Background and overview of preparation and application of 4-chloropyrrolo[3,2-C]pyridine
4-Chloropyrrolo[3,2-C]pyridine is a pharmaceutical intermediate that can be prepared from pyrrole as raw material through a starting reaction. 4-Chloropyrrolo[3,2-C]pyridine can be used to prepare pyridinecarboxylic acid compound 1H-pyrrolo[3,2-c]pyridine-4-carboxylic acid. Pyridine carboxylic acid compounds are widely found in biologically active natural products and drug molecules and have great application value in the treatment of cancer, cardiovascular and neurological diseases. Many derivatives synthesized using this compound as an intermediate have been Proven bioactive compounds that can be used as kinase inhibitors to treat pain. It can be seen that due to its good pharmacological activity and potential medicinal value, the synthesis of pyridine carboxylic acid compounds has attracted much attention at this stage.
Preparation and application of 4-chloropyrrolo[3,2-C]pyridine
(1) After mixing 1.81kg DMF (dimethylformamide) and 2L 1,2-dichloroethane evenly, slowly add 3.806kg POCl into the system at 5℃3 After 80 minutes of dripping, slowly add 1.512kg of compound 1 pyrrole into the system under the condition of 5℃; after 30 minutes, the dripping is completed, the system returns to room temperature and the reaction is stirred; the reaction is complete in 2 hours Then, slowly add the system to 15L of 6N sodium hydroxide aqueous solution, adjust the pH of the solution to 8, filter with suction, add DCM (2L*2) to the aqueous phase for extraction, combine the organic layers, dry with anhydrous sodium sulfate and spin dry. , Compound 2 was obtained as a brown oil crude product 2166g. TLC information: raw material Rf=0.5, product Rf=0.4, developing agent: petroleum ether: ethyl acetate=5:1.
(2) After dissolving 1728g compound 2 in 9L DCM, add 1453g NaOH, 3.4ml aqueous solution and 170g tetrabutylammonium bromide into the system at room temperature; after the system cools to 0°C, start adding 2520g BnCl dropwise, After 1 hour of dripping, raise the temperature to 40°C and reflux, and stir the reaction; after 15 hours of complete reaction, filter the reaction solution, add DCM (2L*2), extract, combine the organic layers, dry with anhydrous sodium sulfate and spin-dry to obtain compound 3. It is 5.25kg of brown oily crude product. TLC information: raw material Rf=0.4, product Rf=0.5, developing agent: petroleum ether: ethyl acetate=5 di-tert-butyl dicarbonate: 1.
(3) After dissolving 4.1Kg compound 3 in 6.15L pyridine, add 3.46kg malonic acid and 1.64kg piperidine into the system at room temperature, raise the temperature to 120°C, reflux, and stir the reaction; after 15 hours of complete reaction, After the reaction solution was concentrated, 8 L of 3N hydrochloric acid aqueous solution was added to adjust the pH to 2. The solid was precipitated and filtered with suction. The filter cake was washed with ethyl acetate (2 L) and the filtrate was discarded to obtain compound 4 as a crude brown solid 2.2 kg. TLC information: raw material Rf=0.4, product Rf=0.2, developing agent: petroleum ether: ethyl acetate=5:1.
(4) Dissolve 2.2kg compound 4 in 10L acetone, then add 2.2L TEA (triethanolamine). After the system cools to 5°C, add 1.58kg ethyl chloroformate dropwise into the system; complete the dripping in 30 minutes. After the addition is completed, tap the plate. After TLC shows that the raw material reaction is complete, add 755g of sodium azide 3L aqueous solution dropwise into the system. After 2 hours of addition, return to room temperature for reaction; after 2 hours of complete reaction, add 5L of sodium carbonate aqueous solution to adjust the pH. to 8, add dichloromethane for extraction twice, combine the organic layers, dry with anhydrous sodium sulfate and then spin dry to obtain 2.4kg of compound 5 as a brown oily crude product. TLC information: raw material Rf = 0.5, product Rf = 0.7, developing agent: petroleum ether: ethyl acetate = dimethyl sulfoxide 3:1.
