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Structure of 289042-10-0

Chemical Structure| 289042-10-0

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Product Details of [ 289042-10-0 ]

CAS No. :289042-10-0
Formula : C28H29FN3O3PS
M.W : 537.59
SMILES Code : CC(C)C1=NC(=NC(C2=CC=C(F)C=C2)=C1CP(=O)(C1=CC=CC=C1)C1=CC=CC=C1)N(C)S(C)(=O)=O
MDL No. :MFCD09839448
Boiling Point : No data available
InChI Key :CVRDGWDBQZPJJI-UHFFFAOYSA-N
Pubchem ID :9937035

Safety of [ 289042-10-0 ]

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

Computational Chemistry of [ 289042-10-0 ] Show Less

Physicochemical Properties

Num. heavy atoms 37
Num. arom. heavy atoms 24
Fraction Csp3 0.21
Num. rotatable bonds 8
Num. H-bond acceptors 6.0
Num. H-bond donors 0.0
Molar Refractivity 148.84
TPSA ?

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

98.42 Ų

Lipophilicity

Log Po/w (iLOGP)?

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

3.21
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

4.68
Log Po/w (WLOGP)?

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

6.67
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.

3.37
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

5.01
Consensus Log Po/w?

Consensus Log Po/w: Average of all five predictions

4.59

Water Solubility

Log S (ESOL):?

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

-6.07
Solubility 0.000454 mg/ml ; 0.000000844 mol/l
Class?

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

Poorly soluble
Log S (Ali)?

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

-6.47
Solubility 0.00018 mg/ml ; 0.000000335 mol/l
Class?

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

Poorly 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

-10.54
Solubility 0.0000000155 mg/ml ; 0.0 mol/l
Class?

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

Insoluble

Pharmacokinetics

GI absorption?

Gatrointestinal absorption: according to the white of the BOILED-Egg

Low
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

No
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

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

Yes
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

Yes
Log Kp (skin permeation)?

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

-6.26 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

1.0
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

1.0
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

1.0 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<3.0
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)

4.47

Application In Synthesis of [ 289042-10-0 ]

* 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.

  • Upstream synthesis route of [ 289042-10-0 ]

