Method for synthesizing macrolide antibiotic telithromycin side chain compound
By reacting 3-acetylpyridine with iodine and calcium oxide in a one-pot system, and then directly reacting with ammonium carbonate and ammonium acetate, the synthesis process of 4-(3-pyridyl)-1H-imidazole was successfully simplified, and the problems of cumbersome steps and environmental pollution in the existing methods were solved, achieving efficient and environmentally friendly synthesis effect.
Patent Information
- Application Number
- CN202510245316.5
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2025-02-22
- Publication Date
- 2025-04-25
AI Technical Summary
The existing 4-(3-pyridyl)-1H-imidazole synthesis methods have problems such as cumbersome reaction steps, high temperature, easy to cause tarization and a large number of by-products. It also releases NO2 highly toxic gases when oxidative desulfurization is used with nitric acid, which is highly polluted to the environment.
Using 3-acetylpyridine as raw material, the reaction was carried out in a one-pot system, and first reacted with iodine and calcium oxide to form the intermediate product 1-(3-pyridyl)-ethanketone aldehyde, without separating the intermediate product, followed by adding ammonium carbonate and ammonium acetate, and the reaction was heated to prepare 4-(3-pyridyl)-1H-imidazole.
It achieves simplification of the synthesis steps, high yield of the target product and convenient operation, is suitable for industrial production, and reduces the risk of environmental pollution.
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Abstract
Description
Technical Field
[0001] The invention belongs to the technical field of organic chemical synthesis and relates to a method for synthesizing a telithromycin side chain compound 4-(3-pyridyl)-1H-imidazole. The compound can be used as an organic synthesis intermediate for the synthesis of a macrolide antibiotic drug telithromycin.
[0002] Specifically, it relates to a method for synthesizing a compound of formula I.
[0003] Background Art
[0004] 4-(3-pyridyl)-1H-imidazole (Structural Formula I) is a side chain compound required for the synthesis of telithromycin. Telithromycin is a macrolide antibiotic with strong in vitro activity against macrolide-sensitive and -resistant Streptococcus pneumoniae. It is mainly used to treat respiratory tract infections, including community-acquired pneumonia caused by drug-resistant bacteria.
[0005] A variety of methods for synthesizing 4-(3-pyridyl)-1H-imidazoles have been developed. There is a document that converts 3-acetylpyridine into pyridyl-aminoketone through multiple steps, then reacts with potassium thiocyanate to obtain 2-mercaptoimidazole, and further desulfurizes to obtain 4-(3-pyridyl)-1H-imidazole (The synthesis of pyridylpyraxoles, Journal of Chemistry Society, 1934, 1739-1741). This method has a long reaction step and releases a large amount of NO2 highly toxic gas when desulfurized by nitric acid oxidation, which is relatively polluting to the environment. There is a patent report that converts 3-acetylpyridine into α-aminoketal first, and then heats and cyclizes with formamide to obtain a method for 4-(3-pyridyl)-1H-imidazoles. The steps are complicated, the reaction temperature is high, tarization is easily produced, and there are more by-products (US Patent, US 6353108, 2002). A patent discloses a new method for preparing 4-(3-pyridyl)-1H-imidazole using pyridyl-α-bromo ketone, a product of bromination of 3-acetylpyridine, as a raw material, first oxidizing it to α-diketone, and then undergoing a Debus reaction (U.S. Patent No. 6649768, 2003), but the final yield is unknown. Summary of the invention
[0006] The object of the present invention is to provide a simple synthesis method of the compound 4-(3-pyridyl)-1H-imidazole, using 3-acetylpyridine (structural formula II) as a raw material, reacting in a one-pot system, synthesizing an intermediate product 1-(3-pyridyl)-ethanone aldehyde (structural formula III), without separating the intermediate product, continuing to add ammonium carbonate and ammonium acetate to the reaction solution, heating the reaction to prepare 4-(3-pyridyl)-1H-imidazole (structural formula I). The method is simple to operate, has few reaction steps, and has a high yield of the target product. The reaction formula of the method is as follows:
[0007]
[0008] The specific synthesis steps of this method are as follows:
[0009] a. Dissolve 3-acetylpyridine (structural formula II) in dimethyl sulfoxide, add iodine and calcium oxide, and react at 40 to 120° C. for 2 to 6 hours to obtain an intermediate product solution.
[0010] b. Add ammonium carbonate and ammonium acetate to the intermediate product solution obtained in step a above, continue heating the reaction, and synthesize 4-(3-pyridyl)-1H-imidazole.
[0011] In the synthesis step a of the present method, the molar ratio of 3-acetylpyridine: iodine: calcium oxide is 1: 0.1-5: 0.3-5, and the volume mass ratio of dimethyl sulfoxide to 3-acetylpyridine is 1-300 mL / g.
[0012] In the synthesis step b of the present method, the molar ratio of ammonium carbonate to 3-acetylpyridine in step a is 0.5 to 20:1.
[0013] In the synthesis step b of the present method, the molar ratio of ammonium acetate to ammonium carbonate is 1:0.5-2, the reaction temperature is 90-110° C., and the reaction time is 30 minutes to 5 hours.