(5) Dissolve 2L tributylamine in 4L diphenyl ether, heat the system to 190°C, then drop 1020g of compound 5 (a small amount of dichloromethane) into it, and stir the reaction under reflux at 190°C; after the reaction is complete for 3 hours, The system was cooled to 60°C, and 5 L of ethyl acetate solution was added to the system. After stirring for 30 minutes, a black solid was obtained by suction filtration. The filtrate was discarded to obtain 440 grams of compound 6 as a crude black solid. TLC information: raw material Rf=0.8, product Rf=0.35, developing agent: methylene chloride: methanol=20:1;
(6) Dissolve 415g of compound 6 in 2L POCl3, control the temperature of the system to 120°C to reflux, and stir the reaction; after 17 hours of complete reaction, concentrate the system, add 500ml of water to the system, and add sodium hydroxide to adjust the pH to 8. Add 2 L of methylene chloride and perform suction filtration. The organic layers are combined, dried over anhydrous sodium sulfate and then spun to dryness to obtain 295 g of crude product. The crude product is passed through a column to obtain compound 7 as a yellow solid 159.34 g. TLC information: raw material Rf=0.35, product Rf=0.5, developing agent: methylene chloride: methanol=10:1.
(7) Dissolve 168.23g of compound 7 in 1.2L THF (tetrahydrofuran), then add 777.80g of potassium tert-butoxide and 541.6g of DMSO (dimethyl sulfoxide) to the system in sequence at room temperature. Reaction; after the reaction is complete in 17 hours, add 4L of saturated ammonium chloride solution to the system, add 4L of ethyl acetate, separate the liquids, combine the organic layers, dry over anhydrous sodium sulfate and spin to dry, to obtain compound 8, which is 4-chloropyrrolo[3 ,2-C]pyridine, 127.68g of crude yellow solid product. TLC information: raw material Rf=0.5, product Rf=0.2, developing agent: petroleum ether: ethyl acetate=3:1.
Preparation and application of 4-chloropyrrolo[3,2-C]pyridine
4-Chloropyrrolo[3,2-C]pyridine can be used to prepare 1H-pyrrolo[3,2-c]pyridine-4-carboxylic acid (11) with the following structure.
(1) At room temperature, dissolve 127.68g 4-chloropyrrolo[3,2-C]pyridine in 1.3L THF, then add 10.22g DMAP (4-dimethylaminopyridine) and 273.95 to the system in sequence g Boc2O; After the reaction was completed for 3 hours, the system was concentrated, and the crude product was passed through a silica gel column (200-300 mesh silica gel) to obtain compound 9, 90.6g of pure product.��White solid (PE produces miscellaneous products, petroleum ether:ethyl acetate=20:1 produces product). TLC information: raw material Rf=0.3, product Rf=0.7, developing agent: petroleum ether: ethyl acetate=3:1.
(2) After dissolving 33g of compound 9 in 660ml of methanol, put 26.4g of TEA and 0.33g of Pd(dppf)Cl2 into the reaction kettle, and replace them with CO three times. 1.4MPa, the reaction was carried out at 120°C; after the reaction was completed in 17 hours, it was filtered and concentrated to obtain 44g of compound 10 as a brown solid crude product. TLC information: raw material Rf=0.6, product Rf=0.2, developing agent: methylene chloride: methanol=10:1.
(3) Dissolve 44g of compound 10 in 440ml of methanol at room temperature, add an aqueous solution of 19.8g NaOH and 300ml, and stir the reaction; after the reaction is complete for 1 hour, concentrate the system, add 100mL of water, filter with suction, and add water Concentrated hydrochloric acid was added to the phase to adjust the pH to 1, and the solid was precipitated, filtered, and dried to obtain the final product 1H-pyrrolo[3,2-c]pyridine-4-carboxylic acid (compound 11) as a white solid, 19 g of pure product. , the two-step yield is 60%. TLC information: raw material Rf=0.6, product Rf=0.2, developing agent: methylene chloride: methanol=10:1. 1H-NMR(DMSO;MHZ)7.29(s,1H)7.83(d,2H)8.22(d,1H)12.40(d,1H)8.425(s,1H).
References
[1] [Chinese invention, Chinese invention authorization] CN201410227465.0 A kind of pyridine carboxylic acid compound and its preparation method [disclosed] / a kind of preparation method of pyridine carboxylic acid compound [authorized]
