Structure of 139290-70-3
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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. : | 139290-70-3 |
Formula : | C13H24N2O4 |
M.W : | 272.34 |
SMILES Code : | O=C(N1CCC(C(N(OC)C)=O)CC1)OC(C)(C)C |
MDL No. : | MFCD07368262 |
InChI Key : | ITCQNWXLNZGEHP-UHFFFAOYSA-N |
Pubchem ID : | 11065582 |
GHS Pictogram: |
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Signal Word: | Warning |
Hazard Statements: | H302 |
Precautionary Statements: | P280-P305+P351+P338 |
Num. heavy atoms | 19 |
Num. arom. heavy atoms | 0 |
Fraction Csp3 | 0.85 |
Num. rotatable bonds | 6 |
Num. H-bond acceptors | 4.0 |
Num. H-bond donors | 0.0 |
Molar Refractivity | 75.19 |
TPSA ? Topological Polar Surface Area: Calculated from |
59.08 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
3.24 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
1.11 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
1.27 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
1.18 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
0.23 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
1.4 |
Log S (ESOL):? ESOL: Topological method implemented from |
-1.83 |
Solubility | 4.01 mg/ml ; 0.0147 mol/l |
Class? Solubility class: Log S scale |
Very soluble |
Log S (Ali)? Ali: Topological method implemented from |
-1.94 |
Solubility | 3.1 mg/ml ; 0.0114 mol/l |
Class? Solubility class: Log S scale |
Very soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-1.07 |
Solubility | 23.0 mg/ml ; 0.0843 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) |
No |
CYP2C19 inhibitor? Cytochrome P450 2C19 inhibitor: SVM model built on 9272 molecules (training set) |
No |
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 |
-7.17 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<0.0 |
Synthetic accessibility? Synthetic accessibility score: from 1 (very easy) to 10 (very difficult) |
2.79 |
* 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 |
---|---|---|
59% | In tetrahydrofuran; at 0 - 20℃; for 2h; | Step 2; To a solution of tert-butyl 4-(methoxy(rnethyl)carbamoyl)piperidine-l-carboxylate (8.0 g, 29.4 mmol) in THF (25 mL) was added PhMgCl (8.0 g, 58.8 mmol) dropwise at 0 0C. After stirring at rt for 2 h, the reaction was quenched with ammonium chloride solution and extracted <n="77"/>with ethyl acetate, dried over anhydrous sodium sulfate and concentrated under vacuum to afford tert-butyl 4-benzoylpiperidine-l-carboxylate (5 g, 59% yield) as a pale yellow solid which was used directly in the next step. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
67% | A solution of the <strong>[1455-20-5]n-butylthiophene</strong> (from Lancaster, 5.0 g, MW 140.26, 1.1 eq) in tetrahydrofuran (80 ml) at 0C was dripped into 1.6 M n-butyllithium in hexanes (from Aldrich, 24 ml, 1.2 EQ). The resulting mixture was stirred at 0C for 0.5 hr under N2. The reaction vessel was then cooled TO-78C. Afterward, a solution OF 4- (METHOXY-METHYL- CARBAMOYL)-PIPERIDINE-L-CARBOXYLIC acid tert-butyl ester (8.7 g, MW 272.34, 1.0 eq) in tetrahydrofuran (30 ml) was slowly added. The dry ice bath was removed, and the mixture was allowed to warm to ambient temperature. After 3 hr, the conversion was complete. The reaction was quenched with water (50 ml). The organic was then removed IRA vacuo. More water (100 ml) was added. The resulting mixture was extracted with diethylether (3X100 ML). Afterward, the organic layers were combined and then washed with water (2x), washed with brine (LX), dried over NA2SO4, and concentrated to afford a brown oil. The oil was chromatographed (ethylacetate: hexanes, 1: 9) to afford 7.5 g of the desired ester as a pale yellow solid (67% crude YIELD). 1H NMR confirmed the presence of the desired ester. The"equivalents"above indicate equivalents relative to charged amount of 4- (METHOXY-METHYL-CARBAMOYL)-PIPERIDINE-1-CARBOXYLIC acid tert-butyl ester. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
