, which need to be recovered after reprocessing, making the process difficult to implement on a large scale; Pd / C is also used to reduce the hydroxyl group in this patent, but patent US2011189794A1 also uses Pd / C, and the yield is unstable, which is not conducive to industrialization. The relevant reaction routes are as follows:

[0021]

[0022] ③ Patents WO0008021A2, WO0008021A3, and US6407240B1 use methyl glyoxylate or its methyl hemiacetal as side chain extension to prepare the corresponding ester derivatives, then chlorinate the hydroxyl group and reduce it, and finally hydrolyze it with dimethylamine to obtain zolpidem. However, the side chain extension reagent used in this method is not easy to obtain, and the reduction of the hydroxyl group uses sodium methanesulfinate or bleaching powder, which is relatively toxic and is also not suitable for industrial scale-up production. The relevant reaction routes are as follows:

[0023]

[0024] From the above, it can be seen that it is a very feasible strategy to prepare zolpidem using α-substituted hydroxy zolpidem derivatives as key intermediates. This series of intermediates directly affects the production, market supply and quality of zolpidem drugs. Its chemical structure is shown below:

[0025]

[0026] As can be seen from the above, there are many problems in reducing hydroxyl groups to alkanes to prepare zolpidem or its intermediates:

[0027] ① The process is carried out by hydroxyl chlorination followed by reduction, which increases the synthesis unit operation and makes the operation complicated;

[0028] ② Using corrosive and irritating SOCl2 or SOCl2 / DMF for chlorination requires high requirements for reaction equipment;

[0029] ③ The use of precious metal catalysts (platinum, palladium, ruthenium, osmium, iridium, or rhodium catalysts) results in high production costs and high operating risks for the corresponding platinum carbon or palladium carbon products;

[0030] ④ Using hydrogen to reduce and prepare related compounds at 1 to 4 atmospheres makes the operation less safe and the yield unstable;

[0031] ⑤ Using sodium methanesulfinate which is not easily available or bleaching powder which is highly toxic to the body for hydroxyl reduction results in high production cost and low operational safety.

[0032] In view of the fact that the current method for preparing zolpidem or its key intermediates from α-hydroxyzolpidem derivatives has many shortcomings in terms of complicated operation, high requirements for production equipment, process safety, production cost, etc., therefore, it is still a problem that needs to be solved to study and find a preparation process suitable for the industrial production of zolpidem or its key intermediates that is simple to operate, mild reaction conditions, safe and simple operation process, high product yield and high purity. Summary of the invention

[0033] Aiming at the problems existing in the current preparation technology of zolpidem or its key intermediates from α-hydroxy zolpidem derivatives, the present invention provides a preparation method of zolpidem and its key intermediates. The method has mild reaction conditions, a safe and simple operation process, and the obtained target product has high purity and yield.

[0034] The specific technical scheme of the present invention is as follows: Under the protection of inert gas, SM is used as a raw material, and trimethylsilyl chloride (TMSCl) and alkali metal iodide (MI) are used to reduce the α-hydroxyl group to obtain compound I, and the reaction route is as follows:

[0035]

[0036] A method for preparing zolpidem and its key intermediates as shown in formula (I), specifically comprising the following steps:

[0037] Under the protection of inert gas, SM, trimethylsilyl chloride (TMSCl) and alkali metal iodide (MI) are added to a dry reaction solvent. After the temperature is controlled until the reaction is completed, the reaction solution is cooled to room temperature and added to purified water. The organic solvent is extracted, washed with sodium thiosulfate solution, purified water, saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated to dryness under reduced pressure to obtain the target product I.

[0038] In a preferred embodiment, the alkali metal iodide is one of sodium iodide (NaI) and potassium iodide (KI) or a combination thereof, wherein sodium iodide is particularly preferred.

[0039] In a preferred embodiment, the reaction solvent is one of acetonitrile, tetrahydrofuran, 1,4-dioxane or a combination thereof, among which acetonitrile is particularly preferred.

[0040] In a preferred embodiment, the molar ratio of SM to TMSCl and alkali metal iodide is 1:4-8:4-8, with 1:5:5 being particularly preferred.

[0041] In a preferred embodiment, the mass volume ratio of the SM to the reaction solvent is 1:6-12, g / ml.

[0042] In a preferred embodiment, the reaction temperature is 50-60°C.

