A kind of preparation method of Zolpidem

Abstract

The invention belongs to the technical field of drug synthesis, and the invention provides a method for preparing zolpidem, by using SM-1 as a starting material, Rh(trop2N)(PPh3) as a catalyst, MMA as a hydrogen acceptor, and dimethylamine through a catalytic dehydrogenation coupling reaction to prepare, and acid-soluble alkali analysis and refinement to obtain a product with higher purity. The preparation process of zolpidem of the present invention can significantly shorten the process route compared to the prior art, and is suitable for industrial production.

Description

Technical Field

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

[0002] Zolpidem tartrate, chemically known as 2-(4-methylphenyl)-N,N,6-trimethylimidazo[1,2-a]pyridine-3-acetamide tartrate, is a non-benzodiazepine hypnotic. 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] The synthesis processes of Zolpidem are mainly as follows:

[0005] 1. US Patents US20070027180 and US4382938 use p-methylacetophenone as the starting material, first bromination to generate 2-bromo-4'-methylacetophenone, then condensation, Mannich reaction, cyano substitution and hydrolysis to obtain 2-[6-methyl-2-(p-methylphenyl)imidazo[1,2-a]pyridin-3-yl]acetic acid, and finally react with a large excess of dimethylamine to obtain the target product. However, the process has long reaction steps and cumbersome operation; and it uses highly toxic iodomethane, sodium cyanide, formaldehyde, as well as environmentally unfriendly phosphorus oxychloride and a large excess of dimethylamine and other reagents, which is not conducive to industrial production. The reaction route is as follows:

[0006]

[0007] 2. Literature Org. Lett., 2012, 14(17): 4580-4583. Using p-methyl-β-nitrostyrene as the starting material, after Michael addition, acylation, ring closure and hydrolysis, the target product is obtained by condensation with dimethylamine under the action of phosphorus pentachloride. However, the starting material of this method is expensive and the production cost is high; the pyridine used is highly irritating and is harmful to health and the environment. The reaction route is as follows:

[0008]

[0009] 3. In the literature Angew.Chem.Int.Ed.Engl.,2010,49(15):2743-2746, p-methylbenzaldehyde is used as the starting material, which is first condensed with 2-amino-5-methylpyridine to generate the corresponding Shiff base, and then cyclized with N,N-dimethylpropynamide under the catalysis of copper trifluoromethanesulfonate [Cu(OTf)2] and cuprous chloride to generate 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. The reaction route is as follows:

[0010]

[0011] 4. In the literature J.Med.Chem., 1997, 40(19):3109-3118, N,N-dimethyl-4-oxo-4-(p-methylphenyl)butyramide is used as the starting material, and after bromination with bromine, it is cyclized with 2-amino-5-methylpyridine to obtain the target product. Although this method has a high degree of greenness and good atom economy, it still has the following shortcomings: 1) The starting material is expensive and the total yield is low, only 17%; 2) The brominated compound is difficult to purify, and it takes 2 to 3 times of refining to obtain a purity of more than 95%, and the yield is low (50% to 60%); 3) There are many impurities in the crude product reaction, and it is difficult to purify the product; except for the product being soluble in acid water to remove some impurities, other impurities can only be removed by multiple refinings, and the yield is very low (30%). The reaction route is as follows:

[0012]

[0013] In summary, the current preparation method of Zolpidem has many shortcomings in terms of process safety, complicated operation, low yield, and high production cost. Therefore, it is still a problem that needs to be solved to study and find a reaction route suitable for industrial production of Zolpidem with mild reaction conditions, simple operation process, high product yield, high purity, and low production cost. Summary of the invention

[0014] Aiming at the problems existing in the current Zolpidem preparation technology, the present invention provides a novel Zolpidem preparation method. The target product prepared by the method has high purity and yield.

[0015] The specific technical solutions of the present invention are as follows:

[0016]

[0017] A method for preparing Zolpidem, comprising the following steps:

[0018] Under the protection of inert gas, SM-1, dimethylamine and methyl methacrylate (MMA) are added to the reaction solvent, and the pre-cooled catalyst is added under temperature control. After being kept warm and stirred evenly, the temperature is raised to room temperature, and the reaction is continued until completion, and Zolpidem is obtained through post-treatment.

[0019] In a preferred embodiment, the reaction solvent is one of diethyl ether, isopropyl ether, methyl tert-butyl ether, tetrahydrofuran, 2-methyltetrahydrofuran or a combination thereof, wherein 2-methyltetrahydrofuran is particularly preferred.