[0014] Beneficial effects of the present invention:
[0015] The synthesis method presented in the present invention has the characteristics of short synthesis steps, high yield, one-pot operation and convenience for industrial production, etc. It can efficiently synthesize the macrolide antibiotic telithromycin side chain compound 4-(3-pyridyl)-1H-imidazole, can be used for the production of telithromycin and the design and synthesis of new macrolide antibiotics, and has broad application prospects. DETAILED DESCRIPTION
[0016] The present invention is explained below by way of examples, but the present invention is not limited to these examples.
[0017] Embodiment 1:
[0018] 3-Acetylpyridine (2g, 16.5mmol) was dissolved in 40mL dimethyl sulfoxide, iodine (1.26g, 4.96mmol) and calcium oxide (0.93g, 16.5mmol) were added in sequence, and the mixture was stirred at 60°C for 5 hours to obtain a reddish brown intermediate product solution. Ammonium carbonate (6.3g, 66mmol) and ammonium acetate (5.1g, 66.1mmol) were directly added to the intermediate product solution without separation, and the mixture was heated at 95°C for 4 hours. The reaction solution was cooled, diluted with 500mL water, extracted with ethyl acetate (50mL×3), the organic layers were combined, washed with saturated brine, dried over anhydrous MgSO, and the solvent was evaporated under reduced pressure to obtain 1.77g of a yellow oil with a yield of 74%. The pure product of 4-(3-pyridyl)-1H-imidazole was obtained by recrystallization with dichloromethane / petroleum ether. The melting point of the product is 117°C to 118°C. 1 H NMR (CDCl3, 400MHz), δ: 7.30 (dd, 1H, H5′), 7.44 (s, 1H, H5), 7.78 (d, 1H, H2), 8.06 (dt, 1H, H4′), 8.43 (dd, 1H, H6′), 8.99 (d, 1H, H2′); 13 C NMR (CDCl3, 100MHz), δ: 115.3, 124.1, 130.3, 132.8, 136.7, 146.1, 147.3; MS (ESI), m / z: 145 (MH + ).
[0019] Embodiment 2:
[0020] 3-Acetylpyridine (3.5 g, 28.9 mmol) was dissolved in 68 mL of dimethyl sulfoxide, and iodine (1.1 g, 4.3 mmol) and calcium oxide (2.4 g, 48.3 mmol) were added in sequence, and the mixture was stirred at 100°C for 2 hours to obtain an intermediate product solution. Ammonium carbonate (5.6 g, 57.8 mmol) and ammonium acetate (6.7 g, 56.8 mmol) were added to the intermediate product solution without separation, and the mixture was heated at 100°C for 1 hour. The reaction solution was cooled, diluted with 800 mL of water, extracted with ethyl acetate (50 mL×3), the organic layers were combined, washed with saturated brine, dried over anhydrous MgSO, and the solvent was evaporated under reduced pressure to obtain 2.2 g of a yellow oil with a yield of 52%.
[0021] Embodiment 3:
[0022] 3-Acetylpyridine (5.8 g, 47.9 mmol) was dissolved in 120 mL of dimethyl sulfoxide, and iodine (12 g, 47.9 mmol) and calcium oxide (4.0 g, 71.9 mmol) were added in sequence, and the mixture was stirred at 120°C for 3 hours to obtain an intermediate product solution. Ammonium carbonate (23 g, 240 mmol) and ammonium acetate (21.8 g, 282 mmol) were directly added to the intermediate product solution without separation, and the mixture was heated at 110°C for 2 hours. The reaction solution was cooled, diluted with 1000 mL of water, extracted with ethyl acetate (50 mL × 3), the organic layers were combined, washed with saturated brine, dried over anhydrous MgSO, and the solvent was evaporated under reduced pressure to obtain 6.9 g of a yellow oil with a yield of 64%.
Claims
1. A method for synthesizing a macrolide antibiotic telithromycin side chain compound as shown in formula I The synthesis steps of the compound of formula I are as follows: (a) dissolving 3-acetylpyridine as shown in formula II in dimethyl sulfoxide, adding iodine and calcium oxide, and reacting at 40 to 120° C. for 2 to 6 hours to obtain an intermediate product solution; (b) adding ammonium carbonate and ammonium acetate to the intermediate product solution obtained in step a, and continuing heating reaction to synthesize 4-(3-pyridyl)-1H-imidazole (I), 2. The method according to claim 1, characterized in that The molar ratio of 3-acetylpyridine: iodine: calcium oxide in step (a) is 1: 0.1-5: 0.3-5, and the volume mass ratio of dimethyl sulfoxide to 3-acetylpyridine is 1-300 mL / g.
3. The method according to claim 1, characterized in that The molar ratio of the ammonium carbonate in step (b) to the 3-acetylpyridine in step a is 0.5 to 20:
1.
4. The method according to claim 1, characterized in that The molar ratio of ammonium acetate to ammonium carbonate in step (b) is 1:0.5-2, the reaction temperature is 90-110° C., and the reaction time is 30 minutes to 5 hours.