Application background and overview of 5-bromo-2-methylpyridine
Pyridine and its derivatives are widely distributed in nature. Many plant components such as alkaloids contain pyridine ring compounds in their structures. They have a wide range of uses and can be used to produce high value-added fine chemical products, playing an important role in the pharmaceutical industry, pesticide industry and chemical industry. They are the basis for the production of many important compounds and are indispensable and important raw materials in the production of medicines, pesticides, fuels, surfactants, rubber additives, feed additives, food additives, adhesives, synthetic materials, etc. 5-Bromo-2-methylpyridine is an important pharmaceutical intermediate with broad prospects in the production of cardiovascular and cerebrovascular drugs and respiratory drugs, and has huge market potential. At present, the main synthesis method used is the direct bromination method. Due to the positioning effect of the substituent, the 3-position isomer will be generated during the reaction. The ratio is 45:55, and the boiling point difference is only 1.5°C. It is difficult to Separation and purification are carried out through traditional methods such as distillation. According to general literature reports, pure products are obtained by column chromatography. This method wastes time, increases costs, and is not suitable for large-scale industrial production.
Applications of 5-bromo-2-methylpyridine
5-Bromo-2-methylpyridine is an important pharmaceutical intermediate with broad prospects in the production of cardiovascular and cerebrovascular drugs and respiratory drugs, and has huge market potential. Examples of its application are as follows:
1. The preparation method of 5-bromo-2-pyridinecarboxylic acid includes the following steps: use 5-bromo-2-methylpyridine as raw material, water as solvent, heat to 80°C, and add permanganic acid in batches Potassium, maintain the reaction temperature at 85-90°C, the heating time at 60-100 minutes, distill the reactants, filter, adjust the pH value of potassium trifluoroborate, and cool and crystallize. The beneficial effects of using the present invention are: mild reaction conditions, easy operation, simple post-processing, easy to scale up production, and very suitable for industrial production; good catalytic effect, high yield; cheap raw material prices and low production costs. The reaction equation is as follows:
The specific steps are as follows: Add 5-bromo-2-methylpyridine (17.1g, 0.1mol) into a 250ml three-necked flask, add 100ml of water, insert a thermometer and condenser tube, raise the temperature to 80°C, and add high temperature in batches Potassium manganate (31.6g, 0.2mol), then maintain the reaction temperature at 85°C for 60 minutes, distill again, filter, adjust the pH to 3-4 with 6mol/l hydrochloric acid, cool to room temperature, and recrystallize with ethanol to obtain the product, mol The yield is 75%.
2. Preparation of 3-bromo-6-methyl-2-pyridinecarboxaldehyde. 3-Bromo-6-methyl-2-pyridinecarboxaldehyde is an important pharmaceutical intermediate with good market prospects. 3-Bromo-6-methyl-2-pyridinecarboxaldehyde can condense with amino groups to form N-containing Schiff base cofactors. In the yoke system, the N atoms on the pyridine ring and the N atoms on the exocyclic imine group C=N can coordinate with metal ions to form functional complexes. Using 5-bromo-2-methylpyridine as the starting material, the product 3-bromo-6-methyl-2-pyridine is prepared through N-oxidation, cyanation, acidification, esterification, reduction and aldehyde reactions. formaldehyde. The 3-bromo-6-methyl-2-pyridinecarboxaldehyde synthesized by this method has high purity and high yield, which reduces production costs. The synthesis method is simple, easy, green and environmentally friendly, providing theoretical and experimental basis for industrial production. The reaction process is as follows:
The specific reaction steps are as follows:
1) N-oxidation reaction: Use m-chloroperoxybenzoic acid (m-CPBA) as the oxidant and chloroform as the solvent to oxidize 5-bromo-2-methylpyridine under low temperature conditions to obtain 5-bromo-2 -Methylpyridine oxide, remove acidic substances through saturated NaHCO3 solution, dry with anhydrous Na2SO4, and finally filter and concentrate to obtain a yellow solid;
2) Cyanation reaction: Use trimethylsilyl cyanide (TMSCN) as the cyanating agent and acetonitrile as the solvent. Add a certain amount of triethylamine and stir the reaction overnight at 00°C for pinacol 1 borate. The mixture obtained by the reaction is purified by a silica gel column to obtain an off-white or white solid product, 3-bromo-6-methyl-2-cyanopyridine;
3) Acidification: Hydrolyze the cyano group into the carboxyl group in concentrated HCl at 110°C, filter, and the filtrate is the acidified crude product. The filter residue is washed with alkali, extracted with ethyl acetate, and dried with anhydrous Na2SO4 to obtain the crude product 2 , combine the above two crude products;
4) Esterification: The obtained carboxylic acid is chlorinated with SOCl2 and then esterified with methanol at 80°C. Purify with a silica gel column to obtain an off-white or white solid 3-bromo-6-methyl-2- Methyl picolinate;
5) Reduction: Use NaBH4 as the reducing agent and ethanol as the solvent to carry out the reduction reaction at 80°C. After the reaction, wash with NaHCO3 solution, extract with ethyl acetate and dry with anhydrous Na2SO4 to obtain the crude product, use a silica gel column Purify the crude product to obtain white liquid 3-bromo-6-methyl-2-pyridinemethanol;
6) Aldehyde: 2-iodoacylbenzoic acid (IBX) is used as the oxidant, acetonitrile is used as the solvent, and the oxidation reaction is carried out at 50°C; the final product is purified by recrystallization to obtain the final product 3-bromo-6-methyl -2-Pyridinecarboxaldehyde.
