Synthetic method of 3-benzylimidazo [1, 5-a] pyridine-1-carboxylic acid ethyl ester
A three-step synthesis using 2-phenyl-N-(pyridin-2-ylmethyl)acetamide, trifluoroacetic anhydride, and iodoethane addresses the inefficiencies of existing methods, providing a high-yield production of 3-benzylimidazolo[1,5-a]pyridine-1-carboxylic acid ethyl ester.
Patent Information
- Application Number
- CN202411301077.2
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2024-09-18
- Publication Date
- 2024-12-17
- Estimated Expiration
- Not applicable · inactive patent
AI Technical Summary
Existing methods for synthesizing 3-benzylimidazo[1,5-a]pyridine-1-carboxylic acid ethyl ester are lengthy and yield low product amounts, lacking an efficient and high-yield synthesis pathway.
A three-step synthesis process using 2-phenyl-N-(pyridin-2-ylmethyl)acetamide, trifluoroacetic anhydride, and iodoethane, involving reactions with tetrahydrofuran, ethyl acetate, methyl tert-butyl ether, and N,N-dimethylformamide, to produce 3-benzylimidazolo[1,5-a]pyridine-1-carboxylic acid ethyl ester.
The method achieves a short synthesis path with high product yield, specifically producing 3-benzylimidazolo[1,5-a]pyridine-1-carboxylic acid ethyl ester efficiently.
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Figure CN119143757A_ABST
Abstract
Description
Technical Field
[0001] The invention relates to the technical field of organic synthesis, and in particular to a method for synthesizing ethyl 3-benzylimidazolo[1,5-a]pyridine-1-carboxylate. Background Art
[0002] 3-Benzyl imidazo[1,5-a]pyridine-1-carboxylic acid ethyl ester is an important fine chemical. Some imidazo[1,5-a]pyridine compounds have good antiviral activity. Imidazolo[1,5-a]pyridine compound I has in vitro anti-varicella-zoster virus activity in human embryonic lung cells, and imidazo[1,5-a]pyridine compound II has in vitro anti-varicella-zoster virus activity and cytomegalovirus activity in human embryonic lung cells. It can be seen that the imidazo[1,5-a]pyridine ring is a pharmacophore with good antiviral activity. Therefore, the synthesis of imidazo[1,5-a]pyridine ring compounds is of great significance.
[0003] 3-Benzyl imidazo[1,5-a]pyridine-1-carboxylic acid ethyl ester is an important pharmaceutical intermediate, so the synthesis research of this compound has important practical significance. Summary of the invention
[0004] The purpose of the present invention is to solve the shortcomings of the prior art and to propose a method for synthesizing 3-benzylimidazolo[1,5-a]pyridine-1-carboxylic acid ethyl ester, which has a short synthesis path and a high product yield.
[0005] In order to achieve the above object, the present invention adopts the following technical solutions:
[0006] A method for synthesizing ethyl 3-benzylimidazolo[1,5-a]pyridine-1-carboxylate comprises the following steps:
[0007] Step 1, tetrahydrofuran was added to the reaction bottle, 2-phenyl-N-(pyridin-2-ylmethyl)acetamide was added, stirring was started, the temperature was lowered to 0°C, trifluoroacetic anhydride was added dropwise, and after the addition was completed, the temperature was raised to 25°C, and the reaction was carried out for 12 hours. After the reaction was completed, tetrahydrofuran was evaporated, water was added, and the mixture was extracted twice with ethyl acetate (2×750 mL), and the organic phase was concentrated and dried to obtain 1-(3-benzyl H-imidazole [1,5-a] pyridin-1-yl)-2,2,2-trifluoroacetophenone;
[0008] Step 2: Add water to the reaction flask, then add 1-(3-benzyl H-imidazole [1,5-a] pyridine-1-yl) -2,2,2-trifluoroacetophenone, sodium hydroxide, methanol, start stirring, raise the temperature to 50 ° C, react for 12 hours, after the reaction is completed, evaporate the methanol, extract twice with methyl tert-butyl ether (2 × 500 mL), adjust the pH value of the aqueous phase to 4-5 with an acid regulator, filter, and dry to obtain 3-benzyl imidazo [1,5-a] pyridine-1-carboxylic acid;
[0009] Step 3. Add N,N-dimethylformamide, 3-benzylimidazole [1,5-a] pyridine-1-carboxylic acid and potassium carbonate to the reaction flask, dissolve under stirring, cool to 10°C, add iodoethane dropwise, react for 5-6h, and react for 12h at 25°C. After the reaction is completed, add water, extract with methyl tert-butyl ether 3 times (3×500mL), combine the organic phases, wash with saturated ammonium chloride aqueous solution 2 times (2×1000mL), wash once with saturated sodium thiosulfate aqueous solution, wash once with saturated brine, and wash once with water. The organic phase is concentrated and dried, and 60-90°C petroleum ether is added for pulping, filtered, and dried to obtain 3-benzylimidazole [1,5-a] pyridine-1-carboxylic acid ethyl ester.
