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

HRID 1527140

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].Cl[C:39]([O:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47])=[O:40]>>[CH3:47][CH2:46][CH2:45][CH2:44][CH2:43][CH2:42][O:41][C:39](/[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:40]

Participants

Reactant 2

HCID 22466Hexyl chloroformate2×

HCID 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)propanoate

Procedure

U.S. Pat. No. 7,202,368 describes an alternative process for the synthesis of dabigatran etexilate (see Scheme 2). Example 3 describes the condensation between ethyl 3-{[3-amino-4-(methylamino)benzoyl](pyridin-2-yl)amino}propanoate (compound II) and 2-[4-(1,2,4-oxadiazol-5-on-3-yl)phenylamino]acetic acid (compound VII) in the presence of a coupling agent such as N,N′-carbonyldiimidazole (CDI), propanephosphonic anhydride (PPA), or pivaloyl chloride, to give ethyl 3-{[(2-{[(4-{1,2,4-oxadiazol-5-on-3-yl}phenyl)amino]methyl}-1-methyl-1H-benzimidazol-5-yl)carbonyl](pyridin-2-yl)amino}propanoate (compound VIII), which is subsequently hydrogenated (Example 4) in the presence of a palladium catalyst to give ethyl 3-{[(2-{[(4-carbamimidoylphenyl)amino]methyl}-1-methyl-1H-benzimidazol-5-yl)carbonyl](pyridin-2-yl)amino}propanoate (compound V). Then, Example 5 describes the acylation of compound V with n-hexyl chloroformate (compound VI) to give dabigatran etexilate. Finally, Example 6 describes the conversion of dabigatran etexilate into its mesylate salt. Although the patent describes the HPLC purities of intermediate compounds II, VII, VIII and V, no information is given neither about the purity of the isolated dabigatran etexilate nor about its mesylate salt.

Sources & evidence

ORD record: ord-5f26f529ae9047e88e4a6d32ab35cf88
Source dataset: uspto-grants-2015_07
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US09086390B2

Linked notes

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