[0020] In a preferred embodiment, the catalyst is Rh(trop2N)(PPh3), whose chemical structure is shown below. It can be obtained commercially or prepared by itself according to existing technologies. It can be directly added to the reaction system or diluted with a reaction solvent before being added.

[0021]

[0022] In a preferred embodiment, the molar ratio of SM-1 to dimethylamine, MMA and catalyst is 1:1.2-2.0:1.5-4.0:0.1%-0.5%, among which 1:1.6:2.8:0.2% is particularly preferred.

[0023] In a preferred embodiment, the dimethylamine can be introduced as a gas or as an organic solvent solution of dimethylamine. The present invention preferably uses a 2 mol / L tetrahydrofuran solution of dimethylamine. It is sufficient to add a proportional amount of dimethylamine.

[0024] In a preferred embodiment, the temperature of the temperature control and catalyst precooling is -20 to 0°C.

[0025] In a preferred embodiment, the post-treatment step is as follows: filtering the reaction solution, concentrating the filtrate to dryness under reduced pressure, dissolving with 1-5 mol / L hydrochloric acid, filtering, washing the filtrate with dichloromethane, adjusting the pH of the acid water layer to 9-11 with 1-5 mol / L sodium hydroxide solution, continuing to stir and crystallize, filtering, washing with purified water until neutral, and drying the obtained filter cake under reduced pressure to obtain Zolpidem.

[0026] In the present invention, the inert gas is usually selected from nitrogen and argon, among which argon is particularly preferred.

[0027] Beneficial effects of the present invention:

[0028] 1. The present invention provides a novel method for preparing zolpidem, the preparation process has simple post-processing operation, and a product with high purity can be obtained by simple acid dissolution and alkali precipitation refining;

[0029] 2. The preparation process of Zolpidem of the present invention can significantly shorten the process route compared with the prior art and is suitable for industrial production. BRIEF DESCRIPTION OF THE DRAWINGS

[0030] Figure 1 This is the liquid phase analysis spectrum of the purity of Zolpidem obtained in Example 1.

[0031] Figure 2 This is the liquid phase analysis spectrum of Zolpidem purity obtained in Example 4. DETAILED DESCRIPTION

[0032] 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.

[0033] The structure of the Zolpidem compound obtained by the present invention is confirmed as follows:

[0034] mp.: 195.3~196.0℃; ESI-HRMS(m / z): 308.1758[M+H] + ; 1 H NMR (400MHz, CD3OD-d4) δ9.56 (s, 1H), 7.61~7.85 (m, 2H), 7.42 (d, J = 7.4Hz, 2H), 7.30 (d, J=7.4Hz,2H),4.50(d,J=5.4Hz,2H),2.80(s,3H),2.48(s,3H),2.43(s,3H),2.41(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.

[0035] The present invention adopts HPLC to measure the purity of Zolpidem, and the chromatographic conditions are as follows:

[0036] Chromatographic column: YMC Triart-C 18 Column (4.6mm×250mm, 5μm) or chromatographic column with equivalent performance;

[0037] 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;

[0038] Column temperature: 35°C;

[0039] Detection wavelength: 248nm;

[0040] Flow rate: 1.0ml / min;

[0041] Injection volume: 20 μl;

[0042] The elution gradient is shown in Table 1:

[0043] Table 1 Elution gradient table

[0044]

[0045] In the following embodiments, various processes and methods not described in detail are conventional methods known in the art.

[0046] Example 1

[0047] Under argon protection, SM-1 (26.63 g, 0.1 mol), a tetrahydrofuran solution of dimethylamine (2 mol / L, 80 mL, 0.16 mol), and methyl methacrylate (MMA, 28.03 g, 0.28 mol) were added to 2-methyltetrahydrofuran (260 ml), and the temperature was controlled at -15 to -10 °C. A 2-methyltetrahydrofuran (10 ml) solution of Rh(trop2N)(PPh3) (0.15 g, 0.2 mmol) precooled at -15 to -10 °C was added, and the mixture was stirred for 2 h. After stirring evenly at -15 to -10 ° C, the reaction solution was heated to room temperature. After the reaction was detected to be complete, it was filtered. The filtrate was concentrated to dryness under reduced pressure, dissolved with hydrochloric acid (3 mol / L, 200 ml), filtered, and the filtrate was washed with dichloromethane (100 ml). The pH of the acid water layer was adjusted to 9 to 11 with 4 mol / L sodium hydroxide solution. A large amount of light yellow solid was precipitated. After continuing to stir and crystallize for 1 to 2 hours, it was filtered and washed with purified water until neutral. The obtained filter cake was dried under reduced pressure to obtain the target product with a yield of 96.5% and a purity of 99.931%.

