Preparation of 6-bromo-4-methoxypyrazolo[1,5-A]pyridine-3-carbonitrile_Industrial additives

Preparation background and overview of 6-bromo-4-methoxypyrazolo[1,5-A]pyridine-3-carbonitrile

Condensed heterocyclic compounds have attracted widespread research interest in recent years due to their significant physiological activities. Among them, pyrazole carbonate lithopyridine compounds are a type of fused heterocyclic compounds that have been studied extensively. Pharmacological studies have shown that this type of compound has good curative effects in sterilization, anti-inflammatory, tumor treatment, asthma, osteoporosis, neurological diseases and Alzheimer’s disease. It is a type of compound with high research value. Pyrazolopyridine derivatives mainly include pyrazole[3,4-b]pyridine, pyrazole[4,3-c]pyridine, pyrazole[1,5-a]pyridine, etc. The most studied ones are the pyrazole[1,5-a]pyridine series compounds. In this series, 6-bromo-4-methoxypyrazolo[1,5-A]pyridine-3-carbonitrile is a very useful synthetic fragment, which can conveniently and quickly synthesize some pharmacologically active compounds. organic molecules.

Preparation of 6-bromo-4-methoxypyrazolo[1,5-A]pyridine-3-carbonitrile

Preparation step 1 of 6-bromo-4-methoxypyrazolo[1,5-A]pyridine-3-carbonitrile: 2,4,6-trimethylbenzenesulfonic acid 3- Preparation of bromo-5-methoxypyridinamine salt:

Dissolve 1000g (5.32mol, 1.0eq) of 3-bromo-5-methoxypyridine in 3L of dichloroethane, and cool to 5°C. Dissolve 1203g (5.59mol, 1.05eq) of 2,4,6-trimethylbenzenesulfonylhydroxylamine in 2L of dichloroethane and add it dropwise to keep the internal temperature below 10°C. After the addition is completed, the mixture is stirred at 10-20°C for 12 hours. Add 10L of n-hexane and stir for 4 hours. Filter, rinse with n-hexane, and dry to obtain 2082 g of off-white solid, with a yield of 97%. ¹HNMR(MHz,DMSO-d6):8.72(s,1H),8.61-8.63(m,3H),8.26(s,1H),6.75(s,2H anhydrous calcium carbonate) ,3.97(s,3H),3.41(s,6H),2.18(s,3H).

Preparation step 2 of 6-bromo-4-methoxypyrazolo[1,5-A]pyridine-3-carbonitrile: 6-bromo-4-methoxyhydro-pyrazole[ Preparation of 1,5-a]pyridine-3-carbonitrile:

Dissolve 2000g of 2,4,6-trimethylbenzenesulfonic acid 3-bromo-5-methoxypyridinamine salt (4.96mol, 1.0eq) and 2-chloropropenyl cyanide (7.44mol, 1.5eq) in 10L of dimethylformamide. Add 684g of potassium carbonate (4.96mol, 1.0eq) and react at 20-30°C for 8h; then add 1132g of diazabicyclo (7.44mol, 1.5eq) dropwise, and heat the reaction to 50-60°C for 20h. Lower to room temperature, pour into 30L of tap water, filter, and wash with water to obtain crude product. The crude product was recrystallized with 10 L of ethanol to obtain 702 g of light yellow solid, with a yield of 56%. ¹HNMR(MHz,CDCl3):8.33(s,1H),8.13(s,1H),6.75(s,1H),4.04(s,3H).．

References

[1][Chinese invention] CN201810556694.5 A synthesis method of 6-bromo-4-methoxyhydrogen-pyrazole [1,5-a]pyridine-3-carbonitrile