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Structure of 1598-63-6

Chemical Structure| 1598-63-6

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Product Details of [ 1598-63-6 ]

CAS No. :1598-63-6
Formula : C5H5FN2O2
M.W : 144.10
SMILES Code : CC1=NC(=O)C(F)=C(O)N1
MDL No. :MFCD11520459
InChI Key :REAPDCOFEGTTLS-UHFFFAOYSA-N
Pubchem ID :233895

Safety of [ 1598-63-6 ]

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

Computational Chemistry of [ 1598-63-6 ] Show Less

Physicochemical Properties

Num. heavy atoms 10
Num. arom. heavy atoms 6
Fraction Csp3 0.2
Num. rotatable bonds 0
Num. H-bond acceptors 4.0
Num. H-bond donors 2.0
Molar Refractivity 31.8
TPSA ?

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

65.98 Ų

Lipophilicity

Log Po/w (iLOGP)?

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

0.68
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

-0.56
Log Po/w (WLOGP)?

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

0.34
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.

-0.39
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

1.48
Consensus Log Po/w?

Consensus Log Po/w: Average of all five predictions

0.31

Water Solubility

Log S (ESOL):?

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

-0.82
Solubility 21.6 mg/ml ; 0.15 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.

-0.36
Solubility 63.5 mg/ml ; 0.441 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

-1.63
Solubility 3.39 mg/ml ; 0.0236 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.

-7.58 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)

1.86

Application In Synthesis of [ 1598-63-6 ]

* 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 [ 1598-63-6 ]

[ 1598-63-6 ] Synthesis Path-Downstream   1~2

  • 1
  • [ 1598-63-6 ]
  • [ 105806-13-1 ]
YieldReaction ConditionsOperation in experiment
79% With trichlorophosphate; at 120℃; for 3h; Part B: 4,6-Dichloro-5-fluoro-2-methylpyrimidine. 5-Fluoro-4,6-dihydroxy-2-methylpyrimidine (assumed 60 g, 0.42 mol) was treated with 300 ml. of POCI3 at 120 0C for 3 h. The reaction mixture was then cooled to room temperature and concentrated in vacuo until the rate of solvent removal slowed to a drop rate of less than 1 drop/second. The product is somewhat volatile and excessive concentration in vacuo will reduce the yield. The crude residue was poured over crushed ice, and the resulting slurry was stirred for 1 h, during which time the solution came to room temperature. A yellow solid formed which was filtered off, washed with water, and air dried briefly until free flowing. This solid was collected and placed in a dessicator over P2O5 until dry, providing pure 4,6-dichloro-5-fluoro-2-methylpyrimidine (59 g, 79%). LCMS: (M+H)+: 181/183 .
79% With trichlorophosphate; at 120℃; for 3h;Inert atmosphere; Part B: 4,6-Dichloro-5-fluoro-2-methylpyrimidine 5-Fluoro-4,6-dihydroxy-2-methylpyrimidine (assumed 60 g, 0.42 mol) was treated with 300 mL of POCI3 at 120 C for 3 h. The reaction mixture was then cooled to room temperature and concentrated in vacuo until the rate of solvent removal slowed to a drop rate of less than 1 drop/second. The product is somewhat volatile and excessive concentration in vacuo will reduce the yield. The crude residue was poured over crushed ice, and the resulting slurry was stirred for 1 h, during which time the solution came to room temperature. A yellow solid formed which was filtered off, washed with water, and air dried briefly until free flowing. This solid was collected and placed in a dessicator over P205 until dry, providing pure 4,6-dichloro-5-fluoro-2- methylpyrimidine (59 g, 79%). LCMS: (M+H)+: 181/183 .
62% With trichlorophosphate; In N,N-dimethyl-aniline; for 2h;Heating / reflux; Part B: A mixture of 4,6-dihydroxy-5-fluoro-2-methylpyrimidine (2.00 g, 13.9 mmol), phosphorous oxychloride (15.0 mL, 161 mmol), and JV,iV-diinethyIaniline (2.00 mL, 15.8 mmol) was heated at reflux for 2 h. The reaction mixture was cooled to RT and concentrated under reduced press. The residue was poured onto ice and allowed to warm to RT as a ppt formed. The solids were collected by suction filtration, washed with water, and air-dried at RT for Ih to give 4,6-dichloro-5-fluoro-2-methylpyrimidine (1.56 g, 62%) as a tan solid. LCMS (m/z): 181,183 (M+H)+
62% With N,N-dimethyl-aniline; trichlorophosphate; for 2h;Heating / reflux; Part B: A mixture of 4,6-dihydroxy-5-fluoro-2-methylpyrimidine (2.00 g, 13.9 mmol), phosphorous oxychloride (15.0 mL, 161 mmol), and N,N-dimethylaniline (2.00 mL, 15.8 mmol) was heated at reflux for 2 h. The reaction mixture was cooled to RT and concentrated under reduced press. The residue was poured onto ice and allowed to warm to RT as a ppt formed. The solids were collected by suction filtration, washed with water, and air-dried at RT for 1 h to give 4,6-dichloro-5-fluoro-2-methylpyrimidine (1.56 g, 62%) as a tan solid. LCMS (m/z): 181,183 (M+H)+
43% In sodium hydroxide; trichlorophosphate; (Step c) Preparation of 2-Methyl-4,6-dichloro-5-fluoropyrimidine A suspension of 1.44 g (10 mmol) of 2-methyl-4,6-dihydroxy-5-fluoropyrimidine in 7.5 mL (12 g, 80 mmol) of phosphorus oxychloride was heated to reflux for 4 hours. The mixture was cooled to 23 C., and poured into an ice/water slurry in which sodium hydroxide (15.0 g) had been dissolved. The mixture was stirred for 20 minutes and then extracted with chloroform. The combined organic extracts were dried (MgSO4), filtered, and concentrated in vacuo to provide product (0.78 g, 43%), m.p. 49-50 C. This crude product was used in subsequent reactions without further purification. 1 H NMR (60 MHz, CDCl3) delta 2.7 (s, 3H); IR (CHCl3) 1520, 1415 cm-1; mass spectrum m/e 180 (M+, 29%), 145 (M+ -Cl, 68%).

  • 2
  • [ 1598-63-6 ]
  • [ 1152107-25-9 ]
 

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Technical Information

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