Structure of 64119-42-2
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The BI-3802 was designed by Boehringer Ingelheim and could be obtained free of charge through the Boehringer Ingelheim open innovation portal opnMe.com, associated with its negative control.
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CAS No. : | 64119-42-2 |
Formula : | C10H9ClN2O2 |
M.W : | 224.64 |
SMILES Code : | O=C(OCC)C1=C(C)N=C(Cl)C(C#N)=C1 |
MDL No. : | MFCD00179894 |
InChI Key : | QXZBVLFURRXJLB-UHFFFAOYSA-N |
Pubchem ID : | 2786689 |
GHS Pictogram: |
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Signal Word: | Warning |
Hazard Statements: | H302 |
Precautionary Statements: | P280-P305+P351+P338 |
Num. heavy atoms | 15 |
Num. arom. heavy atoms | 6 |
Fraction Csp3 | 0.3 |
Num. rotatable bonds | 3 |
Num. H-bond acceptors | 4.0 |
Num. H-bond donors | 0.0 |
Molar Refractivity | 55.01 |
TPSA ? Topological Polar Surface Area: Calculated from |
62.98 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
2.26 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
2.15 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
2.09 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
0.9 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
2.67 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
2.01 |
Log S (ESOL):? ESOL: Topological method implemented from |
-2.69 |
Solubility | 0.464 mg/ml ; 0.00206 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (Ali)? Ali: Topological method implemented from |
-3.1 |
Solubility | 0.176 mg/ml ; 0.000786 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-3.6 |
Solubility | 0.056 mg/ml ; 0.000249 mol/l |
Class? Solubility class: Log S scale |
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 |
Yes |
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) |
Yes |
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) |
No |
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) |
No |
Log Kp (skin permeation)? Skin permeation: QSPR model implemented from |
-6.14 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 |
1.0 alert: heavy_metal |
Leadlikeness? Leadlikeness: implemented from |
No; 1 violation:MW<1.0 |
Synthetic accessibility? Synthetic accessibility score: from 1 (very easy) to 10 (very difficult) |
2.26 |
* 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 |
---|---|---|
54% | With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃; for 3h; | (b) { 1-[3-Cyano-5-(ethoxycarbonyl)-6-inethylpyridin-2-yI]piperdin-3-yl}acetic acid; Ethyl 6-chloro-5-cyano-2-methylnicotinate (1.00 g, 4.45 mmol), piperidin-3-ylacetic acid (0.701 g, 4.90 mmol) and DIPEA (2.33 mL, 13.4 mmol) were dissolved in DMF (30 mL) and stirred at r.t for 3 days. The reaction mixture was diluted with EtOAc (100 mL), washed with saturated NH4Cl (2 x 25 mL), saturated NaHCO3 (2 x25 mL), brine (25 m), dried (Mg5O4) and concentrated under reduced pressure to afford crude material. Flash chromatography (9:1 EPO <DP n="235"/>EtOAc/hexanes with 1% AcOH) gave {1-[3-cyano-5-(ethoxycarbonyl)-6-methylpyridin-2- yl]piperdin-3-yl}acetic acid as a solid. Yield: 0.791 g (54 %).1HNMR (400 MHz, CDCl3): 6 1.37 (3H, t, J= 7.1 Hz), 1.39-1.44 (1H, m), 1.63-1.73 (1H, m), 1.78-1.85 (1H, m), 1.98-2.03 (1H, m), 2.16-2.24 (1H, m), 2.29-2.34 (1H, m), 2.40-2.46 (1H, m), 2.71 (3H, s), 3.08-3.13 (1H, m), 3.26-3.32 (1H, m), 4.31 (2H, q, J= 7.1 Hz), 4.44- 4.50 (1H, m), 4.52-4.56 (1H, m), 8.33 (1H, s). M5 m/z: 330 (M-I). |
54% | With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃; for 3h; | (b) { 1-[3-Cyano-5-(ethoxycarbonyl)-6-inethylpyridin-2-yI]piperdin-3-yl}acetic acid; Ethyl 6-chloro-5-cyano-2-methylnicotinate (1.00 g, 4.45 mmol), piperidin-3-ylacetic acid (0.701 g, 4.90 mmol) and DIPEA (2.33 mL, 13.4 mmol) were dissolved in DMF (30 mL) and stirred at r.t for 3 days. The reaction mixture was diluted with EtOAc (100 mL), washed with saturated NH4Cl (2 x 25 mL), saturated NaHCO3 (2 x25 mL), brine (25 m), dried (Mg5O4) and concentrated under reduced pressure to afford crude material. Flash chromatography (9:1 EPO <DP n="235"/>EtOAc/hexanes with 1% AcOH) gave {1-[3-cyano-5-(ethoxycarbonyl)-6-methylpyridin-2- yl]piperdin-3-yl}acetic acid as a solid. Yield: 0.791 g (54 %).1HNMR (400 MHz, CDCl3): 6 1.37 (3H, t, J= 7.1 Hz), 1.39-1.44 (1H, m), 1.63-1.73 (1H, m), 1.78-1.85 (1H, m), 1.98-2.03 (1H, m), 2.16-2.24 (1H, m), 2.29-2.34 (1H, m), 2.40-2.46 (1H, m), 2.71 (3H, s), 3.08-3.13 (1H, m), 3.26-3.32 (1H, m), 4.31 (2H, q, J= 7.1 Hz), 4.44- 4.50 (1H, m), 4.52-4.56 (1H, m), 8.33 (1H, s). M5 m/z: 330 (M-I). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
