A zolpidem intermediate compound

Abstract

The present invention belongs to the technical field of pharmaceutical synthesis, and specifically relates to a new intermediate compound I-1 of pyrazoline. The present invention uses 6-methyl-2-(4-methylphenyl)imidazo[1,2-a]pyridine as a raw material to synthesize the new intermediate compound I-1. The present invention also provides a new method for synthesizing pyrazoline using the intermediate. Compared with the existing technology, the method can significantly shorten the reaction steps, has low production cost, and is simple to operate. The prepared zolpidem has high purity and yield, and is suitable for industrial production.

Description

Technical Field

[0001] The invention belongs to the technical field of pharmaceutical synthesis and relates to a zolpidem intermediate compound. 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] At present, there are many reports on the synthesis process of zolpidem, such as Chinese patent applications CN106946876A, CN106749237A, CN103360387A, CN106866661A and literature Research on the green synthesis process of zolpidem tartrate, Chinese Journal of Medicinal Chemistry, 2018, 28(1), 39-42, Synthesis of zolpidem tartrate, China Pharmaceutical, 2014, 23(5), 16-17, New synthesis process of zolpidem tartrate, Chinese Journal of Pharmaceutical Industry, 2017, 48 (12), 1726-1730, Study on the Synthesis Process of Zolpidem Tartrate, Tianjin Pharmacy, 2002, 14(l), 69-70, US2006084806A1, US200900799A1, US2011189794A1, WO0214306A1, WO2004087703A1, WO2009007995A1, WO2010122576A1, WO2015011722A2 all reported the preparation methods of Zolpidem and its related intermediates.

[0005] For example, in the literature Org. Lett., 2012, 14(17): 4580-4583, p-methyl-β-nitrostyrene is used as the starting material. After Michael addition, acylation, ring closure, and hydrolysis, it is condensed with dimethylamine in the presence of phosphorus pentachloride to obtain the target product. However, the starting materials of this method are expensive, resulting in high production costs. The pyridine used is highly irritating and harmful to health and the environment.

[0006]

[0007] In addition, the document Angew. Chem. Int. Ed. Engl., 2010, 49(15): 2743-2746 uses p-methylbenzaldehyde as a starting material, which is first condensed with 2-amino-5-methylpyridine to form the corresponding Shiff base, and then cyclized with N,N-dimethylpropynamide under the catalysis of copper trifluoromethanesulfonate [Cu(OTf)2] and cuprous chloride to form the target product. However, the N,N-dimethylpropynamide and Cu(OTf)2 used in this method are extremely expensive, which greatly increases the production cost:

[0008]

[0009] In summary, there are problems in the preparation methods of zolpidem, such as long routes, low yields, and low purity; or high technical requirements and high production costs; therefore, exploring a process route for zolpidem that is simple to operate, has higher yields, and is more suitable for industrial production is still a problem that needs to be solved. Summary of the Invention

[0010] To address the problems of existing zolpidem preparation technologies, such as long routes, cumbersome operations, low yields, low purity, high technical requirements, and high production costs, the present invention provides a new zolpidem intermediate compound I-1, a method for preparing the compound, and a novel method for synthesizing zolpidem using the compound. This method provides a short reaction route for preparing zolpidem, simple operations, and high purity and yield of the resulting zolpidem, making it suitable for industrial production.

[0011] The specific technical solutions of the present invention are as follows:

[0012] A zolpidem intermediate compound as shown in formula Ⅰ-1:

[0013]

[0014] A method for preparing a zolpidem intermediate compound I-1 comprises the following steps: adding SM-1 to a reaction solvent at room temperature, stirring and mixing, adding 1,3-dibromo-5,5-dimethylhydantoin (DBDMH) under temperature control, controlling the temperature until the reaction is complete, and performing post-treatment to obtain the zolpidem intermediate compound I-1. The reaction scheme is as follows:

[0015]

[0016] Preferably, the reaction solvent is selected from dichloromethane, chloroform, and 1,2-dichloroethane, among which dichloromethane is particularly preferred.

[0017] Preferably, the molar ratio of SM-1 to DBDMH is 1:0.55-1.0, with 1:0.7 being particularly preferred.

[0018] Preferably, the temperature when adding DBDMH is -15 to 10°C; the reaction temperature is 0 to 30°C, particularly preferably 20 to 25°C.

[0019] In a preferred embodiment, the post-treatment step is to control the temperature until the reaction is completed, filter out 5,5-dimethylhydantoin (DMH), wash the filtrate with a 10% sodium sulfite aqueous solution, wash with purified water, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to dryness to obtain the target product I-1.

[0020] The compound I-1 is used for preparing zolpidem.

