Citric Acid → 7-[(7S)-7-Amino-7-methyl-5-azaspiro[2.4]heptan-5-yl]-1-cyclopropyl-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid

Temperature

75 °C

A mixture of (7S)-7-(tert-butoxycarbonylamino)-7-methyl-5-azaspiro[2.4]heptane (524 mg, 2.31 mmol), 1-fluorocyclopropyl-7-fluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (503 mg, 1.925 mmol), triethylamine (0.537 mL, 3.85 mmol), and dimethyl sulfoxide (6 mL) was stirred in nitrogen atmosphere in an oil bath at 75° C. for 5 days, and in an oil bath at 85° C. for 2 days. To the reaction mixture was added 10% aqueous solution of citric acid (10 mL), and the mixture was extracted with ethyl acetate (50 mL). The organic layer was washed with water (10 mL×2) and saturated aqueous solution of sodium chloride (10 mL), and dried with anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (silica gel, 10 g; elusion by chloroform→chloroform:methanol, 98:2) to obtain a pale yellow foam solid. The purified pale yellow foam solid was dissolved in concentrated hydrochloric acid (8 mL) at room temperature, and after transferring the resulting acidic aqueous solution to a separatory funnel while washing with 6N hydrochloric acid, the solution was washed with chloroform (50 mL×8). To the aqueous layer was added 10 mol/l aqueous solution of sodium hydroxide to pH 12.0 in an ice bath, and hydrochloric acid was added to adjust the pH to 7.4. The solution was extracted with a mixed solvent of chloroform and methanol (chloroform:methanol, 9:1) (100 mL×3), and the organic layer was dried with anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The concentrate was purified by recrystallization from ethanol, and dried under reduced pressure to obtain 268 mg (0.641 mmol, 2 steps, 33%) of the title compound as a pale yellow powder.

1. waitin an oil bath at 85° C. for 2 days
2. extractionthe mixture was extracted with ethyl acetate (50 mL)
3. washThe organic layer was washed with water (10 mL×2) and saturated aqueous solution of sodium chloride (10 mL)
4. dry with materialdried with anhydrous sodium sulfate
5. filtrationAfter filtration
6. concentrationthe filtrate was concentrated under reduced pressure
7. customThe residue was purified by silica gel column chromatography (silica gel, 10 g; elusion by chloroform→chloroform:methanol, 98:2)
8. customto obtain a pale yellow foam solid
9. washwhile washing with 6N hydrochloric acid
10. washthe solution was washed with chloroform (50 mL×8)
11. additionTo the aqueous layer was added 10 mol/l aqueous solution of sodium hydroxide to pH 12.0 in an ice bath
12. additionhydrochloric acid was added
13. extractionThe solution was extracted with a mixed solvent of chloroform and methanol (chloroform:methanol, 9:1) (100 mL×3)
14. dry with materialthe organic layer was dried with anhydrous sodium sulfate
15. filtrationAfter filtration
16. concentrationthe filtrate was concentrated under reduced pressure
17. customThe concentrate was purified by recrystallization from ethanol
18. customdried under reduced pressure

ORD record

ord-75a813ee12df40aeb8ee1ac5fb388946

Source dataset

uspto-grants-2009_07

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US07563805B2