[ 289042-10-0 ] Synthesis Path-Upstream   1~1

  • 1
  • [ 289042-10-0 ]
  • [ 124752-23-4 ]
  • [ 289042-12-2 ]
YieldReaction ConditionsOperation in experiment
67.7%
Stage #1: With sodium hexamethyldisilazane In tetrahydrofuran at -76 - -74℃; for 1.16667 h;
Stage #2: at -76 - 10℃; for 2.08333 h;
A mixture of DPPO (19.17 g) and THF (227 ml) were warmed briefly to 40 C. until a clear solution had formed then inerted by the sequential application of vacuum and nitrogen (5 cycles). The mixture was immersed in an acetone/CO2 bath cooling the contents to -75 C. Sodium bis(trimethylsilyl)amide (37.4 ml of 1.0 M solution in THF) was added to the reaction mixture over 10 minutes from a pressure equalising dropping funnel maintaining the temperature below -74 C and forming a red solution of the anion. THF (10 ml) was rinsed through the dropping funnel into the mixture and the mixture stirred a further 1 hour at -76 C forming a red suspension. BFA (80 ml of 13.5percent w/w toluene solution) was added in portions to the suspension over 20 minutes from a pressure equalising dropping funnel maintaining the temperature below -73 C. Toluene (20 ml) was rinised through the dropping funnel into the mixture and the mixture stirred a further 15 minutes at -76 C. The chilling bath was lowered and the suspension allowed to warm to 10 C over 1.5 hours. Glacial acetic acid (3.21 g) in water (15 g) was added in one portion raising the temperature to 18 C and dissolving all solids and the mixture was stirred a further 5 minutes. The mixture was concentrated by distillation at atmospheric pressure (jacket 110 C) to a temperature of 94 C collecting a total of 274 ml distillates. The concentrated mixture was cooled to 40 C, water (40 ml) was added and the mixture stirred for 5 minutes then allowed to settle for 15 minutes. The lower aqueous phase was discarded. Sodium hydrogen carbonate (2.99 g) in water (40 ml) was added and the mixture stirred for 5 minutes then allowed to settle for 15 minutes. The lower aqueous phase was discarded. Water (30 ml) was added and the mixture stirred for 5 minutes then allowed to settle for 15 minutes. The lower aqueous phase was discarded. The organic phase was transferred to a distillation apparatus with toluene (20 ml) and concentrated by distillation at atmospheric pressure (jacket 125-130 C) to a temperature of 116 C collecting 85 ml distillates. Vacuum was applied (400-500 mbar) and a further 16.5 ml distillates collected to a temperature of 111 C. The vacuum was released and the concentrated mixture allowed to cool to 80 C. Warm MeOH (140 ml, 50 C) was added with rapid stirring and the batch allowed to self-cool to 20 C over 30 minutes during which time a solid was deposited. The suspension was further cooled to 2 C for 30 minutes then the solid was collected by filtration on a sinter and pulled as dry as possible. The solid was washed with cold MeOH (60 ml, 2C.) and again pulled as dry as possible then transferred to a vacuum oven and dried overnight (50 C, 200 mbar); giving BEM (14.01 g, 67.7percent). 1H NMR (CDCl3, 270 MHz) 7.65 [m, 2H, ArH], 7.09 [m, 2H, ArH], 6.52 [dd, 1H, ArCH=CH], 5.47 [dd, 1H, ArCH=CH], 3.57, 3.50 [2 x s, 6H, NCH3, SO2CH3], 3.38 [hept., 1H, ArCHMe2], 2.45, 2.30 [2x dd, 2H, CH2CO2tBu], 1.55, 1.13 [dt, dd, 2H, acetonide CH2], 1.50, 1.40 [2x s, 6H, acetonide C(CH3)2], 1.45 [s, 9H, CO2C(CH3)3], 1.27 [dd 6H, ArCH(CH3)2]
61%
Stage #1: With sodium hexamethyldisilazane In tetrahydrofuran at -74℃; for 1 h;
Stage #2: at -74 - 10℃; for 3 h;
Stage #3: With acetic acid In tetrahydrofuran; water; toluene at 10 - 40℃; for 0.166667 h;
Sodium bis (trimethylsilyl) amide (1 M in tetrahydrofuran, 23 mi) is added dropwise, AT-74°C, to a suspension of the compound of formula (38) (12 g, 22.3 MMOL) in tetrahydrofuran (130 M .). STIRRING is carried out at-74°C for 1 hour and then a solution of the compound of formula (40) (6.9 g, 26.8 MMOI) in toluene (28 ML) is added dropwise. Stirring is then carried out AT-74°C for 1 hour, then warming to 10°C over the course of 1 hour and stirring for a further 1 hour at that temperature. A mixture of acetic acid (2 ml) and water (8.4 ML) is added, at 10°C, to the resulting yellow suspension and stirring is carried out at room temperature for 5 minutes. The tetrahydrofuran is then distilled off, and, at 40°C, 45 ml of water are added to the reaction mixture and vigorous stirring is carried out for 5 minutes. The aqueous phase is separated off and a solution of sodium hydrogen carbonate (2.27 G) in water (45 ml) is added to the organic phase. Vigorous stirring is again carried out for 5 minutes and then the aqueous phase is removed again. The organic phase is diluted with 250 ML of toluene, washed successively with water and saturated sodium chloride solution and dried (using NA2SO4). The salt mixture is filtered off and the filtrate is concentrated by evaporation. The concentrated residue is then purified by column chromatography on silica gel (hexane: ethyl acetate 8: 1). 2.59 G (61 percent) of the desired product (39) can be obtained in the form of colourless crystals. 'H NMR (300 MHz, CDCI3) : 0.91-1. 08 (m, 1H) ; 1.20 (d, J = 6. 7 HZ, 6H); 1. 24 (S, 3H); 1. 38 (S, 9H); 1.41 (S, 3H); 1.41-1. 56 (m, 1 H) ; 2.21 (dd, J = 15. 2, 7. 9, 1 H) ; 2. 35 (dd, J = 15. 0, 5. 0 HZ, 1H) ; 3. 27-3. 37 (m, 1H) ; 3. 43 (S, 3H); 3.52 (S, 3H); 4.17-4. 24 (m, 1H) ; 4. 47-4. 53 (m, 1H) ; 5.43 (dd, J = 16.4, 5.5 Hz, 1H) ; 6.55 (dd, J = 16.1, 0.8 Hz, 1H) ; 7.24 (dd, J = 8.8, 8.8 HZ, 2H); 7.65 (dd, J = 8.8, 5.6 Hz, 2H). 13C NMR (75 MHz, CDCI3) : 18.7, 20.6, 20.7, 27.0, 29.0, 30.9, 32.0, 35.0, 41.3, 41.4, 64.8, 68.1, 79.6, 97.7, 113.7 (JCF = 21.7 Hz), 120.0, 122.0, 131. 0 (JCF = 8.4 Hz), 133.2 (JCF = 3.2 Hz), 136.3, 156.0, 162.0 (JCF = 249 Hz), 162.2, 168.8, 173.6.
References: [1] Patent: US2004/49036, 2004, A1, . Location in patent: Page 3.
[2] Patent: WO2004/103977, 2004, A2, . Location in patent: Page 25-26.
 

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