1-Methylimidazole → Rivaroxaban

HRID 2207257Notes

Reaction equation

HRID 2207257 reaction equation
CN1C=CN=C1.[Cl:7][C:8]1[S:12][C:11]([C:13]([OH:15])=O)=[CH:10][CH:9]=1.CS(Cl)(=O)=O.[NH2:21][CH2:22][C@@H:23]1[O:27][C:26](=[O:28])[N:25]([C:29]2[CH:34]=[CH:33][C:32]([N:35]3[CH2:40][CH2:39][O:38][CH2:37][C:36]3=[O:41])=[CH:31][CH:30]=2)[CH2:24]1>ClCCl.O>[CH:33]1[C:32]([N:35]2[C:36](=[O:41])[CH2:37][O:38][CH2:39][CH2:40]2)=[CH:31][CH:30]=[C:29]([N:25]2[C:26](=[O:28])[O:27][C@@H:23]([CH2:22][NH:21][C:13]([C:11]3[S:12][C:8]([Cl:7])=[CH:9][CH:10]=3)=[O:15])[CH2:24]2)[CH:34]=1

Participants

7

Reactant 4

HCID 13901-MethylimidazoleHCID 31297Methanesulfonyl chlorideHCID 950485-Chloro-2-thiophenecarboxylic acidHCID 11346837(S)-4-(4-(5-(aminomethyl)-2-oxooxazolidin-3-yl)phenyl)morpholin-3-one

Product 1

HCID 9875401RivaroxabanYield 90%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 6344DichloromethaneSolvent2×

Procedure

1-Methylimidazole (24.6 g, 0.3 mol) was added to a stirred suspension of 5-chlorothiophene-2-carboxylic acid (16.25 g, 0.1 mol) in dichloromethane (162 ml) at 0-5° C. and the resulting solution was stirred for 10 minutes. A solution of methanesulfonyl chloride (12 g, 0.105 mol) in dichloromethane (40 ml) was added to the above solution at −5° C. The resulting solution was stirred for 1 hour at −5° C. to produce a reaction mass containing the sulfonyl ester intermediate, followed by portion wise addition of 4-[4-[(5S)-5-(aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl]morpholine-3-one (29.1 g, 0.1 mol, chiral purity: 99.9%). The reaction mixture was stirred for 2 hours at 25-30° C., followed by the addition of water (162 ml) and then stirring for 15 minutes. The separated solid was filtered, washed with dichloromethane (50 ml) and water (100 ml), and the resulting wet material was dried at 80-85° C. for 3 to 5 hours to produce 39.2 g of pure rivaroxaban as a white crystalline solid (Theoretical Yield: 90%; Purity by HPLC: 99.9%; and Chiral Purity by HPLC: 99.9%).

Workup

  1. stirringThe resulting solution was stirred for 1 hour at −5° C.
  2. customto produce a reaction mass
  3. stirringThe reaction mixture was stirred for 2 hours at 25-30° C.
  4. stirringstirring for 15 minutes
  5. filtrationThe separated solid was filtered
  6. washwashed with dichloromethane (50 ml) and water (100 ml)
  7. customthe resulting wet material was dried at 80-85° C. for 3 to 5 hours

Sources & evidence

ORD record
ord-116e4a047b0c4b26a129652425fa91e9
Source dataset
uspto-grants-2016_06
Patent number
US09376427B2

Reaction notes

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