[0043] In a preferred embodiment, the organic solvent used for the extraction is one of dichloromethane, chloroform, ethyl acetate, methyl tert-butyl ether or a combination thereof.

[0044] In the present invention, the inert gas is usually nitrogen or argon, among which argon is particularly preferred.

[0045] In the present invention, the dry reagent refers to a solvent obtained by removing water through molecular sieves or other desiccants, or by distillation or the like.

[0046] Beneficial effects of the present invention:

[0047] 1. The present invention provides a simple and efficient method for preparing zolpidem or its intermediates. The entire synthetic method is simple to operate, and has high reaction yield and purity;

[0048] 2. The present invention adopts trimethyl iodosilane generated in situ from trimethyl chlorosilane / iodide as a reducing agent to reduce hydroxyl groups to alkyl groups, which can effectively avoid the use of SOCl2, precious metal catalysts, sodium methanesulfinate or bleaching powder, reduce production costs, improve operational safety, and is suitable for industrial production. DETAILED DESCRIPTION

[0049] The present invention is further illustrated by the following examples. It should be correctly understood that the examples of the present invention are only used to illustrate the present invention, rather than to limit the present invention. Therefore, simple improvements to the present invention based on the method of the present invention all fall within the scope of protection claimed by the present invention.

[0050] The structure of the compound obtained by the present invention is confirmed:

[0051]

[0052] mp 194.8~195.6℃; ESI-HRMS(m / z): 308.1760[M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ8.42(d,J=6.4Hz,1H),7.61(d,J=6.6Hz,2H),7.50(d,J=6.6Hz,1H),7 .29~7.23(m,1H),7.17(d,J=7.2Hz,2H),4.05(s,2H),3.00(s,6H),2.39(s,3H),2.37(s,3H); 13C NMR(101MHz,DMSO-d6)δ176.73,140.55,138.15,137.99,133.35,129.89,129.57,129.33,126.69,124.78,119.91,119.00,36.93,36.73,21.13,15.47。

[0053]

[0054] mp 133.6~134.8℃;ESI-HRMS(m / z):295.1443[M+H] + ; 1 H NMR(400MHz,DMSO-d6)δ8.35(d,J=6.2Hz,1H),7.65(d,J=66Hz,2H),7.52(d,J=6.6Hz,1H),7.36~7.24(m,1H),7.16(d,J=7.4Hz,2H),3.94(s,2H),3.77(s,3H),2.46(s,3H),2.39(s,3H); 13 C NMR(101MHz,DMSO-d6)δ173.59,144.30,140.55,137.99,133.35,129.89,129.57,129.33,126.69,124.78,119.00,118.94,51.82,27.80,21.13,15.47。

[0055]

[0056] mp 228.5~229.6℃;ESI-HRMS(m / z):281.1286[M+H] + 、279.1135[M-H] + ; 1 H NMR(400MHz,CD3OD-d4)δ8.30(d,J=6.0Hz,1H),7.60(d,J=6.4Hz,2H),7.49(d,J=6.6Hz,1H),7.34~7.25(m,1H),7.26(d,J=7.6Hz,2H),4.12(s,2H),2.55(s,3H),2.49(s,3H); 13C NMR (101MHz, CD3OD-d4) δ172.24,144.74,140.55,137.99,133.35,129.89,129.57,129.33,126.69,124.78,119.56,119.00,30.40,21.13,15.47.

[0057] In the following embodiments, various processes and methods not described in detail are conventional methods well known in the art.

[0058] Example 1

[0059] Under argon protection, 2-hydroxy-N, N-dimethyl-2-(6-methyl-2-(p-tolyl)imidazo[1,2-a]pyridin-3-yl)acetamide [R = N(CH3)2, named SM-1, 32.34 g, 0.1 mol], trimethylsilyl chloride (TMSCl, 54.32 g, 0.5 mol), sodium iodide (74.95 g, 0.5 mol) were added to dry acetonitrile (300 ml) and the mixture was stirred for 1 h. After the reaction was completed at 55°C, the reaction solution was cooled to room temperature and added into purified water (800 ml), extracted with dichloromethane (300 ml×3), the organic phase was washed with saturated sodium thiosulfate solution (300 ml×3), washed with purified water (300 ml×2), washed with saturated brine (300 ml×2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure to obtain Zolpidem with a yield of 96.4% and a HPLC purity of 99.892%.

