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Chemical Structure| 944804-88-0

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Product Details of [ 944804-88-0 ]

CAS No. :944804-88-0
Formula : C8H11BrN2O2S
M.W : 279.15
SMILES Code : BrC1=CSC(=N1)NC(OC(C)(C)C)=O
MDL No. :MFCD11111844
InChI Key :OVRIFGLINJVMLO-UHFFFAOYSA-N
Pubchem ID :45117837

Safety of [ 944804-88-0 ]

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

Computational Chemistry of [ 944804-88-0 ] Show Less

Physicochemical Properties

Num. heavy atoms 14
Num. arom. heavy atoms 5
Fraction Csp3 0.5
Num. rotatable bonds 4
Num. H-bond acceptors 3.0
Num. H-bond donors 1.0
Molar Refractivity 60.06
TPSA ?

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

79.46 Ų

Lipophilicity

Log Po/w (iLOGP)?

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

2.47
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

2.88
Log Po/w (WLOGP)?

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

3.06
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.

1.4
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

2.48
Consensus Log Po/w?

Consensus Log Po/w: Average of all five predictions

2.46

Water Solubility

Log S (ESOL):?

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

-3.39
Solubility 0.115 mg/ml ; 0.000412 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.

-4.21
Solubility 0.0173 mg/ml ; 0.0000619 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

-3.1
Solubility 0.224 mg/ml ; 0.000804 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

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

Yes
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.

-5.96 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<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)

2.99

Application In Synthesis of [ 944804-88-0 ]

* 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 [ 944804-88-0 ]