[0021] The compound I-1 is used for preparing zolpidem, and the preparation method comprises the following steps: step 1, compound I-1 reacts with pinacol diboron in the presence of a catalyst to obtain an intermediate compound I-2; step 2, intermediate compound I-2 reacts with 2-bromo-N,N-dimethylacetamide in the presence of a catalyst to obtain zolpidem; the reaction synthesis route is as follows:

[0022]

[0023] Preferably, the above steps are further described in detail in the following sections:

[0024] Preparation of compound Zolpidem I:

[0025] The preparation method of compound Zolpidem I comprises the following steps: under inert gas protection, at room temperature, adding compound I-1, diboronic acid pinacol ester, 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; under inert gas protection, continuously adding a base, purified water, and 2-bromo-N,N-dimethylacetamide to the reaction solution containing product I-2, stirring and mixing, controlling the temperature until the reaction is completed, and performing post-treatment to obtain Zolpidem.

[0026] 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.

[0027] Preferably, the base is selected from one of K2CO3, Na2CO3, K3PO4, Na3PO4, NaOAc, and KOAc, with KOAc being particularly preferred.

[0028] Preferably, the molar ratio of the compound I-1 to the diboric acid pinacol ester, 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.

[0029] 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.

[0030] 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.

[0031] Preferably, the reaction temperature is 80-110°C, particularly preferably 95-100°C.

[0032] 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 one of dichloromethane, chloroform, ethyl acetate, and methyl tert-butyl ether, particularly preferably ethyl acetate.

[0033] In the present invention, the inert gas described in the preparation method of compounds I-2 and I is usually nitrogen or argon, with argon being particularly preferred.

[0034] Compared with the prior art, the present invention has the following beneficial effects:

[0035] The present invention provides a new zolpidem intermediate compound I-1 and a new method for synthesizing zolpidem using the compound. The method avoids the use of hazardous chemical reagents, generates no new impurities during the synthesis of the intermediate, has high reaction efficiency, and achieves high zolpidem yield and purity, thereby being suitable for industrial production. DETAILED DESCRIPTION

[0036] 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.

[0037] The structural confirmation data of the intermediate compound I-1 obtained in the present invention are as follows:

[0038] 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);13 C 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.

[0039] The structural confirmation data of the intermediate compound I-2 obtained in the present invention are as follows:

[0040] 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.

[0041] The structure of the Zolpidem compound obtained in the present invention is confirmed as follows:

[0042] 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.

[0043] The present invention adopts HPLC to measure the purity of Zolpidem, and the chromatographic conditions are as follows:

[0044] Chromatographic column: YMC Triart-C 18 Column (4.6 mm × 250 mm, 5 μm) or chromatographic column of equivalent performance;

[0045] 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;

[0046] Column temperature: 35°C;

[0047] Detection wavelength: 248nm;

[0048] Flow rate: 1.0 ml / min;

[0049] Injection volume: 20 μl;

[0050] Among them, the retention time of zolpidem is about 18.7 minutes.

[0051] The elution gradient is shown in Table 1:

[0052] Table 1 Elution gradient

[0053]

[0054] In the following embodiments, various processes and methods not described in detail are conventional methods well known in the art.

[0055] Synthesis of intermediate Ⅰ-1:

[0056] Example 1

[0057] At room temperature, 6-methyl-2-(4-methylphenyl)imidazo[1,2-a]pyridine (SM-1, 22.23 g, 0.1 mol) was added to dichloromethane (150 ml) and stirred. After mixing, 1,3-dibromo-5,5-dimethylhydantoin (DBDMH, 20.01 g, 0.07 mol) was added at a temperature of 0-5°C. The reaction was continued at a temperature of 20-25°C. After the reaction was completed, 5,5-dimethylhydantoin (DMH) was filtered out and the filtrate was washed with 10% aqueous sodium sulfite solution (100 ml × 2) and purified water (100 ml × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure to obtain the target product Ⅰ-1 with a yield of 91.3% and a purity of 99.76%.

[0058] Example 2

[0059] At room temperature, 6-methyl-2-(4-methylphenyl)imidazo[1,2-a]pyridine (SM-1, 22.23 g, 0.1 mol) was added to chloroform (150 ml), stirred and mixed, and then 1,3-dibromo-5,5-dimethylhydantoin (DBDMH, 14.30 g, 0.05 mol) was added at -10 to -5 °C. The reaction was continued at 0 to 10 °C. After the reaction was completed, 5,5-dimethylhydantoin (DMH) was filtered out and the filtrate was washed with 10% aqueous sodium sulfite solution (100 ml × 2) and purified water (100 ml × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure to obtain the target product I-1 with a yield of 80.4% and a purity of 99.18%.