[0010] Preferably, in step 1, the ratio of 2-phenyl-N-(pyridin-2-ylmethyl)acetamide, trifluoroacetic anhydride and tetrahydrofuran is 1:1.39-1.60:4.45-5.35 by mass.
[0011] Preferably, in step 2, the ratio of 1-(3-benzyl H-imidazole [1,5-a] pyridin-1-yl)-2,2,2-trifluoroacetophenone, sodium hydroxide, water and methanol is 1:0.66-0.92:3.95-5.27:3.13-3.46 by mass.
[0012] Preferably, in step 2, the acid regulator is acetic acid.
[0013] Preferably, in step 3, the ratio of 3-benzylimidazolo[1,5-a]pyridine-1-carboxylic acid, iodoethane, potassium carbonate and N,N-dimethylformamide is 1:0.94-1.17:1.38-1.86:7.58-9.42 by mass.
[0014] The present invention has the following beneficial effects:
[0015] The invention uses 2-phenyl-N-(pyridin-2-ylmethyl)acetamide, trifluoroacetic anhydride and iodoethane as raw materials, and synthesizes 3-benzylimidazolo[1,5-a]pyridine-1-carboxylic acid ethyl ester through three-step reactions. The synthesis path is short, the synthesis method is simple, and the product yield is high. BRIEF DESCRIPTION OF THE DRAWINGS
[0016] Figure 1 Schematic diagram of the synthesis method of the present invention. DETAILED DESCRIPTION
[0017] The technical solutions in the embodiments of the present invention will be described clearly and completely below in conjunction with the drawings in the embodiments of the present invention. Obviously, the described embodiments are only part of the embodiments of the present invention, rather than all the embodiments.
[0018] like Figure 1 As shown, the present invention provides a method for synthesizing ethyl 3-benzylimidazolo[1,5-a]pyridine-1-carboxylate, comprising the following steps:
[0019] (1) Add tetrahydrofuran and 2-phenyl-N-(pyridin-2-ylmethyl)acetamide to a reaction flask, start stirring, cool to 0°C, add trifluoroacetic anhydride dropwise, raise the temperature to 25°C, and react for 12 hours. After the reaction is completed, distill off the tetrahydrofuran, add water, extract twice with ethyl acetate (2×750 mL), concentrate the organic phase, and dry to obtain 1-(3-benzyl H-imidazole [1,5-a] pyridin-1-yl)-2,2,2-trifluoroacetophenone;
[0020] (2) Add water to the reaction flask, then add 1-(3-benzyl H-imidazole [1,5-a] pyridine-1-yl) -2,2,2-trifluoroacetophenone, sodium hydroxide, methanol, start stirring, raise the temperature to 50 ° C, react for 12 hours, after the reaction is completed, evaporate the methanol, extract with methyl tert-butyl ether twice (2 × 500 mL), adjust the pH value of the aqueous phase to 4-5 with an acid regulator, filter, and dry to obtain 3-benzyl imidazo [1,5-a] pyridine-1-carboxylic acid;
[0021] (3) Add N,N-dimethylformamide, 3-benzylimidazolo[1,5-a]pyridine-1-carboxylic acid and potassium carbonate to a reaction flask, dissolve under stirring, cool to 10°C, add iodoethane dropwise, react for 5-6 hours, and react for 12 hours at 25°C after the reaction is completed. After the reaction is completed, add water, extract with methyl tert-butyl ether three times (3×500 mL), combine the organic phases, wash with saturated ammonium chloride aqueous solution twice (2×1000 mL), wash with saturated sodium thiosulfate aqueous solution once, wash with saturated brine once, and wash with water once. The organic phase is concentrated and dried, and slurried with 60-90°C petroleum ether, filtered, and dried to obtain 3-benzylimidazolo[1,5-a]pyridine-1-carboxylic acid ethyl ester.
