Methanesulfonic Acid → Edoxaban

HRID 2361002Notes

Reaction equation

HRID 2361002 reaction equation
CS(O)(=O)=O.C([O:10][C:11](=O)[NH:12][C@@H:13]1[CH2:18][C@@H:17]([C:19]([N:21]([CH3:23])[CH3:22])=[O:20])[CH2:16][CH2:15][C@@H:14]1[NH:24][C:25](=[O:36])[C:26]([NH:28][C:29]1[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][N:30]=1)=[O:27])(C)(C)C.Cl.[CH3:39][N:40]1[CH2:45][CH2:44][C:43]2[N:46]=[C:47](C(O)=O)[S:48][C:42]=2[CH2:41]1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>C(#N)C.O.C(N(CC)CC)C>[Cl:35][C:32]1[CH:33]=[CH:34][C:29]([NH:28][C:26](=[O:27])[C:25]([NH:24][C@H:14]2[CH2:15][CH2:16][C@H:17]([C:19](=[O:20])[N:21]([CH3:22])[CH3:23])[CH2:18][C@H:13]2[NH:12][C:11]([C:47]2[S:48][C:42]3[CH2:41][N:40]([CH3:39])[CH2:45][CH2:44][C:43]=3[N:46]=2)=[O:10])=[O:36])=[N:30][CH:31]=1

Participants

9

Reactant 5

HCID 6395Methanesulfonic AcidHCID 757711-HydroxybenzotriazoleHCID 27239391,3-Propanediamine, N'-(ethylcarbonimidoyl)-N,N-dimethyl-, monohydrochlorideHCID 111490315-Methyl-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridine-2-carboxylic acid--hydrogen chloride (1/1)HCID 46911214EthanediaMide iMpurity D

Product 1

HCID 10280735Edoxaban

Reagents, catalysts & solvents 3

HCID 962WaterSolventHCID 6342AcetonitrileSolventHCID 8471TriethylamineSolvent2×

Procedure

Methanesulfonic acid (66 mL) was added at room temperature to a suspension of t-butyl[(1R,2S,5S)-2-({[(5-chloropyridin-2-yl)amino](oxo)acetyl}amino)-5-(dimethylaminocarbonyl)cyclohexyl]carbamate (95.1 g) in acetonitrile (1,900 mL), and the mixture was stirred at the same temperature for 2 hours. Triethylamine (155 mL), 5-methyl-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridine-2-carboxylic acid hydrochloride (52.5 g), 1-hydroxybenzotriazole (33.0 g), and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (46.8 g) were added to the reaction mixture under ice-cooling, and the mixture was stirred at room temperature for 16 hours. Triethylamine and water were added thereto, followed by stirring under ice-cooling for 1 hour. The formed crystals were recovered by filtration, to thereby yield 103.2 g of the title compound.

Workup

  1. temperaturecooling
  2. stirringthe mixture was stirred at room temperature for 16 hours
  3. stirringby stirring under ice-
  4. temperaturecooling for 1 hour
  5. filtrationThe formed crystals were recovered by filtration

Sources & evidence

ORD record
ord-59d598f7456842278ea4066ff6278b9c
Source dataset
uspto-grants-2014_04
Patent number
US08686189B2

Reaction notes

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