Hydrochloric Acid → (2R-cis)-1-[[[4-chloro-5-[[(chloromethyl)sulfonyl]amino]-2-fluorophenyl]amino]carbonyl]4-hydroxy-2-pyrrolidinecarboxylic acid

HRID 1934833

Reaktionsgleichung

Reaktionsgleichung von HRID 1934833
[OH:1][C@H:2]1[CH2:6][NH:5][C@@H:4]([C:7]([OH:9])=[O:8])[CH2:3]1.[Cl:10][CH2:11][S:12]([NH:15][C:16]1[CH:21]=[C:20]([N:22]=[C:23]=[O:24])[C:19]([F:25])=[CH:18][C:17]=1[Cl:26])(=[O:14])=[O:13].Cl>[OH-].[Na+].C(C(C)=O)C(C)C>[Cl:26][C:17]1[C:16]([NH:15][S:12]([CH2:11][Cl:10])(=[O:14])=[O:13])=[CH:21][C:20]([NH:22][C:23]([N:5]2[CH2:6][C@H:2]([OH:1])[CH2:3][C@@H:4]2[C:7]([OH:9])=[O:8])=[O:24])=[C:19]([F:25])[CH:18]=1

Komponenten

6

Edukt 3

HCID 313Hydrochloric AcidHCID 440014Cis-4-Hydroxy-D-ProlineHCID 110774021-chloro-N-(2-chloro-4-fluoro-5-isocyanatophenyl)methanesulfonamide

Produkt 1

HCID 53809153(2R-cis)-1-[[[4-chloro-5-[[(chloromethyl)sulfonyl]amino]-2-fluorophenyl]amino]carbonyl]4-hydroxy-2-pyrrolidinecarboxylic acidAusbeute 90 %

Reagenzien, Katalysatoren, Lösungsmittel 2

HCID 7909Methyl Isobutyl KetoneLösungsmittelHCID 14798Sodium HydroxideLösungsmittel2×

Versuchsvorschrift

To a stirred solution of cis-4-hydroxy-D-proline (262 g, 2 mol) in 2 L of 1 N NaOH at 0° C. was added dropwise 1950 mL of a solution of 1-chloro-N-(2-chloro-4-fluoro-5-isocyanatophenyl)methanesulfonamide in methyl isobutyl ketone over 90 minutes. The temperature was kept between −3° C. and 5° C. The pH wag maintained at 8-9 by the addition of 550 mL of 10% NaOH. Stirring was continued at this temperature for another hour at pH 8 and then the two-phase mixture was allowed to come to room temperature. 70 mL of concentrated HCl was added in order to lower the pH to 6.5. After stirring for 20 minutes, the phases were separated. Methyl isobutyl ketone was added to the aqueous phase and the solution was acidified with concentrated hydrochloric acid to pH 2. After addition of solid sodium chloride and vigorous stirring the organic layer was separated. The solvent was removed to yield 775 g (90%) of the title compound (purity: 95-97% by HPLC). 1H NMR (Me2SO-d6) δ 12.4 (br s, 1H), 10.1 (br s, 1H), 8.2 (s, 1H), 7.7 (d, 1H), 7.5 (d, 1H), 5.1-5.0 (br s, 1H), 5.0-4.9 (s, 2H), 4.4 (m, 1H), 4.3 (m, 1H), 3.7-3.6 (m, 1H); 3.4-3.3 (m, 2H), 2.4-2.3 (m, 1H).

Aufarbeitung

  1. customwas kept between −3° C. and 5° C
  2. waitwas continued at this temperature for another hour at pH 8
  3. customto come to room temperature
  4. stirringAfter stirring for 20 minutes
  5. customthe phases were separated
  6. additionMethyl isobutyl ketone was added to the aqueous phase
  7. additionAfter addition of solid sodium chloride
  8. stirringvigorous stirring the organic layer
  9. customwas separated
  10. customThe solvent was removed

Quellen und Nachweise

ORD-Eintrag
ord-92a1629025f044658d7a06c77bd2ac8f
Quelldatensatz
uspto-grants-2002_05
Patentnummer
US06384234B1

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