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Structure of 1074-82-4

Chemical Structure| 1074-82-4

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Product Details of [ 1074-82-4 ]

CAS No. :1074-82-4
Formula : C8H4KNO2
M.W : 185.22
SMILES Code : O=C(C1=C2C=CC=C1)[N-]C2=O.[K+]
MDL No. :MFCD00005887
InChI Key :FYRHIOVKTDQVFC-UHFFFAOYSA-M
Pubchem ID :3356745

Safety of [ 1074-82-4 ]

GHS Pictogram:
Signal Word:Warning
Hazard Statements:H302-H315-H319
Precautionary Statements:P501-P270-P264-P280-P302+P352-P337+P313-P305+P351+P338-P362+P364-P332+P313-P301+P312+P330

Computational Chemistry of [ 1074-82-4 ] Show Less

Physicochemical Properties

Num. heavy atoms 12
Num. arom. heavy atoms 6
Fraction Csp3 0.0
Num. rotatable bonds 0
Num. H-bond acceptors 3.0
Num. H-bond donors 0.0
Molar Refractivity 40.86
TPSA ?

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

34.14 Ų

Lipophilicity

Log Po/w (iLOGP)?

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

-8.96
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

1.15
Log Po/w (WLOGP)?

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

0.97
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.

1.65
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

1.55
Consensus Log Po/w?

Consensus Log Po/w: Average of all five predictions

-0.73

Water Solubility

Log S (ESOL):?

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

-2.08
Solubility 1.53 mg/ml ; 0.00826 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.

-1.46
Solubility 6.4 mg/ml ; 0.0346 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

-2.76
Solubility 0.325 mg/ml ; 0.00175 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.

-6.61 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

1.0
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<1.0
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)

1.1

Application In Synthesis of [ 1074-82-4 ]

* 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 [ 1074-82-4 ]
  • Downstream synthetic route of [ 1074-82-4 ]

