Water → HCID 66674545, compound

HRID 1809117Notes

Reaction equation

HRID 1809117 reaction equation
[Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][CH2:10][C@@H:11]2[O:15][C:14](=[O:16])[N:13]([C:17]3[CH:22]=[CH:21][C:20]([N:23]4[CH2:28][CH2:27][O:26][CH2:25][C:24]4=[O:29])=[CH:19][CH:18]=3)[CH2:12]2)=[O:8])=[CH:4][CH:3]=1.[H-].[Na+].[OH2:32]>CN(C=O)C>[ClH:1].[NH2:9][CH2:7][CH2:5][CH2:4][CH2:3][C:2]([N:9]([CH2:10][C@@H:11]1[O:15][C:14](=[O:16])[N:13]([C:17]2[CH:18]=[CH:19][C:20]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][C:24]3=[O:29])=[CH:21][CH:22]=2)[CH2:12]1)[C:7]([C:5]1[S:6][C:2]([Cl:1])=[CH:3][CH:4]=1)=[O:8])=[O:32]

Participants

5

Reactant 3

HCID 962WaterHCID 24758Sodium hydrideHCID 9875401Rivaroxaban

Product 1

HCID 66674545HCID 66674545, compound

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent2×

Procedure

2.83 g (6.5 mmol) of compound (A) are dissolved in 100 ml of abs. DMF under argon. 468 mg (19.5 mmol) of sodium hydride are added, and the mixture is stirred at RT for 30 min. Then 7.6 g (19.5 mmol) of Example 10A, dissolved in 10 ml of DMF, are added. Stirring is continued at RT for a further 15 min and the batch is then admixed with 20 ml of water added gradually. Thereafter the batch is concentrated and the residue is stirred up with 150 ml of saturated solution of hydrogen chloride in dichloromethane for 1 h, during which the bis-acyl compound initially formed after enolization, with mass M=1141, is cleaved. This is followed by concentrating and the residue is taken up in 700 ml of ethyl acetate and extracted twice with 200 ml each time of 10% sodium carbonate solution. The organic phase is separated off, concentrated and taken up in 30 ml of ethyl acetate and then admixed with 30 ml of diethyl ether. After brief stirring, undissolved residues are filtered off and the organic phase is concentrated. The residue is purified by flash chromatography on silica gel with ethyl acetate/toluene 4:1 as eluent. The appropriate fractions are concentrated and the residue is taken up in 10 ml of ethyl acetate. 100 ml of cold diethyl ether are added and the batch is left to stand at 0° C. for 30 min. After filtration, the residue is treated once more with 100 ml of diethyl ether. After renewed filtration, the filter residue is collected and dried to obtain 1 g (20% of theory) of the compound fully protected at the amino group.

Workup

  1. additionare added
  2. stirringStirring
  3. waitis continued at RT for a further 15 min
  4. additionadded gradually
  5. concentrationThereafter the batch is concentrated
  6. stirringthe residue is stirred up with 150 ml of saturated solution of hydrogen chloride in dichloromethane for 1 h, during which the bis-acyl compound
  7. custominitially formed after enolization
  8. concentrationby concentrating
  9. extractionextracted twice with 200 ml each time of 10% sodium carbonate solution
  10. customThe organic phase is separated off
  11. concentrationconcentrated
  12. filtrationAfter brief stirring, undissolved residues are filtered off
  13. concentrationthe organic phase is concentrated
  14. customThe residue is purified by flash chromatography on silica gel with ethyl acetate/toluene 4:1 as eluent
  15. concentrationThe appropriate fractions are concentrated
  16. addition100 ml of cold diethyl ether are added
  17. waitthe batch is left
  18. waitto stand at 0° C. for 30 min
  19. filtrationAfter filtration
  20. additionthe residue is treated once more with 100 ml of diethyl ether
  21. filtrationfiltration
  22. customthe filter residue is collected
  23. customdried
  24. customto obtain 1 g (20% of theory) of the compound

Sources & evidence

ORD record
ord-c698bdede08b40279c0a93b02dab3241
Source dataset
uspto-grants-2013_01
Patent number
US08362015B2

Reaction notes

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