Dimethyl Sulfoxide → HCID 10862657, compound

Temperature

150 °C

A 649 mg (1.8 mmol) portion of (3R)-1-benzyloxycarbonyl-3-(1-tert-butoxycarbonylaminomethylcyclopropyl)pyrrolidine was dissolved in 20 ml of methanol to which was subsequently added 200 mg of 5% (v/v) palladium-carbon to carry out 2 hours of hydrogenation under normal pressure with warming by an infrared lamp. After completion of the reaction, 5% (v/v) palladium-carbon was removed by filtration and methanol was evaporated. The resulting residue was dissolved in 20 ml of dimethyl sulfoxide to which were subsequently added 2 ml of triethylamine and 312 mg (1 mmol) of 5-amino-6,7-difluoro-[(1R,2S)-2-fluorocyclopropyl]-1,4-dihydro-8-methyl-4-oxoquinoline-3-carboxylic acid, followed by 18 hours of stirring at 150° C. After completion of the reaction, dimethyl sulfoxide was evaporated, and the resulting residue was mixed with 100 ml of chloroform and washed with 10% citric acid (100 ml×1) and saturated brine (100 ml×1) in that order. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated. A 10 ml portion of concentrated hydrochloric acid was added dropwise to the resulting residue under ice cooling, followed by 1 hour of stirring at room temperature. After completion of the reaction, the reaction solution was washed with dichloromethane (20 ml×1). The aqueous layer was adjusted to pH 12 with sodium hydroxide aqueous solution and then to pH 7.4 with hydrochloric acid, followed by extraction with chloroform (100 ml×4). The organic layers were combined and dried over anhydrous sodium sulfate, and then the solvent was evaporated. The resulting residue was subjected to a silica gel thin layer chromatography, and the silica gel collected after development by the lower layer of a mixture solvent system of chloroform:methanol:water=7:3:1 was extracted with the same solvent. Thereafter, the thus obtained crude product was recrystallized from chloroform-isopropyl ether to afford 101.5 mg (24%) of the title compound.

1. temperaturewith warming by an infrared lamp
2. customwas removed by filtration and methanol
3. customwas evaporated
4. dissolutionThe resulting residue was dissolved in 20 ml of dimethyl sulfoxide to which
5. waitfollowed by 18 hours
6. customwas evaporated
7. additionthe resulting residue was mixed with 100 ml of chloroform
8. washwashed with 10% citric acid (100 ml×1) and saturated brine (100 ml×1) in that order
9. dry with materialThe organic layer was dried over anhydrous sodium sulfate
10. customthe solvent was evaporated
11. additionA 10 ml portion of concentrated hydrochloric acid was added dropwise to the resulting residue under ice cooling
12. waitfollowed by 1 hour
13. stirringof stirring at room temperature
14. customAfter completion of the reaction
15. washthe reaction solution was washed with dichloromethane (20 ml×1)
16. extractionto pH 7.4 with hydrochloric acid, followed by extraction with chloroform (100 ml×4)
17. dry with materialdried over anhydrous sodium sulfate
18. customthe solvent was evaporated
19. customthe silica gel collected after development by the lower layer of a mixture solvent system of chloroform
20. extractionmethanol:water=7:3:1 was extracted with the same solvent
21. customThereafter, the thus obtained crude product
22. customwas recrystallized from chloroform-isopropyl ether

ORD record

ord-6b213dd134b447e18b9994327f326190

Source dataset

uspto-grants-1998_12

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US05849757