Triethylamine → 5-Amino-7-[trans-4-(1-aminocyclopropyl)-3-hydroxymethyl-1-pyrrolidinyl]-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methyl-4-oxoquinoline-3-carboxylic acid

Trans-1-benzyl-4-(1-tert-butoxycarbonylaminocyclopropyl)-3-hydroxymethylpyrrolidine (1.10 g, 3.18 mmol) was dissolved in ethanol (50 ml), and the solution was mixed with palladium hydroxide (500 mg) and stirred for 1.5 hours at room temperature under a hydrogen atmosphere. The reaction suspension was subjected to celite filtration (ethanol washing) and the solvent was evaporated. The resulting residue and 5-amino-1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methyl-4-oxoquinoline-3-carboxylic acid (471 mg, 1.60 mmol) were dissolved in dimethyl sulfoxide (20 ml) and, under a nitrogen atmosphere, the solution was mixed with triethylamine (5 ml) and stirred at 150° C. for 19 hours. After evaporating the solvent, the resulting residue was mixed with 10% citric acid aqueous solution (50 ml) and extracted with chloroform (50 ml×2), and the extract was dried over anhydrous sodium sulfate. After evaporating the solvent, the resulting residue was mixed with concentrated hydrochloric acid (5 ml) and stirred for 1 hour. This was mixed with water (50 ml) and washed with chloroform (50 ml×2). The aqueous layer was adjusted to pH 12.00 with a sodium hydroxide aqueous solution and washed with chloroform (50 ml×2). Finally, the aqueous layer was adjusted to pH 7.40 with 1 N hydrochloric acid and extracted with chloroform (300 ml×5). The extract was dried over anhydrous sodium sulfate, the solvent was evaporated and then the resulting residue was recrystallized from ethanol to obtain 165 mg (38%) of the title compound.

1. filtrationThe reaction suspension was subjected to celite filtration (ethanol washing)
2. customthe solvent was evaporated
3. stirringstirred at 150° C. for 19 hours
4. customAfter evaporating the solvent
5. additionthe resulting residue was mixed with 10% citric acid aqueous solution (50 ml)
6. extractionextracted with chloroform (50 ml×2)
7. dry with materialthe extract was dried over anhydrous sodium sulfate
8. customAfter evaporating the solvent
9. additionthe resulting residue was mixed with concentrated hydrochloric acid (5 ml)
10. stirringstirred for 1 hour
11. additionThis was mixed with water (50 ml)
12. washwashed with chloroform (50 ml×2)
13. washwashed with chloroform (50 ml×2)
14. extractionextracted with chloroform (300 ml×5)
15. dry with materialThe extract was dried over anhydrous sodium sulfate
16. customthe solvent was evaporated
17. customthe resulting residue was recrystallized from ethanol

ORD record

ord-fbc495306be94b46a98a83ec76ba002b

Source dataset

uspto-grants-2001_02

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US06184388B2