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Chemical Structure| 503614-91-3 Chemical Structure| 503614-91-3

Structure of FaX-IN-1
CAS No.: 503614-91-3

Chemical Structure| 503614-91-3

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Product Details of [ 503614-91-3 ]

CAS No. :503614-91-3
Formula : C27H28N4O5
M.W : 488.54
SMILES Code : O=C(C1=NN(C2=CC=C(OC)C=C2)C3=C1CCN(C4=CC=C(N5C(CCCC5)=O)C=C4)C3=O)OCC
MDL No. :MFCD18072444
InChI Key :PULNLYVCJSOXKS-UHFFFAOYSA-N
Pubchem ID :22240488

Safety of [ 503614-91-3 ]

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

Computational Chemistry of [ 503614-91-3 ] Show Less

Physicochemical Properties

Num. heavy atoms 36
Num. arom. heavy atoms 17
Fraction Csp3 0.33
Num. rotatable bonds 7
Num. H-bond acceptors 6.0
Num. H-bond donors 0.0
Molar Refractivity 140.69
TPSA ?

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

93.97 Ų

Lipophilicity

Log Po/w (iLOGP)?

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

4.45
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

3.58
Log Po/w (WLOGP)?

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

3.02
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.

2.84
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

3.13
Consensus Log Po/w?

Consensus Log Po/w: Average of all five predictions

3.4

Water Solubility

Log S (ESOL):?

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

-5.01
Solubility 0.00475 mg/ml ; 0.00000973 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.

-5.24
Solubility 0.00281 mg/ml ; 0.00000576 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

-6.56
Solubility 0.000136 mg/ml ; 0.000000278 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

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

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

Yes
Log Kp (skin permeation)?

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

-6.74 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<2.0
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)

3.81

Application In Synthesis of [ 503614-91-3 ]

* 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 [ 503614-91-3 ]

