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

HRID 1503223Notes

Reaction equation

HRID 1503223 reaction equation
Cl.[C:2]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][CH2:12][C:13]2[N:17]([CH3:18])[C:16]3[CH:19]=[CH:20][C:21]([C:23]([N:25]([CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=4)=[O:24])=[CH:22][C:15]=3[N:14]=2)=[CH:7][CH:6]=1)(=[NH:4])[NH2:3].C(N(CC)CC)C.Cl[C:47]([O:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH3:55])=[O:48].O>C(Cl)Cl>[CH3:55][CH2:54][CH2:53][CH2:52][CH2:51][CH2:50][O:49][C:47](/[N:4]=[C:2](\[NH2:3])/[C:5]1[CH:6]=[CH:7][C:8]([NH:11][CH2:12][C:13]2[N:17]([CH3:18])[C:16]3[CH:19]=[CH:20][C:21]([C:23]([N:25]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=4)[CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])=[O:24])=[CH:22][C:15]=3[N:14]=2)=[CH:9][CH:10]=1)=[O:48]

Participants

6

Reactant 4

HCID 962WaterHCID 8471TriethylamineHCID 22466Hexyl chloroformateHCID 18412337Ethyl 3-(2-(((4-carbamimidoylphenyl)amino)methyl)-1-methyl-N-(pyridin-2-yl)-1H-benzo(d)imidazole-5-carboxamido)propanoate hydrochloride2×

Product 1

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

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent2×

Procedure

73 gm ethyl 3-(2-((4-carbamimidoylphenylamino)methyl)-1-methyl-N-(pyridin-2-yl)-1H-benzo[d]imidazole-5-carboxamido)propanoate hydrochloride of Formula (E) in 1460 mL methylene dichloride were stirred 25° C. to 35° C. and cooled to 0° C. to 5° C. To the reaction mixture was treated with 61.1 mL triethylamine at 0° C. to 5° C. and stirred for 30 minutes followed by addition of n-hexyl chloroformate solution (31.35 mL in 365 mL methylene dichloride for 2 hrs. The residue was treated with 730 mL water and extracted with 370 mL methylene dichloride. The methylene dichloride was distilled and the residue was purified using mixture of methylene dichloride and ethanol to afforded amorphous form of dabigatran Etexilate of Formula (F). The amorphous form of dabigatran etexilate of Formula (F) is characterized by x-ray powder diffraction pattern as depicted in FIG. 4.

Workup

  1. temperaturecooled to 0° C. to 5° C
  2. extractionextracted with 370 mL methylene dichloride
  3. distillationThe methylene dichloride was distilled
  4. customthe residue was purified
  5. additionmixture of methylene dichloride and ethanol

Sources & evidence

ORD record
ord-2f3c47148c8d492ea81f87d82db2e604
Source dataset
uspto-grants-2015_12
Patent number
US09212166B2

Reaction notes

Loading…