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Structure of 634468-96-5

Chemical Structure| 634468-96-5

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Product Details of [ 634468-96-5 ]

CAS No. :634468-96-5
Formula : C13H20N4O2
M.W : 264.32
SMILES Code : O=C(N1CCN(C2=CN=CN=C2)CC1)OC(C)(C)C
MDL No. :MFCD11872512
InChI Key :JWFIRRWHYFDUCF-UHFFFAOYSA-N
Pubchem ID :67325143

Safety of [ 634468-96-5 ]

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

Computational Chemistry of [ 634468-96-5 ] Show Less

Physicochemical Properties

Num. heavy atoms 19
Num. arom. heavy atoms 6
Fraction Csp3 0.62
Num. rotatable bonds 4
Num. H-bond acceptors 4.0
Num. H-bond donors 0.0
Molar Refractivity 79.23
TPSA ?

Topological Polar Surface Area: Calculated from
Ertl P. et al. 2000 J. Med. Chem.

58.56 Ų

Lipophilicity

Log Po/w (iLOGP)?

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

2.62
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

0.98
Log Po/w (WLOGP)?

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

0.77
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.

0.44
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

0.58
Consensus Log Po/w?

Consensus Log Po/w: Average of all five predictions

1.08

Water Solubility

Log S (ESOL):?

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

-2.07
Solubility 2.27 mg/ml ; 0.00859 mol/l
Class?

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

Soluble
Log S (Ali)?

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

-1.8
Solubility 4.21 mg/ml ; 0.0159 mol/l
Class?

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

Very 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

-2.34
Solubility 1.22 mg/ml ; 0.00461 mol/l
Class?

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

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

Yes
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

No
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

No
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

No
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.

-7.22 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)

2.59

Application In Synthesis of [ 634468-96-5 ]

* 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 [ 634468-96-5 ]

