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CAS No. : | 132866-11-6 | MDL No. : | MFCD07773089 |
Formula : | C36H42ClN3O6 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | WMFYOYKPJLRMJI-UHFFFAOYSA-N |
M.W : | 648.19 | Pubchem ID : | 157917 |
Synonyms : |
Lercanidipine (hydrochloride);Lercanidipine hydrochloride
|
Num. heavy atoms : | 46 |
Num. arom. heavy atoms : | 18 |
Fraction Csp3 : | 0.33 |
Num. rotatable bonds : | 14 |
Num. H-bond acceptors : | 7.0 |
Num. H-bond donors : | 1.0 |
Molar Refractivity : | 187.05 |
TPSA : | 113.69 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) : | -4.76 cm/s |
Log Po/w (iLOGP) : | 0.0 |
Log Po/w (XLOGP3) : | 7.74 |
Log Po/w (WLOGP) : | 6.9 |
Log Po/w (MLOGP) : | 3.67 |
Log Po/w (SILICOS-IT) : | 4.67 |
Consensus Log Po/w : | 4.6 |
Lipinski : | 1.0 |
Ghose : | None |
Veber : | 1.0 |
Egan : | 1.0 |
Muegge : | 2.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -8.1 |
Solubility : | 0.00000514 mg/ml ; 0.0000000079 mol/l |
Class : | Poorly soluble |
Log S (Ali) : | -9.97 |
Solubility : | 0.0000000694 mg/ml ; 0.0000000001 mol/l |
Class : | Poorly soluble |
Log S (SILICOS-IT) : | -9.99 |
Solubility : | 0.000000066 mg/ml ; 0.0000000001 mol/l |
Class : | Poorly soluble |
PAINS : | 0.0 alert |
Brenk : | 3.0 alert |
Leadlikeness : | 3.0 |
Synthetic accessibility : | 5.86 |
Signal Word: | Danger | Class: | 6.1 |
Precautionary Statements: | P264-P270-P301+P310+P330-P405-P501 | UN#: | 2811 |
Hazard Statements: | H301 | Packing Group: | Ⅲ |
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 |
---|---|---|
95% | Stage #1: With potassium carbonate In dichloromethane; water Stage #2: With hydrogenchloride In dichloromethane; water |
10 mmol I oxalate (Example 4) was dissolved in 100 ml dichloromethane and 20 mmol potassium carbonate in 20 ml water was added. The organic phase was separated. The aqueous phase was extracted with 2 x 10 ml dichloromethane. The combined organic phases were treated with 20 ml 1N hydrochloric acid. The organic phase was separated and was evaporated. The residue was treated with 2,000 ml of water containing 2 ml of 1N hydrochloride acid and 5 ml of water saturated with sodium chloride to form I hydrochloride hemihydrate, which was filtered. Yield:6.2 g (95 percent) Purity:99.8 percent (HPLC) Melting point:118-122 °C HPLC method:Column RP 18, 125 x 3 mm ID, 5 μm, det: 233 nm Eluent:0.01 mol Na2HPO4/MeOH/can : 25/65/10 tr ~ 15 min. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
42% | Stage #1: With triethylamine In propan-1-ol; dichloromethane at 25 - 30℃; Stage #2: at 75 - 80℃; for 10 h; Stage #3: With hydrogenchloride In propan-1-ol at 20 - 30℃; for 0.5 h; |
EXAMPLE 1[0076] Preparation of Lercanidipine Hydrochloride[0077] Into a 2L 4-neck round bottom flask, butanoic acid, 2-[(3- nitrophenyl)methylene]-3-oxo-2-[(3,3-diphenyl propyl)methylamino]- 1,1 -dimethyl ethyl ester hydrochloride (30 g) in methylene dichloride (39 ml) and n-propanol (300 ml), were charged at a temperature ranging from about 25°C to about 300C. Triethylamine (15 g) was added to adjust the pH to about 8 to about 9, as tested on pH paper. Methyl 3-amino crotonate (6.28 g) was added. The reaction mixture was heated to a temperature ranging from about 75°C to about 800C and stirred for about 10 hours. The reaction mixture was cooled and n-propanol was distilled out under vacuum completely at a temperature ranging from about 500C to about 550C. The residue was dissolved in n-propanol (150 ml) at a temperature ranging from about 300C to about 35°C and then cooled to a temperature ranging from about 25°C to about 300C. N-propanol/HCl (10 ml, 20percent HCl) was slowly added while maintaining the reaction mass at room temperature to adjust the pH to about 3 to about 4, as tested on pH paper. The reaction mixture was maintained for EPO <DP n="24"/>about 30 minutes