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CAS No. : | 1142363-52-7 | MDL No. : | MFCD30489233 |
Formula : | C27H35N5O2 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | BNVPFDRNGHMRJS-UHFFFAOYSA-N |
M.W : | 461.60 | Pubchem ID : | 25230468 |
Synonyms : |
JNJ-527;JNJ-40346527
|
Chemical Name : | 5-Cyano-N-(2-(4,4-dimethylcyclohex-1-en-1-yl)-6-(2,2,6,6-tetramethyltetrahydro-2H-pyran-4-yl)pyridin-3-yl)-1H-imidazole-2-carboxamide |
Num. heavy atoms : | 34 |
Num. arom. heavy atoms : | 11 |
Fraction Csp3 : | 0.56 |
Num. rotatable bonds : | 5 |
Num. H-bond acceptors : | 5.0 |
Num. H-bond donors : | 2.0 |
Molar Refractivity : | 134.34 |
TPSA : | 103.69 Ų |
GI absorption : | Low |
BBB permeant : | No |
P-gp substrate : | Yes |
CYP1A2 inhibitor : | No |
CYP2C19 inhibitor : | Yes |
CYP2C9 inhibitor : | Yes |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -6.08 cm/s |
Log Po/w (iLOGP) : | 4.27 |
Log Po/w (XLOGP3) : | 4.28 |
Log Po/w (WLOGP) : | 5.78 |
Log Po/w (MLOGP) : | 1.93 |
Log Po/w (SILICOS-IT) : | 5.56 |
Consensus Log Po/w : | 4.36 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 0.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -5.31 |
Solubility : | 0.00227 mg/ml ; 0.00000492 mol/l |
Class : | Moderately soluble |
Log S (Ali) : | -6.17 |
Solubility : | 0.000312 mg/ml ; 0.000000676 mol/l |
Class : | Poorly soluble |
Log S (SILICOS-IT) : | -7.93 |
Solubility : | 0.00000536 mg/ml ; 0.0000000116 mol/l |
Class : | Poorly soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 2.0 |
Synthetic accessibility : | 4.25 |
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 |
---|---|---|
40% | In ethanol; at 20.0℃; for 1.0h; | Example 24 4-Cyano-1H-imidazole-2-carboxylic acid[2-(4,4-dimethyl-cyclohex-1-enyl)-6-(2,2,6,6-tetramethyl-tetrahydro-pyran-4-yl)-pyridin-3-yl]-amide methanesulfonic acid salt A solution of <strong>[1142363-52-7]4-cyano-1H-imidazole-2-carboxylic acid[2-(4,4-dimethyl-cyclohex-1-enyl)-6-(2,2,6,6-tetramethyl-tetrahydro-pyran-4-yl)-pyridin-3-yl]-amide</strong> (50.0 mg, 0.108 mmol, as prepared in Example 15, step (h)) in EtOH (2 mL) was treated with methanesulfonic acid (7.0 muL, 0.108 mmol) at room temperature for 1 h. The solvents were evaporated in vacuo, and the residue was dried under high vacuum overnight. The solid was dissolved in a minimum amount of EtOH (2 mL) with sonication and heating. While warm, the solution was slowly treated with hexanes (3 mL) to the cloud point. The mixture was heated again until clear, the sides of the vial were scratched, and the mixture was allowed to cool. The solid was filtered and air-dried to afford the title compound (24 mg, 40%) as white crystals. Mass spectrum (APCI, m/z): Calcd. for C27H35N5O2, 462.3 (M+H), found 462.3. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | In ethanol; at 20.0℃; for 1.0h; | Example 25 4-Cyano-1H-imidazole-2-carboxylic acid[2-(4,4-dimethyl-cyclohex-1-enyl)-6-(2,2,6,6-tetramethyl-tetrahydro-pyran-4-yl)-pyridin-3-yl]-amide(1S)-(+)-10-camphorsulfonic acid salt A solution of <strong>[1142363-52-7]4-cyano-1H-imidazole-2-carboxylic acid[2-(4,4-dimethyl-cyclohex-1-enyl)-6-(2,2,6,6-tetramethyl-tetrahydro-pyran-4-yl)-pyridin-3-yl]-amide</strong> (52.4 mg, 0.113 mmol, as prepared in Example 15, step (h)) in EtOH (2 mL) was treated with (1S)-(+)-10-camphorsulfonic acid (26.4 mg, 0.113 mmol) at room temperature for 1 h. The solvents were evaporated in vacuo, and the residue was dried under high vacuum overnight. The solid was dissolved in a minimum amount of EtOH (1 mL) with sonication and heating. While warm, the solution was slowly treated with hexanes until first precipitate was seen at the surface of the solution. The mixture was allowed to stir 30 min at room temperature while material continued to precipitate. The solid was filtered and air-dried to afford the title compound (66.2 mg, 84%) as white crystals. 