Methanesulfonic Acid → Edoxaban

HRID 707489Notes

Reaction equation

HRID 707489 reaction equation
CS(O)(=O)=O.[Cl:6][C:7]1[CH:8]=[CH:9][C:10]([NH:13][C:14](=[O:37])[C:15]([NH:17][C@H:18]2[CH2:23][CH2:22][C@H:21]([C:24]([N:26]([CH3:28])[CH3:27])=[O:25])[CH2:20][C@H:19]2[NH:29][C:30](=O)[O:31]C(C)(C)C)=[O:16])=[N:11][CH:12]=1.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:6][C:7]1[CH:8]=[CH:9][C:10]([NH:13][C:14](=[O:37])[C:15]([NH:17][C@H:18]2[CH2:23][CH2:22][C@H:21]([C:24]([N:26]([CH3:27])[CH3:28])=[O:25])[CH2:20][C@H:19]2[NH:29][C:30]([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:31])=[O:16])=[N:11][CH:12]=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 10280735EdoxabanYield 92.7%

Reagents, catalysts & solvents 3

HCID 962WaterSolventHCID 6342AcetonitrileSolventHCID 8471TriethylamineSolvent2×

Procedure

Methanesulfonic acid (66 ml) was added to a suspension of tert-butyl [(1R,2S,5S)-2-({[(5-chloropyridin-2-yl)amino](oxo)acetyl}amino)-5-(dimethylaminocarbonyl)cyclohexyl]carbamate (8) (95.1 g) in acetonitrile (1900 ml) at room temperature, and the mixture was stirred at this temperature for 2 hours. To the reaction solution, triethylamine (155 ml), 5-methyl-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridine-2-carboxylic acid hydrochloride (10) (52.5 g), 1-hydroxybenzotriazole (33.0 g), and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (46.8 g) were added under ice cooling, and the mixture was stirred at room temperature for 16 hours. Triethylamine and water were added thereto, and the mixture was stirred for 1 hour under ice cooling. Then, crystals were collected by filtration to obtain the title compound (A) (103.2 g).

Workup

  1. stirringthe mixture was stirred at room temperature for 16 hours
  2. stirringthe mixture was stirred for 1 hour under ice cooling
  3. filtrationThen, crystals were collected by filtration

Sources & evidence

ORD record
ord-539846edb53f498ab2d0cd1cb53cfe60
Source dataset
uspto-grants-2015_11
Patent number
US09175012B2

Reaction notes

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