[0048] Example 2

[0049] Under argon protection, SM-1 (26.63 g, 0.1 mol), a tetrahydrofuran solution of dimethylamine (2 mol / L, 60 mL, 0.12 mol), and MMA (28.03 g, 0.28 mol) were added to tetrahydrofuran (260 ml), and the temperature was controlled at -5 to 0 ° C. A tetrahydrofuran solution of Rh (trop2N) (PPh3) (0.15 g, 0.2 mmol) precooled at -5 to 0 ° C (10 ml) was added, and the temperature was controlled at -5 to 0 ° C and stirred. After homogenization, the reaction solution was warmed to room temperature. After the reaction was detected to be complete, it was filtered. The filtrate was concentrated to dryness under reduced pressure, dissolved with hydrochloric acid (2mol / L, 300ml), filtered, and the filtrate was washed with dichloromethane (150ml). The pH of the acid water layer was adjusted to 9-11 with 5mol / L sodium hydroxide solution. A large amount of light yellow solid precipitated. After continuing to stir and crystallize for 1-2h, it was filtered and washed with purified water until neutral. The obtained filter cake was dried under reduced pressure to obtain the target product with a yield of 93.2% and a purity of 99.882%.

[0050] Example 3

[0051] Under argon protection, SM-1 (26.63 g, 0.1 mol), tetrahydrofuran solution of dimethylamine (2 mol / L, 55 mL, 0.11 mol), and MMA (28.03 g, 0.28 mol) were added to ether (260 ml), and the temperature was controlled at -5 to 0 ° C. Rh (trop2N) (PPh3) (0.15 g, 0.2 mmol) in ether (10 ml) precooled at -5 to 0 ° C was added, and the mixture was stirred at -5 to 0 ° C. , the reaction solution was heated to room temperature, and after the reaction was detected to be complete, it was filtered, the filtrate was concentrated to dryness under reduced pressure, dissolved with hydrochloric acid (2mol / L, 300ml), filtered, and the filtrate was washed with dichloromethane (150ml), and the pH of the acid water layer was adjusted to 9-11 with 5mol / L sodium hydroxide solution. A large amount of light yellow solid precipitated, and the crystallization was continued by stirring for 1-2h and then filtered, and washed with purified water until neutral. The obtained filter cake was dried under reduced pressure to obtain the target product, with a yield of 90.5% and a purity of 99.876%.

[0052] Example 4

[0053] Under argon protection, SM-1 (26.63 g, 0.1 mol), a tetrahydrofuran solution of dimethylamine (2 mol / L, 100 mL, 0.20 mol), and MMA (28.03 g, 0.28 mol) were added to methyl tert-butyl ether (260 ml), and the temperature was controlled at -15 to -10 °C. A methyl tert-butyl ether (10 ml) solution of Rh(trop2N)(PPh3) (0.15 g, 0.2 mmol) precooled at -15 to -10 °C was added, and the temperature was kept at -15 to -10 °C. After stirring evenly at 10°C, the reaction solution was warmed to room temperature. After the reaction was detected to be complete, it was filtered. The filtrate was concentrated to dryness under reduced pressure, dissolved with hydrochloric acid (4 mol / L, 150 ml), filtered, and the filtrate was washed with dichloromethane (75 ml). The pH of the acid water layer was adjusted to 9-11 with 2.5 mol / L sodium hydroxide solution. A large amount of light yellow solid precipitated. After continuing to stir and crystallize for 1-2 hours, it was filtered and washed with purified water until neutral. The filter cake obtained was dried under reduced pressure to obtain the target product with a yield of 96.2% and a purity of 99.897%.

[0054] Example 5

[0055] Under argon protection, SM-1 (26.63 g, 0.1 mol), a tetrahydrofuran solution of dimethylamine (2 mol / L, 105 mL, 0.21 mol), and MMA (28.03 g, 0.28 mol) were added to isopropyl ether (260 ml), and the temperature was controlled at -15 to -10 °C. A precooled -15 to -10 °C isopropyl ether (10 ml) solution of Rh(trop2N)(PPh3) (0.15 g, 0.2 mmol) was added, and the temperature was kept at -15 to -10 °C. ℃, and then the reaction solution was heated to room temperature. After the reaction was detected to be complete, it was filtered. The filtrate was concentrated to dryness under reduced pressure, dissolved with hydrochloric acid (5mol / L, 120ml), filtered, and the filtrate was washed with dichloromethane (60ml). The pH of the acid water layer was adjusted to 9-11 with 2mol / L sodium hydroxide solution. A large amount of light yellow solid was precipitated. After continuing to stir and crystallize for 1-2h, it was filtered and washed with purified water until neutral. The filter cake obtained was dried under reduced pressure to obtain the target product with a yield of 95.6% and a purity of 99.872%.

