Structure of 137973-76-3
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CAS No. : | 137973-76-3 |
Formula : | C26H23ClN2O3 |
M.W : | 446.93 |
SMILES Code : | CC1=C(C=CC=C1)C(=O)NC1=CC(C)=C(C=C1)C(=O)N1CCCC(=O)C2=C1C=CC(Cl)=C2 |
MDL No. : | MFCD19440797 |
InChI Key : | VENGMROMZOKURN-UHFFFAOYSA-N |
Pubchem ID : | 11362843 |
GHS Pictogram: |
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Signal Word: | Warning |
Hazard Statements: | H302-H315-H319 |
Precautionary Statements: | P261-P305+P351+P338 |
Num. heavy atoms | 32 |
Num. arom. heavy atoms | 18 |
Fraction Csp3 | 0.19 |
Num. rotatable bonds | 5 |
Num. H-bond acceptors | 3.0 |
Num. H-bond donors | 1.0 |
Molar Refractivity | 130.54 |
TPSA ? Topological Polar Surface Area: Calculated from |
66.48 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
3.46 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
4.97 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
5.26 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
4.09 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
5.57 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
4.67 |
Log S (ESOL):? ESOL: Topological method implemented from |
-5.83 |
Solubility | 0.000664 mg/ml ; 0.00000148 mol/l |
Class? Solubility class: Log S scale |
Moderately soluble |
Log S (Ali)? Ali: Topological method implemented from |
-6.1 |
Solubility | 0.000351 mg/ml ; 0.000000786 mol/l |
Class? Solubility class: Log S scale |
Poorly soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-8.98 |
Solubility | 0.000000465 mg/ml ; 0.000000001 mol/l |
Class? Solubility class: Log S scale |
Poorly soluble |
GI absorption? Gatrointestinal absorption: according to the white of the BOILED-Egg |
High |
BBB permeant? BBB permeation: according to the yolk of the BOILED-Egg |
No |
P-gp substrate? P-glycoprotein substrate: SVM model built on 1033 molecules (training set) |
No |
CYP1A2 inhibitor? Cytochrome P450 1A2 inhibitor: SVM model built on 9145 molecules (training set) |
No |
CYP2C19 inhibitor? Cytochrome P450 2C19 inhibitor: SVM model built on 9272 molecules (training set) |
Yes |
CYP2C9 inhibitor? Cytochrome P450 2C9 inhibitor: SVM model built on 5940 molecules (training set) |
Yes |
CYP2D6 inhibitor? Cytochrome P450 2D6 inhibitor: SVM model built on 3664 molecules (training set) |
No |
CYP3A4 inhibitor? Cytochrome P450 3A4 inhibitor: SVM model built on 7518 molecules (training set) |
Yes |
Log Kp (skin permeation)? Skin permeation: QSPR model implemented from |
-5.5 cm/s |
Lipinski? Lipinski (Pfizer) filter: implemented from |
0.0 |
Ghose? Ghose filter: implemented from |
None |
Veber? Veber (GSK) filter: implemented from |
0.0 |
Egan? Egan (Pharmacia) filter: implemented from |
0.0 |
Muegge? Muegge (Bayer) filter: implemented from |
0.0 |
Bioavailability Score? Abbott Bioavailability Score: Probability of F > 10% in rat |
0.55 |
PAINS? Pan Assay Interference Structures: implemented from |
0.0 alert |
Brenk? Structural Alert: implemented from |
0.0 alert: heavy_metal |
Leadlikeness? Leadlikeness: implemented from |
No; 1 violation:MW<2.0 |
Synthetic accessibility? Synthetic accessibility score: from 1 (very easy) to 10 (very difficult) |
3.04 |
* 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 |
---|---|---|
96% | at 0℃; for 2 h; | 7-chloro-5-hydroxy-2,3,4,5-tetrahydro-1H-1- benzazepine (19.0g, 42.51mmol) was dissolved in methanol (200ml) in a solvent, at 0 for Conditional batch of sodium borohydride (2.42g, 63.77mmol), after the addition was complete stirring was continued for 2h, TLC the reaction was complete. The reaction mixture was poured into water, extracted with methylene chloride, dried over anhydrous sodium sulfate, filtration and vacuum distillation of crude with methanol: petroleum ether (2: 1) and recrystallized to give a white solid tolvaptan (18.33g , 96.0percent). |