[ 503614-91-3 ] Synthesis Path-Downstream   1~7

  • 1
  • chloro((4-methoxyphenyl)hydrazono]acetic acid ethyl ester [ No CAS ]
  • [ 545445-44-1 ]
  • [ 503614-91-3 ]
YieldReaction ConditionsOperation in experiment
With hydrogenchloride; triethylamine; In ethyl acetate; Example 55 1-(4-Methoxy-phenyl)-7-oxo-6-[4-(2-oxo-piperidin-1-yl)-phenyl]-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid ethyl ester (65). A solution of chloro[(4-methoxyphenyl)hydrazono]acetic acid ethyl ester (34, 470 mg, 1.3 mmol) in EtOAc (4 mL) was treated with 3-morpholin-4-yl-1-[4-(2-oxo-piperidin-1-yl)-phenyl]-5,6-dihydro-1H-pyridin-2-one (63, 334 mg, 1.3 mmol, 1.0 equiv) at 0-5 C. under N2, and the resulting reaction mixture was treated with triethylamine (TEA, 263 mg, 0.33 mL, 2.6 mmol, 2.0 equiv) at 0-5 C. under N2. The reaction mixture was then warmed up to room temperature for 30 min before being warmed up to reflux for an additional 6 h. When HPLC and TLC showed that the reaction was complete, the reaction mixture was cooled down to 5-10 C. before being treated dropwise with a 4.0 N aqueous HCl solution (1.7 mL, 6.5 mmol, 5.0 equiv) at 0-5 C. The resulting mixture was stirred at 5-20 C. for 4 h. The resulting slurry was then treated with water (10 mL) and EtOAc (10 mL) before the two layers were separated. The aqueous layer was extracted with EtOAc (2*10 mL). The combined organic extracts were washed with saturated NaCl aqueous solution (5 mL), dried over MgSO4, and concentrated in vacuo. The residue was directly purified by flash column chromatography (SiO2, 15-40% EtOAc/hexane gradient elution) to afford the desired 1-(4-methoxy-phenyl)-7-oxo-6-[4-(2-oxo-piperidin-1-yl)-phenyl]-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid ethyl ester (65, 423 mg, 635 mg theoretical, 67% for two steps) as pale-yellow solids, which solidified upon standing in vacuo at room temperature. For 65, CIMS m/z 489 (M++H, C27H28N4O5).
  • 3
  • [ 545445-44-1 ]
  • [ 473927-63-8 ]
  • [ 503614-91-3 ]
YieldReaction ConditionsOperation in experiment
85% With triethylamine; potassium iodide; In dichloromethane; at 42 - 45℃; Product of example-VA (14.2 g, 0.04 mol), TEA (17 mL, 0.12 mol), and KI (0.64 g, 0.004 mol) were added to a solution of the product of example-VI (11.3 g, 0.044 mol) in MDC (80 mL) at room temperature. The mixture was stirred at 42-45 C. for 12-15 hrs and then cooled to 0 C. To the resulting mixture was added 4.0N hydrochloric acid (50 mL, 0.02 mol) drop wise and stirred at room temperature for 2-4 hrs. Thereafter water (100 mL) was added to the mixture to separate the organic layer. The aqueous layer was extracted with MDC, 50 mL and then the combined organic extracts were washed with brine (2*100 mL), and concentrated to dryness. Recrystallization of the residue from EtOAc and drying in vacuum afforded product as cream colored solid. Yield: 16.58 g, 85%. Purity: 99.5+%
35 g Example-10 Preparation of ethyl 1-(4-methoxyphenyl)-7-oxo-6-(4-(2-oxopiperidin-1-yl)phenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylate (Formula-11) A mixture of 3-morpholino-1-(4-(2-oxopiperidin-1-yl)phenyl)-5,6-dihydropyridin-2(1H)-one compound of formula-8 (30 g), sodium carbonate (26.83 g) and acetone (150 ml) was heated to 45-50 C. (Z)-ethyl 2-chloro-2-(2-(4-methoxyphenyl)hydrazono)acetate compound of formula-9 (32.5 g) was added to the reaction mixture at 45-50 C. and stirred for 3 hours at the same temperature. Cooled the reaction mixture to 25-30 C. and aqueous hydrochloric acid (50 ml) in 50 ml of water was added to it at 25-30 C. Stirred the reaction mixture for 2 hours at 25-30 C. Water was slowly added to the reaction mixture and stirred for 45 minutes at 25-30 C. Filtered the obtained solid and washed with water. The obtained solid was recrystallized from toluene (150 ml) to get the title compound. Yield: 35 gm; MR: 155-160 C.; HPLC purity: 97%.
  • 6
  • [ 545445-44-1 ]
  • [ 27143-07-3 ]
  • [ 503614-91-3 ]
YieldReaction ConditionsOperation in experiment
89.9% With triethylamine; potassium iodide; In ethyl acetate; for 24h;Reflux; (14 mmol) of the compound of the formula (IV) and 4. 0 g (16 mmol)The compound of structure (V) was added to 150 mL of ethyl acetate,0.35 g (2 mmol) of KI, 6.8 ml (49 mmol) of triethylamine was added and refluxed for 24 h, Cooled to 0C degrees, dropping 4M dilute hydrochloric acid 20mL, stirring at room temperature 2h, filtration, a small amount of cold ethyl acetate washing, water hit the public, about 50 C blast drying,To obtain crude product 6. 5g, yield 94. 6%, and then recrystallized from ethyl acetate, To obtain 5.8 g of a solid, powdery product,The yield was 89% and the purity was 99.8%.
76% With triethylamine; In ethyl acetate; toluene; at 85℃; for 7h; Toluene (25 mL) was added to the reaction flask.Triethylamine (2.60 g, 25.7 mmol) and ethyl acetate (25 mL),Starting material A (2.80 g, 10.9 mmol) and starting material B (3.00 g, 8.4 mmol),The temperature was raised to 85 ° C by heating and stirred for 7 hours.The reaction solution was cooled to 25 °C. Adding a hydrochloric acid solution to the reaction solution,The dropping time is controlled at 25 minutes and the temperature is controlled at 30 °C.After the dropwise addition was completed, the reaction was stirred at 30 ° C for 1 hour.15 mL of purified water was added and stirred for 30 minutes. Filter the filter cake,Add 20 mL of isopropanol for washing.Drying apixaban intermediate 1 13.12g,The molar yield was 76.0percent.
54 mg With triethylamine; potassium iodide; In ethyl acetate; at 25 - 80℃; for 24h; In 3 lit four neck equipped round bottomed flask (RBF) equipped, ethyl acetate (2.5L), 3- morpholino-l-[4-(2-oxopiperidin-l-yl)phenyl]-5,6-dihydropyridin-2(1H)-one (50gm,), acetic acid 2-chloro-2-[-(4-methoxyphenyl)hydrazinylidene]ethyl ester (36.1 gm) , ethyl amine (57 gm) and potassium iodide (2.4 gm) were added sequentially at about 25-30C . The reaction mass was heated to about 75-80C for about 24 hrs. After completion, the reaction mass was cooled to about 0 - 5C and dilute hydrochloric acid was added slowly to the reaction mass at about 0- 5C. The temperature of the reaction mass was raised to about 25-30C and stirred for 2 hrs. Water was added to the reaction mass and stirred for 15 min. The layers were separated and the organic layer was washed with aq. sodium carbonate solution followed by water. The organic layer was partially concentrated under vacuum and cooled to about 25-30C. Isopropyl ether was added to the reaction mass and stirred for 1 hr. The precipitated solid was filtered and washed with isopropyl ether. The solid was dried under vacuum at 45-50C for 12hrs to afford 54 gm of 1-(4-methoxy-phenyl)-7-oxo-6-[4-(2-oxo-piperidin-1-yl)-phenyl]-4,5,6,7-tetrahydro-1H- pyrazolo[3,4-c]pyridine-3-carboxylic acid ethyl ester (HPLC purity>99%)
The compound of formula (VIII) was prepared according to the method disclosed in the Journal Synthetic Communication, 2013, vol. 43, pag. 72-79, in particular, the paragraph entitled "Ethyl 1 -(4-methoxyphenyl)-7-oxo-6-(4-(2-oxopiperidin-1-yl)phenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylate (2)" at pag.78, starting from the compound of formula (IX) prepared according to the example 2.

  • 7
  • [ 545445-44-1 ]
  • [(4-methoxyphenyl)hydrazino]chloroacetic acid ethyl ester [ No CAS ]
  • [ 503614-91-3 ]
YieldReaction ConditionsOperation in experiment
89.6% To a 5 L reaction flask was added compound 2220 g (0.62 mol), 3.2 L of toluene, and the compound VI (0.76 g), 197.2 g (1.86 mol) of sodium carbonate and 423.6 g of TEBA (1.863 mol) were heated and refluxed for 3.0 h. The reaction was complete by HPLC. The reaction was quenched by adding ice water (3.8 kg) 3X1.5L extraction, the organic phase with saturated brine 2L wash, organic layer dry, filtered and concentrated to get 369g yellow solid material, adding 3.2L dichloromethane to the system and adding 60% sulfuric acid solution 303.8mL, room temperature stirring 3.5h, After adding water to the quenching reaction, the aqueous phase was extracted with dichloromethane 3X1.0L, the organic layers were combined, dried, filtered and the solvent was removed to obtain 298.1 g (yield: 89.6%) of yellow solid compound IX, HPLC: 98.3%.
 

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