Application background and overview of 3-methoxypyridineBarium carbonate
With the rapid development of biomedicine and new pesticides, 3-methoxypyridine and its derivatives as basic raw materials are now widely used in the production of medicines, pesticides, food additives and other fields. There are currently two methods for the synthesis of 3-methoxypyridine and its derivatives that have been reported at home and abroad. One is to react 3-hydroxypyridine with methylating reagents or methanol as raw materials; the other method is to use 3-hydroxypyridine and methylating reagents or methanol as raw materials. It is synthesized from halopyridine and sodium methoxide or methanol as raw materials. For example, it was reported in 2006 that 3-hydroxypyridine was used as raw material and reacted with NaH in DMF to generate the corresponding sodium salt and then reacted with methyl iodide to obtain the target compound with a yield of 80%; in 2012, Reddy et al. reported that 3-hydroxypyridine and methanol were used React in a pressure cooker at 120°C under ultrasonic and microwave conditions for 5 minutes to obtain 3-methoxypyridine with a yield of 92%. In addition, Gowrisankar et al. reported that 3-hydroxypyridine and methanol were also used as raw materials in a pressure tube. CeCO3, Pd(OAc)2 and a phosphorus-containing heterocyclic compound were catalyzed and reacted at 80°C for 24 hours to obtain 3-methoxypyridine with a yield of 92%. Among the above three synthesis methods, the cost is higher and the raw materials are not easy to obtain. And it has poor safety and is not suitable for industrial production. For example, 3-chloropyridine and methanol are used as raw materials, refluxed for 3 hours under the catalysis of Pd2(dba)3 and phosphorus- and nitrogen-containing compounds, and 3-methoxypyridine is obtained through column chromatography; Lloung et al. reported that 3-halopyridine and potassium methoxide as raw materials in a microwave reactor, using 18-crown-6 as the catalyst, and reacted for 15 minutes to obtain the target compound. In the above-mentioned synthesis method, highly toxic and complex compounds are used as catalysts. The cost is also high, the raw materials are not easy to obtain, the safety is poor, and it is not suitable for industrial production.
Applications of 3-methoxypyridine
As basic raw materials, 3-methoxypyridine and its derivatives are now widely used in the production of medicines, pesticides, food additives, calcium tetraborate and other fields. For example, they can be used to synthesize cisapride. Cisapride (cisapride) is a third-generation gastrointestinal motility drug developed by Janssen Pharmaceuticals. It can selectively stimulate the release of acetylcholine in the intestinal myoplexus, activate 5-HT receptors, act through the cholinergic nervous system, and promote Movements of the esophagus, stomach, and intestines. The synthesis of intermediate (cis)-N-(3-(4-fluorophenoxy)propyl)-4-amino-3-methoxypiperidine is a key step in the preparation of cisapride, which is common in industry ( The synthesis of cis)-N-(3-(4-fluorophenoxy)propyl)-4-amino-3-methoxypiperidine is based on 4-piperidone as the starting material, protected by carbonyl group, and oxidized , methylation, hydrolysis deprotection, N-alkylation, oximation, and reduction. The starting materials of this synthesis scheme are expensive, the synthesis route is long, and the yield is low. Using 4-piperidone as the starting material, it is prepared by carbonyl protection, oxidation, methylation, hydrolysis and deprotection, N-alkylation, oximation and reduction. The starting materials of this synthesis scheme are expensive, the synthesis route is long, and the yield is low. There is research and development of a low-cost, easy-to-operate preparation of cisapride intermediate (cis)-N-(3-(4-fluorophenoxy)propyl)-4-amino-3-methoxypiperidine. Method, the specific operations are as follows:
a. Dissolve 3-chloropyridine and potassium methoxide in N,N-dimethylformamide under ice bath conditions. After adding, heat to constant temperature to prepare 3-methoxypyridine. The DMF used is polar. Inert solvent has good solubility for reactants and can maintain the chemical stability of the reactants. When the mass ratio of the reactants 3-chloropyridine and sodium methoxide is 1 to 2:1, the reaction temperature is 60 to 80°C and the reaction When the time is 7 to 9 hours, the reaction can proceed smoothly. The specific reactions are as follows:
b. Dissolve the 3-methoxypyridine prepared in step a in the acidic solution, add concentrated nitric acid dropwise under ice bath conditions, after the dropwise addition is completed, slowly warm the reaction system to room temperature to prepare 4-nitro-3 -Methoxypyridine, the acidity is glacial acetic acid conditions, the nitration reaction has strong nitrification ability under glacial acetic acid conditions, and nitration can be carried out under low temperature conditions. When the mass ratio of the reactant 3-methoxypyridine and concentrated nitric acid is 0.3～0.6:1, the reaction can proceed smoothly if the reaction condition is 4～6h. The specific reactions are as follows:
c. Dissolve 4-nitro-3-methoxypyridine and 1-(3-bromopropoxy)-4-fluorobenzene prepared in step b in an organic solvent, and heat to reflux to prepare 4 -Nitro-3-methoxy-N-(3-(4-fluorophenoxy)propyl)pyridine quaternary ammonium salt, the 4-nitro-3-methoxypyridine and 1-(3- Bromopropoxy)-4-fluorobenzene reaction is used for quaternization reaction. The solvent used is ethanol, ethyl acetate or one of ethanol. When the mass ratio of reactants is 1:1~2, the reflux time is The reaction can proceed smoothly in 5 to 7 hours. The specific reactions are as follows:
d. Prepare cisapride by catalytically hydrogenating the 4-nitro-3-methoxy-N-(3-(4-fluorophenoxy)propyl)pyridine quaternary ammonium salt prepared in step c The key intermediate (cis)-N-(3-(4-fluorophenoxy)propyl)-4-amino-3-methoxypiperidine, the reducing agent in the hydrogenation reaction is palladium carbon, and the palladium carbon catalyst is mainly For the catalytic hydrogenation of unsaturated hydrocarbons or CO, when the added amount is 0.4 to 0.6g and the reflux reaction time is 5 to 7 hours, the reaction can proceed smoothly. The specific reactions are as follows:
Application and preparation of 3-methoxypyridine [2, 4-5]
A method for synthesizing heterocyclic compound 3-methoxypyridine, including the following steps:
(1) Put the raw materials 3-halopyridine, hydrogen peroxide, and acetic acid into a 500mL three-mouth boiler in a molar ratio of 10:3:4., react at 40-80°C for 4-8 hours under stirring conditions, recover acetic acid, add saturated sodium carbonate solution and stir to make the system alkaline, evaporate the water, add chloroform for washing, filter out the salt, recover chloroform, and vacuum Distillation gives N-oxy-3-halopyridine;
(2) Add the N-oxy-3-halopyridine and alkoxy salt obtained in (1) into a 500mL three-necked flask in a molar ratio of 1:1.2, add catalyst A and alcohol, and stir while Reflux the reaction under the conditions for 5-8 hours, cool, neutralize to neutrality, recover the alcohol, evaporate the water, and rectify to obtain N-oxygen-3-alkoxypyridine;
(3) Add the N-oxy-3-alkoxypyridine, ferric chloride and hydrazine hydrate obtained in (2) into a 500mL three-necked flask in a molar ratio of 20:3:40, then add activated carbon and Ethanol, react at 70°C for 3 hours, cool to room temperature, filter off the activated carbon, evaporate the alcohol, and obtain 3-methoxypyridine by vacuum distillation.