1H-NMR (CD3OD; 400 MHz): delta 9.17 (d, 1H, J=8.4 Hz), 8.10 (s, 1H), 7.95 (d, 1H, J=8.4 Hz), 6.39-6.32 (m, 1H), 3.76-3.64 (m, 1H), 3.38-3.34 (m, 2H), 2.80-2.75 (m, 1H), 2.75-2.65 (m, 1H), 2.54-2.45 (m, 2H), 2.40-2.30 (m, 1H), 2.25-2.18 (m, 2H), 2.10-2.00 (m, 2H), 1.98-1.86 (m, 3H), 1.76-1.66 (m, 4H), 1.65-1.56 (m, 1H), 1.47-1.38 (m, 7H), 1.30 (s, 6H), 1.15 (m, 9H), 0.87 (s, 3H). Mass spectrum (APCI, m/z): Calcd. for C27H35N5O2, 462.3 (M+H), found 462.3. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
38% | With hydrogenchloride; In 1,4-dioxane; ethanol; at 20.0℃; for 1.5h; | Example 23 4-Cyano-1H-imidazole-2-carboxylic acid[2-(4,4-dimethyl-cyclohex-1-enyl)-6-(2,2,6,6-tetramethyl-tetrahydro-pyran-4-yl)-pyridin-3-yl]-amide hydrochloride salt A solution of <strong>[1142363-52-7]4-cyano-1H-imidazole-2-carboxylic acid[2-(4,4-dimethyl-cyclohex-1-enyl)-6-(2,2,6,6-tetramethyl-tetrahydro-pyran-4-yl)-pyridin-3-yl]-amide</strong> (49.2 mg, 0.107 mmol, as prepared in Example 15, step (h)) in EtOH (2 mL) was treated with HCl (26.6 muL, 0. 107 mmol, 4 M in dioxane) at room temperature for 1.5 h. The solvents were evaporated in vacuo, and the residue was dried under high vacuum overnight. The solid was dissolved in a minimum amount of EtOH (900 muL) with sonication and heating. While warm, the solution was slowly treated with hexanes (3 mL) to the cloud point. The mixture was heated again until clear, the sides of the vial were scratched, and the mixture was allowed to cool. The solid was filtered and air-dried to afford the title compound (20mg, 38%) as white crystals. 1H-NMR (CD3OD; 400 MHz): delta 9.17 (d, 1H, J=8.4 Hz), 8.10 (s, 1H), 7.95 (d, 1H, J=8.4 Hz), 6.38-6.32 (m, 1H), 3.76-3.65 (m, 1H), 2.54-2.46 (m, 2H), 2.25-2.19 (m, 2H), 1.98-1.91 (m, 2H), 1.76-1.65 (m, 4H), 1.43 (s, 6H), 1.30 (s, 6H), 1.15 (s, 6H). Mass spectrum (APCI, m/z): Calcd. for C27H35N5O2, 462.3 (M+H), found 462.3. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sulfuric acid; In water; acetonitrile; at 20.0℃; | Example 31 4-Cyano-1H-imidazole-2-carboxylic acid[2-(4,4-dimethyl-cyclohex-1-enyl)-6-(2,2,6,6-tetramethyl-tetrahydro-pyran-4-yl)-pyridin-3-yl]-amide sulfate salt A suspension of <strong>[1142363-52-7]4-cyano-1H-imidazole-2-carboxylic acid[2-(4,4-dimethyl-cyclohex-1-enyl)-6-(2,2,6,6-tetramethyl-tetrahydro-pyran-4-yl)-pyridin-3-yl]-amide</strong> (24.8 mg, 0.0537 mmol), as prepared in Example 15, in acetonitrile (1.0 mL) was heated to yield a solution. To the solution was added a solution of concentrated sulfuric acid (0.0062 mL) in water (0.5 mL) at room temperature. The solution was reduced via evaporation with flowing nitrogen gas (approximately 1.0 mL). The solution was then allowed to sit overnight at room temperature in a sealed vial. The resulting crystals were then collected via filtration and air-dried. The white solid was characterized by Powder X-Ray Diffraction (PXRD), Differential Scanning Calorimetry (DSC), Thremogravimetric Analysis (TGA), and