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Chemical Structure| 330786-24-8 Chemical Structure| 330786-24-8

Structure of Ibrutinib deacryloylpiperidine
CAS No.: 330786-24-8

Chemical Structure| 330786-24-8

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Product Details of [ 330786-24-8 ]

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

Safety of [ 330786-24-8 ]

GHS Pictogram:
Signal Word:Warning
Hazard Statements:H302-H315-H319-H335
Precautionary Statements:P261-P305+P351+P338

Computational Chemistry of [ 330786-24-8 ] Show Less

Physicochemical Properties

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
Ertl P. et al. 2000 J. Med. Chem.

89.71 Ų

Lipophilicity

Log Po/w (iLOGP)?

iLOGP: in-house physics-based method implemented from
Daina A et al. 2014 J. Chem. Inf. Model.

2.06
Log Po/w (XLOGP3)?

XLOGP3: Atomistic and knowledge-based method calculated by
XLOGP program, version 3.2.2, courtesy of CCBG, Shanghai Institute of Organic Chemistry

3.01
Log Po/w (WLOGP)?

WLOGP: Atomistic method implemented from
Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.

3.4
Log Po/w (MLOGP)?

MLOGP: Topological method implemented from
Moriguchi I. et al. 1992 Chem. Pharm. Bull.
Moriguchi I. et al. 1994 Chem. Pharm. Bull.
Lipinski PA. et al. 2001 Adv. Drug. Deliv. Rev.

2.39
Log Po/w (SILICOS-IT)?

SILICOS-IT: Hybrid fragmental/topological method calculated by
FILTER-IT program, version 1.0.2, courtesy of SILICOS-IT, http://www.silicos-it.com

2.74
Consensus Log Po/w?

Consensus Log Po/w: Average of all five predictions

2.72

Water Solubility

Log S (ESOL):?

ESOL: Topological method implemented from
Delaney JS. 2004 J. Chem. Inf. Model.

-4.09
Solubility 0.0244 mg/ml ; 0.0000804 mol/l
Class?

Solubility class: Log S scale
Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly

Moderately soluble
Log S (Ali)?

Ali: Topological method implemented from
Ali J. et al. 2012 J. Chem. Inf. Model.

-4.56
Solubility 0.00838 mg/ml ; 0.0000276 mol/l
Class?

Solubility class: Log S scale
Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly

Moderately soluble
Log S (SILICOS-IT)?

SILICOS-IT: Fragmental method calculated by
FILTER-IT program, version 1.0.2, courtesy of SILICOS-IT, http://www.silicos-it.com

-6.57
Solubility 0.0000818 mg/ml ; 0.00000027 mol/l
Class?

Solubility class: Log S scale
Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly

Poorly soluble

Pharmacokinetics

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)
and tested on 415 molecules (test set)
10-fold CV: ACC=0.72 / AUC=0.77
External: ACC=0.88 / AUC=0.94

Yes
CYP1A2 inhibitor?

Cytochrome P450 1A2 inhibitor: SVM model built on 9145 molecules (training set)
and tested on 3000 molecules (test set)
10-fold CV: ACC=0.83 / AUC=0.90
External: ACC=0.84 / AUC=0.91

Yes
CYP2C19 inhibitor?

Cytochrome P450 2C19 inhibitor: SVM model built on 9272 molecules (training set)
and tested on 3000 molecules (test set)
10-fold CV: ACC=0.80 / AUC=0.86
External: ACC=0.80 / AUC=0.87

Yes
CYP2C9 inhibitor?

Cytochrome P450 2C9 inhibitor: SVM model built on 5940 molecules (training set)
and tested on 2075 molecules (test set)
10-fold CV: ACC=0.78 / AUC=0.85
External: ACC=0.71 / AUC=0.81

No
CYP2D6 inhibitor?

Cytochrome P450 2D6 inhibitor: SVM model built on 3664 molecules (training set)
and tested on 1068 molecules (test set)
10-fold CV: ACC=0.79 / AUC=0.85
External: ACC=0.81 / AUC=0.87

Yes
CYP3A4 inhibitor?

