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CAS No. : | 915385-81-8 | MDL No. : | MFCD22666355 |
Formula : | C23H25ClN2O | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | CAOTVXGYTWCKQE-UHFFFAOYSA-N |
M.W : | 380.91 | Pubchem ID : | 15604015 |
Synonyms : |
Opaganib
|
Num. heavy atoms : | 27 |
Num. arom. heavy atoms : | 12 |
Fraction Csp3 : | 0.48 |
Num. rotatable bonds : | 5 |
Num. H-bond acceptors : | 2.0 |
Num. H-bond donors : | 1.0 |
Molar Refractivity : | 107.86 |
TPSA : | 41.99 Ų |
GI absorption : | High |
BBB permeant : | Yes |
P-gp substrate : | Yes |
CYP1A2 inhibitor : | No |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | Yes |
CYP2D6 inhibitor : | Yes |
CYP3A4 inhibitor : | Yes |
Log Kp (skin permeation) : | -5.31 cm/s |
Log Po/w (iLOGP) : | 3.4 |
Log Po/w (XLOGP3) : | 4.67 |
Log Po/w (WLOGP) : | 4.74 |
Log Po/w (MLOGP) : | 4.05 |
Log Po/w (SILICOS-IT) : | 5.25 |
Consensus Log Po/w : | 4.42 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 0.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -5.14 |
Solubility : | 0.00274 mg/ml ; 0.0000072 mol/l |
Class : | Moderately soluble |
Log S (Ali) : | -5.28 |
Solubility : | 0.002 mg/ml ; 0.00000526 mol/l |
Class : | Moderately soluble |
Log S (SILICOS-IT) : | -7.79 |
Solubility : | 0.00000623 mg/ml ; 0.0000000164 mol/l |
Class : | Poorly soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 2.0 |
Synthetic accessibility : | 4.48 |
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 |
---|---|---|
In tetrahydrofuran | 1 As an example, a process for the synthesis of Compound 62 is described in Scheme 1. The direct bromination of adamantane-1-carboxylic acid (1) in the presence of aluminum chloride (AlCl3) gave 3-bromide derivative (2) of 1 which was converted to (3) by the reaction of Friedel-Crafts reaction. 3 was reacted with thionyl chloride (SOCl2) to give 3-R-substituted-1-adamantanecarbonyl chlorides 4. By reaction 4 with a substituted amine, for example, 4-aminomethylpyridin (5), in THF, (6, also represented as Compound 62) and related amide compounds were obtained. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In toluene | 1; 2 3 reacted with an equimolar amount of 1,1'-carbonyl diimidazole (CDI) to give intermediate 3-R-substituted-1-adamantanecarbonyl imidazole (4). By reaction of 4 with a substituted amine, the corresponding adamantylamide was obtained. For example, reaction of 3 with 4-aminomethylpyridine (5), in toluene, produced {3-(4-Chloro-phenyl)-adamantane-1-carboxylic acid (pyridin-4-ylmethyl)-amide} (6 also represented as Compound 62) with a yield of 92.6% and a melting point of 128-130° C. 1H NMR(300 MHz, CDCl3) δ 1.72-2.25(m, 12H, Admant-CH), 4.44-4.46 (d, J=6 Hz, 2H, CH2-Py), 6.18 (m, 1H, HN), 7.13-7.15 (d, J=6 Hz, 2H, H-Py), 7.15-7.30 (m, 4H, H-Ph), 8.52-8.54 (d, J=6 Hz, 2H, H-Py); 13C NMR(300 MHz, CDCl3) δ 28.98, 35.73, 36.71, 38.77, 42.18, 42.37, 44.88, 122.38, 125.30, 126.57, 128.56, 129.26, 148.39, 150.20 177.76; MS m/z (rel intensity) 381.50 (MH+, 100), 383.41 (90), 384.35(80). Example 2 A Second Method for the Synthesis of Compound 62 A second method for the synthesis of Compound 62 and related adamantylamides is described in Scheme 2. 3-phenyl substituted intermediate (3) was prepared as described above. 3 reacted with 1,1'-carbonyldiimidazole (CDI) to give 3-R-substituted-1-adamantanecarbonylimidazole intermediate (4). By reaction of 4 with a substituted amine, for example 4-aminomethylpyridine 5, in toluene, 6 {3-(4-Chloro-phenyl)-adamantane-1-carboxylic acid(pyridin-4-ylmethyl)-amide} was obtained. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83.99 % | Stage #1: 3-(4-chlorophenyl)adamantane-1-carboxylic acid With oxalyl dichloride In toluene at 15 - 25℃; Large scale; Stage #2: 4-(aminomethyl)pyridine With triethylamine In toluene at 0 - 25℃; Large scale; | 6.S2; 7.S2; 8.S2 Small test is carried out to step S2, and its test concrete operation is: The specific operation of the test is as follows: add 4kg of toluene to a 10L three-mouth bottle equipped with mechanical stirring and thermometer, open the stirring, add 1.5kg (5.16 moles) 3-(4-chlorophenyl)-1-adamantanecarboxylic acid and 753g oxalyl chloride (5.93 moles) in turn, keep warm 15~25 °C and stir for 2-3h, the system is concentrated under reduced pressure at 40 °C until no liquid is produced, add 1kg of toluene, stir evenly and continue to concentrate at 40 °C under reduced pressure until no liquid is released, The resulting white solid was dissolved with 4kg of toluene to form a slightly turbid solution, which was recorded as an acid chloride solution for backup.Add 1kg of toluene, 614g (5.67 moles) of 4-aminomethylpyridine and 574g (5.67 moles) of triethylamine to another 10L three-mouth bottle equipped with mechanical stirring and thermometer; Turn on stirring, the system is cooled to 0~10 °C, the acid chloride solution prepared in advance is added to the reaction system droplets, after the dropwise addition is completed, the system is heated at 15~25 °C for stirring for 2h, the reaction system is concentrated under reduced pressure at no more than 55 °C until no liquid is released, add 3.0kg 1.0% hydrochloric acid aqueous solution, stir at room temperature for 20min, stand, filter, recrystallize the filter cake with toluene, filter, obtain a white to light yellow solid filter cake, dry the filter cake in a blast drying box at 40 °C to constant weight, weigh, The white to off-white solid was 1.65kg, the liquid phase purity was 99.12%, and the yield was 83.99%. |