single-crystal X-ray diffraction. The DSC for the sulfate salt showed a 241 degree Celsius endotherm maximum. The PXRD of the sulfate salt product is shown in and the prominent peaks are shown in the table below. Representative 2-Theta peaks of the sulfate salt product are shown below: |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | With tetrabutyl ammonium fluoride; In N,N-dimethyl-formamide; at 70.0℃; | h) 4-Cyano-1H-imidazole-2-carboxylic acid[2-(4,4-dimethyl-cyclohex-1-enyl)-6-(2,2,6,6-tetramethyl-tetrahydro-pyran-4-yl)-pyridin-3-yl]-amide To a solution of 4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylic acid[2-(4,4-dimethyl-cyclohex-1-enyl)-6-(2,2,6,6-tetramethyl-tetrahydro-pyran-4-yl)-pyridin-3-yl]-amide (as prepared in the previous example, 17.6 g, 0.0290 mol) in DMF (30 mL) was added solid TBAF hydrate (16.6 g, 0.0630 mol). The resulting mixture was heated at 70 C. overnight. The reaction mixture was allowed to cool to RT and partitioned between EtOAc (200 mL) and water (200 mL). The organic layer was separated, the aqueous layer was washed with EtOAc (3*100 mL) and the organic layers were combined, dried (Na2SO4) and concentrated. The resulting residue was dried under high vacuum to remove residual DMF. The residue was purified on silica gel (0-50% EtOAc/hexane). The resulting solid was then suspended in 25% ether/hexane and sonicated for 10 min. The product was collected by suction filtration and dried in a vacuum oven at 60 C. for 12 h to obtain the title compound as a white solid (10.2 g, 75%.) 1H-NMR (DMSO; 400 MHz): delta 14.26 (s, 1H), 10.02 (s, 1H), 8.32 (s, 1H), 8.12 (d, 1H, J=8.3 Hz), 7.24 (d, 1H, J=8.3 Hz), 5.86 (br s, 1H), 3.23 (m, 1H), 2.40 (m, 2H), 1.91 (m, 2H), 1.74 (dd, 2H, J=12.9, 3.3 Hz), 1.48 (m, 4H), 1.30 (s, 6H), 1.15 (s, 6H), 0.96 (s, 6H). Mass spectrum (ESI, m/z): Calcd. for C27H35N5O2, 462.2 (M+H), found 462.3. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sulfuric acid; In acetone; at 40.0℃; for 0.5h; | The salts and solid residues of Compound A were prepared using nine different acidic counter-ions, (wherein the acidic counter-ion is provided by the corresponding acid i.e., sulfuric, phosphoric, methanesulfonic, p-toluenesulfonic, benzenesulfonic, malonic, citric, 1 -malic, and acetic acids), using the following synthetic procedure; Nine samples of Compound A (about 20 mg) prepared as described in Example 1 were added to nine separate 4 mE vials. About 1.1 molar equivalents of the acid (i.e., sulfuric acid, phosphoric acid, methanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, malonic acid, citric acid, 1-malic acid, and acetic acid) solutions (0.1 M in acetone, freshly prepared) was independently added to each vial. The vials were stirred at 500 rpm and heat was applied as necessary. All solutions formed suspensions upon addition of the acid solution to Compound A, with the exception that the acetic acid solution remained a clear mixture. The suspensions were then heated to 40 C. with stirring for about 30 minutes, but no additional clear solutions were observed. Since the solubility of Compound A in acetone is about 130 mg/mE, the formation of a suspension was interpreted as an indication that a salt or other non-free base material (e.g. solvate, co-crystal, etc.) had formed. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In water; | The hydrochloride salt of Compound A was prepared as described in U.S. Pat. No. 8,497,376. Water (150 mL) was added to the hydrochloride salt of Compound A (about 10 g). The formed solution was stirred using a stir plate. After several days, the solution was filtered using a Buchner glass filter under vacuum until the majority of the water was removed. A flow of N2 gas was then applied onto the surface of the precipitate for about 1 hour to ensure complete removal of the solvent. The glass filter was weighed before and afier the filtration and the net weightwas recorded. | |
