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Dimethyl Sulfoxide → 5-Amino-7-[(3R,4R)-3-(1-aminocyclopropyl)-4-methyl-1-pyrrolidinyl]-6-fluoro-1-[(1R,2S)-2-fluorocyclopropyl]-1,4-dihydro-8-methyl-4-oxoquinoline-3-carboxylic acid

HRID 635070
Notizen
Druckvorschau

Reaktionsgleichung

Reaktionsgleichung von HRID 635070
C(O[C:9]([N:11]1[CH2:15][C@H:14]([CH3:16])[C@@H:13]([C:17]2([NH:20]C(OC(C)(C)C)=O)[CH2:19][CH2:18]2)[CH2:12]1)=O)C1C=CC=CC=1.C(N(CC)CC)C.[NH2:35][C:36]1[C:45]([F:46])=[C:44](F)[C:43](C)=[C:42]2[C:37]=1[C:38](=[O:56])[C:39]([C:53]([OH:55])=[O:54])=[CH:40][N:41]2[C@@H:49]1[CH2:51][C@@H:50]1[F:52].CS(C)=O>C(O)C.[C].[Pd]>[NH2:35][C:36]1[C:45]([F:46])=[C:9]([N:11]2[CH2:15][C@H:14]([CH3:16])[C@@H:13]([C:17]3([NH2:20])[CH2:18][CH2:19]3)[CH2:12]2)[C:43]([CH3:44])=[C:42]2[C:37]=1[C:38](=[O:56])[C:39]([C:53]([OH:55])=[O:54])=[CH:40][N:41]2[C@@H:49]1[CH2:51][C@@H:50]1[F:52]
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Komponenten

7

Edukt 4

HCID 679Dimethyl SulfoxideHCID 8471TriethylamineHCID 110233625-amino-6,7-difluoro-1-[(1R,2S)-2-fluorocyclopropyl]-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acidHCID 54433189(3R,4R)-1-Benzyloxycarbonyl-3-(1-tert-butoxycarbonylaminocyclopropyl)-4-methylpyrrolidine

Produkt 1

HCID 9845680
5-Amino-7-[(3R,4R)-3-(1-aminocyclopropyl)-4-methyl-1-pyrrolidinyl]-6-fluoro-1-[(1R,2S)-2-fluorocyclopropyl]-1,4-dihydro-8-methyl-4-oxoquinoline-3-carboxylic acid
Ausbeute 4,4 %

Reagenzien, Katalysatoren, Lösungsmittel 2

HCID 178418390HCID 178418390, VerbindungKatalysatorHCID 702EthanolLösungsmittel

Reaktionsbedingungen

Temperatur
150 °C

Versuchsvorschrift

(3R,4R)-1-Benzyloxycarbonyl-3-(1-tert-butoxycarbonylaminocyclopropyl)-4-methylpyrrolidine (793 mg, 2.12 mmol) was dissolved in ethanol (50 ml), and the solution was mixed with 5% palladium-carbon (790 mg) to carry out hydrogenation under a pressure of 5 atmospheres. After completing the reaction, the 5% palladium carbon was removed by filtration and ethanol was evaporated. The thus obtained residue was dissolved in dimethyl sulfoxide (8 ml), and the solution was mixed with triethylamine (2 ml) and 5-amino-6,7-difluoro-1-[(1R,2S)-2-fluorocyclopropyl)-1,4-dihydro-8-methyl-4-oxoquinoline-3-carboxylic acid (330 mg, 1.06 mmol) and stirred at 150° C. for 18 hours. After completing the reaction, dimethyl sulfoxide was evaporated, and the thus obtained residue was mixed with chloroform (100 ml) and washed with 10% citric acid (100 ml) and saturated brine (100 ml) in that order. The organic layer was dried over anhydrous sodium sulfate and then the solvent was evaporated. To the thus obtained residue, which was cooled in an ice bath, was added dropwise concentrated hydrochloric acid (10 ml), followed by 1 hour of stirring at room temperature. After completing the reaction, the reaction solution was washed with dichloromethane (20 ml). The aqueous layer was adjusted to pH 12 with a sodium hydroxide aqueous solution and then to pH 7.4 with hydrochloric acid, subsequently carrying out extraction with chloroform (100 ml×4). The organic layers were combined and dried over anhydrous sodium sulfate and then the solvent was evaporated. The thus obtained residue was subjected to silica gel thin layer chromatography and developed with the bottom layer of a mixture solvent of chloroform:methanol=3:1, and then the resulting silica gel was scratched off and extracted with the same solvent system. The solvent was evaporated and the thus obtained residue was dissolved in a 1 N hydrochloric acid aqueous solution (6 ml) and stirred at room temperature for 10 minutes. After evaporating the solvent, the resulting crude product was recrystallized from isopropyl alcohol to obtain 20.1 mg (4%) of the title compound.

Aufarbeitung

  1. customthe reaction
  2. customthe 5% palladium carbon was removed by filtration and ethanol
  3. customwas evaporated
  4. dissolutionThe thus obtained residue was dissolved in dimethyl sulfoxide (8 ml)
  5. customwas evaporated
  6. additionthe thus obtained residue was mixed with chloroform (100 ml)
  7. washwashed with 10% citric acid (100 ml) and saturated brine (100 ml) in that order
  8. dry with materialThe organic layer was dried over anhydrous sodium sulfate
  9. customthe solvent was evaporated
  10. temperatureTo the thus obtained residue, which was cooled in an ice bath
  11. additionwas added dropwise concentrated hydrochloric acid (10 ml)
  12. waitfollowed by 1 hour
  13. stirringof stirring at room temperature
  14. customthe reaction
  15. washthe reaction solution was washed with dichloromethane (20 ml)
  16. extractionextraction with chloroform (100 ml×4)
  17. dry with materialdried over anhydrous sodium sulfate
  18. customthe solvent was evaporated
  19. extractionextracted with the same solvent system
  20. customThe solvent was evaporated
  21. dissolutionthe thus obtained residue was dissolved in a 1 N hydrochloric acid aqueous solution (6 ml)
  22. stirringstirred at room temperature for 10 minutes
  23. customAfter evaporating the solvent
  24. customthe resulting crude product was recrystallized from isopropyl alcohol

Quellen und Nachweise

ORD-Eintrag
ord-e1b4878aa90a452c85e373833efa7731
Quelldatensatz
uspto-grants-2001_02
DOI
10.6084/m9.figshare.5104873.v1
Patentnummer
US06184388B2

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