[ 634468-96-5 ] Synthesis Path-Downstream   1~11

  • 1
  • [ 634468-96-5 ]
  • [ 202135-70-4 ]
YieldReaction ConditionsOperation in experiment
196 mg With trifluoroacetic acid; In dichloromethane; at 20℃; for 1h; General procedure: 2-Chloro-4-iodotoluene (250muL, 1.78mmol), 1-Boc-piperazine (398mg, 2.14mmol), Pd2(dba)3 (40.8mg, 0.045mmol), Xantphos (103mg, 0.178mmol) and potassium tert-butoxide (280mg, 2.50mmol) were dissolved in toluene (5mL) and heated at reflux for 16h under N2. The reaction was then concentrated and dissolved in EtOAc (20mL), filtered through celite and washed with additional EtOAc (50mL). The organic layer was washed with water (2×20mL) and brine (2×20mL), then dried with Na2SO4 and concentrated in vacuo. The crude residue was then purified by column chromatography (100% CyHex to 10% EtOAc/CyHex) to obtain the protected intermediate as an oil (436mg, 79%). MS, m/z=311 (100) [M+H]+, 313 (30). The intermediate was then dissolved in a 1:3 mixture of TFA/DCM (4mL) and stirred at 20C for 1h. The solvent was then evaporated in vacuo and the crude residue dissolved in EtOAc (10mL) which was then successively washed with a 10% NaHCO3 solution (10mL), water (10mL) and brine (10mL). The organic layer was then dried with Na2SO4 and concentrated in vacuo to obtain 106 as a solid (288mg, 97%).
  • 2
  • [ 4595-59-9 ]
  • [ 57260-71-6 ]
  • [ 634468-96-5 ]
YieldReaction ConditionsOperation in experiment
58.7% With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; In toluene; at 90℃; for 12h; (1) Preparation of tert-butyl 4-(pyrimidin-5-yl)piperazin-1-carboxylate To a 100 mL eggplant-shaped bottle were added 5-bromopyrimidine (3.16 g, 20 mmol), tert-butyl piperazin-1-carboxylate (3.72 g, 20 mmol), 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (2.49 g, 4 mmol), cesium carbonate (13.0 g, 40 mmol) and tris(dibenzylideneacetone)dipalladium (1.83 g, 2 mmol); and toluene (80 mL) was added. The reaction was carried out at 90Cunder the protection of nitrogen for 12 h. The mixture was filtrated under suction, the filtrate was concentrated, and the crude product was purified by silica gel column chromatography (dichloromethane: methanol=50:1) to get the title compound (3.1 g, yield: 58.7%).
Argon is bubbled for 15 minutes into a mixture of 9.3 g of tert-butyl 1-piperazinecarboxylate, 7.95 g of 5-bromopyrimidine and 6.5 g of sodium tert-butoxide in 250 ml of toluene, which is then heated at reflux, 0.277 g of palladium acetate and 1.7 ml of tri-tert-butylphosphine are added and reflux is continued for 24 hours. 0.277 g of palladium acetate is added and the mixture is heated at reflux for 8 hours. The reaction mixture is cooled to AT, water is added, the mixture is subjected to extraction with AcOEt, the organic phase is filtered and dried over Na2SO4 and the solvent is evaporated under vacuum. The residue is chromatographed on silica gel, eluting with DCM, then with a DCM/AcOEt (50/50; v/v) mixture and finally with a DCM/MeOH (95/5; v/v) mixture. This gives 3.95 g of the expected product following recrystallization from a DCM/hexane/iso ether mixture.
With tris-(dibenzylideneacetone)dipalladium(0); potassium tert-butylate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In toluene; for 16h;Reflux; Inert atmosphere; General procedure: 2-Chloro-4-iodotoluene (250muL, 1.78mmol), 1-Boc-piperazine (398mg, 2.14mmol), Pd2(dba)3 (40.8mg, 0.045mmol), Xantphos (103mg, 0.178mmol) and potassium tert-butoxide (280mg, 2.50mmol) were dissolved in toluene (5mL) and heated at reflux for 16h under N2. The reaction was then concentrated and dissolved in EtOAc (20mL), filtered through celite and washed with additional EtOAc (50mL). The organic layer was washed with water (2×20mL) and brine (2×20mL), then dried with Na2SO4 and concentrated in vacuo. The crude residue was then purified by column chromatography (100% CyHex to 10% EtOAc/CyHex) to obtain the protected intermediate as an oil (436mg, 79%). MS, m/z=311 (100) [M+H]+, 313 (30). The intermediate was then dissolved in a 1:3 mixture of TFA/DCM (4mL) and stirred at 20C for 1h. The solvent was then evaporated in vacuo and the crude residue dissolved in EtOAc (10mL) which was then successively washed with a 10% NaHCO3 solution (10mL), water (10mL) and brine (10mL). The organic layer was then dried with Na2SO4 and concentrated in vacuo to obtain 106 as a solid (288mg, 97%).
  • 3
  • [ 634468-96-5 ]
  • 5-(piperazine-1-yl)pyrimidine hydrochloride [ No CAS ]
YieldReaction ConditionsOperation in experiment
With hydrogenchloride; In 1,4-dioxane; diethyl ether; at 20℃; for 1h; A mixture of 3.5 g of the compound obtained in the preceding step in 20 ml of dioxane is admixed at AT with 50 ml of a 2N solution of HCl in ether, which is left with stirring at AT for 1 hour and concentrated under vacuum. This gives a yellow solid which is used as it is.
  • 4
  • [ 634468-96-5 ]
  • tert-butyl 4-(2-((5-fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazol-6-yl)pyridin-2-yl)amino)pyrimidin-5-yl)piperazin-1-carboxylate [ No CAS ]
  • 5
  • [ 634468-96-5 ]
  • N-(5-fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazol-6-yl)pyridin-2-yl)-5-(piperazin-1-yl)pyrimidin-2-amine [ No CAS ]
  • 6
  • [ 634468-96-5 ]
  • N-(5-fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazol-6-yl)pyridin-2-yl)-5-(4-(oxacyclobutan-3-yl)piperazin-1-yl)pyrimidin-2-amine [ No CAS ]
  • 7
  • [ 634468-96-5 ]
  • 5-(4-(cyclopropylmethyl)piperazin-1-yl)-N-(5-fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazol-6-yl)pyridin-2-yl)pyrimidin-2-amine [ No CAS ]
  • 8
  • [ 634468-96-5 ]
  • tert-butyl 4-(2-bromopyrimidin-5-yl)piperazin-1-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
1.17% With 5-(bromomethyl)-2-chloropyrimidine; In acetonitrile; at 25℃; for 16h; (2) Preparation of tert-butyl 4-(2-bromopyrimidin-5-yl)piperazin-1-carboxylate Tert-butyl 4-(pyrimidin-5-yl)piperazin-1-carboxylate (2.64 g, 10 mmol) was weighed and added to acetonitrile (125 mL). N-bromobutanimide (1.78 g, 10 mmol) was added under stirring, and the mixture was stirred at 25C for 16 h. The reaction solution was concentrated. Acetic ether (100 mL) and water (100 mL) were added to separate the phases. The organic phase was concentrated and then subjected to silica gel column chromatography (dichloromethane: methanol=30:1) to get the title compound (40 mg, yield: 1.17%).
YieldReaction ConditionsOperation in experiment
With palladium diacetate; caesium carbonate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; In toluene; at 120℃;Inert atmosphere; General procedure: o-Bromofluorobenzene (500 mg, 2.86 mmol) was dissolved in 10 mL of toluene, and N-BOC pyridazine hydrochloride (586 mg, 3.14 mmol, 1.1 eq.) 1,1'-binaphthyl-2,2'- Bis-diphenylphosphine (356 mg, 0.57 mmol, 0.2 equivalent) of cesium carbonate(1.12g, 3.43mmol, 1.2 equivalents),Palladium acetate (64 mg, 0.286 mmol, 0.1 eq.) was replaced with nitrogen three times and allowed to react overnight at 120 C. Evaporate the solvent under reduced pressure and add ethyl acetate.Wash with water and saturated brine in sequence, and dry.Evaporation and column chromatography gave Intermediate 19 (600 mg, white solid)The yield was 74.7%.
  • 10
  • [ 634468-96-5 ]
  • N-(5-methylthiazol-2-yl)-4-(pyrimidin-5-yl)piperazine-1-carboxamide [ No CAS ]
  • 11
  • [ 634468-96-5 ]
  • N-(5-chlorothiazol-2-yl)-4-(pyrimidin-5-yl)piperazine-1-carboxamide [ No CAS ]
 

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Technical Information

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