[0022] The specific synthesis path is as follows:
[0023] Specifically, tetrahydrofuran is added to the reaction bottle, 2-phenyl-N-(pyridin-2-ylmethyl)acetamide is added, stirring is started, the temperature is lowered to 0°C, trifluoroacetic anhydride is added dropwise, the addition is completed, the temperature is raised to 25°C, and the reaction is carried out for 12 hours. After the reaction is completed, tetrahydrofuran is evaporated, water is added, and ethyl acetate is extracted twice (2×750mL), the organic phase is concentrated and dried to obtain 1-(3-benzyl H-imidazole [1,5-a] and pyridin-1-yl)-2,2,2-trifluoroacetophenone. In the present invention, the amount ratio of 2-phenyl-N-(pyridin-2-ylmethyl)acetamide, trifluoroacetic anhydride and tetrahydrofuran is 1:1.39-1.60:4.45-5.35 by mass.
[0024] Add water to the reaction flask, then add 1-(3-benzyl H-imidazole [1,5-a] pyridine-1-yl) -2,2,2-trifluoroacetophenone, sodium hydroxide, methanol, start stirring, heat to 50 ° C, react for 12 hours, after the reaction is completed, distill methanol, extract twice with methyl tert-butyl ether (2 × 500mL), adjust the pH value of the aqueous phase to 4-5 with an acid regulator, filter, and dry to obtain 3-benzyl imidazole [1,5-a] pyridine-1-carboxylic acid. In the present invention, the amount ratio of 1-(3-benzyl H-imidazole [1,5-a] pyridine-1-yl) -2,2,2-trifluoroacetophenone, sodium hydroxide, water and methanol is 1:0.66-0.92:3.95-5.27:3.13-3.46 by mass; the acid regulator is acetic acid.
[0025] Add N,N-dimethylformamide, 3-benzylimidazolo[1,5-a]pyridine-1-carboxylic acid and potassium carbonate to the reaction flask, dissolve under stirring, cool to 10°C, add iodoethane dropwise, react for 5-6h, and react for 12h at 25°C after the addition is complete. After the reaction is completed, add water, extract with methyl tert-butyl ether 3 times (3×500mL), combine the organic phases, wash with saturated ammonium chloride aqueous solution 2 times (2×1000mL), wash with saturated sodium thiosulfate aqueous solution once, wash with saturated brine once, and wash with water once. The organic phase is concentrated and dried, slurried with 60-90°C petroleum ether, filtered, and dried to obtain 3-benzylimidazolo[1,5-a]pyridine-1-carboxylic acid ethyl ester. In the present invention, the usage ratio of 3-benzylimidazolo[1,5-a]pyridine-1-carboxylic acid, iodoethane, potassium carbonate and N,N-dimethylformamide is 1:0.94-1.17:1.38-1.86:7.58-9.42 by mass.
[0026] Example 1
[0027] (1) Synthesis of 1-(3-benzyl H-imidazo[1,5-a]pyridin-1-yl)-2,2,2-trifluoroacetophenone:
[0028] 1024 g of tetrahydrofuran and 230 g of 2-phenyl-N-(pyridin-2-ylmethyl)acetamide were added to the reaction flask, stirring was started, the temperature was lowered to 0°C, 320 g of trifluoroacetic anhydride was added dropwise, and after the addition was completed, the temperature was raised to 25°C and the reaction was carried out for 12 hours. After the reaction was completed, tetrahydrofuran was evaporated, 1500 mL of water was added, and the mixture was extracted twice with ethyl acetate (2×750 mL). The organic phase was concentrated and dried to obtain 196.8 g of 1-(3-benzyl H-imidazole [1,5-a] pyridin-1-yl)-2,2,2-trifluoroacetophenone with a product yield of 63.63%.
