Structure of 534595-51-2
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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. : | 534595-51-2 |
Formula : | C13H26N2O2 |
M.W : | 242.36 |
SMILES Code : | CC(C)NC1CCN(CC1)C(=O)OC(C)(C)C |
MDL No. : | MFCD07367732 |
InChI Key : | GVPSIFSYYZXVQC-UHFFFAOYSA-N |
Pubchem ID : | 20801236 |
GHS Pictogram: |
![]() |
Signal Word: | Warning |
Hazard Statements: | H317-H319 |
Precautionary Statements: | P280-P305+P351+P338 |
Num. heavy atoms | 17 |
Num. arom. heavy atoms | 0 |
Fraction Csp3 | 0.92 |
Num. rotatable bonds | 5 |
Num. H-bond acceptors | 3.0 |
Num. H-bond donors | 1.0 |
Molar Refractivity | 73.82 |
TPSA ? Topological Polar Surface Area: Calculated from |
41.57 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
3.41 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
2.04 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
2.0 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
1.71 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
1.36 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
2.11 |
Log S (ESOL):? ESOL: Topological method implemented from |
-2.3 |
Solubility | 1.22 mg/ml ; 0.00504 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (Ali)? Ali: Topological method implemented from |
-2.54 |
Solubility | 0.697 mg/ml ; 0.00288 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-2.15 |
Solubility | 1.7 mg/ml ; 0.007 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 |
-6.33 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 |
0.0 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) |
2.45 |
* 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 |
---|---|---|
With dmap; N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; dichloromethane; at 20℃; for 2.0h; | To a solution of tert-butyl 4-(isopropyIamino)piperidine-carboxylate (0.25 g) (prepared using similar chemistry described in Step 1 , Example 1) in CH2Cl2 (10 ml) were added 3- trifluoromethylsulfinylchloride (1.4 mL; 0.8 M in THF solution) [J. Org. Chem. USSR (Engl. Transl.) 13: 2086-2087 (1977)], N,N-dimethyIamnopyridine (2 grains), diisopropylethylamine (0.71 mL). The resulting reaction mixture was stirred at room temperature two hours, and then diluted with ether (50 mL), washed with IN HCl (50 mL) and then 50 ml 5 % KOH. The organic phase was washed with water, dried over Na2SOi, filtered and concentrated. The residue obtained was purified by silica gel <n="39"/>chromatography using ethyl acetate/hexane (1 :3) to afford the titled compound as a white solid (110 mg). 1H NMR (CDCl3): 7.94 (s, IH), 7.87 (d, J=7.8 Hz5 IH), 7.76 (d, J=8.0 Hz, IH), 7.66 (t, J=7.8 Hz, IH), 4.2 (b, 2H)5 3.57 (qint, J=4.6 Hz5 IH)5 3.23 (m, IH), 2.74 (b5 IH), 2.60 (b, IH), 2.15 (m5 IH)5 1.95 (m5 IH)5 1.75 (m, 1 H), 1.48 (s, 9H), 1.43 (d, J=5.6 HZ5 3H)5 1.15 (b5 3H). MS: m/e 435 (M-H )+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
41% | With sodium cyanoborohydride; acetic acid; In methanol; at 20℃; for 1.0h; | To the solution of tert-butyl 4-oxopiperidine-1-carboxylate (5.0 g, 25.09 mmol) in methanol (35 mL) was added isopropylamine (1.07 mL, 12.54 mmol), acetic acid (0.94 mL, 16.30 mmol) and sodium cyanoborohydride (1.0 g, 16.30 mmol). The resulting solution was stirred at room temperature for 1 hour, then quenched with water. The solution was concentrated in vacuo and redissolved in ethyl ether. The organics were extracted with 0.1 N HCl. The aqueous extracts were basified with 1 N NaOH (pH >8) and extracted with ethyl ether. The organic extracts were dried over anhydrous Na2SO4, filtered, and concentrated in vacuo, to afford tert-butyl 4-(isopropylamino)piperidine-1-carboxylate (1.2 g, 41%) as a clear liquid |