In water; | The hydrochloride salt of Compound A was prepared as described in US Patent No. 8,497,376. Water (150 mL) was added to the hydrochloride salt of Compound A (about 10g). The formed solution was stirred using a stir plate. After several days, the solution was filtered using a Buchner glass filter under vacuum until the majority of the water was removed. A flow of N2 gas was then applied onto the surface of the precipitate for about 1 hour to ensure complete removal of the solvent. The glass filter was weighed before and after the filtration and the net weight was recorded.A portion of the precipitate was analyzed using XRD and the results confirmed the conversion of the salt to the free base, Form I of Compound A. The glass filter was placed in a vacuum oven at 60C overnight to ensure complete dryness until a constant weight was obtained. The isolated solid (Form I of Compound A, as a freebase) was characterized using XRPD, DSC, TGA, and DVS. The isolated solid (Compound A, as a freebase) was a white crystalline solid, hygroscopic and insoluble in water as determined by USP methods. The isolated solid displayed an XRPD spectrum consistent with Compound A, Form I, having sharp and intense reflections indicating a crystalline form (as shown in Figure 10). The XRD for Form I of Compound A differed from the XRD of a sample of the HC1 salt of Compound A (e.g., Figure 15). The DSC spectmm of the isolated solid (Compound A, Form I) showed a broad endothermic peak up to 110C due to surface water loss followed by melting with onset and peak temperatures at187.5C and 204.6C, respectively, and a heat of fusion of 56.2 J/g (as shown in Figure 11). This also differed from the DSC spectrum of the HC1 salt of Compound A as shown in Figure16. Thermogravimetric analysis of the isolated solid (Compound A, Form I) showed a two-step weight loss of 0.9% between room temperature (RT, about 20C) and 182C (equivalent to 0.23 mole of water) due to surface water loss and 0.5% between 182C and 2 19C due to melting/decomposition (as shown in Figure 12). This differed from the TGA spectrum of the HC1 salt of Compound A (e.g., Figure 17).DVS of the isolated solid (Compound A, Form I) showed that it was hygroscopic with moisture adsorption of 41.8% up to 90%RH. The isolated solid (Compound A, Form I) also showed little hysteresis and retained 1.8% moisture (equivalent to 0.47 mole of water, hemihydrate form) at the end of a second moisture sorption-desorption cycle (as shown in Figure 13). A comparison of XRPD analysis of the isolated solid (before DVS) and the solid residue after DVS showed a substantially similar diffraction pattern, with only a single extra peak at 6.7 20 (Figure 14), indicating that the crystalline form did not change upon humidity cycling. The DVS spectra differed from the DVS for the HC1 salt of Compound A as shown in Figure 18. |
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