[0060] Example 2

[0061] Under argon protection, 2-hydroxy-N,N-dimethyl-2-(6-methyl-2-(p-tolyl)imidazo[1,2-a]pyridin-3-yl)acetamide [R=N(CH3)2, SM-1, 32.34 g, 0.1 mol], trimethylsilyl chloride (TMSCl, 43.46 g, 0.4 mol), sodium iodide (59.96 g, 0.4 mol) were added to dry acetonitrile (300 ml) and the temperature was controlled. After the reaction is completed at 60°C, the reaction solution is cooled to room temperature and added to purified water (800 ml), extracted with chloroform (300 ml×3), the organic phase is washed with saturated sodium thiosulfate solution (300 ml×3), washed with purified water (300 ml×2), washed with saturated brine (300 ml×2), dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated to dryness under reduced pressure to obtain Zolpidem with a yield of 95.9% and a HPLC purity of 99.873%.

[0062] Example 3

[0063] Under argon protection, 2-hydroxy-N,N-dimethyl-2-(6-methyl-2-(p-tolyl)imidazo[1,2-a]pyridin-3-yl)acetamide [R=N(CH3)2, SM-1, 32.34 g, 0.1 mol], trimethylsilyl chloride (TMSCl, 38.02 g, 0.35 mol), sodium iodide (52.46 g, 0.35 mol) were added to dry acetonitrile (300 ml) and the temperature was controlled. After the reaction was completed at 55°C, the reaction solution was cooled to room temperature and added into purified water (800 ml), extracted with ethyl acetate (300 ml×3), the organic phase was washed with saturated sodium thiosulfate solution (300 ml×3), washed with purified water (300 ml×2), washed with saturated brine (300 ml×2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure to obtain Zolpidem with a yield of 92.9% and a HPLC purity of 99.791%.

[0064] Example 4

[0065] Under argon protection, 2-hydroxy-N,N-dimethyl-2-(6-methyl-2-(p-tolyl)imidazo[1,2-a]pyridin-3-yl)acetamide [R=N(CH3)2, SM-1, 32.34 g, 0.1 mol], trimethylsilyl chloride (TMSCl, 86.91 g, 0.8 mol), sodium iodide (119.91 g, 0.8 mol) were added to dry acetonitrile (300 ml) and the temperature was controlled at 5 After the reaction is completed, the reaction solution is cooled to room temperature and added into purified water (800 ml), extracted with methyl tert-butyl ether (300 ml×3), the organic phase is washed with saturated sodium thiosulfate solution (300 ml×3), washed with purified water (300 ml×2), washed with saturated brine (300 ml×2), dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated to dryness under reduced pressure to obtain Zolpidem with a yield of 96.0% and a HPLC purity of 99.710%.

[0066] Example 5

[0067] Under nitrogen protection, 2-hydroxy-N,N-dimethyl-2-(6-methyl-2-(p-tolyl)imidazo[1,2-a]pyridin-3-yl)acetamide [R=N(CH3)2SM-1, 32.34 g, 0.1 mol], trimethylsilyl chloride (TMSCl, 92.34 g, 0.85 mol), sodium iodide (127.41 g, 0.85 mol) were added to dry acetonitrile (300 ml) and the temperature was controlled. After the reaction was completed at 55°C, the reaction solution was cooled to room temperature and added to purified water (800 ml), extracted with dichloromethane (300 ml×3), the organic phase was washed with saturated sodium thiosulfate solution (300 ml×3), washed with purified water (300 ml×2), washed with saturated brine (300 ml×2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure to obtain Zolpidem with a yield of 95.1% and a HPLC purity of 99.690%.

[0068] Example 6

[0069] Under argon protection, 2-hydroxy-N, N-dimethyl-2-(6-methyl-2-(p-tolyl)imidazo[1,2-a]pyridin-3-yl)acetamide [R = N(CH3)2, named SM-1, 32.34 g, 0.1 mol], trimethylsilyl chloride (TMSCl, 54.32 g, 0.5 mol), sodium iodide (74.95 g, 0.5 mol) were added to dry acetonitrile (300 ml) and the mixture was stirred for 1 h. After the reaction is completed at 45°C, the reaction solution is cooled to room temperature and added into purified water (800 ml), extracted with dichloromethane (300 ml×3), the organic phase is washed with saturated sodium thiosulfate solution (300 ml×3), washed with purified water (300 ml×2), washed with saturated brine (300 ml×2), dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated to dryness under reduced pressure to obtain Zolpidem with a yield of 85.4% and a HPLC purity of 99.592%.