Application and preparation of 5-bromo-2-methylpyridine [3-4]
Method 1: A synthesis method of 5-bromo-2-methyl-pyridine, including the following steps:
1) Use 6-methyl-3-pyridinecarboxylic acid as raw material, react with ethanol at 30-80°C in the presence of acid to produce ethyl 6-methyl-3-pyridinecarboxylate;
2) Add 6-methyl-3-pyridinecarboxylic acid ethyl ester to ammonia water and react at -5 to 60°C for 4 to 10 hours to obtain 6-methyl-3-pyridinecarboxamide;
3) Dissolve 6-methyl-3-pyridinecarboxamide in a sodium hydroxide solution containing halogen at a temperature of 20React at ~100°C for 1 to 6 hours to obtain 6-methyl-3-aminopyridine;
4) Add 6-methyl-3-aminopyridine to the HBr solution, add NaNO2 solution dropwise in the presence of a catalytic amount of CuBr, control the temperature at -10~20°C, and react for 1~6 hours to get 5 -Bromo-2-methylpyridine.
Method 2: Preparation method of 5-bromo-2-methylpyridine, the steps are as follows:
1) Diethyl malonate reacts with alkali metal to form a salt, then 5-nitro-2-chloropyridine is added dropwise for condensation reaction, and then decarboxylated under acidic conditions to obtain 5-nitro-2-methyl Pyridine;
2) 5-nitro-2-methylpyridine is hydrogenated and reduced under the catalysis of Pd/C catalyst, filtered and evaporated to dryness to obtain 5-amino-2-methylpyridine;
3) 5-amino-2-methylpyridine first forms a salt with acid, cools to 0~-10℃, adds bromine dropwise, and then adds sodium nitrite aqueous solution dropwise, then adjust the solution to alkaline, and then proceed Extract, dry and evaporate to dryness to obtain 5-bromo-2-methylpyridine. The synthesis route is as follows:
The details are as follows: The mixture of diethyl malonate (42mL, 1.28mol) and sodium hydrogen (4.8g, 0.2mol) was slowly heated to 90°C, stirred for 1h, then heated to 120°C, stirred for 30min and then cooled to room temperature. A solution of 5-nitro-2-chloropyridine (2) (25g, 0.16mol) in toluene (200mL) was added dropwise. After the dropwise addition was completed, the reaction solution was heated to 110°C for 1.5h, then cooled to room temperature and stirred for 15h. The solvent was evaporated under reduced pressure, 6NHCl (200 mL) was added, the temperature was raised to reflux for 4 hours, and then cooled to room temperature. Adjust sodium carbonate to alkaline, extract with ethyl acetate (6 × 100 mL), combine the organic phases, and dry over anhydrous sodium sulfate for 6 hours. After filtering, the filtrate was evaporated to dryness under reduced pressure to obtain crude 5-nitro-2-methylpyridine (3), 20.4g, 94%. 1HNMR (MHz, CDCl3): δ9.34 (s, 1H), 8.41 (m, 1H), 7.37 (m, 1H), 2.74 (s, 3H).