[0056] Example 6

[0057] Under argon protection, SM-1 (26.63 g, 0.1 mol), a tetrahydrofuran solution of dimethylamine (2 mol / L, 80 mL, 0.16 mol), and MMA (15.02 g, 0.15 mol) were added to 2-methyltetrahydrofuran (260 ml), and the temperature was controlled at -10 to -5 °C. A 2-methyltetrahydrofuran (10 ml) solution of Rh(trop2N)(PPh3) (0.15 g, 0.2 mmol) precooled at -10 to -5 °C was added, and the temperature was kept at -10 After stirring evenly at 5 ℃ ~ -5 ℃, the reaction solution was warmed to room temperature. After the reaction was detected to be complete, it was filtered. The filtrate was concentrated to dryness under reduced pressure, dissolved with hydrochloric acid (4 mol / L, 150 ml), filtered, and the filtrate was washed with dichloromethane (75 ml). The pH of the acid water layer was adjusted to 9-11 with 3 mol / L sodium hydroxide solution. A large amount of light yellow solid precipitated. After continuing to stir and crystallize for 1-2 hours, it was filtered and washed with purified water until neutral. The filter cake obtained was dried under reduced pressure to obtain the target product with a yield of 93.5% and a purity of 99.853%.

[0058] Example 7

[0059] Under argon protection, SM-1 (26.63 g, 0.1 mol), a tetrahydrofuran solution of dimethylamine (2 mol / L, 80 mL, 0.16 mol), and MMA (14.02 g, 0.14 mol) were added to 2-methyltetrahydrofuran (260 ml), and the temperature was controlled at -10 to -5 °C. A 2-methyltetrahydrofuran (10 ml) solution of Rh(trop2N)(PPh3) (0.15 g, 0.2 mmol) precooled at -10 to -5 °C was added, and the temperature was kept at -10 to -5 °C. After stirring evenly at -5°C, the reaction solution was warmed to room temperature. After the reaction was detected to be complete, it was filtered. The filtrate was concentrated to dryness under reduced pressure, dissolved with hydrochloric acid (2.5 mol / L, 240 ml), filtered, and the filtrate was washed with dichloromethane (120 ml). The pH of the acid water layer was adjusted to 9-11 with 4 mol / L sodium hydroxide solution. A large amount of light yellow solid precipitated. After continuing to stir and crystallize for 1-2 hours, it was filtered and washed with purified water until neutral. The obtained filter cake was dried under reduced pressure to obtain the target product with a yield of 91.5% and a purity of 99.786%.

[0060] Example 8

[0061] Under argon protection, SM-1 (26.63 g, 0.1 mol), a tetrahydrofuran solution of dimethylamine (2 mol / L, 80 mL, 0.16 mol), and MMA (40.05 g, 0.40 mol) were added to 2-methyltetrahydrofuran (260 ml), and the temperature was controlled at -15 to -10 °C. A 2-methyltetrahydrofuran (10 ml) solution of Rh(trop2N)(PPh3) (0.15 g, 0.2 mmol) precooled at -15 to -10 °C was added, and the temperature was kept at -15 to -10 °C. After stirring evenly at -10°C, the reaction solution was warmed to room temperature. After the reaction was detected to be complete, it was filtered. The filtrate was concentrated to dryness under reduced pressure, dissolved with hydrochloric acid (3 mol / L, 200 ml), filtered, and the filtrate was washed with dichloromethane (100 ml). The pH of the acid water layer was adjusted to 9-11 with 2.5 mol / L sodium hydroxide solution. A large amount of light yellow solid precipitated. After continuing to stir and crystallize for 1-2 hours, it was filtered and washed with purified water until neutral. The obtained filter cake was dried under reduced pressure to obtain the target product with a yield of 94.2% and a purity of 99.812%.

[0062] Example 9

[0063] Under argon protection, SM-1 (26.63 g, 0.1 mol), a tetrahydrofuran solution of dimethylamine (2 mol / L, 80 mL, 0.16 mol), and MMA (41.05 g, 0.41 mol) were added to 2-methyltetrahydrofuran (260 ml), and the temperature was controlled at -15 to -10 °C. A 2-methyltetrahydrofuran (10 ml) solution of Rh(trop2N)(PPh3) (0.15 g, 0.2 mmol) precooled at -15 to -10 °C was added, and the temperature was kept at -15 to -10 °C. After stirring evenly at -10°C, the reaction solution was warmed to room temperature. After the reaction was detected to be complete, it was filtered. The filtrate was concentrated to dryness under reduced pressure, dissolved with hydrochloric acid (2 mol / L, 300 ml), filtered, and the filtrate was washed with dichloromethane (150 ml). The pH of the acid water layer was adjusted to 9-11 with 2.5 mol / L sodium hydroxide solution. A large amount of light yellow solid precipitated. After continuing to stir and crystallize for 1-2 hours, it was filtered and washed with purified water until neutral. The obtained filter cake was dried under reduced pressure to obtain the target product with a yield of 93.1% and a purity of 99.759%.