[ 1074-82-4 ] Synthesis Path-Upstream   1~1

  • 1
  • [ 1252018-10-2 ]
  • [ 1074-82-4 ]
  • [ 446292-07-5 ]
YieldReaction ConditionsOperation in experiment
93% at 20 - 100℃; for 3 h; Example 3:Preparation of 2-((2R)-2-Hydroxy-3-[4-(3-oxomorpholin-4-yl)- phenyl]amino}proply)-1 /-/-isoindole-1 ,3(2H)-dione (7a): Potassium phthalimide (7.16 g, 38.632 mmoL) was added in one portion to a mechanically stirred mixture of 4-[4-(N-(3-chloro-2R-hydroxy-1-propyl)amino)phenyl]morpholin-3- one (10 g, 35.119 mmoL) in DMF (60 mL). The suspension was stirred at room temperature and was heated to 100 °C, stirred at that temperature for 3 h and then cooled to room temperature. Water (60 mL) was charged and the suspension stirred for another 15 min. The suspension was filtered through a Buchner funnel. The solid was washed with water (2 x 40 mL) and dried under vacuum at 50°C for 10 h to yield 2-((2f?)-2-Hydroxy-3-[4-(3-oxomorpholin-4- yl)-phenyl]amino}proply)-1 7-isoindole-1 ,3(2/-/)-dione (12.55 g, 93percent) as a crystalline white solid.1HNMR (400MHz, DMSO-d6) δ 2.99-3.05 (m, 1 H), 3.14-3.2 (m, 1 H), 3.59-3.69 (m, 4H), 3.91-3.94 (m, 2H), 3.97-4.05 (m, 1 H), 4.14 (s, 2H), 5.16 (d, J=5.2 Hz, 1 H), 5.66 (t, J=6.0 Hz, 1 H), 6.61 (d, J=8.7 Hz, 2H), 7.03 (d, J=8.8 Hz, 2H), 7.82-7.88 (m, 4H).
92%
Stage #1: With sodium hydroxide In dichloromethane; water at 20℃; for 8 h;
Stage #2: at 100℃; for 3 h;
The above 57.6 g of intermediate 4 and 400 mL of dichloromethane were charged into a 1 L three-necked flask,A solution of 17.8 g of Na0H and 60 mL of water was added dropwise at room temperature,After stirring at room temperature for 6 h, the organic layer was washed with 120 mL of water and then with 60 mL of saturated brine,The organic layer was dried over anhydrous sodium sulfate,Filtered, concentrated to 180mL of liquid, by adding 360mL n-hexane heated reflux 30min,System cooling to room temperature and then stirring 2h,The filter cake was washed with dichloromethane and n-hexane (1: 3)The filter cake was dried in vacuo for 12 h to give 48.2 g of white crystals.48 g (0.17 mol) of the above solid and 240 mL of the 4-dioxane were charged into a 500 mL three-necked flask,34.4 g (0.19 mol) of potassium phthalimide potassium salt was added with stirring,System gradually heated to 100 ° C, stirring 3h, cooling to room temperature, add 60mL water stirring 15min,Filter, filter cake washed with 2X1 OOmL,White crystals were obtained at 50 ° C in vacuum and dried 1 Oh to give 60.2 g of compound 6 (92percent) mp. = 211.7-211.9 ° C.
87.8% for 10 h; Reflux The reaction flask, and the resulting 32.7g (0.115mol) of intermediate V with 300ml of anhydrous methanol was dissolved, followed by addition of 29.1g (0.157mol) of potassium phthalimide and heated at reflux for 9 hours, TLC in the control (ethyl acetate: methanol = 10: 1, volume ratio) to complete the reaction, filtered hot, the filtrate was lowered to room temperature (about 25 ) was stirred for 2 hours, filtered, the filter cake was rinsed with 75ml of anhydrous methanol, and drying under reduced pressure, intermediate VI to give an off-white about 39.9g (0.101mol), intermediate V molar yield intermediate VI is prepared from about 87.8percent.
87.8% for 9 h; Reflux In the reaction flask, the obtained 32.7 g (0.115 mol) of the intermediate V was dissolved with 300 ml of anhydrous methanol,Then, 29.1 g (0.157 mol) of potassium phthalimide was added and the mixture was heated to reflux for 9 hours.The reaction was completed by TLC (ethyl acetate:methanol=10:1, volume ratio) and the reaction was complete. The filtrate was cooled to room temperature (about 25° C.) and stirred for 2 hours. The mixture was filtered, and the filter cake was rinsed with 75 ml of anhydrous methanol. drying,About 39.9 g (0.101 mol) of the off-white intermediate VI was obtained, and about 87.8percent of the intermediate V was produced in the molar yield of the intermediate VI.
51.4 g for 10 h; Reflux In the reaction flask, the obtained 42.6 g (0.15 mol)Intermediate V was dissolved with 400 ml anhydrous methanol.Then 38.8 g (0.21 mol) of potassium phthalimide was added,The mixture was heated at reflux for 10 hours, and the reaction was completed by TLC (ethyl acetate: methanol = 10:1, volume ratio).Heat filtered, the filtrate was cooled to room temperature (about 25°C) and stirred for 2 hours, filtered,The filter cake was rinsed with 100 ml of anhydrous methanol and dried under reduced pressure to obtain about 51.4 g (0.13 mol) of the off-white intermediate VI. The intermediate V produced the intermediate VI in a molar yield of about 86.7percent.

References: [1] Patent: WO2012/51692, 2012, A1, . Location in patent: Page/Page column 42-43.
[2] Patent: CN103951661, 2017, B, . Location in patent: Paragraph 0043-0044.
[3] Patent: CN104974105, 2017, B, . Location in patent: Paragraph 0073.
[4] Patent: CN104974149, 2018, B, . Location in patent: Paragraph 0074; 0075; 0077; 0081; 0083.
[5] Patent: WO2012/32533, 2012, A2, . Location in patent: Page/Page column 15.
[6] Patent: CN104974148, 2017, B, . Location in patent: Paragraph 0073; 0074; 0076; 0082.
 

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