Application examples of 3-chloro-2-nitropyridine_Industrial additives

Background and overview of application examples of 3-chloro-2-nitropyridine

3-Chloro-2-nitropyridine is a pharmaceutical intermediate that can be used to prepare pharmaceutical compositions for the treatment of osteoarthritis and a diazacarbazole derivative used in the field of organic electroluminescence. . There are reports in the literature that it can be prepared from 3-amino-2-nitropyridine through a continuous flow reaction.

Application examples of 3-chloro-2-nitropyridine

Example report on the application of 3-chloro-2-nitropyridine 1.

3-Chloro-2-nitropyridine can be used to prepare a diazacarbazole derivative. Carbazole compounds have a sufficiently high triplet state, good hole transport ability, photochemical stability, high carrier mobility, strong absorption in the ultraviolet range and a band gap of about 3.20eV, as well as valuable With characteristics such as blue light, a variety of high-efficiency luminescent materials can be obtained by substituting modifications on carbon atoms at the 3, 6, 9-position or other positions. The luminescent material obtained by bonding the electron-deficient carbazole-like diazacarbazole group with different groups can also realize the adjustable triplet state and molecular orbital energy level of the material. This can fundamentally realize the efficient recombination of carriers in organic electroluminescent devices and obtain efficient and energy-saving OLED devices. It can also be widely used in the field of organic electroluminescence.

Step 1, preparation of compound 1

In a 500ml single-neck flask, add 3-chloro-2-nitropyridine (5g, 31.63mmol), 3-pyridineboronic acid (3g, 37.75mmol), 50ml of 2M potassium carbonate aqueous solution dissolved in 50ml of ethanol, and 100ml of toluene in the solvent. Under the protection of N₂, add PdCl₂(PPh₃)₂(0.75g, 0.98 mmol). The temperature was slowly raised to 100°C, and the mixture was reacted under reflux for 24 hours. After cooling, the liquids were separated, the organic layer was rotary evaporated, and petroleum ether and ethyl acetate (1.5:1) were used to pass through the column to obtain 4.5g of light yellow solid with a yield of 65%. MS(APCI)m/z calcd for C10H7N3O2:201.20,found[M+]:201.89.

Step 2, preparation of compound 2

In a 250ml one-neck flask, add 3-(2-nitropyridin-3-yl)pyridine (4.06g, 20.25mmol) and triphenylphosphine (13.3g, 50.65mmol) solvent in 100ml of o-dichloro in benzene solvent. Under the protection of N₂, the temperature was raised to 180°C and the reaction was refluxed for 24 hours. After the reaction is completed, first distill under reduced pressure, concentrate the reaction solvent to 40 ml, and pass through the column with dichloromethane and methanol (15:1) to obtain 2 g of white solid with a yield of 60%. MS(APCI)m/z calcd forC10H7N3：169.20,Found[M+]:169.69.

Step 3, preparation of compound 3

Add compound 2 (1g, 6mmol), o-bromoiodobenzene (2g, 7.2mmol), copper powder (1.2g, 18mmol), K₂CO₃ (2.5g, 18mmol) was dissolved in 100ml dry DMF solvent. Under the protection of N₂, the temperature was raised to 150°C and the reaction was carried out for 48 hours. After the reaction is terminated, cool to room temperature, extract, spin dry, and pass through a column to obtain a light yellow liquid with a yield of 70%. MS(APCI)m/z calcd for C16H10BrN3：323.00,Found[M+]:324.04.

Step 4, preparation of compound C001

Add compound 3 (1.0g, 3.1mmol), carbazole (0.87g, 4.75mmol), copper iodide (0.03g, 0.125mmol), K₂CO3 (1.73g, 12.5mmol) and 18-crown-6 (0.033g, 0.125mmol) were dissolved into 3ml DMPU solution. Under the protection of N₂, the temperature was raised to 180°C and the reaction was carried out for 48 hours. After the reaction is terminated, cool to room temperature, extract, spin dry, and pass dichloromethane: methanol 15:1 through the column, yield: 60%. MS(APCI)m/z calcd for C28H18N4：410.20,Found[M+]:411.10.

Example report on the application of 3-chloro-2-nitropyridine 2.

CN201810371168.1 provides a preparation method of a pharmaceutical composition for treating osteoarthritis, including the following steps:

Step A: At 0°C, add ethyl cyanoacetate dropwise to the dimethyl sulfoxide suspension of 3-chloro-2-nitropyridine and anhydrous potassium carbonate, and heat to 100°C after the addition. Leave overnight, cool, pour into ice water, stir for 15 minutes, filter and collect the solid to obtain ethyl 2-cyano-2-(2-nitropyridin-3-yl)acetate;

Step B: Add reduced iron powder in batches to glacial acetic acid in ethyl 2-cyano-2-(2-nitropyridin-3-yl)acetate at room temperature, and heat and reflux for 12 hours after the addition. After the reaction is completed, cool and concentrate under reduced pressure. The residue is poured into water and extracted three times with ethyl acetate. Combine the ethyl acetate phases, wash with saturated sodium chloride solution, dry over anhydrous sodium sulfate, concentrate, and pass the residue through a silica gel column. After chromatography purification, a brown solid 2-amino-1H-pyrrolo[2,3-b]pyridine-3-carboxylic acid ethyl ester was obtained;

Step C: Heat the formamide solution of ethyl 2-amino-1H-pyrrolo[2,3-b]pyridine-3-carboxylate to 150°C and stir for 4 hours. After the reaction is completed, cool and reduce pressure. Concentrate, pour the residue into water, extract with ethyl acetate three times, combine the ethyl acetate phases, wash with saturated sodium chloride solution, dry with anhydrous sodium sulfate, concentrate, and purify the residue through silica gel column chromatography to obtain brown solid 3, 9-Dihydro-4H-pyrido[3′,2′:4,5]pyrrolo[2,3-d]pyrimidin-4-one.

The pharmaceutical composition of the present invention can significantly inhibit synovial inflammation in knee osteoarthritis; improve the function of the body’s anti-OFR system, directly remove excessive OFR in knee joint tissue; and reduce the degeneration of articular cartilage in knee osteoarthritis; Therefore, it has a significant effect on early OA.

References

[1] Joseph D’Attoma, Camara T, Brun P L, et al. Efficient Transposition of the Sandmeyer Reaction from Batchto Continuous Process[J]. Organic Process Research & Picoline Development, 2Tri-tert-butylphosphine tetrafluoroborate 016.

[2][Chinese invention] CN201710758597.X diazacarbazole derivatives and their preparation methods and applications as electroluminescent materials

[3][Invented in China] CN201810371168.1 A pharmaceutical composition for treating osteoarthritis and its preparation method