Cytochrome P450 3A4 inhibitor: SVM model built on 7518 molecules (training set)
and tested on 2579 molecules (test set)
10-fold CV: ACC=0.77 / AUC=0.85
External: ACC=0.78 / AUC=0.86

No
Log Kp (skin permeation)?

Skin permeation: QSPR model implemented from
Potts RO and Guy RH. 1992 Pharm. Res.

-6.01 cm/s

Druglikeness

Lipinski?

Lipinski (Pfizer) filter: implemented from
Lipinski CA. et al. 2001 Adv. Drug Deliv. Rev.
MW ≤ 500
MLOGP ≤ 4.15
N or O ≤ 10
NH or OH ≤ 5

0.0
Ghose?

Ghose filter: implemented from
Ghose AK. et al. 1999 J. Comb. Chem.
160 ≤ MW ≤ 480
-0.4 ≤ WLOGP ≤ 5.6
40 ≤ MR ≤ 130
20 ≤ atoms ≤ 70

None
Veber?

Veber (GSK) filter: implemented from
Veber DF. et al. 2002 J. Med. Chem.
Rotatable bonds ≤ 10
TPSA ≤ 140

0.0
Egan?

Egan (Pharmacia) filter: implemented from
Egan WJ. et al. 2000 J. Med. Chem.
WLOGP ≤ 5.88
TPSA ≤ 131.6

0.0
Muegge?

Muegge (Bayer) filter: implemented from
Muegge I. et al. 2001 J. Med. Chem.
200 ≤ MW ≤ 600
-2 ≤ XLOGP ≤ 5
TPSA ≤ 150
Num. rings ≤ 7
Num. carbon > 4
Num. heteroatoms > 1
Num. rotatable bonds ≤ 15
H-bond acc. ≤ 10
H-bond don. ≤ 5

0.0
Bioavailability Score?

Abbott Bioavailability Score: Probability of F > 10% in rat
implemented from
Martin YC. 2005 J. Med. Chem.

0.55

Medicinal Chemistry

PAINS?

Pan Assay Interference Structures: implemented from
Baell JB. & Holloway GA. 2010 J. Med. Chem.

0.0 alert
Brenk?

Structural Alert: implemented from
Brenk R. et al. 2008 ChemMedChem

0.0 alert: heavy_metal
Leadlikeness?

Leadlikeness: implemented from
Teague SJ. 1999 Angew. Chem. Int. Ed.
250 ≤ MW ≤ 350
XLOGP ≤ 3.5
Num. rotatable bonds ≤ 7

No; 1 violation:MW<0.0
Synthetic accessibility?

Synthetic accessibility score: from 1 (very easy) to 10 (very difficult)
based on 1024 fragmental contributions (FP2) modulated by size and complexity penaties,
trained on 12'782'590 molecules and tested on 40 external molecules (r2 = 0.94)

2.57

Application In Synthesis of [ 330786-24-8 ]

* 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.

  • Downstream synthetic route of [ 330786-24-8 ]

[ 330786-24-8 ] Synthesis Path-Downstream   1~4

  • 1
  • [ 330786-24-8 ]
  • [ 1147557-97-8 ]
  • [ 1448850-34-7 ]
YieldReaction ConditionsOperation 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).
  • 2
  • [ 940890-90-4 ]
  • [ 330786-24-8 ]
  • [ 1022150-11-3 ]
YieldReaction ConditionsOperation 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).
  • 3
  • [ 940890-90-4 ]
  • [ 330786-24-8 ]
  • (R)-3-(4-phenoxyphenyl)-1-(piperidin-3-yl)-1H-pyrazolo[3,4-d]pyrimidine-4-amine hydrochloride [ No CAS ]
YieldReaction ConditionsOperation 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
  • 4
  • [ 269410-26-6 ]
  • [ 151266-23-8 ]
  • [ 330786-24-8 ]
YieldReaction ConditionsOperation 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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