[0060] Example 3

[0061] At room temperature, 6-methyl-2-(4-methylphenyl)imidazo[1,2-a]pyridine (SM-1, 22.23 g, 0.1 mol) was added to 1,2-dichloroethane (150 ml). After stirring and mixing, 1,3-dibromo-5,5-dimethylhydantoin (DBDMH, 15.73 g, 0.055 mol) was added at -5 to 0°C, and the reaction was continued at 10 to 15°C. After the reaction was completed, 5,5-dimethylhydantoin (DMH) was filtered out and the filtrate was washed with 10% aqueous sodium sulfite solution (100 ml × 2) and purified water (100 ml × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure to obtain the target product Ⅰ-1 with a yield of 85.2% and a purity of 99.21%.

[0062] Example 4

[0063] At room temperature, 6-methyl-2-(4-methylphenyl)imidazo[1,2-a]pyridine (SM-1, 22.23 g, 0.1 mol) was added to dichloromethane (150 ml) and stirred until thoroughly mixed. 1,3-Dibromo-5,5-dimethylhydantoin (DBDMH, 28.59 g, 0.1 mol) was then added at -15 to -10°C. The reaction was continued at 15 to 20°C. After the reaction was complete, 5,5-dimethylhydantoin (DMH) was removed by filtration. The filtrate was washed with 10% aqueous sodium sulfite solution (100 ml x 2) and purified water (100 ml x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure to obtain the target product I-1 with a yield of 87.6% and a purity of 99.65%.

[0064] Example 5

[0065] At room temperature, 6-methyl-2-(4-methylphenyl)imidazo[1,2-a]pyridine (SM-1, 22.23 g, 0.1 mol) was added to chloroform (150 ml), stirred and mixed, and then 1,3-dibromo-5,5-dimethylhydantoin (DBDMH, 34.31 g, 0.12 mol) was added at a temperature of 5-10°C. The reaction was continued at a temperature of 20-35°C. After the reaction was completed, 5,5-dimethylhydantoin (DMH) was filtered out and the filtrate was washed with 10% aqueous sodium sulfite solution (100 ml × 2) and purified water (100 ml × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure to obtain the target product Ⅰ-1 with a yield of 83.3% and a purity of 99.51%.

[0066] Synthesis of Compound I:

[0067] Example 6

[0068] Under argon protection and room temperature, compound I-1 (30.12 g, 0.10 mol), diboronic acid pinacol ester (30.47 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 (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 89.6% and a purity of 99.93%.

[0069] Example 7

[0070] Under argon protection at room temperature, compound I-1 (30.12 g, 0.10 mol), bipyralidoboric acid pinacol ester (27.93 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; 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 82.4% and a purity of 99.78%.

[0071] Example 8

[0072] Under argon protection and room temperature, compound I-1 (30.12 g, 0.10 mol), bipyralidoboric acid pinacol ester (25.39 g, 0.1 mol), sodium carbonate (12.90 g, 0.15 mol), Pd (PPh3) 2Cl2 (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 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 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 77.8% and a purity of 99.06%.

[0073] Example 9

[0074] Under argon protection at room temperature, compound I-1 (30.12 g, 0.10 mol), diboronic acid pinacol ester (35.55 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 84.1% and a purity of 99.87%.

[0075] Example 10

[0076] Under argon protection at room temperature, compound I-1 (30.12 g, 0.10 mol), diboronic acid pinacol ester (43.17 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 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 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 77.2% and a purity of 98.95%.

[0077] Example 11

[0078] Under argon protection and room temperature, compound I-1 (30.12 g, 0.10 mol), bipyralidoboric acid pinacol ester (30.47 g, 0.12 mol), potassium acetate (11.78 g, 0.12 mol), and 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, 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 completed, a reaction solution containing compound I-2 was obtained. The solution was filtered through diatomaceous earth, and the filtrate was added to purified water (800 ml), 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 82.8% and a purity of 99.90%.

[0079] Example 12

[0080] Under argon protection at room temperature, compound I-1 (30.12 g, 0.10 mol), diboronic acid pinacol ester (30.47 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 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 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 77.7% and a purity of 99.05%.

[0081] Example 13

[0082] Under argon protection at room temperature, compound I-1 (30.12 g, 0.10 mol), diboronic acid pinacol ester (30.47 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. reflux reaction was carried out. 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 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 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 83.5% and a purity of 99.79%.

[0083] Example 14

[0084] Under argon protection at room temperature, compound I-1 (30.12 g, 0.10 mol), diboronic acid pinacol ester (30.47 g, 0.12 mol), potassium acetate (20.61 g, 0.21 mol), 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. reflux reaction, and after detection, the reaction was completed to obtain a reaction solution containing compound I-2; 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 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 76.7% and a purity of 98.95%.

[0085] Example 15

[0086] Under argon protection and room temperature, compound I-1 (30.12 g, 0.10 mol), diboronic acid pinacol ester (30.47 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; 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 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 84.7% and a purity of 99.67%.