[0029] (2) Synthesis of 3-benzylimidazolo[1,5-a]pyridine-1-carboxylic acid:
[0030] Add 600 g of water to the reaction flask, then add 151.8 g of 1-(3-benzyl H-imidazole [1,5-a] pyridine-1-yl) -2,2,2-trifluoroacetophenone, 100 g of sodium hydroxide, and 475 g of methanol. Start stirring, raise the temperature to 50 ° C, and react for 12 hours. After the reaction is completed, distill off the methanol, extract twice with methyl tert-butyl ether (2×500 mL), adjust the pH value of the aqueous phase to 4-5 with an acid regulator, filter, and dry to obtain 92.7 g of 3-benzyl imidazo [1,5-a] pyridine-1-carboxylic acid, and the product yield is 73.61%.
[0031] 1 HNMR (400MHz, CD 3 OD)δ8.10(dd,J=21.9,8.2Hz,2H),7.34–7.27(m,2H),7.26–7.16(m,4H),6.84(t,J=6.8Hz,1H),4.52(s,2H).
[0032] (3) Synthesis of ethyl 3-benzylimidazo[1,5-a]pyridine-1-carboxylate:
[0033] Add 455 g of N,N-dimethylformamide, 60 g of 3-benzylimidazole [1,5-a] pyridine-1-carboxylic acid, and 82.8 g of potassium carbonate to the reaction flask, dissolve under stirring, cool to 10°C, add 56.1 g of iodoethane dropwise, and react for 5-6 h. After the reaction is completed, the reaction time is 12 h at 25°C. After the reaction is completed, add 1500 mL of water, extract with methyl tert-butyl ether 3 times (3×500 mL), combine the organic phases, wash with saturated ammonium chloride aqueous solution 2 times (2×1000 mL), wash once with 1000 mL of saturated sodium thiosulfate aqueous solution, wash once with 1000 mL of saturated brine, and wash once with 1000 mL of water. The organic phase is concentrated and dried, 300 mL of 60-90°C petroleum ether is added for pulping, filtered, and dried to obtain 43.0 g of ethyl 3-benzylimidazole [1,5-a] pyridine-1-carboxylate, with a product yield of 64.11%.
[0034] 1 H NMR (400 MHz, CDCl 3 )δ8.27–8.04(m,1H),7.68(d,J=7.1Hz,1H),7.32–7.25(m,2H),7.25–7.21(m,1H),7.21–7.16(m,2 H),7.06(ddd,J=9.2,6.5,0.8Hz,1H),6.68–6.61(m,1H),4.54–4.44(m,4H),1.47(t,J=7.1Hz,3H).
[0035] Example 2
[0036] (1) Synthesis of 1-(3-benzyl H-imidazo[1,5-a]pyridin-1-yl)-2,2,2-trifluoroacetophenone:
[0037] 1127 g of tetrahydrofuran and 230 g of 2-phenyl-N-(pyridin-2-ylmethyl)acetamide were added to the reaction flask, stirring was started, the temperature was lowered to 0°C, 343.8 g of trifluoroacetic anhydride was added dropwise, and after the addition was completed, the temperature was raised to 25°C and the reaction was carried out for 12 hours. After the reaction was completed, tetrahydrofuran was evaporated, 1500 mL of water was added, and the mixture was extracted twice with ethyl acetate (2×750 mL). The organic phase was concentrated and dried to obtain 207.6 g of 1-(3-benzyl H-imidazole [1,5-a] pyridin-1-yl)-2,2,2-trifluoroacetophenone with a product yield of 67.12%.
[0038] (2) Synthesis of 3-benzylimidazolo[1,5-a]pyridine-1-carboxylic acid:
[0039] Add 700 g of water to the reaction flask, then add 151.8 g of 1-(3-benzyl H-imidazole [1,5-a] pyridine-1-yl) -2,2,2-trifluoroacetophenone, 120 g of sodium hydroxide, and 500 g of methanol, start stirring, raise the temperature to 50 ° C, and react for 12 hours. After the reaction is completed, distill off the methanol, extract twice with methyl tert-butyl ether (2×500 mL), adjust the pH value of the aqueous phase to 4-5 with an acid regulator, filter, and dry to obtain 96.8 g of 3-benzyl imidazo [1,5-a] pyridine-1-carboxylic acid, and the product yield is 76.91%.
