1,1'-Carbonyldiimidazole → Rivaroxaban

HRID 241237Notes

Reaction equation

HRID 241237 reaction equation
[OH:1][C@H:2]([CH2:13][NH:14][C:15]1[CH:20]=[CH:19][C:18]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][C:22]2=[O:27])=[CH:17][CH:16]=1)[CH2:3][NH:4][C:5]([C:7]1[S:8][C:9]([Cl:12])=[CH:10][CH:11]=1)=[O:6].[C:28](N1C=CN=C1)(N1C=CN=C1)=[O:29]>C1(C)C=CC=CC=1.CN1CCCC1=O>[Cl:12][C:9]1[S:8][C:7]([C:5]([NH:4][CH2:3][C@@H:2]2[O:1][C:28](=[O:29])[N:14]([C:15]3[CH:16]=[CH:17][C:18]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][C:22]4=[O:27])=[CH:19][CH:20]=3)[CH2:13]2)=[O:6])=[CH:11][CH:10]=1

Participants

5

Reactant 2

HCID 682631,1'-CarbonyldiimidazoleHCID 100015745-Chloro-N-((2R)-2-hydroxy-3-((4-(3-oxo-4-morpholinyl)phenyl)amino)propyl)-2-thiophenecarboxamide

Product 1

HCID 9875401RivaroxabanYield 90%

Reagents, catalysts & solvents 2

HCID 1140TolueneSolventHCID 13387N-methyl-2-pyrrolidoneSolvent

Conditions

Temperature
80 °C

Procedure

Under an atmosphere of nitrogen to a suspension of 14.85 g of 5-chlorothiophen-2-carboxylic acid-{(R)-2-hydroxy-3-[4-(3-oxomorpholin-4-yl)phenylamino]propyl}amide (MW=409.89; 1 eq.) in 145 mL toluene and 22 mL N-methylpyrrolidone were added 7.13 g (MW=162.15; 1.2 eq.) of 1,1′-carbonyldiimidazol. The reaction mixture was heated to 80° C. After stirring for 30 minutes the mixture was heated to 110° C. and stirred at this temperature for 2 hours. Then the mixture was cooled to 22° C. After stirring for 1 hour at ambient temperature the product was isolated by filtration and washed with 60 mL of toluene and 60 mL of water. The wet product was dried at 30° C. in vacuo to yield 15.99 g (MW=435.89; 1.013 eq.) of the title compound (90% of theory).

Workup

  1. temperaturewas heated to 110° C.
  2. stirringstirred at this temperature for 2 hours
  3. temperatureThen the mixture was cooled to 22° C
  4. stirringAfter stirring for 1 hour at ambient temperature the product
  5. customwas isolated by filtration
  6. washwashed with 60 mL of toluene and 60 mL of water
  7. customThe wet product was dried at 30° C. in vacuo

Sources & evidence

ORD record
ord-3b237dcc19b34c4786590ad77ba784a8
Source dataset
uspto-grants-2014_02
Patent number
US08648189B2

Reaction notes

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