Background and overview of the preparation method of 2-hydroxymethyl-3,4-dimethoxypyridine
2-Hydroxymethyl-3,4-dimethoxypyridine is a pyridine derivative that can be used to prepare pantoprazole intermediate 2-chloromethyl-3,4-dimethoxypyridine hydrochloride Salt.
Preparation method of 2-hydroxymethyl-3,4-dimethoxypyridine Preparation method
2-Hydroxymethyl-3,4-dimethoxypyridine is compound 5. The preparation method is as follows:
Preparation of 3-hydroxy-2-methyl-4-pyridone:
Add 40g 3-hydroxy-2-methyl-4-pyrone and 120g methanol into the reaction bottle, slowly heat up until dissolved, slowly add 100g ammonium carbonate at 40°C, incubate at 40°C for 2 hours, slowly add 70g ammonium carbonate, 40 Insulate at ℃ for 3 hours, 60°C for 2 hours, slowly increase the temperature to reflux and maintain reflux for 5 hours, then cool to -10°C, filter and rinse with a small amount of ice-methanol, and dry to obtain 30g of 3-hydroxy-2-methyl-4-pyridone. (Yield 75.8%); MS: m/z=125.2[M]+.1H NMR ([D6]DMSO, Hz): δ2.17 (s ,3H, CH3), 6.07-6.10(d,1H,5-H),7.38-7.57 (d,1H,6-H),11.4(s,1H,NH).
Preparation of 3,4-dimethoxy-2-methylpyridine:
Add 38g 3-hydroxy-2-methyl-4-pyridone, 90g water, and 35g potassium hydroxide into the reaction bottle, stir and dissolve, add 75g dimethyl sulfate dropwise at 10 to 20°C, keep it warm for 20 hours after addition, add Stir 80g methylene chloride for 15 minutes and then separate into layers. Stir the water layer with 20g methylene chloride for 15 minutes and then separate into layers. Combine the methylene chloride layers and distill under reduced pressure to dryness to obtain 44g of basic copper carbonate oil. 3,4-dimethyl Oxy-2-methylpyridine;1H NMR (CDCl3, Hz):δ2.46(s,3H,CH3) ,3.3.79(s,3H,OCH3),3.86(s,3H,OCH3), 6.18(d,1H,5-H),8.11(d,1H, 6-H).
Preparation of 3,4-dimethoxy-2-methylpyridine nitrogen oxide:
Add 44g 3,4-dimethoxy-2-methylpyridine, 50g glacial acetic acid, and 0.2g sodium tungstate into the reaction bottle, stir and dissolve, add 35g hydrogen peroxide (50%) dropwise at 40 to 45°C, and finish adding Slowly raise the temperature to 95°C and keep it for 4 hours, then distill under reduced pressure until it is dry. Add 90g methanol dilute alkali solution to adjust the pH to 7~8, filter 10g methanol wash material, and evaporate the filtrate to dryness under reduced pressure to obtain 45g 3,4-dimethoxy-2-methylpyridine nitrogen oxide (yield 92.6%); mp: 112-113℃;1H NMR(CDCl3, Hz):δ2.50(s,3H,CH3),3.85(s ,3H,OCH3),3.93 (s,3H,OCH3),6.71 (d,1H,5-H),8.10(d,1H,6-H).
Preparation of 2-hydroxymethyl-3,4-dimethoxypyridine:
Add 45g 3,4-dimethoxy-2-methylpyridine nitrogen oxide and 132g acetic anhydride into the reaction bottle, slowly raise the temperature to reflux, maintain reflux for 4 hours, evaporate the acetic anhydride to dryness under reduced pressure, add 150g water, and lye Adjust pH to 8~9, add 20g sodium hydroxide, heat to 80°C, keep warm for 4 hours, cool to 25~30°C, extract with 100g+100g+70g of methylene chloride, and evaporate to dryness under reduced pressure to obtain 41g of 2-hydroxymethyl-3. Tricyclohexylphosphine fluoroborate 4-dimethoxypyridine (yield 91%); mp: 94-95℃; 1H NMR (CDCl3,Hz):δ3.85(s,3H,OCH3),3.93(s, 3H,OCH3), 4.76(s,2H,CH2O), 6.82(d,1H,5-H), 8.22(d,1H,6-H).
Preparation method and application of 2-hydroxymethyl-3,4-dimethoxypyridine [1]
Can be used to prepare pantoprazole intermediate 2-chloromethyl-3,4-dimethoxypyridine hydrochloride.
Add 41g 2-hydroxymethyl-3,4-dimethoxypyridine and 100g methylene chloride into the reaction bottle, stir to dissolve, slowly add 30g thionyl chloride dropwise at 0 to 5°C, and then slowly raise the temperature to 10 ~15°C, keep for 2 hours, evaporate methylene chloride to dryness under reduced pressure, add 90g of absolute ethanol, cool to 0°C, filter with suction, and dry to obtain 51g of 2-chloromethyl-3,4-dimethoxypyridine hydrochloride. (Yield 93.9%); mp: 157-158 ℃; 1H NMR (CDCl3, Hz):δ4.09 (s ,3H,OCH3),4.23(s,3H,OCH3),5.06(s,2H, CH2Cl), 7.56(d,1H,5-H),8.56(d,1H, 6-H).