at room temperature. N-propanol was stripped out with isopropyl acetate (60 ml) at a temperature ranging from about 300C to about 35°C. The residue was dissolved in isopropyl acetate (180 ml) and washed with water (2 X 180 ml). [0078] Activated charcoal (3 g) was added to the organic layer and stirred for about 15 minutes at a temperature ranging from about 25°C to about 300C. The organic layer was filtered through a hyflo bed and washed with isopropyl acetate (30 ml). The isopropyl acetate was distilled out completely under vacuum at a temperature below about 35°C and degassed for about 2 hours at a temperature below about 35°C. The residue was dissolved in methanol (15 ml) and isopropyl acetate (300 ml) at room temperature. The solution was seeded with pure lercanidipine hydrochloride in polymorph form V (30 g) and stirred with at about 15 rpm to about 18 rpm for about 24 hours. The solids were filtered and washed with isopropyl acetate (30 ml). The wet cake weighed about 25 grams. The product was dried in an oven at a temperature ranging from about 500C to about 55°C for about 8 hours wherein the loss on drying (LOD) was less than about 10.0percent. The dried product was lercanidipine hydrochloride weighing about 15 grams, with a yield of about 42percent and purity of about 98.5percent as determined by HPLC. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With hydrogenchloride In diethyl ether; tert-butyl methyl ether | 1.1 eq. of 2N HCl in Et2O was added dropwise under stirring to a solution of 1 g of lercanidipine free base in 20 mL of MTBE. The precipitate formed was filtered under vacuum, rinsed with MTBE and dried under vacuum (0.15 mmHg) at 300C for 4h affording a dry powder (Yield: 90percent), HPLC assay: 99,6percent. |
90% | With hydrogenchloride In ethanol; tert-butyl methyl ether | 1.1 eq. of 2N HCl in EtOH was added dropwise under stirring to a solution of 1 g of lercanidipine free base in 20 mL of methylterbutyl ether (MTBE). The precipitate formed was filtered under vacuum, rinsed with MTBE and dried under vacuum (0.15 mmHg) at 300C for 4h affording a dry powder (Yield: 90percent), HPLC assay: 99,6percent. |
85% | With hydrogenchloride In water; acetone for 0.0833333 - 24 h; | 1.1 eq of aqueous IN HCl was added under continuous stirring to a solution of 1 g of lercanidipine free base in 5 mL of acetone. Afterwards, 20 mL of water was added dropwise over a period of 5 min. to the viscous solution obtained. A gummy solid was formed that was isolated by centrifugation, rinsed with water, <n="8"/>decanted and dried under vacuum at 300C (0.15 mmHg) for 4 h affording a dry powder (Yield: 90percent). HPLC assay: 99,6percent.; Example IB:1.1 eq of aqueous IN HCl was added under continuous stirring to a solution of 1 g of lercanidipine free base in 5 rnL of acetone. The solution obtained after the HCl addition was dropped under stirring into 40 mL of water over a period of 5 min. obtaining a suspension. After 24 hours a gummy solid was formed that was isolated by centrifugation, rinsed with water, filtered, and dried under vacuum (0.15 mmHg) at 300C for 4 h affording a dry powder (Yield: 85percent), HPLC assay: 99,6percent. |
85% | With hydrogenchloride In ethanol; water for 0.0833333 h; | 1.1 eq of aqueous IN HCl was added under continuous stirring to a solution of Ig of lercanidipine free base in 5 mL of EtOH. The solution obtained after the HCl addition was dropped under stirring into 40 mL of water over a period of 5 min. A gummy solid was formed and was isolated by centrifugation, rinsed with water, filtered and dried under vacuum (0.15 mmHg) at 300C for 4 h affording a dry powder (Yield: 85percent), HPLC assay: 99,6percent. The DSC of lercanidipine hydrochloride obtained according to the present example is reported in figure 1. |
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