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A process for preparation of ethyl 3-(2-(((4-(N-((hexyloxy)carbonyl) carbamimidoyl)phenyl)amino)methyl)-1-methyl-N-(pyridin-2-yl)-1Hbenzo[ d]imidazole -5-carboxamido)propanoate

IP.com Disclosure Number: IPCOM000237228D
Publication Date: 2014-Jun-09
Document File: 5 page(s) / 101K

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A process for preparation of ethyl 3-(2-(((4-(N-((hexyloxy)carbonyl)

carbamimidoyl)phenyl)amino)methyl)-1-methyl-N-(pyridin-2-yl)-1H-

benzo[d]imidazole -5-carboxamido)propanoate

    Disclosed herein after is a process for the preparation of ethyl 3-(2-(((4-(N- ((hexyloxy)carbonyl) carbamimidoyl)phenyl)amino)methyl)-1-methyl-N-(pyridin-2- yl)-1H-benzo[d]imidazole -5-carboxamido)propanoate, referred to as Compound I, of the following structure:

The process comprises:

1. Converting 4-aminobenzonitrile to ethyl 2-((4-cyanophenyl)amino)acetate (Compound A));

2. Converting Compound A to an oxime intermediate ethyl 2-((4-(N'- hydroxycarbamimidoyl)phenyl)amino) acetate (Compound B-i), followed by hydrogenation to obtain an amidine intermediate, ethyl 2-((4- carbamimidoylphenyl)amino)acetate (Compound B);

3. Converting Compound B to its carbamate form, ethyl 2-((4-(N- ((hexyloxy)carbonyl)carbamimidoyl)phenyl)amino) acetate (Compound C);

4. Hydrolyzing Compound C to 2-((4-(N-((hexyloxy) carbonyl)carbamimidoyl)phenyl)amino)acetic acid (Compound D); and

5. Coupling Compound D and ethyl 3-(3-amino-4-(methylamino)-N-(pyridin- 2-yl)benzamido)propanoate ( Compound E) to obtain Compound I.


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Step I: Synthesis of ethyl 2-((4-cyanophenyl)amino)acetate (Compound A)

4-Aminobenzonitrile (15 g, 1.0 eq, 0.127 mol) and N,N-diisopropylethylamine ("DIPEA", 45.3 ml, 2.05 eq, 0.260 mol) were mixed in 120 ml of acetonitrile and heated to 60 °C. Ethyl bromoacetate (14 ml, 1.0 eq, 0.127 mol) was added dropwise into the reaction mixture within 1 h and the reaction mixture was stirred at 60 °C overnight. Additional amount of ethyl bromoacetate (2.82 ml, 0.2 eq,
0.025 mol) was added dropwise and the reaction mixture was stirred at 65 °C for additional 16 h. Additional amount of ethyl bromoacetate (7.13 ml, 0.5 eq, 0.064 mol) was added dropwise and the temperature was raised up to 75 °C and stirred for additional 16 h. The reaction mixture was evaporated; water (100 ml) was added and extracted with ethyl acetate ("EtOAc", 3×40 ml). The combined organic layers were washed with brine (50 ml), dried over anhydrous Na2SO4, and evaporated to yield crude product which was recrystallized from EtOAc / cyclohexane to obtain 21.41 g of Compound A (yield = 82.6 %).

UPLC-UV purity: 95 %

Step II: Synthesis of ethyl 2-((4-(N'-hydroxycarbamimidoyl)phenyl)amino) acetate (Compound B-i)

Triethylamine (9.5 ml, 3.5 eq, 68.55 mmol) was added to hydroxylamine hydrochloric acid (4.76 g, 3.5 eq, 68.55 mmol) solution in DMSO (28 ml) and the reaction was stirred for 10 min at room temperature under argon atmosphere. The salt was filtered off and the filtrate was added directly to Compound A (4.0 g,
1.0 eq, 19.58 mmol) solution in DMSO (28 ml). The reaction mixture was then stirred at 70 °C for 6 h. DMSO was distilled off. The resulting residue was diluted with sodium bicarbonate (100 ml) and extracted with EtOAc (3×30 ml). Combined organic layers were dried over anh...