INTERMEDIATE 17; (5-Chloro-2-methylphenyl)(piperidin-4-yl)methanone hydrochloride; Step 1 : fert-Butyl 4-(5-chloro-2-methylbenzoyl)piperidine-l-carboxylate; To a solution of rc-butylmagnesium chloride (1.5 mL, 3.0 mmol) in THF (15 mL) stirred at -78 °C, ft-BuLi (3.75 mL, 6.0 mmol) was added drop wise followed by the addition of 2-bromo-4-chloro-l-methylbenzene (2.00 mL, 15.0 mmol) drop wise. The mixture was stirred at -30 °C for 1 h. Then l-Boc-4-(methoxy-methyl-carbamoyl)piperidine (1.36 g, 5.0 mmol) was added and the mixture was stirred at rt overnight. The reaction was worked up by the addition of aqueous citric acid, extracted with ethyl acetate, dried over Na2SO4, and evaporated. The residue was purified by combiflash (0-20percent EtOAc/hexanes) to afford the desired product tert-butyl 4-(5- chloro-2-methylbenzoyl)piperidine-l-carboxylate as clear oil. 1H NMR (500 MHz, DMSO-d6): delta 7.75 (s, IH), 7.48 (d, IH), 7.34 (d, IH), 3.93 (d, 2H), 3.25-3.35 (m, IH), 2.85 (br s, 2H), 2.28 (s, 3H), 1.73 (d, 2H), 1.40 (s, 9H), 1.35 (d, 2H). MS (ESI, Q+) m/z 360 (M+Na) | ||
Step 1:tert-Butyl 4-(5-chloro-2-methylbenzoyl)piperidine-1-carboxylateTo a solution of n-butylmagnesium chloride (1.5 mL, 3.0 mmol) in THF (15 mL) stirred at -78° C., n-BuLi (3.75 mL, 6.0 mmol) was added drop wise followed by the addition of <strong>[27139-97-5]2-bromo-4-chloro-1-methylbenzene</strong> (2.00 mL, 15.0 mmol) drop wise.The mixture was stirred at 30° C. for 1 h.Then 1-Boc-4-(methoxy-methyl-carbamoyl)piperidine (1.36 g, 5.0 mmol) was added and the mixture was stirred at rt overnight.The reaction was worked up by the addition of aqueous citric acid, extracted with ethyl acetate, dried over Na2SO4, and evaporated.The residue was purified by combiflash (0-20percent EtOAc/hexanes) to afford the desired product tert-butyl 4-(5-chloro-2-methylbenzoyl)piperidine-1-carboxylate as clear oil. 1H NMR (500 MHz, DMSO-d6): delta 7.75 (s, 1H), 7.48 (d, 1H), 7.34 (d, 1H), 3.93 (d, 2H), 3.25-3.35 (m, 1H), 2.85 (br s, 2H), 2.28 (s, 3H), 1.73 (d, 2H), 1.40 (s, 9H), 1.35 (d, 2H). MS (ESI, Q+) m/z 360 (M+Na) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
35.5% | In tetrahydrofuran; at 0 - 20℃; | To a stirred solution of tert-butyl 4-(methoxy(methyl)carbamoyl)piperidine-l- carboxylate (0.5 g, 1.83 mmol) in THF (1.5 mL) was added a 1M solution of phenyl magnesium bromide in THF (3.67 mL, 3.67 mmol) at 0 C. The reaction was stirred overnight at RT. The reaction completion was monitored by TLC and the reaction was quenched with ammonium chloride solution and extracted with ethyl acetate. The organic layer was separated, washed with brine, dried using Na2S04 and concentrated under reduced pressure to a residue. The residue was purified by column chromatography to obtain tert-butyl 4-benzoylpiperidine-l-carboxylate (0.188 g, 35.5%) LCMS: m/z = 190.1 (M+H) +. |
In tetrahydrofuran; diethyl ether; at -78 - 20℃; for 18h;Inert atmosphere; | To a solution of tert-butyl 4-(methoxy(methyl)carbamoyl)piperidine-1- carboxylate (9.5 g, 34.9 mmol) in THF (100 mL) was added phenylmagnesium bromide (23.25 mL, 69.8 mmol) (3 M in Et2O) at -78 C under N2. The reaction was stirred for 18 h with temperature naturally raised to RT. The reaction was quenched with aq. NH4Cl (50 mL), diluted with H2O (50 mL), extracted by EtOAc (50 mL* 3). The organic layers were collected, washed with brine (50 mL), dried over Na2SO4, and filtered. The filtrate was concentrated in vacuo. The residue was purified by silica gel chromatography (Petroleum ether:EtOAc=20:1 to 15:1) to give the title compound as an oil.; LCMS m/z [M+Na]+ 312.2. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
3.41 g | To a solution of <strong>[101335-11-9]2-chloro-4-fluoroiodobenzene</strong> (11.6 g) in THF (80 mL) was added dropwise isopropylmagnesium chloride-lithium chloride complex (1.3M THF solution, 34.8 mL) over 20 min at -78 C., and the mixture was stirred at -15 C. for 1.5 hr. To this mixture was added tert-butyl 4-(methoxy(methyl)carbamoyl)piperidine-1-carboxylate (6.16 g), and the mixture was stirred at room temperature for 48 hr. The reaction was quenched with aqueous ammonium chloride solution at 0 C., and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (3.41 g). 1H NMR (300 MHz, CDCl3) delta1.46 (9H, s), 1.54-1.71 (2H, m), 1.79-1.94 (2H, m), 2.72-2.94 (2H, m), 3.17-3.31 (1H, m), 4.01-4.19 (2H, m), 7.01-7.09 (1H, m), 7.17 (1H, dd, J=8.5, 2.5 Hz), 7.39 (1H, dd, J=8.6, 5.9 Hz). |
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