43% | With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20.0℃; | (e) 1-[3-Cyano -5-(ethoxycarbonyl) -6-methylpyridin-2 -yl] -4-methylpiperidine -4- carboxylic acid; Ethyl 6-chloro-5-cyano-2-methylnicotinate (0.28 g, 1.3 mmol) and 4-methylpiperidine-4- carboxylic acid hydrochloride (0.34 g, 1.9 mmol) were suspended in DMF (20 mL) and DIPEA (1.1 mL, 6.3 mmol) was added. The reaction mixture was stirred at r.t until complete consumption of the starting materieal was observed by HPLC analysis. The reaction mixture was diluted with EtOAc (100 mL) and washed with saturated NH4Cl (70 mL), water (2 X 70 mL) and brine (50 mL). The organics were dried (Mg5O4) and concentrated under reduced pressure to afford the crude material. Flash column chromatography (1:3 EtOAc/hexanes, 0.5 % AcOH to 1:2 EtOAc/hexanes, 0.5 % AcOH) gave 1-[3-cyano-5-(ethoxycarbonyl)-6- methylpy?din-2-yl]-4-methylpiperidine-4-carboxylic acid as a solid. Yield: 0.179 g (43%). 1H NMR (400 MHz, DM5O- d6): 6 1.20 (3H, s), 1.30 (3H, t, J= 7.1Hz), 1.44-1.54 (2H, m), 2.02-2.11 (2H, m), 2.63 (3H, s), 3.39-3.48 (2H, m), 4.15-4.29 (4H, m), 8.32 (1H, s), 12.52 (1H, br s). M5 m/z: 332 (M+l). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl acetamide; at 80℃; for 2h; | (a) Ethyl 6-(4-(^rT-butoxycarbonyl)piperidin-1-yl)-5-cyano-2-methyInicotinate; A solution of ethyl 6-chloro-5-cyano-2-methylnicotinate (6.00 g, 26.7 mmol), tert -butyl piperidine-4-carboxylate hydrochloride (6.51, 29.4 mmol) and DIPEA (23.3 mL, 134 mmol) in DMA (50 mL) were heated to 8O°C for 2 h. After cooling to room temperature, the reaction mixture was diluted with EtOAc (300 mL), washed with saturated NH4Cl (4 x 50 mL), brine (50 mL), dried (Mg5O4), passed through silica gel and concentrated. Flash chromatography produced Ethyl 6-(4-(tert-butoxycarbonyl)piperidin-1-yl)-5-cyano-2-methylnicotinate as a solid. Yield 8.85 g (89 percent). EPO <DP n="146"/>1HNMR (400 MHz, CDCl3): 6 1.37 (3H, t, J= 7.1 Hz), 1.45 (9H, s), 1.75-1.84 (2H3 m), 1.99- 2.03 (2H, m), 2.49-2.57 (1H, m), 2.72 (3H, s), 3.24-3.31 (2H, m), 4.31 (2H, q, J= 7.1 Hz), 4.55-4.60 (2H, m), 8.34 (1H, s). M5 "Vz: 374 (M+l). |
89% | With N-ethyl-N,N-diisopropylamine; In DMA; at 80℃; for 2h; | A solution of ethyl 6-chloro-5-cyano-2-methyhiicotinate (6.00 g, 26.7 mmol), <strong>[892493-65-1]tert-butyl piperidine-4-carboxylate hydrochloride</strong> (6.51, 29.4 mmol) and DBPEA (23.3 mL, 134 mmol) in DMA (50 mL) were heated to 80 °C for 2 h. After cooling to r.t, the reaction mixture was diluted with EtOAc (300 mL), washed with saturated NH4Cl (4 x 50 mL), brine (50 mL), dried (MgSO4), passed through silica gel and concentrated. Flash chromatography produced ethyl 6-(4-(tert-butoxycarbonyl)piperidm-l-yl)-5-cyano-2-memylnicotinate as a solid. Yield: 8.85 g (89 percent). EPO <DP n="138"/>1H NMR (400 MHz, CDCl): delta 1HNMR (400 MHz, CDCl5): delta 1.37 (3H, t, J= 7.1 Hz), 1.45 (9H, s), 1.75-1.84 (2H, m), 1.99-2.03 (2H, m), 2.49-2.57 (IH, m), 2.72 (3H, s), 3.24-3.31 (2H, m), 4.31 (2H, q, J= 7.1 Hz), 4.55-4.60 (2H, m), 8.34 (IH, s). MS m/z: 374 (M+l). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
77% | With triethylamine; In acetonitrile; at 100℃; for 0.0833333h;Microwave irradiation; | (d) Ethyl 6-[4-(tert-butoxycarbonyl)piperidin-l-yl]-5-cyano-2-methylnicotinateA 20 mL microwave vial was charged with ethyl 6-chloro-5-cyano-2-methylnicotinate (5 g, 22.3 mmol), <strong>[138007-24-6]ter<strong>[138007-24-6]t-butyl piperidine-4-carboxylate</strong></strong> (4.11 g, 22.3 mmol), TEA (4.5 g, 44.5 mmol) and MeCN and heated, single nodeheating, to 100 0C for 5 minutes. The reaction was concentrated and MeCN/water was added to precipitate the product. Filtration of the solid and drying gave ethyl 6-[4-(tert-butoxycarbonyl)piperidin-l-yl]-5-cyano-2- methylnicotinate as an orange colored solid. Yield: 6.99 g (77percent). 1H NMR (400 MHz, DMSO-d6): delta 1.30 (3H, t), 1.40 (9H, s), 1.32-1.64 (2H, m), 1.88-1.96 (2H, m), 2.55-2.60 (IH, m), 2.63 (3H, s), 3.20-3-30 (2H, m), 4.24 (2H, q), 4.39-4.47 (2H, m), 8.31 (IH, s). |