41% | With sodium cyanoborohydride; acetic acid; In methanol; at 20℃; for 1.0h; | Example 41 Preparation of N-(1-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)phenyl)piperidin-4-yl)-N-isopropylacetamide To the solution of tert-butyl 4-oxopiperidine-1-carboxylate (5.0 g, 25.09 mmol) in methanol (35 mL) was added isopropylamine (1.07 mL, 12.54 mmol), acetic acid (0.94 mL, 16.30 mmol) and sodium cyanoborohydride (1.0 g, 16.30 mmol). The resulting solution was stirred at room temperature for 1 hour, then quenched with water. The solution was concentrated in vacuo and redissolved in ethyl ether. The organics were extracted with 0.1 N HCl. The aqueous extracts were basified with 1 N NaOH (pH>8) and extracted with ethyl ether. The organic extracts were dried over anhydrous Na2SO4, filtered, and concentrated in vacuo, to afford tert-butyl 4-(isopropylamino)piperidine-1-carboxylate (1.2 g, 41%) as a clear liquid. |
500 mg (2.51 mmol, 1 eq) 1-Boc-4-piperidinone are placed in 7 mL of 1,2-dichloroethane, 214 muL (2.51 mmol, 1 eq) isopropylamine are added and the mixture is stirred for 20 min at RT. After the addition of 145 muL (2.51 mmol, 1 eq) glacial acetic acid, 745 mg (3.5 mmol, 1.4 eq) sodium trisacetoxyborohydride are added batchwise and the mixture is stirred overnight at RT. The reaction mixture is combined with 25 mL saturated, aqueous NaHCO3 solution, then after the development of gas has ended it is extracted 3 times with 20 mL DCM, the combined organic phases are dried on MgSO4, the solvent is eliminated in vacuo and 527 mg of the amine product is obtained, which is used without any further purification. |
With sodium tris(acetoxy)borohydride; In 1,2-dichloro-ethane; at 0 - 20℃; for 24.0h;Molecular sieve; | EXAMPLE 1; N-Isopropyl-N-piperidin-4-yl-3 -trifluoromethylbenzenesulfonamide (6); [0480] NaB(OAc)3H (14 g, 66 mmol, Aldrich) was added to a mixture of compound 1 (10 g, 50 mmol, Aldrich), compound 2 (3 g, 52.5 mmol, Aldrich), molecular sieves (4A beads, 2Og, Aldrich) in DCE (200 mL) at 0 0C. The resulting mixture was stirred at room temperature for 24 hours. The reaction mixture was quenched with MeOH (2mL), filtered over celite, washed with water, 2N NaOH and concentrated under vacuum to afford crude compound 3 as a colorless oil. Compound 4 (12 g, 49 mmol, Aldrich) was added to a mixture of the above crude compound 3, TEA (10 mL) and DCM (10 mL) at room temperature. The resulting mixture was heated and stirred at 37 0C for 2 days. The reaction mixture was then cooled to room temperature, washed with water (10 mL), brine, concentrated and purified by column (silica gel, EtOAc/hexanes 3/7) to obtain compound 5 as a sticky oil (10 g, yield 45% in two steps), which was dissolved in 100 mL of 1,4-dioxane. HCl (10 mL, concentrated aq.) was added to the 1,4-dioxane solution at room temperature. The resulting mixture was stirred at room temperature for 48 hours, and concentrated under vacuum. The residue was washed with ethyl ether, and dried to obtain the title compound 6 as HCl-salt, which was suspended in EtOAc, and neutralized with IN <n="152"/>NaOH aq, concentrated and dried under vacuum to give compound 6 as colorless oil (5 g, yield 65%). | |
Example 1; N-Isopropyl-N-piperidin-4-yl-3-trifluoromethyl-benzenesulfonamide (6); NaB(OAc)3H (14 g, 66 mmol, Aldrich) was added to a mixture of compound 1 (10 g, 50 mmol, Aldrich), compound 2 (3 g, 52.5 mmol, Aldrich), molecular sieves (4 beads, 20 g, Aldrich) in DCE (200 mL) at 0 C. The resulting mixture was stirred at room temperature for 24 hours. The reaction mixture was quenched with MeOH (2 mL), filtered over celite, washed with water, 2N NaOH and concentrated under vacuum to afford crude compound 3 as a colorless oil. Compound 4 (12 g, 49 mmol, Aldrich) was added to a mixture of the above crude compound 3, TEA (10 mL) and DCM (10 mL) at room temperature. The resulting mixture was heated and stirred at 37 C. for 2 days. The reaction mixture was then cooled to room temperature, washed with water (10 mL), brine, concentrated and purified by column (silica gel, EtOAc/hexanes 3/7) to obtain compound 5 as a sticky oil (10 g, yield 45% in two steps), which was dissolved in 100 mL of 1,4-dioxane. HCl (10 mL, concentrated aq.) was added to the 1,4-dioxane solution at room temperature. The resulting mixture was stirred at room temperature for 48 hours, and concentrated under vacuum. The residue was washed with ethyl ether, and dried to obtain the title compound 6 as HCl-salt, which was suspended in EtOAc, and neutralized with 1N NaOH aq, concentrated and dried under vacuum to give compound 6 as colorless oil (5 g, yield 65%). | ||
