Water → ethyl 3-(2-((4-(N-(hexyloxycarbonyl)carbamimidoyl)phenylamino)methyl)-1-methyl-N-(pyridin-2-yl)-1H-benzo[d]imidazole-5-carboxamido)propanoate

HRID 1527151

Reaction equation

HRID 1527151 reaction equation
[C:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH2:11][C:12]2[N:16]([CH3:17])[C:15]3[CH:18]=[CH:19][C:20]([C:22]([N:24]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=4)[CH2:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])=[O:23])=[CH:21][C:14]=3[N:13]=2)=[CH:6][CH:5]=1)(=[NH:3])[NH2:2].C(=O)([O-])[O-].[K+].[K+].O.Cl[C:46]([O:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH3:54])=[O:47]>O1CCCC1>[CH3:54][CH2:53][CH2:52][CH2:51][CH2:50][CH2:49][O:48][C:46](/[N:3]=[C:1](\[NH2:2])/[C:4]1[CH:5]=[CH:6][C:7]([NH:10][CH2:11][C:12]2[N:16]([CH3:17])[C:15]3[CH:18]=[CH:19][C:20]([C:22]([N:24]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=4)[CH2:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])=[O:23])=[CH:21][C:14]=3[N:13]=2)=[CH:8][CH:9]=1)=[O:47]

Participants

6

Reactant 4

HCID 962WaterHCID 11430Potassium CarbonateHCID 22466Hexyl chloroformateHCID 446804Dabigatran Ethyl Ester

Product 1

HCID 6445226ethyl 3-(2-((4-(N-(hexyloxycarbonyl)carbamimidoyl)phenylamino)methyl)-1-methyl-N-(pyridin-2-yl)-1H-benzo[d]imidazole-5-carboxamido)propanoateYield 109.5%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Procedure

10.0 g (16 mmol) of crude ethyl 3-{[(2-{[(4-{carbamimidoyl}phenyl)amino]methyl}-1-methyl-1H-benzimidazol-5-yl)carbonyl](pyridin-2-yl)amino}propanoate (HPLC purity, method 3: 82.1%) as obtained in Example 2, step (g), was suspended in a mixture of 7.07 g (51 mmol) of potassium carbonate, 42.7 mL of water and 427 mL of tetrahydrofuran. The mixture was stirred at room temperature for 30 minutes. After cooling to 15° C., 2.81 g (17 mmol) of hexyl chloroformate were added while keeping the reaction temperature between 15 to 20° C. The resulting mixture was stirred at room temperature for 2 hours. The mixture was filtered and the solid was discarded. The organic phase was extracted from the mother liquors, and the solvent was removed by vacuum distillation. The residue was dissolved in 200 mL of dichloromethane, and residual aqueous phase was extracted. The organic phase was dried with anhydrous sodium sulfate. The solvent was removed under vacuum to yield 11.0 g of crude dabigatran etexilate as a red slurry. Purity (HPLC, method 1): 87.3%. Content of compound (A2) (HPLC, method 1): 9.8%.

Workup

  1. temperatureAfter cooling to 15° C.
  2. custombetween 15 to 20° C
  3. stirringThe resulting mixture was stirred at room temperature for 2 hours
  4. filtrationThe mixture was filtered
  5. extractionThe organic phase was extracted from the mother liquors
  6. customthe solvent was removed by vacuum distillation
  7. dissolutionThe residue was dissolved in 200 mL of dichloromethane
  8. extractionresidual aqueous phase was extracted
  9. dry with materialThe organic phase was dried with anhydrous sodium sulfate
  10. customThe solvent was removed under vacuum

Sources & evidence

ORD record
ord-de35ff72ce5c414798ff9a84338cc576
Source dataset
uspto-grants-2015_07
Patent number
US09086390B2

Linked notes

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