[0040] (3) Synthesis of ethyl 3-benzylimidazo[1,5-a]pyridine-1-carboxylate:
[0041] Add 510 g of N,N-dimethylformamide, 60 g of 3-benzylimidazole [1,5-a] pyridine-1-carboxylic acid, and 97.3 g of potassium carbonate to the reaction flask, dissolve under stirring, cool to 10°C, add 63.2 g of iodoethane dropwise, and react for 5-6 h. After the reaction is completed, the reaction time is 12 h at 25°C. After the reaction is completed, add 1500 mL of water, extract with methyl tert-butyl ether 3 times (3×500 mL), combine the organic phases, wash with saturated ammonium chloride aqueous solution 2 times (2×1000 mL), wash once with 1000 mL of saturated sodium thiosulfate aqueous solution, wash once with 1000 mL of saturated brine, and wash once with 1000 mL of water. The organic phase is concentrated and dried, 300 mL of 60-90°C petroleum ether is added for pulping, filtered, and dried to obtain 45.3 g of ethyl 3-benzylimidazole [1,5-a] pyridine-1-carboxylate, with a product yield of 67.52%.
[0042] Example 3
[0043] (1) Synthesis of 1-(3-benzyl H-imidazo[1,5-a]pyridin-1-yl)-2,2,2-trifluoroacetophenone:
[0044] 1230 g of tetrahydrofuran and 230 g of 2-phenyl-N-(pyridin-2-ylmethyl)acetamide were added to the reaction flask, stirring was started, the temperature was lowered to 0°C, 367.6 g of trifluoroacetic anhydride was added dropwise, and after the addition was completed, the temperature was raised to 25°C and the reaction was carried out for 12 hours. After the reaction was completed, tetrahydrofuran was evaporated, 1500 mL of water was added, and the mixture was extracted twice with ethyl acetate (2×750 mL). The organic phase was concentrated and dried to obtain 189.9 g of 1-(3-benzyl H-imidazole [1,5-a] pyridin-1-yl)-2,2,2-trifluoroacetophenone with a product yield of 61.39%.
[0045] (2) Synthesis of 3-benzylimidazolo[1,5-a]pyridine-1-carboxylic acid:
[0046] Add 800 g of water to the reaction flask, then add 151.8 g of 1-(3-benzyl H-imidazole [1,5-a] pyridine-1-yl) -2,2,2-trifluoroacetophenone, 140 g of sodium hydroxide, and 525 g of methanol. Start stirring, raise the temperature to 50 ° C, and react for 12 hours. After the reaction is completed, distill off the methanol, extract twice with methyl tert-butyl ether (2×500 mL), adjust the pH value of the aqueous phase to 4-5 with an acid regulator, filter, and dry to obtain 88.9 g of 3-benzyl imidazo [1,5-a] pyridine-1-carboxylic acid, and the product yield is 70.58%.
[0047] (3) Synthesis of ethyl 3-benzylimidazo[1,5-a]pyridine-1-carboxylate:
[0048] Add 565g of N,N-dimethylformamide, 60g of 3-benzylimidazole [1,5-a] pyridine-1-carboxylic acid, and 111.8g of potassium carbonate to the reaction flask, dissolve under stirring, cool to 10°C, add 70.2g of iodoethane dropwise, react for 5-6h, and react for 12h at 25°C after the reaction is completed. After the reaction is completed, add 1500mL of water, extract with methyl tert-butyl ether 3 times (3×500mL), combine the organic phases, wash with saturated ammonium chloride aqueous solution 2 times (2×1000mL), wash once with 1000mL of saturated sodium thiosulfate aqueous solution, wash once with 1000mL of saturated brine, and wash once with 1000mL of water. The organic phase is concentrated and dried, 300mL of 60-90°C petroleum ether is added for pulping, filtered, and dried to obtain 41.8g of ethyl 3-benzylimidazole [1,5-a] pyridine-1-carboxylate, with a product yield of 62.31%.