[ 944804-88-0 ] Synthesis Path-Downstream   1~1

  • 1
  • [ 405939-39-1 ]
  • [ 944804-88-0 ]
YieldReaction ConditionsOperation in experiment
100% With lithium diisopropyl amide; In tetrahydrofuran; hexane; water; at 20℃; for 12.25h; Diisopropylamine (2.3 mL, 16 mmol) was taken up in 30 mL of THF and chilled to 0 C. Butyllithium, 2.5M in hexane (6.4 mL, 16 mmol), was added to the reaction mixture, and the mixture was stirred for 20 minutes. tert-Butyl 5-bromothiazol-2-ylcarbamate (1.5 g, 5.4 mmol) was then added slowly in 8 mL of THF. After 15 minutes, approximately 2 mL of water was added, and the mixture was warmed to room temperature and stirred for 12 hours. The mixture was diluted with 30 mL of 1/2 saturated aqueous NH4Cl and transferred to a separatory funnel. The mixture was extracted twice with 5 mL of EtOAc, and the combined organic extracts were washed with brine and dried over MgSO4. Filtration and concentration under reduced pressure afforded tert-butyl 4-bromothiazol-2-ylcarbamate (1.5 g, 100% yield) as a brown solid.
100% With n-butyllithium; diisopropylamine; In tetrahydrofuran; hexane; at 20℃; t-Butyl 4-bromothiazol-2-ylcarbamate: Diisopropylamine (2.3 mL, 16 mmol, Aldrich) was taken up in 30 mL of THF, and the mixture was chilled to 0 0C. Butyllithium (2.5 M in hexane (6.4 mL, 16 mmol, Aldrich)) was added to the reaction mixture, and the mixture was stirred for 20 minutes. tert-Butyl 5-bromothiazol-2- ylcarbamate (1.5 g, 5.4 mmol, prepared as shown in Scheme 2) was then added slowly in 8 mL of THF. After 15 minutes, approximately 2 mL of water was added, and the mixture was warmed to room temperature and stirred for 12 hours. The mixture was diluted with 30 mL of 1/2 saturated aqueous NH4Cl and transferred to a separatory funnel. The mixture was extracted twice with 5 mL of EtOAc, and the combined organic extracts were washed with brine and dried over MgSO4. Filtration and concentration under reduced pressure afforded tert-butyl 4-bromothiazol-2-ylcarbamate (1.5 g, 100 %) as a brown solid
96% With lithium diisopropyl amide; In tetrahydrofuran; hexanes; water; at 0 - 7℃; for 0.6h; 4.3 Synthesis of tert-butyl (4-bromo-1,3-thiazol-2-yl)carbamate (507) Tetrahydrofuran (160 mL) and N,N-diisopropylamine (14 mL, 97 mmol) were combined in a 3-neck 500 mL RBF equipped with a stirbar, septum, and an internal temperature probe. The resulting solution was cooled to 0.8 C., and n-butyllithium in hexanes (2.50 M, 38 mL, 95 mmol) was added slowly over ca. 5 min to produce a light yellow solution (Tint max=10 C.), which was stirred and allowed to re-cool to near 0 C. A solution of tert-butyl (5-bromo-1,3-thiazol-2-yl)carbamate, 506 (8.74 g, 31.3 mmol) in tetrahydrofuran (30.0 mL) was added dropwise to the above solution over 16 min (Tit varied from 0.9 C. to a maximum of 7 C.). The now deep brown reaction mixture was stirred for 15 min before being quenched with water (13 mL), and stirred for an additional 5 minutes. Aqueous saturated NH4Cl (250 mL) and ethyl acetate (250 mL) were added, and the layers were separated. The aqueous was extracted with ethyl acetate, and the combined organics were washed with brine, dried with MgSO4, filtered, and concentrated in vacuo. The crude material was adsorbed onto silica gel with ethyl acetate, and elute through a plug of silica gel with 2 liters of 9:1 hex:EtOAc The eluent was collected, and the solvents were removed to give 507 (8.41 g, 96%) as a colorless solid. Data for 507: 1H NMR (400 MHz, DMSO-d6) d 12.75 (br s, 1 H), 7.24 (s, 1 H), and 1.48 (s, 9 H) ppm. 13C NMR (400 MHz, CDCl3) d 160.6, 152.7 (br), 119.8, 110.6, 81.7, and 27.9 ppm. MS (ESI+) m/z (rel. intensity): 225.1 (100, M81Br-(CH3)2C=CH2+), 223.1 (100, M79Br-(CH3)2C=CH2+).
96% Tetrahydrofuran (160 mL) and N,N-diisopropylamine (14 mL, 97 mmol) were combined in a 3-neck 500 mL RBF equipped with a stirbar, septum, and an internal temperature probe. The resulting solution was cooled to 0.8 C., and n-butyllithium in hexanes (2.50 M, 38 mL, 95 mmol) was added slowly over ca. 5 min to produce a light yellow solution (Tint max=10 C.), which was stirred and allowed to re-cool to near 0 C. A solution of tert-butyl (5-bromo-1,3-thiazol-2-yl)carbamate, 506 (8.74 g, 31.3 mmol) in tetrahydrofuran (30.0 mL) was added dropwise to the above solution over 16 min (Tint varied from 0.9 C. to a maximum of 7 C.). The now deep brown reaction mixture was stirred for 15 min before being quenched with water (13 mL), and stirred for an additional 5 minutes. Aqueous saturated NH4Cl (250 mL) and ethyl acetate (250 mL) were added, and the layers were separated. The aqueous was extracted with ethyl acetate, and the combined organics were washed with brine, dried with MgSO4, filtered, and concentrated in vacuo. The crude material was adsorbed onto silica gel with ethyl acetate, and elute through a plug of silica gel with 2 liters of 9:1 hex:EtOAc The eluent was collected, and the solvents were removed to give 507 (8.41 g, 96%) as a colorless solid. Data for 507: 1H NMR (400 MHz, DMSO-d6) d 12.75 (br s, 1H), 7.24 (s, 1H), and 1.48 (s, 9H) ppm. 13C NMR (400 MHz, CDCl3) d 160.6, 152.7 (br), 119.8, 110.6, 81.7, and 27.9 ppm. MS (ESI+) m/z (rel. intensity): 225.1 (100, M81Br-(CH3)2CCH2+), 223.1 (100, M79Br-(CH3)2CCH2+).
78% With n-butyllithium; diisopropylamine; In tetrahydrofuran; at 0℃; for 2h;Inert atmosphere; To a solution of 158 diisopropylamine (64mL, 446mmol) in 154 THF (100mL) was added dropwise 159 n-BuLi (2.5M, 173mL) under N2 atmosphere at 0C. After that a solution of 156 47 (40g, 143.9mmol) in THF (400mL) was added dropwise at 0C. The reaction mixture was stirred at the same temperature for 2h, and then quenched with sat. 160 NH4Cl (500mL) and extracted with ethyl acetate (3×300mL). The combined organic layers were washed with brine (100mL) and dried over anhydrous Na2SO4. The organic layers were evaporated to dryness and the crude product was purified by silica gel flash chromatography (eluting with ethyl acetate in 74 petroleum ether 1-30%) to give the 20 title compound 48 as a white solid (31.2g, yield=78%). 1H NMR (400MHz, CDCl3) delta 8.05 (br, 1H), 6.78 (s, 1H), 1.56 (s, 9H); LC/MS (ESI, m/z) 222.98 [M+H-56]+.
77.5% With n-butyllithium; diisopropylamine; In tetrahydrofuran; at 0℃; for 2h;Inert atmosphere; A solution of diisopropylamine (64 ml, 446 mmol) in 200 mL of tetrahydrofuran was added to a dry three-neck bottle, which was protected under nitrogen, and cooled to 0 C, and then n-butyllithium (2.5M, 173ml, 431.7mmol) was added. The reaction was conducted for 1 hour after addition was completed. A solution of <strong>[405939-39-1]tert-butyl 5-bromothiazol-2-ylcarbamate</strong> in 400 mL of tetrahydrofuran was added dropwise at 0 C, and the reaction was conducted for 2 hours after addition was completed. TLC showed the reaction was completed. At 0 C, the reaction was quenched by slow addition of ice water (5 mL), stirred for 30 min, then saturated ammonium chloride (500mL) aqueous solution was added, and separated. The aqueous layer was extracted with dichloromethane (2 × 300 mL). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was recrystallized with petroleum ether : ethyl acetate = 30:1 to give 31g of tert-butyl 4-bromothiazol-2-ylcarbamate as a white solid, yield 77.5%, MS(ESI): m/z 278.98 (M + H)+.

 

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Technical Information

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