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CAS No. : | 1373268-67-7 | MDL No. : | N/A |
Formula : | C24H34N6O | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | XNUNVQKARNSSEO-UHFFFAOYSA-N |
M.W : | 422.57 | Pubchem ID : | 56961879 |
Synonyms : |
|
Num. heavy atoms : | 31 |
Num. arom. heavy atoms : | 12 |
Fraction Csp3 : | 0.54 |
Num. rotatable bonds : | 6 |
Num. H-bond acceptors : | 5.0 |
Num. H-bond donors : | 1.0 |
Molar Refractivity : | 135.66 |
TPSA : | 64.6 Ų |
GI absorption : | High |
BBB permeant : | Yes |
P-gp substrate : | Yes |
CYP1A2 inhibitor : | No |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | Yes |
CYP3A4 inhibitor : | Yes |
Log Kp (skin permeation) : | -6.77 cm/s |
Log Po/w (iLOGP) : | 3.26 |
Log Po/w (XLOGP3) : | 2.97 |
Log Po/w (WLOGP) : | 1.78 |
Log Po/w (MLOGP) : | 1.7 |
Log Po/w (SILICOS-IT) : | 1.99 |
Consensus Log Po/w : | 2.34 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 0.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -4.22 |
Solubility : | 0.0254 mg/ml ; 0.0000601 mol/l |
Class : | Moderately soluble |
Log S (Ali) : | -3.99 |
Solubility : | 0.0433 mg/ml ; 0.000102 mol/l |
Class : | Soluble |
Log S (SILICOS-IT) : | -5.45 |
Solubility : | 0.0015 mg/ml ; 0.00000356 mol/l |
Class : | Moderately soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 3.93 |
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 |
---|---|---|
2% |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
67.3% | With sodium tris(acetoxy)borohydride; In dichloromethane; at 20℃; for 20h; | Intermediate 2 (4.88 g, 16.4 mmol) was dissolved in DCM (200 mL). 1 -(Propan- 2-yl)piperidin-4-one (4.88 mL, 32.8 mmol) and sodium triacetoxyborohydride (17.4 g, 82.1 mmol) were added and the reaction mixture stirred for 20 h. The reaction mixture was diluted with DCM (200 mL) and quenched with sat aq Na2C03 solution (100 mL). The aqueous layer was extracted with DCM (100 mL). The organic layers were combined, washed with brine (50 mL), dried (MgS04) and the solvents removed in vacuo. The residue was purified by crystallisation from MeCN followed by reverse phase column chromatography. The residue was partitioned between DCM (300 mL) and sat aq Na2C03 solution (100 mL). The aqueous layer was extracted with DCM (50 mL) and the organic layers were combined, washed with brine (50 mL), dried (MgS04) and the solvents removed in vacuo. The residue was crystallised from MeCN to give the title compound (4.66 g, 67.3%) as a light yellow solid. (0068) HPLC: Rt 3.47 min, 100% purity (0069) LCMS (ES+): 423.2 [MH]+ (0070) H NMR (500 MHz, DMSO-d6) deltaEta 10.31 (1 H, s, NH), 8.52-8.50 (2H, m, ArH), (0071) 7.84-7.82 (2H, m, ArH), 7.70 (1 H, dd, J 8.5 and 7.3 Hz, ArH), 7.30 (1 H, d , J 7.2 Hz, ArH), 6.93 (1 H, d, J 8.7 Hz, ArH), 3.80 (2H, m, NCH_2), 3.76 (2H, m, NCH2), 2.82-2.79 (2H, m, NCH2), 2.77-2.73 (2H, m, NCH2), 2.62 (1 H, spt, J 6.6 Hz, (0072) CHMe), 2.58-2.56 (2H, m, NCH2), 2.39-2.33 (1 H, m, NCHCH2), 2.05-1 .88 (2H, m, NCH2), 1 .85-1 .78 (2H, m, CH2), 1 .65-1 .60 (2H, m, NCHCH2), 1 .36 (2H, qd, J (0073) 1 1 .7 and 3.4 Hz, NCHCH2), 0.91 (6H, d, J 6.6 Hz, CH(CH3)2) (0074) IR (solid) vmax/cm"1 3328, 2936, 2358, 2162, 1982, 1682, 1597, 1582, 1510, 1485, 1459, 1418, 1404, 1383, 1364, 1336, 1282, 1246, 1211, 1 179, 1 161, 1 125, 1070, 1030, 994, 972, 926, 898, 878, 824, 814, 758, 681 and 617 (0075) Melting point: 157-159 C. |