EXAMPLE 10; N-Isopropyl-N-piperidin-4-yl-3-trifluoromethylbenzenesulfonamide (19); [0258] NaB(OAc)3H (14 g, 66 mmol, Aldrich) was added to a mixture of compound 14 (10 g, 50 mmol, Aldrich), compound 15 (3 g, 52.5 mmol, Aldrich), molecular sieves (4A beads, 2Og, Aldrich) in DCE (200 ml) at 0 0C. The resulting mixture was stirred at room temperature for 24 hours. The reaction mixture was quenched with MeOH (2ml), filtered over celite, washed with water, 2N NaOH and concentrated under vacuum to afford crude compound 16 as a colorless oil. Compound 17 (12 g, 49 mmol, Aldrich) was added to a mixture of the above crude compound 16, TEA (10 ml) and DCM (10 ml) at room temperature. The resulting mixture was heated and stirred at 37 0C for 2 days. The reaction mixture was then cooled to room temperature, washed with water (10 ml), brine, concentrated and purified by column (silica gel, EtOAc/hexanes 3/7) to obtain compound 18 as a sticky oil (10 g, yield 45% in two steps), which was dissolved in 100 ml of 1,4-dioxane. HCl (10 ml, concentrated aq.) was added to the 1,4-dioxane solution at room temperature. The resulting mixture was stirred at room temperature for 48 hours, and concentrated under vacuum. The residue was washed with ethyl ether, and dried to obtain the title compound 19 as HCl-salt, which was suspended in EtOAc, and neutralized with IN <n="87"/>NaOH aq, concentrated and dried under vacuum to give compound 19 as colorless oil (5 g, yield 65%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; In dichloromethane; at 20 - 37℃; for 48.0h; | EXAMPLE 1; N-Isopropyl-N-piperidin-4-yl-3 -trifluoromethylbenzenesulfonamide (6); [0480] NaB(OAc)3H (14 g, 66 mmol, Aldrich) was added to a mixture of compound 1 (10 g, 50 mmol, Aldrich), compound 2 (3 g, 52.5 mmol, Aldrich), molecular sieves (4A beads, 2Og, Aldrich) in DCE (200 mL) at 0 0C. The resulting mixture was stirred at room temperature for 24 hours. The reaction mixture was quenched with MeOH (2mL), filtered over celite, washed with water, 2N NaOH and concentrated under vacuum to afford crude compound 3 as a colorless oil. Compound 4 (12 g, 49 mmol, Aldrich) was added to a mixture of the above crude compound 3, TEA (10 mL) and DCM (10 mL) at room temperature. The resulting mixture was heated and stirred at 37 0C for 2 days. The reaction mixture was then cooled to room temperature, washed with water (10 mL), brine, concentrated and purified by column (silica gel, EtOAc/hexanes 3/7) to obtain compound 5 as a sticky oil (10 g, yield 45% in two steps), which was dissolved in 100 mL of 1,4-dioxane. HCl (10 mL, concentrated aq.) was added to the 1,4-dioxane solution at room temperature. The resulting mixture was stirred at room temperature for 48 hours, and concentrated under vacuum. The residue was washed with ethyl ether, and dried to obtain the title compound 6 as HCl-salt, which was suspended in EtOAc, and neutralized with IN <n="152"/>NaOH aq, concentrated and dried under vacuum to give compound 6 as colorless oil (5 g, yield 65%). | |
With triethylamine; In dichloromethane; at 37℃; for 48.0h; | Example 1; N-Isopropyl-N-piperidin-4-yl-3-trifluoromethyl-benzenesulfonamide (6); NaB(OAc)3H (14 g, 66 mmol, Aldrich) was added to a mixture of compound 1 (10 g, 50 mmol, Aldrich), compound 2 (3 g, 52.5 mmol, Aldrich), molecular sieves (4 beads, 20 g, Aldrich) in DCE (200 mL) at 0 C. The resulting mixture was stirred at room temperature for 24 hours. The reaction mixture was quenched with MeOH (2 mL), filtered over celite, washed with water, 2N NaOH and concentrated under vacuum to afford crude compound 3 as a colorless oil. Compound 4 (12 g, 49 mmol, Aldrich) was added to a mixture of the above crude compound 3, TEA (10 mL) and DCM (10 mL) at room temperature. The resulting mixture was heated and stirred at 37 C. for 2 days. The reaction mixture was then cooled to room temperature, washed with water (10 