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Chemical Structure| 675126-27-9

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Product Details of [ 675126-27-9 ]

CAS No. :675126-27-9
Formula : C15H21N3O3
M.W : 291.35
SMILES Code : COC1=CC(N)=C(C=C1OCCCN1CCOCC1)C#N
MDL No. :MFCD11110477

Safety of [ 675126-27-9 ]

GHS Pictogram:
Signal Word:Warning
Hazard Statements:H302
Precautionary Statements:P280-P305+P351+P338

Computational Chemistry of [ 675126-27-9 ] Show Less

Physicochemical Properties

Num. heavy atoms 21
Num. arom. heavy atoms 6
Fraction Csp3 0.53
Num. rotatable bonds 6
Num. H-bond acceptors 5.0
Num. H-bond donors 1.0
Molar Refractivity 83.17
TPSA ?

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

80.74 Ų

Lipophilicity

Log Po/w (iLOGP)?

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

2.75
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

1.47
Log Po/w (WLOGP)?

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

0.88
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.

-0.12
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

1.82
Consensus Log Po/w?

Consensus Log Po/w: Average of all five predictions

1.36

Water Solubility

Log S (ESOL):?

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

-2.39
Solubility 1.19 mg/ml ; 0.00409 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.

-2.77
Solubility 0.492 mg/ml ; 0.00169 mol/l
Class?

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

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

-3.39
Solubility 0.12 mg/ml ; 0.000411 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

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

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.

-7.03 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

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<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)

2.48

Application In Synthesis of [ 675126-27-9 ]

* 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 [ 675126-27-9 ]
  • Downstream synthetic route of [ 675126-27-9 ]

[ 675126-27-9 ] Synthesis Path-Upstream   1~6

  • 1
  • [ 675126-26-8 ]
  • [ 675126-27-9 ]
YieldReaction ConditionsOperation in experiment
99% With sodium dithionite In water at 50℃; for 2 h; Sodium DITHIONITE (89percent, 81.4 kg) was added to a stirred slurry of 4-methoxy- 5-(3-MORPHOLINOPROPOXY)-2-NITROBENZONITRILE (48.8 kg) in water (867 litres) and the resultant mixture was heated to 50°C for approximately 2 hours to complete the reaction. The temperature of the reaction mixture was raised to approximately 70°C and a concentrated aqueous hydrochloric acid solution (36percent, 270 kg) was added over 3 hours. The resultant mixture was cooled to 20-25°C and sodium hydroxide liquor (47percent, 303.7 kg) was added whilst stirring of the reaction mixture was continued. The reaction mixture was extracted with two portions of methylene chloride (1082 kg and 541 kg respectively) and the combined organic extracts were washed with water (510 litres). The organic phase was evaporated to give 2- AMINO-4-METHOXY-5- (3-MORPHOLINOPROPOXY) benzonitrile (46.3 kg, 99percent yield); mp. 87. 5°C ; NMR Spectrum: (DMSOd6) 1.79 (M, 2H), 2.36 (t, 4H), 2.36 (t, 2H), 3.56 (t, 4H), 3.73 (s, 3H), 3. 86 (t, 2H), 5.66 (br s, 2H), 6.4 (s, 1H), 6.89 (s, 1H) ; Mass Spectrum : M+H+ 292.
99%
Stage #1: With sodium dithionite In water at 50℃; for 2 h;
Stage #2: With hydrogenchloride In water at 70℃; for 3 h; Acidic aqueous solution
Stage #3: With sodium hydroxide In water at 20 - 25℃; Alkaline aqueous solution
Sodium dithionite (89percent, 81.4 kg) was added to a stirred slurry of 4-methoxy- [5- (3-MORPHOLINOPROPOXY)-2-NITROBENZONITRILE] (48.8 kg) in water (867 litres) and the resultant mixture was heated to [50°C] for approximately 2 hours to complete the reaction. The temperature of the reaction mixture was raised to approximately [70°C] and a concentrated aqueous hydrochloric acid solution (36percent, 270 kg) was added over 3 hours. The resultant mixture was cooled to [20-25°C] and sodium hydroxide liquor (47percent, 303.7 kg) was added whilst stirring of the reaction mixture was continued. The reaction mixture was extracted with two portions of methylene chloride (1082 kg and 541 kg respectively) and the combined organic extracts were washed with water (510 litres). The organic phase was concentrated by distillation to remove 800 litres of solvent. There was thus obtained a methylene chloride solution (503.5 kg) containing 2-amino-4-methoxy-5- (3-morpholinopropoxy) benzonitrile (46.3 kg, 99percent yield) suitable for use in the next stage. [A portion of the [2-AMINO-4-METHOXY-5- (3-MORPHOLINOPROPOXY)] benzonitrile was isolated using the following procedure:- A sample of the methylene chloride solution was evaporated. There was thus obtained [2-AMINO-4-METHOXY-5- (3-MORPHOLINOPROPOXY)] benzonitrile as a solid, m. p. 87. [5°C] ; NMR Spectrum: [(DMSOD6)] 1.79 (m, 2H), 2.36 (t, 4H), 2.36 (t, 2H), 3.56 (t, 4H), 3.73 (s, 3H), 3.86 (t, 2H), 5.66 (br s, 2H), 6.4 (s, 1H), 6.89 (s, 1H); Mass Spectrum : [M+HS 292.]]
95%
Stage #1: With sodium thiosulphite In water at 45℃; for 2 h;
Stage #2: With hydrogenchloride In water at 70℃; for 0.833333 h;
The (11.1g, 64.0mmol) mixed nitro-4-methoxy-5- [3- (4-morpholinyl) propoxy] benzonitrile (10.0g, 31.1mmol) and sodium thiosulfite , was added 80mL of water, the reaction mixture was stirred at 45 2 hours, warmed to 70 , added dropwise with stirring 36percent concentrated hydrochloric acid 25mL, 30min addition was complete, the reaction was continued to maintain 70 20min, heating was stopped, cooled to room temperature.Was slowly added dropwise under ice-cooling to a mixture of 40percent NaOH, the pH was adjusted to about 10, and extracted with dichloromethane (100mL × 3), combined organic phase was washed with water until neutral, dried over anhydrous magnesium sulfate, filtered, and evaporated under reduced pressure dichloromethane to give brown viscous liquid, namely 2-amino-4-methoxy-5- [3- (4-morpholinyl) propoxy] benzonitrile (8.6g, 95percent yield ).
95.3% With 15% palladium on carbon; ammonium formate In ethanol at 60 - 65℃; for 2 h; Add 14g (43.6mmol) to a 250mL three-necked flask 4-methoxy-5-(3-morpholinopropoxy)-2-nitrobenzonitrile and 140 mL of anhydrous ethanol, after stirring and dissolving, 5.5 g (87.2 mmol) of ammonium formate 1.4 g palladium carbon (content 15percent) was added.The temperature was raised to 60-65°C and the reaction was carried out for 2 hours. The reaction was monitored by TLC. It is filtered with Celite,Ethyl acetate extraction, the organic layer was concentrated,Obtained 12.1 g (95.3percent) of a yellow oil.
95% With iron; ammonium chloride In ethanolReflux (3) In the reaction flask, compound A (0.2 mol), anhydrous ethanol 700 g, and reduced iron powder 45 g were sequentially added.(0.8 mol) and ammonium chloride (4.4 g, 0.08 mol), after the addition is completed, the temperature is raised to reflux, and the reaction is carried out for 2-3 hours.The filter cake was washed with absolute ethanol, and the filtrate was combined. The ethanol was distilled off under reduced pressure, cooled to 20 ° C for 30 min, filtered, and reduced at 60 ° C.Dry to constant weight, brown color acicular solid compound B 55g, yield 95percent
84%
Stage #1: With sodium dithionite In water at 50℃; for 2.5 h;
Stage #2: With hydrogenchloride In water at 70℃; for 2 h;
To a suspension compound 4 (2.0 g,6.2 mmol) in water (30.4 mL), sodium dithionite (3.6 g, 20.7 mmol) was added. The mixture was stirred at 50 °C for 2.5 h. After the mixture was heated to 70 °C, 37percent HCl (25 mL) was added slowly in a period of 2 h. Heating was continued for another 1 h. After cooling to room temperature, the mixture was basified to pH 11 with 50percent NaOH aqueous solution. The mixture was extracted by CH2Cl2 for three times. The solution was evaporated, and the residue was purified by silica gel chromatography with eluent (20:1 CH2Cl2/EtOH) to give a viscous liquid 5 (1.5g, 84percent). For 1H-NMR (300 MHz, DMSO-d6) δ (ppm): 6.89 (s, 1H), 6.40 (s, 1H), 5.63 (s, 2H), 3.84–3.88 (t, 2H), 3.73 (s, 3H), 3.56 (m, 4H), 2.35 (m, 6H),1.77–1.81 (m, 2H). 13C-NMR (75 MHz, DMSO-d6) δ (ppm): 155.4, 148.9, 139.9, 119.1, 116.4, 99.4, 84.2,68.1, 66.7, 55.8, 55.3, 53.8, 26.5.

