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CAS No. : | 211915-06-9 | MDL No. : | MFCD16038312 |
Formula : | C34H41N7O5 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | KSGXQBZTULBEEQ-UHFFFAOYSA-N |
M.W : | 627.73 | Pubchem ID : | 135565674 |
Synonyms : |
BIBR 1048
|
Num. heavy atoms : | 46 |
Num. arom. heavy atoms : | 21 |
Fraction Csp3 : | 0.35 |
Num. rotatable bonds : | 19 |
Num. H-bond acceptors : | 8.0 |
Num. H-bond donors : | 2.0 |
Molar Refractivity : | 178.89 |
TPSA : | 154.03 Ų |
GI absorption : | Low |
BBB permeant : | No |
P-gp substrate : | Yes |
CYP1A2 inhibitor : | No |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | Yes |
CYP2D6 inhibitor : | Yes |
CYP3A4 inhibitor : | Yes |
Log Kp (skin permeation) : | -6.12 cm/s |
Log Po/w (iLOGP) : | 4.98 |
Log Po/w (XLOGP3) : | 5.65 |
Log Po/w (WLOGP) : | 5.26 |
Log Po/w (MLOGP) : | 2.19 |
Log Po/w (SILICOS-IT) : | 4.87 |
Consensus Log Po/w : | 4.59 |
Lipinski : | 2.0 |
Ghose : | None |
Veber : | 2.0 |
Egan : | 1.0 |
Muegge : | 4.0 |
Bioavailability Score : | 0.17 |
Log S (ESOL) : | -6.38 |
Solubility : | 0.000265 mg/ml ; 0.000000421 mol/l |
Class : | Poorly soluble |
Log S (Ali) : | -8.65 |
Solubility : | 0.00000141 mg/ml ; 0.0000000022 mol/l |
Class : | Poorly soluble |
Log S (SILICOS-IT) : | -9.66 |
Solubility : | 0.000000137 mg/ml ; 0.0000000002 mol/l |
Class : | Poorly soluble |
PAINS : | 0.0 alert |
Brenk : | 3.0 alert |
Leadlikeness : | 3.0 |
Synthetic accessibility : | 4.72 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H302-H315-H319-H335 | Packing Group: | N/A |
GHS Pictogram: |
* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
63.3% | Stage #1: With potassium carbonate In tetrahydrofuran; water at 20℃; for 0.333333 h; Stage #2: at 20℃; for 5 h; |
General procedure: Compound 1 (2 g, 3.7 mmol) was dissolved in 60 mL of THF and 12 mL of water. Potassium carbonate (1.55 g, 11.2 mmol) was added, and the mixture was stirred at room temperature for 20 min. Then, n-hexyl chloroformate (0.74 g, 4.5 mmol) was added drop-wise and stirring was continued for another 5 h. The organic phase was separated, dried over anhydrous sodium sulfate, and concentrated in vacuum. The residue was chromatographed (silica gel, dichloromethane/methanol 25:1) to afford the title compound 1.47 g as colorless crystals: yield 63.3percent, m.p. [4] 130-132 °C, 1H NMR (300 MHz DMSO-d6) δ (ppm): 0.87 (3H, t, J = 6.9 Hz, -CH2CH2CH3), 1.12 (3H, t, J = 7.2 Hz, -CH2CH3), 1.27-1.29 (6H, m, -CH2CH2CH2CH2CH3), 1.57 (2H, q, J = 6.6 Hz, -OCH2CH2CH2-), 2.68 (2H, t, J = 6.9 Hz, >NCH2CH2-), 3.77 (3H, s, >NCH3), 3.94-4.00 (4H, m, -OCH2CH3, -OCH2CH2CH2-), 4.22, (2H, t, J = 6.9 Hz, >NCH2CH2-), 4.59 (2H, d, J = 5.4 Hz, -CH2NH-), 6.76 (2H, d, J = 8.7 Hz, ArH), 6.88 (1H, d, J = 8.1 Hz, ArH), 6.98 (1H, m, NH), 7.10-7.17 (2H, m, ArH), 7.39 (1H, d, J = 8.4 Hz, ArH), 7.47 (1H, s, ArH), 7.54 (1H, t, J = 7.7 Hz, ArH), 7.79 (2H, d, J = 8.7 Hz, ArH), 8.39 (1H, d, J = 4.8 Hz, ArH), 8.60-9.30 (2H, brs, -NH2); ESI-MS(m/z): 628.4[M + H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
16.4 g | Stage #1: With potassium carbonate In water; acetonitrile at 27℃; for 0.5 h; Stage #2: at 12 - 20℃; for 2 h; |