mL), brine, concentrated and purified by column (silica gel, EtOAc/hexanes 3/7) to obtain compound 5 as a sticky oil (10 g, yield 45% in two steps), which was dissolved in 100 mL of 1,4-dioxane. HCl (10 mL, concentrated aq.) was added to the 1,4-dioxane solution at room temperature. The resulting mixture was stirred at room temperature for 48 hours, and concentrated under vacuum. The residue was washed with ethyl ether, and dried to obtain the title compound 6 as HCl-salt, which was suspended in EtOAc, and neutralized with 1N NaOH aq, concentrated and dried under vacuum to give compound 6 as colorless oil (5 g, yield 65%). | |
With triethylamine; In dichloromethane; at 20 - 37℃; for 48.0h; | EXAMPLE 10; N-Isopropyl-N-piperidin-4-yl-3-trifluoromethylbenzenesulfonamide (19); [0258] NaB(OAc)3H (14 g, 66 mmol, Aldrich) was added to a mixture of compound 14 (10 g, 50 mmol, Aldrich), compound 15 (3 g, 52.5 mmol, Aldrich), molecular sieves (4A beads, 2Og, Aldrich) in DCE (200 ml) at 0 0C. The resulting mixture was stirred at room temperature for 24 hours. The reaction mixture was quenched with MeOH (2ml), filtered over celite, washed with water, 2N NaOH and concentrated under vacuum to afford crude compound 16 as a colorless oil. Compound 17 (12 g, 49 mmol, Aldrich) was added to a mixture of the above crude compound 16, TEA (10 ml) and DCM (10 ml) at room temperature. The resulting mixture was heated and stirred at 37 0C for 2 days. The reaction mixture was then cooled to room temperature, washed with water (10 ml), brine, concentrated and purified by column (silica gel, EtOAc/hexanes 3/7) to obtain compound 18 as a sticky oil (10 g, yield 45% in two steps), which was dissolved in 100 ml of 1,4-dioxane. HCl (10 ml, concentrated aq.) was added to the 1,4-dioxane solution at room temperature. The resulting mixture was stirred at room temperature for 48 hours, and concentrated under vacuum. The residue was washed with ethyl ether, and dried to obtain the title compound 19 as HCl-salt, which was suspended in EtOAc, and neutralized with IN <n="87"/>NaOH aq, concentrated and dried under vacuum to give compound 19 as colorless oil (5 g, yield 65%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium cyanoborohydride; acetic acid; In acetonitrile; at 20℃; for 16.0h; | (i) 4-Isopropylamino-piperidine-1-carboxylic acid tert-butyl ester To a solution of 1.5 g 4-Amino-piperidine-1-carboxylic acid tert-butyl ester in 20 ml acetonitrile, 2.6 ml acetone, 0.94 g Na(CN)BH3 and 0.3 ml acetic acid were added. After stirring for 16 h at RT the solvent was removed under reduced pressure and the residue was partitioned between 30 ml of water and 30 ml of ethyl acetate. The organic layer was washed with saturated Na2CO3 solution, water and was dried over Na2SO4. Removal of the solvent under reduced pressure yields a white solid. Yield: 2.8 g MS (ES+): m/e=243. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
59% | With triethylamine; In dichloromethane; at 0℃; for 2.5h; | To a 0 C. solution of <strong>[534595-51-2]tert-butyl 4-(isopropylamino)piperidine-1-carboxylate</strong> (1.2 g, 5.19 mmol) in CH2Cl2 (18 mL) was added Et3N (1.44 mL, 10.38 mmol) followed by acetyl chloride (0.55 mL, 7.78 mmol). The resulting solution was stirred for 2.5 hours, then concentrated in vacuo. The material was purified by flash chromatography on silica gel, eluting with 0% to 5% of EtOAc/CH2Cl2, to afford tert-butyl 4-(N-isopropylacetamido)piperidine-1-carboxylate (0.88 g, 59%) |
59% | With triethylamine; In dichloromethane; for 2.5h; | To a 0 C. solution of <strong>[534595-51-2]tert-butyl 4-(isopropylamino)piperidine-1-carboxylate</strong> (1.2 g, 5.19 mmol) in CH2Cl2 (18 mL) was added Et3N (1.44 mL, 10.38 mmol) followed by acetyl chloride (0.55 mL, 7.78 mmol). The resulting solution was stirred for 2.5 hours, then concentrated in vacuo. The material was purified by flash chromatography on silica gel, eluting with 0% to 5% of EtOAc/CH2Cl2, to afford tert-butyl 4-(N-isopropylacetamido)piperidine-1-carboxylate (0.88 g, 59%). |
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