[0049] In summary, the present invention uses 2-phenyl-N-(pyridin-2-ylmethyl)acetamide, trifluoroacetic anhydride and iodoethane as raw materials to synthesize 3-benzylimidazolo[1,5-a]pyridine-1-carboxylic acid ethyl ester through three-step reactions. The synthesis path is short, the synthesis method is simple, and the product yield is high.
[0050] The above description is only a preferred specific implementation manner of the present invention, but the protection scope of the present invention is not limited thereto. Any technician familiar with the technical field can make equivalent replacements or changes according to the technical scheme and inventive concept of the present invention within the technical scope disclosed by the present invention, which should be covered by the protection scope of the present invention.
Claims
1. A method for synthesizing ethyl 3-benzylimidazolo[1,5-a]pyridine-1-carboxylate, characterized in that: The following steps are involved: Step 1, tetrahydrofuran is added to a reaction bottle, 2-phenyl-N-(pyridin-2-ylmethyl)acetamide is added, stirring is started, the temperature is lowered to 0°C, trifluoroacetic anhydride is added dropwise, and after the addition is completed, the temperature is raised to 25°C, and the reaction is carried out for 12 hours. After the reaction is completed, tetrahydrofuran is evaporated, water is added, and the mixture is extracted twice with ethyl acetate. The organic phase is concentrated and dried to obtain 1-(3-benzyl H-imidazole [1,5-a] pyridin-1-yl)-2,2,2-trifluoroacetophenone; Step 2, add water to the reaction bottle, then add 1-(3-benzyl H-imidazole [1,5-a] pyridine-1-yl) -2,2,2-trifluoroacetophenone, sodium hydroxide, methanol, start stirring, raise the temperature to 50 ° C, react for 12 hours, after the reaction is completed, evaporate the methanol, extract twice with methyl tert-butyl ether, adjust the pH value of the aqueous phase to 4-5 with an acid regulator, filter, and dry to obtain 3-benzyl imidazo [1,5-a] pyridine-1-carboxylic acid; Step 3. Add N,N-dimethylformamide, 3-benzylimidazole [1,5-a] pyridine-1-carboxylic acid and potassium carbonate to the reaction flask, dissolve under stirring, cool to 10°C, add iodoethane dropwise, react for 5-6 hours, and react for 12 hours at 25°C after the reaction is completed. After the reaction is completed, add water, extract with methyl tert-butyl ether three times, combine the organic phases, wash with saturated ammonium chloride aqueous solution twice, saturated sodium thiosulfate aqueous solution once, saturated brine once, and water once. Concentrate and dry the organic phase, add 60-90°C petroleum ether for pulping, filter, and dry to obtain 3-benzylimidazole [1,5-a] pyridine-1-carboxylic acid ethyl ester.
2. The method for synthesizing ethyl 3-benzylimidazo[1,5-a]pyridine-1-carboxylate according to claim 1, characterized in that: In the step 1, the ratio of 2-phenyl-N-(pyridin-2-ylmethyl)acetamide, trifluoroacetic anhydride and tetrahydrofuran is 1:1.39-1.60:4.45-5.35 by mass.
3. The method for synthesizing ethyl 3-benzylimidazolo[1,5-a]pyridine-1-carboxylate according to claim 1, characterized in that: In the step 2, the ratio of 1-(3-benzyl H-imidazole [1,5-a] pyridin-1-yl)-2,2,2-trifluoroacetophenone, sodium hydroxide, water and methanol is 1:0.66-0.92:3.95-5.27:3.13-3.46 by mass.
4. The method for synthesizing ethyl 3-benzylimidazo[1,5-a]pyridine-1-carboxylate according to claim 1, characterized in that: In step 2, the acid regulator is acetic acid.
5. The method for synthesizing ethyl 3-benzylimidazo[1,5-a]pyridine-1-carboxylate according to claim 1, characterized in that: In the step 3, the ratio of 3-benzylimidazolo[1,5-a]pyridine-1-carboxylic acid, iodoethane, potassium carbonate and N,N-dimethylformamide is 1:0.94-1.17:1.38-1.86:7.58-9.42 by mass.