94% | at 20℃; for 5 h; | The compound (X) (20.0 g, 44.75 mmol) was dissolved in methanol (200 mL), sodium borohydride (3.39 g, 89.50 mmol) was added at room temperature and stirred for 5 h at room temperature. The reaction solution was poured into an ice-water bath (100 mL), quenched, the methanol was removed, the residue was extracted with dichloromethane (3 x 100 mL), the organic phases were combined and the organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulphate , Filtered and evaporated under reduced pressure to give a crude product which was recrystallized from methanol: petroleum ether (2: 1) to give tolvaptan as a white solid (18.89 g, 94percent). |
94.2% | With sodium bis(2-methoxyethoxy)aluminium dihydride In tetrahydrofuran at -5 - 20℃; | 5 g of the compound of Formula II is added to a 100 mL three-necked bottle,Then add 25mL of tetrahydrofuran,Stir and dissolveCool down to -5 ~ 0 °C,Temperature control -5 ~ 0 °C,1.73g of a 70wtpercent solution of sodium dihydrobis(2-methoxyethoxy)aluminate in toluene was added dropwise.After the completion of heating up to 10 ~ 20 °C,The reaction was stirred for 2 h.When the HPLC reaction is complete,Temperature control 10 ~ 20 °C,Add 50mL of water,There is a solid precipitated,Continue stirring for 1-2 hours, suction filtration, filter cake recrystallized with aqueous methanol,Drying under reduced pressureA white crystal of tolvaptan 4.73 g was obtained with a yield of 94.2percent.HPLC purity was 99.97percent, dechlorination impurity IV was not detected. |
92% | for 1 h; | To a 1 L reactor was added 7-chloro-1- [2-methyl-4 - [(2-methylbenzoyl) amino] benzoyl] -5-oxo-2,3,4,5-tetrahydro- 1 H- 1 -benzazepine .0 g, 179.00 mmol) and methanol (675 ml), and the mixture was stirred for 30 minutes. Sodium borohydride (2.37 g, 62.65 mmol) was added to the reaction mixture and stirred for 1 hour. Thereafter, 0.5percent dilute hydrochloric acid (232 ml) was gradually added to the reaction mixture, and the mixture was gradually cooled at room temperature. When crystals were precipitated, the reaction mixture was filtered, and the resulting filtrate was dried under reduced pressure to obtain 7-chloro-5-hydroxy-1- [2-methyl-4- (2- methylbenzoylamino) benzoyl ] -2,3,4,5-tetrahydro-1 H-1-benzazepine (73.9 g, 92percent). |
91.2% | With sodium tetrahydroborate In methanol; water at 25℃; for 1 h; | 7-chloro-1-[2-methyl-4-(2-methyl benzoyl amino) benzoyl]-5 oxo-2,3,4,5-tetrahydro-1H-1-benzazepine (25 gm.) was suspended in methanol (600 ml) & water (180 ml) and then added sodium borohydride (2.95 gm.) at 25° C. and the reaction mixture was stirred for 1hr. To the reaction mixture was added hydrochloric acid (150 ml). Then the reaction mixture was stirred for 2 hours. The solid obtained was collected by filtration and dried to give 7-chloro-5-hydroxy-1-[2-methyl-4-(2-methyl benzoyl amino) benzoyl]-2,3,4,5-tetrahydro-1H-1-benzazepine (22.8 gm). Yield—91.2percent; Purity (HPLC)—98.92percent; Dehalogenated Impurity—0.01percent |
79.6% | at 15 - 30℃; for 1 h; | 10.0 g of intermediate compound IV,110ml of methanol into 250ml reaction flask, stirring, less than 15 under the conditions of adding 0.56g NaBH4, heated to 30 reaction,The solid gradually precipitated. After 1h, the sample TLC showed no raw material. After 2h, 0.75percent hydrochloric acid was added dropwise to terminate the reaction. After stirring for 0.5h, the mixture was cooled to 0 ° C and stirred for 2h. The mixture was filtered to obtain 9.0g of a white solid. The resulting solid methanol and water were recrystallized, filtered,Drying in vacuo at 60 ° C for 8 hours afforded 8.0 g of a white solid with a yield of 79.6percent HPLC purity of 99.9percent. |