[0064] Example 10

[0065] Under argon protection, SM-1 (26.63 g, 0.1 mol), tetrahydrofuran solution of dimethylamine (2 mol / L, 80 mL, 0.16 mol), and MMA (28.03 g, 0.28 mol) were added to tetrahydrofuran (260 ml), and the temperature was controlled at -5 to 0 ° C. A tetrahydrofuran (10 ml) solution of Rh (trop2N) (PPh3) (76 mg, 0.1 mmol) precooled at -5 to 0 ° C was added, and the temperature was maintained at -5 to 0 ° C and stirred evenly. After that, the reaction solution was heated to room temperature. After the reaction was detected to be complete, it was filtered. The filtrate was concentrated to dryness under reduced pressure, dissolved with hydrochloric acid (3 mol / L, 200 ml), filtered, and the filtrate was washed with dichloromethane (100 ml). The pH of the acid water layer was adjusted to 9-11 with 4 mol / L sodium hydroxide solution. A large amount of light yellow solid precipitated. After continuing to stir and crystallize for 1-2 hours, it was filtered and washed with purified water until neutral. The obtained filter cake was dried under reduced pressure to obtain the target product with a yield of 92.5% and a purity of 99.868%.

[0066] Embodiment 11

[0067] Under nitrogen protection, SM-1 (26.63 g, 0.1 mol), a tetrahydrofuran solution of dimethylamine (2 mol / L, 80 mL, 0.16 mol), and MMA (28.03 g, 0.28 mol) were added to 2-methyltetrahydrofuran (260 ml), and the temperature was controlled at -15 to -10 °C. A 2-methyltetrahydrofuran (10 ml) solution of Rh(trop2N)(PPh3) (0.38 g, 0.5 mmol) precooled at -15 to -10 °C was added, and the temperature was kept at -15 °C. After stirring evenly at ~-10℃, the reaction solution was warmed to room temperature. After the reaction was detected to be complete, it was filtered. The filtrate was concentrated to dryness under reduced pressure, dissolved with hydrochloric acid (3mol / L, 200ml), filtered, and the filtrate was washed with dichloromethane (100ml). The pH of the acid water layer was adjusted to 9-11 with 4mol / L sodium hydroxide solution. A large amount of light yellow solid precipitated. After continuing to stir and crystallize for 1-2h, it was filtered and washed with purified water until neutral. The obtained filter cake was dried under reduced pressure to obtain the target product with a yield of 95.4% and a purity of 99.867%.

Claims

1. A method for preparing zolpidem, characterized in that: Zolpidem is prepared by reacting SM-1, dimethylamine and methyl methacrylate as raw materials under the action of a catalyst; the route is as follows: ； Specifically, the steps include: adding SM-1, dimethylamine and methyl methacrylate to a reaction solvent under inert gas protection, adding a pre-cooled catalyst under temperature control, keeping the temperature and stirring evenly, heating to room temperature, continuing the reaction until completion, and obtaining zolpidem through post-treatment; The reaction solvent is one of diethyl ether, isopropyl ether, methyl tert-butyl ether, tetrahydrofuran, 2-methyltetrahydrofuran or a combination thereof; The catalyst is Rh(trop2N)(PPh3); The temperature of the temperature control and catalyst precooling is -20 to 0°C.

2. The preparation method according to claim 1, characterized in that The molar ratio of SM-1 to dimethylamine, methyl methacrylate and catalyst is 1:1.2-2.0:1.5-4.0:0.1%-0.5%.

3. The preparation method according to claim 1, characterized in that: The dimethylamine is gas or a tetrahydrofuran solution of dimethylamine.

4. The preparation method according to claim 1, characterized in that: The post-treatment step is as follows: filtering the reaction solution, concentrating the filtrate to dryness under reduced pressure, dissolving with 1-5 mol / L hydrochloric acid, filtering, washing the filtrate with dichloromethane, adjusting the pH of the acid water layer to 9-11 with 1-5 mol / L sodium hydroxide solution, continuing to stir and crystallize, filtering, washing with purified water to neutrality, and drying the obtained filter cake under reduced pressure to obtain Zolpidem.

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