Methanol → Methyl 6-methylpyrimidine-4-carboxylate

1.77 g (16.37 mmol) of 4,6-dimethylpyrimidine was dissolved in 20 ml of water and stirred. 5.69 g (36.01 mmol) of potassium permanganate solution in 60 ml of water was added thereto and heated at temperature of 70° C. to 75° C. After the color of potassium permanganate disappeared, the mixture was filtered with celite and extracted with dichloromethane to collect the remaining starting material. The aqueous layer was removed under reduced pressure to obtain potassium 6-methylpyrimidine-4-carboxylate (Intermediate compound 57). 3.45 g of the intermediate compound 57 was mixed with 250 ml of methanol and 1.7 ml of conc. sulfuric acid, and the mixture was refluxed under heating for 6 hours. The solvent in the mixture was then removed under reduced pressure. The residue was diluted with ethyl acetate and water, and neutralized by sodium bicarbonate solution, and then extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The concentrated product was purified by the column chromatography (ethylacetate:hexane=1:1) to obtain 6-methylpyrimidine-4-carboxylic acid methyl ester (Intermediate compound 58, 930 mg, Yield of the first and second steps: 37%). The intermediate compound 58 was then subjected to the fifth step in the reaction of Example 1 to obtain 6-methylpyrimine-4-carboxylic acid (Intermediate compound 59, Yield of the third step: 62%). Next, the intermediate compound 59 and (−)-thiodeacetyl colchicine were subjected to the sixth step in the reaction of Example 1 to obtain the title compound 21 (Yield of the fourth step: 37%).

1. temperaturethe mixture was refluxed
2. temperatureunder heating for 6 hours
3. customThe solvent in the mixture was then removed under reduced pressure
4. additionThe residue was diluted with ethyl acetate and water
5. extractionextracted with ethyl acetate
6. dry with materialThe organic layer was dried over anhydrous magnesium sulfate
7. filtrationfiltered
8. concentrationconcentrated under reduced pressure
9. customThe concentrated product was purified by the column chromatography (ethylacetate:hexane=1:1)

ORDレコード

ord-202459c511624cec9eadb853c1e9aa4b

出典データセット

uspto-grants-2009_11

DOI

10.6084/m9.figshare.5104873.v1

特許番号

US07622612B2