Reference Example-2: Preparation of Dabigatran etexilate free base To a stirred suspension of p-TSA salt of l-methyl-2-[N-(4-amidinophenyl)-aminomethyl]- benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide(20g) in acetonitrile (80 mL), at 27°C, was charged a solution of potassium carbonate (24.7 g) in DM water (50 mL).The reaction mass was stirred for 30 min, and then cooled to 12-15°C. n-Hexyl chloroformate (4.9g) was added and stirred for 30 min. The temperature of the reaction mass was raised 17°C and stirred for 30 min. Second lot of n-hexylchloroformate (1.49 g) was charged and the reaction mass stirred for another hour at 16-20°C, when analytical HPLC revealed completion of the reaction. DM water (50mL) was added and the reaction mass slurred for 15 min at 30°C. The precipitate was filtered, washed with water, dried under vacuum, at 50°C, to afford Dabigatran Etexilate as off-white solid material ( 16.4g, >96percent hplc pure). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | at 26 - 36℃; Industry scale | Ethyl 3 - [(2- { [4-(hexyloxycarbonylarninoimmomemyl)phenylammo]methyl } -1 - methyl- lH-benzimidazole-5-carbonyl)pyridm-2-ylamino]propionate base (52.6 kg) (which has preferably been purified beforehand by recrystallization from ethyl acetate) is placed in an agitator apparatus which has been rendered inert and then 293 kg of acetone is added. The contents of the apparatus are heated to 40° C to 46° C with stirring. After a clear solution has formed, the contents of the apparatus is filtered into a second agitator apparatus through a lens filter and then cooled to 30° C to 36° C. 33 kg of acetone precooled to 0° C to 5° C, 7.9 kg of 99.5percent methanesulfonic acid, and for rinsing another 9 kg of acetone are placed in the suspended container of the second apparatus. The contents of the suspended container are added in metered amounts to the solution of ethyl 3-[(2-[4-(hexyloxycarbonylamino- iminomethyl)phenylamino]methyl} - 1 -methyl- 1 H-benzimidazole-5-carbonyl)pyridin-2- ylamino]propionate base at 26° C to 36° C within 15 to 40 minutes. Then the mixture is stirred for 40 to 60 minutes at 26° C to 33° C. It is then cooled to 17° C to 23° C and stirred for a further 40 to 80 minutes. The crystal suspension is filtered through a filter dryer and washed with a total of 270 L of acetone. The product is dried in vacuum at a maximum of 50° C for at least 4 hours. Yield: 54.5-59.4 kg;90percent-98percent of theory based on ethyl 3-[(2-[4-(hexyloxycarbonyl- ammoiminomethyl)phenylamino]methyl} - 1 -methyl- 1 H-benzimidazole-5-carbonyl)- pyridm-2-ylamino]propionate base. |
24 g | at 28 - 45℃; for 1 h; | A solution of Dabigatran Etexilate (23g) in acetone (184 mL), at 39-45°C was filtered and then cooled to 30°C. Pre-cooled solution of methanesuiphonic acid (3.24g) inacetone (23 mL) was, slowly, added to the reaction mass and then stirred for lh, at 28-32°C. The reaction mass was cooled to 19-23°C and slurred for another hour. The precipitated product was filtered, washed with acetone and dried, under vacuum, at 50°C, to afford mesylate salt of Dabigatran Etexilate as pale yellow colored solid material (24 g, >99percent HPLC pure). |