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Chemical Structure| 1240390-28-6

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Product Details of [ 1240390-28-6 ]

CAS No. :1240390-28-6
Formula : C5H3Cl2N3O
M.W : 192.00
SMILES Code : O=C(C1=CN=C(Cl)N=C1Cl)N
MDL No. :MFCD16658133
InChI Key :OACCNUGECQQVLB-UHFFFAOYSA-N
Pubchem ID :21223080

Safety of [ 1240390-28-6 ]

GHS Pictogram:
Signal Word:Warning
Hazard Statements:H302-H315-H319-H332-H335
Precautionary Statements:P261-P280-P305+P351+P338

Computational Chemistry of [ 1240390-28-6 ] Show Less

Physicochemical Properties

Num. heavy atoms 11
Num. arom. heavy atoms 6
Fraction Csp3 0.0
Num. rotatable bonds 1
Num. H-bond acceptors 3.0
Num. H-bond donors 1.0
Molar Refractivity 40.15
TPSA ?

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

68.87 Ų

Lipophilicity

Log Po/w (iLOGP)?

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

1.22
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

1.0
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.

0.01
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

1.4
Consensus Log Po/w?

Consensus Log Po/w: Average of all five predictions

0.9

Water Solubility

Log S (ESOL):?

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

-2.0
Solubility 1.93 mg/ml ; 0.01 mol/l
Class?

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

Very soluble
Log S (Ali)?

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

-2.04
Solubility 1.77 mg/ml ; 0.00922 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

-2.48
Solubility 0.64 mg/ml ; 0.00333 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

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

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.

-6.76 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

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<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)

1.67

Application In Synthesis of [ 1240390-28-6 ]

* 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 [ 1240390-28-6 ]