References: [1] Patent: WO2005/23783, 2005, A1, . Location in patent: Page/Page column 18.
[2] Patent: WO2004/24703, 2004, A1, . Location in patent: Page 10.
[3] Organic Process Research and Development, 2007, vol. 11, # 5, p. 813 - 816.
[4] Patent: CN105503749, 2016, A, . Location in patent: Paragraph 0053; 0054; 0055.
[5] Patent: CN107586279, 2018, A, . Location in patent: Paragraph 0008; 0018.
[6] Patent: CN108503597, 2018, A, . Location in patent: Paragraph 0026; 0034-0036.
[7] Molecules, 2017, vol. 22, # 10, .
[8] Bioorganic and Medicinal Chemistry Letters, 2006, vol. 16, # 15, p. 4102 - 4106.
  • 2
  • [ 675126-28-0 ]
  • [ 675126-27-9 ]
References: [1] Bioorganic and Medicinal Chemistry Letters, 2006, vol. 16, # 15, p. 4102 - 4106.
[2] Patent: CN105503749, 2016, A, .
[3] Molecules, 2017, vol. 22, # 10, .
[4] Patent: CN107586279, 2018, A, .
  • 3
  • [ 52805-46-6 ]
  • [ 675126-27-9 ]
References: [1] Bioorganic and Medicinal Chemistry Letters, 2006, vol. 16, # 15, p. 4102 - 4106.
[2] Patent: CN105503749, 2016, A, .
[3] Molecules, 2017, vol. 22, # 10, .
[4] Patent: CN107586279, 2018, A, .
  • 4
  • [ 621-59-0 ]
  • [ 675126-27-9 ]
References: [1] Bioorganic and Medicinal Chemistry Letters, 2006, vol. 16, # 15, p. 4102 - 4106.
[2] Molecules, 2017, vol. 22, # 10, .
[3] Patent: CN107586279, 2018, A, .
  • 5
  • [ 7357-67-7 ]
  • [ 675126-27-9 ]
References: [1] Bioorganic and Medicinal Chemistry Letters, 2006, vol. 16, # 15, p. 4102 - 4106.
[2] Patent: CN105503749, 2016, A, .
  • 6
  • [ 102714-71-6 ]
  • [ 675126-27-9 ]
References: [1] Patent: CN108503597, 2018, A, .
 

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