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Chemical Structure| 814918-95-1 Chemical Structure| 814918-95-1

Structure of 814918-95-1

Chemical Structure| 814918-95-1

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Product Details of [ 814918-95-1 ]

CAS No. :814918-95-1
Formula : C6H2BrClN2S
M.W : 249.52
SMILES Code : ClC1=C(C(Br)=CS2)C2=NC=N1
MDL No. :MFCD11042739
InChI Key :IKCKRHCJPVDELP-UHFFFAOYSA-N
Pubchem ID :45480299

Safety of [ 814918-95-1 ]

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

Computational Chemistry of [ 814918-95-1 ] Show Less

Physicochemical Properties

Num. heavy atoms 11
Num. arom. heavy atoms 9
Fraction Csp3 0.0
Num. rotatable bonds 0
Num. H-bond acceptors 2.0
Num. H-bond donors 0.0
Molar Refractivity 50.13
TPSA ?

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

54.02 Ų

Lipophilicity

Log Po/w (iLOGP)?

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

2.15
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

3.21
Log Po/w (WLOGP)?

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

3.11
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.

2.01
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

4.0
Consensus Log Po/w?

Consensus Log Po/w: Average of all five predictions

2.9

Water Solubility

Log S (ESOL):?

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

-4.01
Solubility 0.0241 mg/ml ; 0.0000967 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.

-4.02
Solubility 0.024 mg/ml ; 0.0000962 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

-4.07
Solubility 0.0212 mg/ml ; 0.0000849 mol/l
Class?

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

Moderately 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

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

Yes
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.

-5.54 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<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)

2.43

Application In Synthesis of [ 814918-95-1 ]

* 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 [ 814918-95-1 ]

