Water → Rivaroxaban

HRID 2207258Notes

Reaction equation

HRID 2207258 reaction equation
[Cl:1][C:2]1[S:6][C:5]([C:7]([OH:9])=O)=[CH:4][CH:3]=1.C1(C)C=CC(S(Cl)(=O)=O)=CC=1.[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.O>CN(C1C=CN=CC=1)C.ClCCl>[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:7]([C:5]3[S:6][C:2]([Cl:1])=[CH:3][CH:4]=3)=[O:9])[CH2:24]2)[CH:34]=1

Participants

7

Reactant 4

HCID 962WaterHCID 73974-Toluenesulfonyl chlorideHCID 950485-Chloro-2-thiophenecarboxylic acidHCID 11346837(S)-4-(4-(5-(aminomethyl)-2-oxooxazolidin-3-yl)phenyl)morpholin-3-one

Product 1

HCID 9875401RivaroxabanYield 85.6%

Reagents, catalysts & solvents 2

HCID 142844-(Dimethylamino)pyridineCatalystHCID 6344DichloromethaneSolvent2×

Procedure

4-(N,N-dimethylamino)pyridine (36.6 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 mixture of p-toluenesulfonyl chloride (19.05 g, 0.1 mol) and dichloromethane (50 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 37.3 g of pure rivaroxaban as a white crystalline solid (Theoretical Yield: 85.6%; Purity by HPLC: 99.9%; and Chiral Purity by HPLC: 99.9%).

Workup

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

Sources & evidence

ORD record
ord-a5340af100744783880a99b58e8d67c1
Source dataset
uspto-grants-2016_06
Patent number
US09376427B2

Reaction notes

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