67.3% | With sodium tris(acetoxy)borohydride; In dichloromethane; for 20h; | Intermediate 2 (4.88 g, 16.4 mmol) was dissolved in DCM (200 mL). 1 - (Propan-2-yl)piperidin-4-one (4.88 mL, 32.8 mmol) and sodium triacetoxyborohydride (17.4 g, 82.1 mmol) were added and the reaction mixture stirred for 20 h. The reaction mixture was diluted with DCM (200 mL) and quenched with sat aq Na2C03 solution (100 mL). The aqueous layer was extracted with DCM (100 mL). The organic layers were combined, washed with brine (50 mL), dried (MgS04) and the solvents removed in vacuo. The residue was purified by crystallisation from MeCN followed by reverse phase column chromatography. The residue was partitioned between DCM (300 mL) and sat aq Na2C03 solution (100 mL). The aqueous layer was extracted with DCM (50 mL) and the organic layers were combined, washed with brine (50 mL), dried (MgS04) and the solvents removed in vacuo. The residue was crystallised from MeCN to give the title compound (4.66 g, 67.3%) as a light yellow solid. (0103) HPLC: Rt 3.47 min, 100% purity (0104) LCMS (ES+): 423.2 [MH]+ (0105) H NMR (500 MHz, DMSO-d6) deltaEta 10.31 (1 H, s, NH), 8.52-8.50 (2H, m, ArH), (0106) 7.84-7.82 (2H, m, ArH), 7.70 (1 H, dd, J 8.5 and 7.3 Hz, ArH), 7.30 (1 H, d , J 7.2 Hz, ArH), 6.93 (1 H, d, J 8.7 Hz, ArH), 3.80 (2H, m, NCH_2), 3.76 (2H, m, NCH2), (0107) 2.82-2.79 (2H, m, NCH2), 2.77-2.73 (2H, m, NCH2), 2.62 (1 H, spt, J 6.6 Hz, (0108) CHMe), 2.58-2.56 (2H, m, NCH2), 2.39-2.33 (1 H, m, NCHCH2), 2.05-1 .88 (2H, m, NCH2), 1 .85-1 .78 (2H, m, CH2), 1 .65-1 .60 (2H, m, NCHCH2), 1 .36 (2H, qd, J (0109) 1 1 .7 and 3.4 Hz, NCHCH2), 0.91 (6H, d, J 6.6 Hz, CH(CH3)2) (0110) IR (solid) Vmax/cm"1 3328, 2936, 2358, 2162, 1982, 1682, 1597, 1582, 1510, 1485, 1459, 1418, 1404, 1383, 1364, 1336, 1282, 1246, 1211, 1 179, 1 161, 1 125, 1070, 1030, 994, 972, 926, 898, 878, 824, 814, 758, 681 and 617 (0111) Melting point: 157-159 C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1.1: oxalyl dichloride; N,N-dimethyl-formamide / dichloromethane / 0.5 h / 20 °C 1.2: 0 - 20 °C 2.1: N,N-dimethyl acetamide / 0.5 h / 180 °C 3.1: sodium tris(acetoxy)borohydride / dichloromethane / 20 h / 20 °C | ||
Multi-step reaction with 3 steps 1.1: oxalyl dichloride; N,N-dimethyl-formamide / dichloromethane / 0.5 h 1.2: 0.5 h / 0 - 20 °C 2.1: 0.5 h / 180 °C / Microwave irradiation 3.1: sodium tris(acetoxy)borohydride / dichloromethane / 20 h | ||
Multi-step reaction with 3 steps 1.1: oxalyl dichloride / N,N-dimethyl-formamide; dichloromethane / 1 h / 15 - 25 °C 1.2: 3 h / 15 - 25 °C 2.1: N,N-dimethyl acetamide / 3 h / 40 - 120 °C 3.1: acetic acid / dichloromethane / 0.5 h / 15 - 25 °C 3.2: 5 h |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1.1: oxalyl dichloride; N,N-dimethyl-formamide / dichloromethane / 0.5 h / 20 °C 1.2: 0 - 20 °C 2.1: N,N-dimethyl acetamide / 0.5 h / 180 °C 3.1: sodium tris(acetoxy)borohydride / dichloromethane / 20 h / 20 °C | ||
Multi-step reaction with 3 steps 1.1: oxalyl dichloride; N,N-dimethyl-formamide / dichloromethane / 0.5 h 1.2: 0.5 h / 0 - 20 °C 2.1: 0.5 h / 180 °C / Microwave irradiation 3.1: sodium tris(acetoxy)borohydride / dichloromethane / 20 h | ||
Multi-step reaction with 3 steps 1.1: oxalyl dichloride / N,N-dimethyl-formamide; dichloromethane / 1 h / 15 - 25 °C 1.2: 3 h / 15 - 25 °C 2.1: N,N-dimethyl acetamide / 3 h / 40 - 120 °C 3.1: acetic acid / dichloromethane / 0.5 h / 15 - 25 °C 3.2: 5 h |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: C16H19N5O*ClH With sodium hydroxide In dichloromethane at 20 - 30℃; for 0.5h; Stage #2: 1-Isopropyl-4-piperidone With acetic acid In dichloromethane at 15 - 25℃; for 0.5h; Stage #3: With sodium tris(acetoxy)borohydride In dichloromethane at 5℃; | 1.3 Step 3 - Preparation of Stage 3 To a vessel was added dichloromethane (10 volumes) and the solution from Step 2 (0.5 eq.). A solution of 0.5 M sodium hydroxide was added (5 volumes) and the mixture was stirred at 20°C - 30°C for at least 30 minutes. The bottom organic layer was discharged to drums and the