[ 814918-95-1 ] Synthesis Path-Downstream   1~3

  • 1
  • [ 56844-12-3 ]
  • [ 814918-95-1 ]
YieldReaction ConditionsOperation in experiment
67.1% With n-butyllithium; diisopropylamine; In tetrahydrofuran; at -78℃; for 1h;Inert atmosphere; [0123] To diisopropylamine (1.028 ml, 7.21 mmol, 1.8 equiv) in 10 mL THF at 0 C was added n-butyl lithium (3.76 ml, 6.01 mmol, 1.5 equiv). After 1 h, the LDA solution was transferred to a solution of <strong>[56844-12-3]6-bromo-4-chlorothieno[2,3-d]pyrimidine</strong> (1.0 g, 4.01 mmol, 1.0 equiv) in 35 mL THF at -78 C under nitrogen. The solution stirred for 1 h at -78 C after which a mixture of 1.25 mL water and 5 mL THF was added slowly. The mixture was then warmed to 0 C, poured into 60 mL water, and extracted with dichloromethane. The combined organic extracts were then dried over Na2SC> , filtered, and concentrated in vacuo to give a yellow solid which was chromatographed with 20% EtOAc/Hexanes gradient elution to give 5-bromo-4-chlorothieno[2,3-d]pyrimidine (671 mg, 67.1 % yield) as a tan solid. NMR (400 MHz, chloroform- ) delta ppm 8.85 (s, 1 H), 7.64 (s, 1 H).
56% With lithium diisopropyl amide; In tetrahydrofuran; n-heptane; ethylbenzene; at -78℃; for 1h;Inert atmosphere; Step 4: To a stirred solution of 6-bromo-4-chlorothieno[2,3-c]pyrimidine (3 g, 12.048 mmol) in THF (120 mL) was added 2M LDA solution in THF/heptane/ethylbenzene (9 mL, 18.072 mmol) at -78 C under nitrogen. The reaction mixture was stirred for 1 h at -78 C, a mixture of 3.75 mL water and 15 mL THF was added slowly. The mixture was warmed to 0 C, poured onto water (180 mL). The reaction mixture was extracted with dichloromethane (2 x 50 mL). The combined organic extracts were dried over Na2S04, filtered, and concentrated in vacuo to give crude product. The crude product was purified by flash column chromatography with 80 g silica column and 10% EtOAc in Hexanes as eluent to give 5-bromo-4-chlorothieno[2,3- cdpyrimidine as yellow solid (1.7 g, 56%). LCMS (ES) m/z = 248.9, 250.9 [M+H]+. H NMR (400 MHz, CDCI3) delta ppm 7.66 (s, 1 H), 8.87 (s, 1 H).
55% Lithium diisopropylamine (LDA) was prepared by addition of 2.5 molar BuLi (3.0 mL, 7.6 mmol) in hexanes to a ca. -50 C. solution of diisopropylamine (1.1 mL, 790 mg, 7.8 mmol) in anhydrous THF (15 mL). The solution was warmed to 0 C. for 10 min and then added dropwise to a solution of <strong>[56844-12-3]6-bromo-4-chlorothieno[2,3-d]pyrimidine</strong> (which was prepared as disclosed in WO 2003053446) (2.0 g, 8.0 mmol) in THF (30 mL) cooled to -100 C. The mixture was maintained at -90 to -100 C. for 45 minutes and then quenched with saturated aqueous NH4Cl. The mixture was diluted with ethyl acetate (30 mL) and the separated organic phase was washed with water, brine, dried (Na2SO4) and evaporated. The residue was recrystallized from aqueous ethanol and the isolated solid was dissolved in dichloromethane and passed through a silica gel plug eluting with dichloromethane to yield 900 mg of material. A further 200 mg of product was obtained from the evaporated, recrystallization filtrate by reverse phase High Pressure Liquid Chromatography (HPLC) on a 50 mm×250 mm YMC-AQ eluting with 70/30 acetonitrile/0.1 percent v/v water-conc. H2PO4. Total yield was 1.1 g (55 percent). In later runs the crude bromide was recrystallized from acetonitrile.
46% With lithium diisopropyl amide; In tetrahydrofuran; at -78℃; for 1h;Inert atmosphere; To a stirred solution of 6-bromo-4-chlorothieno[2,3-c]pyrimidine (1 g, 4.0 mmol, 1 equiv) in THF (40 mL) was added 2M LDA in THF solution (3 mL, 6.0 mmol, 1.5 equiv) drop wise at -78 C under nitrogen. The reaction was stirred for 1 h at -78 C after which a mixture of water (1.25 mL) and THF (5 mL) was added slowly. The mixture was then warmed to 0 C, poured onto water (60 mL), and extracted with DCM (2 x 30 mL). The combined organic extracts were combined and dried over Na2S04, filtered and concentrated. Purification: Purified by flash column chromatography, 24g silica column with 10% EtOAc in hexane as mobile phase to give 5-bromo-4-chlorothieno[2,3-c]pyrimidine as yellow solid. Yield (0.46 g, 46 %). LC-MS (ES) m/z = 248.9 [M+H]+. H NMR (400 MHz, CDCI3) delta 7.66 (s, 1 H), 8.87 (s, 1 H).
A stirred solution of <strong>[56844-12-3]6-bromo-4-chlorothieno[2,3-d]pyrimidine</strong> (4.0g, 0.016mol) in anhydrous tetrahydrofuran (100ml) was cooled in a dry-ice/acetone bath and treated, under a nitrogen atmosphere, with lithium diisopropylamide (1.8M solution in tetrahydrofuran, 9.0ml, 0.016mol) over about 20 minutes. The resultant dark solution was stirred in the cold for 1 hour and then treated with a mixture of water (5ml) and tetrahydrofuran (20ml) over about 20 minutes. The mixture was then allowed to warm up to about 0C before being poured into water (250ml) and extracted with dichloromethane (SxlOOml). The combined organic extracts were dried (MgSO4) and the solvent removed in vacuo to give the crude product. Purification by flashchromatography (silica) eluting with dichloromethane gave 5-bromo-4-chlorothieno[2,3-cQpyrimidine as a pale brown solid (3.8g).

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  • [ 1239460-82-2 ]
  • [ 814918-95-1 ]
  • 3
  • [ 56844-40-7 ]
  • [ 814918-95-1 ]
 

Historical Records

Technical Information

Categories

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