Structure of Ibrutinib deacryloylpiperidine
CAS No.: 330786-24-8
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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. : | 330786-24-8 |
| Formula : | C17H13N5O |
| M.W : | 303.32 |
| SMILES Code : | NC1=C2C(NN=C2C3=CC=C(OC4=CC=CC=C4)C=C3)=NC=N1 |
| MDL No. : | MFCD20270360 |
| InChI Key : | YYVUOZULIDAKRN-UHFFFAOYSA-N |
| Pubchem ID : | 22346757 |
| GHS Pictogram: |
|
| Signal Word: | Warning |
| Hazard Statements: | H302-H315-H319-H335 |
| Precautionary Statements: | P261-P305+P351+P338 |
| Num. heavy atoms | 23 |
| Num. arom. heavy atoms | 21 |
| Fraction Csp3 | 0.0 |
| Num. rotatable bonds | 3 |
| Num. H-bond acceptors | 4.0 |
| Num. H-bond donors | 2.0 |
| Molar Refractivity | 88.04 |
| TPSA ? Topological Polar Surface Area: Calculated from |
89.71 Ų |
| Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
2.06 |
| Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
3.01 |
| Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
3.4 |
| Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
2.39 |
| Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
2.74 |
| Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
2.72 |
| Log S (ESOL):? ESOL: Topological method implemented from |
-4.09 |
| Solubility | 0.0244 mg/ml ; 0.0000804 mol/l |
| Class? Solubility class: Log S scale |
Moderately soluble |
| Log S (Ali)? Ali: Topological method implemented from |
-4.56 |
| Solubility | 0.00838 mg/ml ; 0.0000276 mol/l |
| Class? Solubility class: Log S scale |
Moderately soluble |
| Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-6.57 |
| Solubility | 0.0000818 mg/ml ; 0.00000027 mol/l |
| Class? Solubility class: Log S scale |
Poorly 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 |
No |
| P-gp substrate? P-glycoprotein substrate: SVM model built on 1033 molecules (training set) |
Yes |
| 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) |
Yes |
| 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 |
-6.01 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<0.0 |
| Synthetic accessibility? Synthetic accessibility score: from 1 (very easy) to 10 (very difficult) |
2.57 |
* 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 |
|---|---|---|
| 78 mg | With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 20℃;Inert atmosphere; | [00131] To a mixture of 3-(4-phenoxyphenyl)-1 H-pyrazolo[3,4-d]pyrimidin-4- amine (100 mg, 0.33 mmol), tert-butyl 6-hydroxy-2-azaspiro[3.3]heptane-2- carboxylate (141 mg, 0.66 mmol, 2 eq), triphenylphosphine (173 mg, 0.66 mmol, 2 eq) in a 40 ml reaction vial under vacuum, 5 mL of THF is added via a syringe. The mixture is refilled with N2 and DIAD (0.13 mL, 0.66 mmol, 2 eq) is added dropwise at rt. The mixture is then stirred at rt overnight. TLC showed that the reaction is almost completed. Then solvent is evaporated and the residue is purified with a 24 g silica gel cartridge by combi-flash (0-10percent gradient of methanol in DCM to afford 78 mg of tert-butyl 6-(4-amino-3-(4-phenoxyphenyl)- 1 H-pyrazolo[3,4-d]pyrimidin-1 -yl)-2-azaspiro[3.3]heptane-2-carboxylate. 1HNMR (300 MHz, acetone-d6): delta 8.26 (s, 1 H), 7.78 (d, 2 H), 7.46 (t, 2 H), 7.10- 7.23 (m, 5 H), 5.30-5.45 (m, 1 H), 4.11 (s, 2 H), 4.05 (s, 2 H), 2.71-3.0 (m, 4 H), 1.44 (s, 9 H). |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 80% | Intermediate 1 (5g) was dissolved in dry DMF (50 mL) and potassium carbonate (8.8 g) was added. The suspension was stirred at ambient temperature for 2 h. After dropwise addition of Intermediate 2 (9 g) dissolved in DMF (10 mL) the reaction mixture was heated at 80°C for 14 h. The organic layer was separated and the water layer extracted with EtOAc (3x20 mL). The organic layers were combined and dried over Na2SC>4. Solvent evaporation at reduced pressure and recrystallization result in 6.3g (80percent) tert-butyl-(3R)-3-[4-amino-3-(4-phenoxyphenyl)pyrazolo [3,4-d] pyrimidin- 1 -yl]piperidine - 1 -carboxylate. | |
| 70% | With dmap; caesium carbonate; In N,N-dimethyl-formamide; at 90℃; for 8h; | 3-(4-phenoxyphenyl) lH-pyrazolo [3,4-d] pyrimidin-4-amine (1.14g, 3.76mmol)was dissolved DMF (30mL) in, and then the reaction solution was added (S)-tert-butyl 3-((methylsulfonyl) oxy) piperidine-1-carboxylate (4.2g, 15.04mmol), cesium carbonate(0.64mL, 8.21 mmol), 4- dimethylaminopyridine pyridine (3.67g, 11.28mmol). Was stirredat 90 deg.] C 8h, the reaction was completed, distilled under reduced pressure of DMF,and extracted with dichloromethane (150mL × 3), brine (60mL), dried over anhydroussodium sulfate, the solvent was distilled off under reduced pressure, the crude productwas silica gel column Analysis of separation and purification (methylene chloride /methanol (V / V) = 40/1), to give the product (1.28g, 70percent). |
[ 940890-90-4 ]
[ 330786-24-8 ]
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 78.4% | The solution of (S)-1-boc-3-methylsulfonyloxy piperidine (115.5 g) indimethylacetamide (300 ml) was added to the reaction mixture of 3-(4-phenoxyphenyl)- 1 H-pyrazolo[3 ,4-d]pyrimidine-4-amine (50 g), cesium carbonate(13.4 g) and potassium carbonate (108.3 g) in dimethylacetamide (450 ml) at 55°C.The reaction mass was heated to 85°C, stirred for 14h, filtered and concentrated.The concentrated mass was dissolved in 1:1 mixture of methanol-toluene (1250 ml)and added hydrochloric acid (117 ml; 18percent w/v). The reaction mixture was stirredfor 6 h at 45°C, separated the aqueous layer and concentrated under vacuum. The concentrated mass was stirred with methanol (100 ml) and ethyl acetate (625 ml), filtered the solid and dried to yield (R)-3-(4-phenoxyphenyl)-1-(piperidin-3-yl-1H- pyrazolo[3 ,4-d]pyrimidine-4-amine hydrochloride (59 g; 78.4percent).HPLC Purity: 99.6percent |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 37% | With potassium phosphate; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In water; N,N-dimethyl-formamide; at 120℃; for 12h;Inert atmosphere; | 3-Iodo-1H-[3,4-d]pyrazolopyrimidin-4-amine (435 mg, 1.7 mmol)Dissolved in N, N- mixed solvent of dimethylformamide in H2O,Add 2-(4-phenoxyphenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxolaneborane(1.5g, 5.0mmol),Potassium Phosphate (531 mg, 2.5 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloride dichloromethane complex(69 mg, 0.08 mmol), heated to 120C under nitrogen protection for 12 hours.After the reaction was completed, water was added and a large amount of solids precipitated.Extract three times with ethyl acetate, combine the organic phases, wash three times with water, dry with anhydrous sodium sulfate, spin dry the solvent, and purify by column to obtain the target compound (187 mg). The yield is 37%. |

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