Browse Prior Art Database

Impurities of Ethyl 3-{[(2-{[(4-{N'-[(hexyloxy)carbonyl]carbamimidoyl}-phenyl)amino] methyl}-1-methyl-1H-benzimidazol-5-yl)carbonyl] (2-pyridinyl)-amino}propanoate mesylate

IP.com Disclosure Number: IPCOM000234163D
Publication Date: 2014-Jan-15
Document File: 9 page(s) / 73K

Publishing Venue

The IP.com Prior Art Database

This text was extracted from a PDF file.
This is the abbreviated version, containing approximately 27% of the total text.

Page 01 of 9

Impurities of Ethyl 3-{[(2-{[(4-{N'-[(hexyloxy)carbonyl]carbamimidoyl}-phenyl)amino] methyl}-1-methyl-1H-benzimidazol-5-yl)carbonyl] (2-pyridinyl)-amino}propanoate mesylate

    Disclosed hereinafter are impurities of intermediates of Ethyl 3-{[(2-{[(4-{N'- [(hexyloxy)carbonyl]carbamimidoyl}-phenyl)amino] methyl}-1-methyl-1H-benzimidazol-5- yl)carbonyl] (2-pyridinyl)-amino}propanoate mesylate (referred to as Compound A). The impurities may be formed in the synthesis of the intermediates of Compound A, and react in subsequent stages, thus forming the corresponding impurities of Compound A.

N-(3-Amino-3-oxopropyl)-2-((4-carbamimidoylphenylamino) methyl)-1-methyl-N-(pyridin-

2-yl)-1H-benzo[d]imidazole-5-carboxamide, referred to as Compound 2:

Compound-2

Preparation of Compound -2:

Ethyl 3-(2-(((4-carbamimidoylphenyl)amino)methyl)-1-methyl-N-(pyridin-2-yl)-1H- benzo[d]imidazole-5-carboxamido)propanoate acetate salt ( 10 g, 17.86 mmol) is suspended in 25% NH3/H2O (435 mL, 23.09 mmol) and the reaction mixture is stirred at room temperature for 64 hours and afterwards concentrated to half a volume by evaporation. Acetone (200 mL) is added to the remaining suspension, stirred for 1.5 hours at room temperature and another 1.5 hours at 0-5 °C and the solid is filtered off. Mother liquor is evaporated to dryness, the residue is suspended in water (80 mL) and dissolved by addition of acetone (12 mL). The cyystallization occurs by drop wise addition of potassium carbonate (2.1 g, 15.2 mmol) solution in water (20 mL),. Obtained suspension is stirred for 30 minutes at room temperature and another 30 minutes at 0-5°C. The solid is filtered off, washed with acetone/water mixture (1:8, 2×20 mL) and dried at 40 °C / 10 mbar/ 5 hours.

1


Page 02 of 9

1H NMR: (400 MHz,) 3.78 (s, 3H),7.48 (m, 1H), 7.12 (m,1H), 7.41(d,1H,J=8.43), 4.64 (d,2H, J=5.17), 7.48 (1NH), 6.87 (d,2H,J=8.67), 7.61 (d, 2H, J=8.68),8.91(2NH),8.66(2NH),4.12(t, 2H, J=6.91),2.68(t, 2H, J=6.91), 8.39(dd, 1H,J=5.26,J=1.32),6.91(d, 1H,J=8.18),


7.15(m,1H),7.56(dt,1H,J=7.41,J=1.84).

13CNMR:(100MHz)30.40,153.51,141.22,119.86,113.69,121.76,109.94,141.22,40.07,153.81,112. 18,130.13,137.58,164.74,170.81,45.53,34.49,172.69,156.66,149.11,122.40,123.25,138.51.

Iso-Propyl 3-{[(2-{[(4-{N'-[(hexyloxy)carbonyl]carbamimidoyl}phenyl)amino]methyl}-1-

methyl-1H-benzimidazol-5-yl)carbonyl](2-pyridinyl)amino}propanoate, referred to as

Compound-7:

Preparation of Compound -7:


(Z)-3-(2-(((4-(N'-((hexyloxy)carbonyl)carbamimidoyl)phenyl)amino)methyl)-1-methyl-N- (pyridin-2-yl)-1H-benzo[d]imidazole-5-carboxamido)propanoic acid (500mg, 0,83mmol) is suspended at room temperature in isopropyl alcohol (10mL) and sulphuric acid is added


(0.9mL). Suspension is heated to reflux. Obtained solution is stirred at reflux for 2 hours. Reaction mixture is then cooled to room temperature and concentrated by evaporation. The residue was dissolved by addition of water (3.8 mL) and extracted with dichloromethane(5x5mL). Organic la...