[0087] Example 16

[0088] Under argon protection at room temperature, compound I-1 (30.12 g, 0.10 mol), diboronic acid pinacol ester (30.47 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; 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 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 79.6% and a purity of 98.92%.

[0089] Example 17

[0090] Under argon protection at room temperature, compound I-1 (30.12 g, 0.10 mol), diboronic acid pinacol ester (30.47 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; 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 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 84.5% and a purity of 99.66%.

[0091] Example 18

[0092] Under argon protection at room temperature, compound I-1 (30.12 g, 0.10 mol), diboronic acid pinacol ester (30.47 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 110-105 ° 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), 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 78.1% and a purity of 99.51%.

[0093] Example 19

[0094] Under argon protection at room temperature, compound I-1 (30.12 g, 0.10 mol), diboronic acid pinacol ester (30.47 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 to 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 (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 79.8% and a purity of 99.21%.

[0095] Example 20

[0096] Under argon protection and room temperature, compound I-1 (30.12 g, 0.10 mol), bipyralidoboric acid pinacol ester (30.47 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, acetic acid was continued to be added to the reaction solution. A solution of potassium (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), 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 74.7% and a purity of 99.03%.

[0097] Example 21

[0098] Under argon protection and room temperature, compound I-1 (30.12 g, 0.10 mol), diboronic acid pinacol ester (30.47 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 (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) 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 82.1% and a purity of 99.45%.

[0099] Example 22

[0100] Under argon protection and room temperature, compound I-1 (30.12 g, 0.10 mol), diboronic acid pinacol ester (30.47 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 (16.68 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 80.7% and a purity of 99.37%.

[0101] Example 23

[0102] Under argon protection and room temperature, compound I-1 (30.12 g, 0.10 mol), bipyralidoboric acid pinacol ester (30.47 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, 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 (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), 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 76.4% and a purity of 99.35%.

[0103] Example 24

[0104] Under argon protection and room temperature, compound I-1 (30.12 g, 0.10 mol), diboronic acid pinacol ester (30.47 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 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 79.6% and a purity of 99.67%.

[0105] Example 25

[0106] Under argon protection and room temperature, compound I-1 (30.12 g, 0.10 mol), diboronic acid pinacol ester (30.47 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 (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 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) 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 82.1% and a purity of 99.71%.

[0107] Example 26

[0108] Under argon protection at room temperature, compound I-1 (30.12 g, 0.10 mol), bipyralidoboric acid pinacol ester (30.47 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 100-110°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 80.4% and a purity of 99.57%.

Claims

1. A zolpidem intermediate compound, characterized in that The structure is shown in Formula I-1: 。 2. A method for preparing the pyrazoline intermediate compound I-1 according to claim 1, characterized in that: The preparation method comprises the following steps: adding compound SM-1 to reaction solvent A at room temperature, stirring and mixing, then adding 1,3-dibromo-5,5-dimethylhydantoin to reaction solvent A under temperature control, and controlling the reaction temperature until the reaction is complete to obtain intermediate compound I-1. The reaction scheme is as follows: 。 3. The preparation method according to claim 2, characterized in that The reaction solvent A is selected from one of dichloromethane, chloroform and 1,2-dichloroethane.

4. The preparation method according to claim 2, characterized in that The molar ratio of the compound SM-1 to 1,3-dibromo-5,5-dimethylhydantoin is 1:0.55-1.

0.

5. The preparation method according to claim 2, characterized in that The temperature when adding 1,3-dibromo-5,5-dimethylhydantoin is -15 to 10°C; the reaction temperature is controlled to be 0 to 30°C.

6. Use of the Zolpidem intermediate compound according to claim 1 for preparing Zolpidem.

7. Use of the Zolpidem intermediate compound according to claim 6 for preparing Zolpidem, characterized in that: The steps include: (1) Under inert gas protection and room temperature, compound I-1, compound SM-2, a base, and a catalyst are added to a reaction solvent B, and the temperature is controlled until the reaction is complete to obtain a reaction solution containing compound I-2; (2) Under inert gas protection, continue to add the aqueous base solution and compound SM-3 to the reaction system, control the temperature until the reaction is completed, and then perform post-treatment to obtain Zolpidem. The reaction synthesis route is as follows: 。 8. The use according to claim 7, 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.

9. The use according to claim 7, 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.

10. The use according to claim 7, characterized in that The reaction solvent B described in step (1) is selected from one of dimethyl sulfoxide, N,N-dimethylformamide, 1,4-dioxane, and N,N-dimethylacetamide; the catalyst described in step (1) is selected from one of Pd(PPh3)4, Pd(PPh3)2Cl2, and Pd(dppf)Cl2; the base described in step (1) and step (2) is selected from one of K2CO3, Na2CO3, K3PO4, Na3PO4, NaOAc, and KOAc; the reaction temperature described in step (1) and step (2) is 80-110°C.

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