[ 1240390-28-6 ] Synthesis Path-Downstream   1~1

  • 1
  • [ 2972-52-3 ]
  • [ 1240390-28-6 ]
YieldReaction ConditionsOperation in experiment
93% With ammonium hydroxide; In tetrahydrofuran; at 0℃; for 0.5h; This embodiment provides a method for synthesizing 2,4-dichloro-5-pyrimidinecarboxamide.The synthesis steps are as follows:(1) Take 100g of 2,4-dichloro-5-pyrimidinecarboxyl chloride and dissolve it in 600ml of anhydrous tetrahydrofuran.The temperature was lowered to 0 C; (2) 100 ml of concentrated ammonia water was added dropwise thereto, and stirred at 0 C for 0.5h; (3) the pure product was filtered and washed with water to obtain 88g, the purity was greater than 96%, and the yield was 93%.
88% With ammonium hydroxide; In dichloromethane; water; at -20 - -15℃;Product distribution / selectivity; Example 18Synthesis of 5-Carboxyamide-2,4-DichloropyrimidineConcentrated ammonium hydroxide solution in H2O (assumed to be 8.5M; 14.1 mL; 120 mmol) was added over 15-20 minutes to a stirred solution of <strong>[2972-52-3]2,4-dichloropyrimidine-5-carbonyl chloride</strong> (12.5 g; 60 mmol; Manchester Organics, Sutton Weaver, England) in CH2Cl2 (300 mL) at -15 to -20 C. (internal temperature) [n.b.: a precipitate is formed during the addition]. After complete addition, the mixture was filtered (the filter cake comprises desired product and an impurity-for purification see below). H2O (50 mL) was added to the filtrate, which was partitioned. The organic layer was dried (NaSO4), filtered and the solvent removed under vacuum to give the title compound (1.1 g) as a solid. The filter cake from above was triturated with hot (ca. 50 C.) EtOAc (300 mL) and the mixture filtered-this was repeated another 2 times. The combined filtrates from the trituration were concentrated under vacuum to give another 9.1 g of the title compound. The total yield from the reaction is 10.2 g (88%). Data identical to those of Example 17.
88.1% With ammonium hydroxide; In dichloromethane; at -20℃; for 3h; Dissolve <strong>[2972-52-3]2,4-dichloropyrimidine-5-carbonyl chloride</strong> (12.5g, 60mmol) in DCM (300mL), add ammonia water (14mL) dropwise at -20C, add dropwise, react at -20C for 3 hours, filter , The filtrate was washed with water (100 mL), the filter cake was added to ethyl acetate (300 mL), stirred at 60C for 10 min, filtered hot, and the filter cake was repeated once.Combine the ethyl acetate layer and the dichloromethane layer,The product was concentrated to obtain 10 g, with a yield of 88.1%.
80% With ammonia; In 1,4-dioxane; at 0 - 20℃; for 12h; To a solution of 2,4-dichloropyrimidine-5- carbonyl chloride (6.2 g, 29.3 mmol) in 1,4-dioxane (50 mL) was added ammonia (1.0 g, 58.3 mmol) in 1,4-dioxane (50 mL) dropwise at 0 C, and the resulting solution was stirred for 12 h at ambient temperature. The mixture was diluted with ethyl acetate (50 mL), and washed with water (2 x 80 mL) and brine (2 x 80 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated to afford the title compound as a white solid (4.5 g, 80%). MS (ESI): m/z = 191.8 [M + H]+.
35% With ammonium hydroxide; In dichloromethane; at -20℃; for 0.5h; Under stirring at -20C, ammonia water (14ml) was added dropwise to the dichloromethane (30ml) solution of compound T004-2 (8.8g, 41.5mmol), a white solid appeared. Stir at -20C for 30 min. Filtered, washed with water, and dried to obtain 2.8 g of white solid with a yield of 35%.
With ammonia; In 1,4-dioxane;Inert atmosphere; Ice cooling; 2,4-dichloro-5-pyrimidinecarboxamideA solution of ammonia (14g) in 1 ,4-dioxane (500ml) was added drop-wise to an ice- cooled stirred solution of 2,4-dichloro-5-pyrimidinecarbonyl chloride (78g, crude) in 1 ,4-dioxane (400ml) under nitrogen. The ice-bath was removed and the solution was stirred for 30min and concentrated. The solid residue was partitioned between ethyl acetate (500ml) and saturated aqueous sodium bicarbonate (500ml), the organic washed with saturated aqueous sodium bicarbonate (500ml, x2), followed by brine (300ml). The organic phase was dried (sodium sulphate) and concentrated to give a yellow solid. To the residue was added diethyl ether (50ml) and the resulting suspension was treated under ultrasonic wave for 8min then filtered. The residue was washed with ethyl ether (50ml) to give the title compound as a white solid (3Og).MS: MH+ 1921 H NMR (400 MHz, D6-DMSO): δH 8.90(1 H, s), 8.19 (1 H, s), 8.07 (1 H, s).
With ammonium hydroxide; In 1,4-dioxane; at -5 - 0℃; Example 3 Synthesis of 5-carboxyamide-2,4-dichloropyrimidine To a 2 L round bottom flask equipped with water condenser and a CaCl2 drying tube, 2,4-dihydroxypyrimidine (25 g, 0.16 mole) was added to PCl5 (117 g, 0.56 mole), and POCl3 (250 ml, 2.6 mole). The mixture was heated at 115 C. overnight to give a clear, slightly light yellow solution. The mixture was cooled to room temperature, and was concentrated under reduced pressure to give pale yellowish oil. To this oil, anhydrous 1,4-dioxane (300 ml) was added and the mixture was cooled to 0 C. in an ice/water bath. 35 ml of NH3 in water (28%) was added dropwise to the mixture with stirring, temperature was kept below 5 C. The mixture changed from clear to white with precipitate forming, and was stirred for 1 hour at 0 C., reaction was followed by TLC (1:1 Hexanes:Ethyl Acetate). Ethyl acetate (700 ml) and water (500 ml) were added to the mixture, the 2 layers were separated. The organic layer was dried with Na2SO4, and filtered. The solution was concentrated under reduced pressure to give a light yellow solid. This light yellow solid was sonicated with methylene chloride (200 ml), and filtered to give a pale yellow solid (16 g). This pale yellow solid was dissolved into ethyl acetate (1.5 L) and washed with sat. NaHCO3 (500 ml). The organic layer was dried with Na2SO4, filtered, and concentrated under reduced pressure to give 13.1 g of product as a white solid (44% yield). 1H NMR (DMSO-d6, 300 MHz): δ 8.86 (s, 1H), 8.14 (bs, 1H), 8.02 (bs, 1H).
3.13 g With ammonium hydroxide; In dichloromethane; water; at -10℃; for 0.0833333h; 5.1.32 2,4-Dichloropyrimidine-5-carboxamide (27) To a solution of 2,4-dihydroxypyrimidine-5-carboxylic acid (25) (2.98 g, 19.1 mmol) in POCl3 (7.10 mL, 76.4 mmol) was added PCl5 (13.1 g, 63.0 mmol) and the reaction mixture was refluxed for 4.5 h. After cooling, the reaction mixture was concentrated in vacuo. To the resulting residue, toluene (20 mL) was added and the mixture was concentrated in vacuo again. The residue was dissolved in CH2Cl2 (20 mL) and filtered. The filtrate was concentrated in vacuo to give <strong>[2972-52-3]2,4-dichloropyrimidine-5-carbonyl chloride</strong> (26) as a yellow oil (4.38 g). This compound was used for next reaction without further purification. To a solution of 26 (4.38 g) in CH2Cl2 (5 mL) were added 28% NH3 aqueous solution (3 mL) and H2O (3 mL) at -10 C, and the reaction mixture was stirred at -10 C for 5 min. The organic solvent was removed under reduced pressure and the resulting precipitate was collected by filtration to give the title compound (3.13 g, 16.3 mmol, 85% from 25) as a pale yellow solid. 1H NMR (DMSO-d6) δ: 8.05 (1H, s), 8.17 (1H, s), 8.90 (1H, s); MS (ESI) m/z: 192 (M+H)+.
With ammonia; In 2-methyltetrahydrofuran; for 1h;Cooling; 1.9 to 2.0 equivalents of gaseous ammonia were bubbled into a solution of Compound F-i in MeTHF in 1 hr at -15 C or at -5 C under anhydrous conditions until conversion of Compound F-i to Compound E-i completed. The excess of NH3 was removed with three cycle of vacuum/nitrogen.

 

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Technical Information

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