57 g | Stage #1: With sodium tetrahydroborate In methanol at 20℃; for 1 h; Stage #2: With hydrogenchloride In water |
Example 5 Preparation of Tolvaptan 7-Chloro-1-[2-methyl-4-[(2-methylbenzoyl)amino]benzoyl]-5-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine (63 gm) as obtained in example 4 was dissolved in methanol (570 ml) and then added sodium borohydride (2.07 gm) at room temperature. The reaction mass was stirred for 1 hour and pH of the reaction mass was adjusted to 6.0 to 7.0 with hydrochloric acid solution (1percent, 630 ml). The separated solid was filtered and dried to obtain 57 gm of tolvaptan. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | Stage #1: With sodium tetrahydroborate In methanol for 1 h; Stage #2: With hydrogenchloride In methanol; water at 20℃; |
Example 2; Preparation of 7-chloro-5-hydroxy- l-[2-methyl-4-(2-methyl- benzoylamino)benzoyl]-2,3,4,5-tetrahydro- IH- 1-benzazepine; 7-Chloro-l-[2-methyl-4-(2-methylbenzoylamino)benzoyl]-2, 3,4,5- tetrahydro-lH-l-benzazepin-5-one (3.2 g, 7.1 mM) is suspended in methanol (27 mL), and thereto is added at one time crystalline sodium borohydride (96 mg = 2.5 mM), and the mixture is reacted for about one hours. To the reaction mixture is added dropwise 0.5percent diluted hydrochloric acid (9.3 mL), and the mixture is stirred at room temperature and then cooled. The precipitated crystals are separated by filtration, and dried at room temperature to give the desired 7- chloro-5-hydroxy- 1 - [2 -methyl-4- (2 -methylbenzoylamino) benzoyl] - 2,3,4,5-tetrahydro- IH- 1-benzazepine (2.97 g) as white powder (Yield 92 percent, Mp 224.5-225.5°C). The pure 7-chloro-5-hydroxy-l-[2-methyl-4~(2-methylbenzoyl- amino)benzoyl]-2,3,4,5-tetrahydro- IH- 1-benzazepine is obtained by recrystallizing the above product from methanol/ water (4 : 1). The product thus obtained is while crystalline powder (yield of recrystallization, 90 percent, purity more than 99.5 percent, Mp 226-227.5°C). The 7-chloro-5-hydroxy-l-[2-methyl-4-(2-methylbenzoylamino)- benzoyl]-2,3,4,5-tetrahydro- IH- 1-benzazepine thus obtained has the following physical data; (1) NMR spectrum data, (2) IR spectrum data, (3) MS spectrum data and (4) powder X-ray diffraction spectrum data. (1) NMR spectrum: 1H NMR (300MHz, DMSO-d6): major conformational isomer δ= 1.49 (br EPO <DP n="35"/>ddd, J= I 1.3Hz, J= I 1.3Hz, J= I 1.3Hz, IH), 1.74 (br d, J= I 1.3Hz, IH), 1.95 (br ddd, J= I 1.3Hz, J= I 1.3Hz, J=I 1.3Hz, IH), 2.11 (br d, J= I 1.3Hz, IH), 2.34 (s, 6H), 2.68 (br dd, J= I 1.3Hz, J= I 1.3Hz, IH), 4.64 (br d, J=I 1.3Hz, IH), 4.90 (br d, J= 11.3Hz, IH), 5.70 (br d, J=4.6Hz, IH), 6.74 (d, J=8.2Hz, IH), 6.76 (d, J= 10. IHz, IH), 7.05 (dd, J=8.2Hz, J=2.3Hz, IH), 7.25-7.29 (m, 3H), 7.37 (dd, J=7.3Hz, J=7.3Hz, IH), 7.41 (d, J=7.3Hz, IH), 7.50 (d, J=2.3Hz, IH), 7.60 (s, IH), 10.2 (s, IH)(2) IR spectrumIR (KBr): 3397, 3221, 2926, 1657, 1622, 1609, 1395, 1304, 1094, 866, 827, 745 cm-1(3) MS spectrumMS (FAB): m/z = 449 (MH+); (4) Powder X-ray diffraction spectrum 2Ψ = 4.7, 15.4, 18.7, 21.7, 23.5°. The purity is measured by high performance liquid chromatography (HPLC) under the following conditions:Detector: Ultraviolet absorptiometer (UV 254 nm), column: YMC- Pack ODS-A A-312, column temperature: around 25°C, mobile phase: acetonitrile/ water/ phosphoric acid solution (500 : 500 : 1) or acetonitrile/water/phosphoric acid solution (700 : 300 : 1). |
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