[0070] Example 7

[0071] Under argon protection, 2-hydroxy-N, N-dimethyl-2-(6-methyl-2-(p-tolyl)imidazo[1,2-a]pyridin-3-yl)acetamide [R = N(CH3)2, named SM-1, 32.34 g, 0.1 mol], trimethylsilyl chloride (TMSCl, 54.32 g, 0.5 mol), sodium iodide (74.95 g, 0.5 mol) were added to dry acetonitrile (300 ml) and the mixture was stirred for 1 h. After the reaction is completed at 65°C, the reaction solution is cooled to room temperature and added into purified water (800 ml), extracted with dichloromethane (300 ml×3), the organic phase is washed with saturated sodium thiosulfate solution (300 ml×3), washed with purified water (300 ml×2), washed with saturated brine (300 ml×2), dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated to dryness under reduced pressure to obtain Zolpidem with a yield of 83.4% and a HPLC purity of 99.326%.

[0072] Example 8

[0073] Under argon protection, methyl 2-hydroxy-2-(6-methyl-2-(p-tolyl)imidazo[1,2-a]pyridin-3-yl)acetate (R=OCH3, SM-2, 31.04 g, 0.1 mol), trimethylsilyl chloride (TMSCl, 54.32 g, 0.5 mol), sodium iodide (74.95 g, 0.5 mol) were added to dry tetrahydrofuran (350 ml), and the temperature was controlled at 55°C until the reaction was completed. The reaction solution was cooled to room temperature and purified The product was added into water (800 ml), extracted with dichloromethane (300 ml×3), the organic phase was washed with saturated sodium thiosulfate solution (300 ml×3), purified water (300 ml×2), saturated brine (300 ml×2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure to obtain methyl 2-(6-methyl-2-(p-tolyl)imidazo[1,2-a]pyridin-3-yl)acetate. The yield was 94.3% and the HPLC purity was 99.865%.

[0074] Example 9

[0075] Under argon protection, 2-hydroxy-2-(6-methyl-2-(p-tolyl)imidazo[1,2-a]pyridin-3-yl)acetic acid (R=OH, SM-3, 29.63 g, 0.1 mol), trimethylsilyl chloride (TMSCl, 54.32 g, 0.5 mol), potassium iodide (83.00 g, 0.5 mol) were added to dry 1,4-dioxane (350 ml), and the temperature was controlled at 55°C until the reaction was completed. After the reaction solution was cooled to room temperature, pure The organic phase was washed with saturated sodium thiosulfate solution (300 ml × 3), purified water (300 ml × 2), saturated brine (300 ml × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure to obtain 2-(6-methyl-2-(p-tolyl)imidazo[1,2-a]pyridin-3-yl)acetic acid with a yield of 96.5% and a HPLC purity of 99.785%.

Claims

1. A method for preparing zolpidem and its key intermediates, characterized in that: Using SM as the raw material, trimethylsilyl chloride and alkali metal iodide (MI) are used to reduce the α-hydroxyl group to obtain compound I. The reaction route is as follows: 。 2. The preparation method according to claim 1, characterized in that The specific steps include: Under the protection of inert gas, SM, trimethylsilyl chloride (TMSCl), and alkali metal iodide are added to a dry reaction solvent, and the temperature is controlled until the reaction is completed. The reaction solution is cooled to room temperature and added to purified water. The organic solvent is extracted, and the organic phase is washed with sodium thiosulfate solution, purified water, saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated to dryness under reduced pressure to obtain compound I; The organic solvent used for the extraction is one of dichloromethane, chloroform, ethyl acetate, methyl tert-butyl ether or a combination thereof.

3. The preparation method according to claim 2, characterized in that: The reaction solvent is one of acetonitrile, tetrahydrofuran, 1,4-dioxane or a combination thereof.

4. The preparation method according to claim 2, characterized in that: The alkali metal iodide is sodium iodide, potassium iodide or a combination thereof.

5. The preparation method according to claim 2, characterized in that: The feeding molar ratio of SM to TMSCl and alkali metal iodide is 1:4-8:4-8.

6. The preparation method according to claim 2, characterized in that: The reaction temperature is 50-60°C.

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