aqueous layer was re-extracted with more dichloromethane (2.5 volumes). The bottom organic layer was discharged to drums and the aqueous layer to waste. The above operation was repeated on the second 0.5 equivalent of the solution from Step 2. The combined organic layers are added back to the vessel and dichloromethane was distilled at atmospheric pressure to concentrate the batch down to approximately 1 1 volumes. The batch temperature was adjusted to 15°C - 25°C and then 1 - isopropyl-4-piperidone (1.25 eq.) and acetic acid (1.2 eq.) were added, followed by a dichloromethane line rinse. The mixture was stirred for at least 30 minutes and then charged with sodium triacetoxyborohydride (1.5 eq.) and additional dichloromethane (1.8 volumes). The mixture was stirred for not less than 5 hours before sampling for reaction completion. The reaction was quenched by charging 1 M sodium carbonate solution (8.3 volumes) over 1 hour and stirring for an additional 2 hours. The layers are separated and the organic phase was washed with water (3 volumes). The organic phase was transferred to a separate vessel and dichloromethane was distilled at atmospheric pressure down to approximately 3.6 volumes. The vessel was charged with methyl ethyl ketone (11 volumes) and distilled at atmospheric pressure down to a level of 5 volumes. The mixture was cooled to 0°C - 5°C, stirred for 1 hour and then transferred to the filter. The wet cake was washed with methyl ethyl ketone (1.1 volumes) at 0°C - 5°C and dried for at least 12 hours at room temperature until the LOD (method discussed above) was not more than 2%. | |
Stage #1: 1-Isopropyl-4-piperidone; C16H19N5O*ClH With acetic acid In dichloromethane at 15 - 25℃; for 0.5h; Stage #2: With sodium tris(acetoxy)borohydride In dichloromethane for 5h; | 1.3 Step 3 - Preparation of Stage 3 To a vessel was added dichloromethane (10 volumes) and the solution from Step 2 (0.5 eq.). A solution of 0.5 M sodium hydroxide was added (5 volumes) and the mixture was stirred at 20°C - 30°C for at least 30 minutes. The bottom organic layer was discharged to drums and the aqueous layer was re-extracted with more dichloromethane (2.5 volumes). The bottom organic layer was discharged to drums and the aqueous layer to waste. The above operation was repeated on the second 0.5 equivalent of the solution from Step 2. The combined organic layers are added back to the vessel and dichloromethane was distilled at atmospheric pressure to concentrate the batch down to approximately 1 1 volumes. The batch temperature was adjusted to 15°C - 25°C and then 1 - isopropyl-4-piperidone (1.25 eq.) and acetic acid (1.2 eq.) were added, followed by a dichloromethane line rinse. The mixture was stirred for at least 30 minutes and then charged with sodium triacetoxyborohydride (1.5 eq.) and additional dichloromethane (1.8 volumes). The mixture was stirred for not less than 5 hours before sampling for reaction completion. The reaction was quenched by charging 1 M sodium carbonate solution (8.3 volumes) over 1 hour and stirring for an additional 2 hours. The layers are separated and the organic phase was washed with water (3 volumes). The organic phase was transferred to a separate vessel and dichloromethane was distilled at atmospheric pressure down to approximately 3.6 volumes. The vessel was charged with methyl ethyl ketone (11 volumes) and distilled at atmospheric pressure down to a level of 5 volumes. The mixture was cooled to 0°C - 5°C, stirred for 1 hour and then transferred to the filter. The wet cake was washed with methyl ethyl ketone (1.1 volumes) at 0°C - 5°C and dried for at least 12 hours at room temperature until the LOD (method discussed above) was not more than 2%. |