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Chemical Structure| 4175-77-3 Chemical Structure| 4175-77-3

Structure of 2,4-Dibromothiazole
CAS No.: 4175-77-3

Chemical Structure| 4175-77-3

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Product Details of [ 4175-77-3 ]

CAS No. :4175-77-3
Formula : C3HBr2NS
M.W : 242.92
SMILES Code : C1=C(N=C(Br)S1)Br
MDL No. :MFCD01318994
InChI Key :MKEJZKKVVUZXIS-UHFFFAOYSA-N
Pubchem ID :2763297

Safety of [ 4175-77-3 ]

GHS Pictogram:
Signal Word:Danger
Hazard Statements:H302-H315-H318-H335
Precautionary Statements:P261-P264-P270-P271-P280-P301+P312+P330-P302+P352-P304+P340+P312-P305+P351+P338+P310-P332+P313-P403+P233-P405-P501

Computational Chemistry of [ 4175-77-3 ] Show Less

Physicochemical Properties

Num. heavy atoms 7
Num. arom. heavy atoms 5
Fraction Csp3 0.0
Num. rotatable bonds 0
Num. H-bond acceptors 1.0
Num. H-bond donors 0.0
Molar Refractivity 37.51
TPSA ?

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

41.13 Ų

Lipophilicity

Log Po/w (iLOGP)?

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

1.96
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

3.0
Log Po/w (WLOGP)?

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

2.67
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.

1.38
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

3.74
Consensus Log Po/w?

Consensus Log Po/w: Average of all five predictions

2.55

Water Solubility

Log S (ESOL):?

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

-3.76
Solubility 0.0418 mg/ml ; 0.000172 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.

-3.53
Solubility 0.072 mg/ml ; 0.000296 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

-3.0
Solubility 0.24 mg/ml ; 0.000989 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

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.

-5.65 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)

2.79

Application In Synthesis of [ 4175-77-3 ]

* 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 [ 4175-77-3 ]

[ 4175-77-3 ] Synthesis Path-Downstream   1~5

  • 2
  • [ 4175-77-3 ]
  • [ 34259-99-9 ]
YieldReaction ConditionsOperation in experiment
99% a) Synthesis of 4-bromothiazol A solution of 10.0 g (41.2 mmol) 2,4-dibromothiazol in ether (210 ml) was cooled to -78° C. and 28.3 ml (45.3 mmol, 15percent in hexane) n-butyllithium was added in drops at this temperature. After 30 min of stirring, 3.3 ml (82.3 mmol) methanol was added at -78° C. to the reaction mixture. Heating was subsequently performed to RT over a period of 16 h. The reaction mixture was filtered over silica gel and washed with a n-hexane/AE mixture (2:1). The filtrate was concentrated in a vacuum, whereby 6.7 g (40.9 mmol, 99percent) 4-bromothiazol was obtained.
With sodium hydroxide; In dichloromethane; acetic acid; Reference Example 2 4-Bromothiazole Following the procedure of M. Robba and R. C. Moreau, Annales pharm. franc. 22, #3, 201-210 (1965); 10 g of 2,4-dibromothiazole and 5 g of powdered zinc in 40 ml of glacial acetic acid is stirred at 60°-65° C. for 45 minutes. The mixture is cooled in an ice bath, as 40 ml of 10 N sodium hydroxide is added in portions. Stirring is continued for 30 minutes. Ten milliliters of 10 N sodium hydroxide is added and the reaction is extracted with diethyl ether followed by methylene chloride. The combined organic layers are dried over sodium sulfate, filtered and concentrated in vacuo to give 5.4 g of the product as a yellow oil.
2,4-Dibromothiazole (5.00 g, 20.7 mmol) is placed in a flask which has been back filled with Argon three times. Anhydrous ether (82 mL) is added and the solution is cooled to -78°C. n-Butyllithium (2.5 M in cyclohexane, 10.0 mL) is added and the reaction mixture is stirred for 90 minutes at -78°C before quenching with HCl/ether solution (2.0 m x 15 mL). The reaction mixture is warmed to room temperature. The mixture is washed with NaHCpsi3 (saturated aqueous solution, 60 mL) and the organic phase is dried with Na2SO4. After evaporation, 4-bromothiazole is obtained as a crude product.
  • 3
  • [ 1696-20-4 ]
  • [ 4175-77-3 ]
  • [ 208264-53-3 ]
YieldReaction ConditionsOperation in experiment
79.5% A solution of 2,4-dibromothiazole B.31 (5.0128 g, 20.63 mmol) in ether (52 mL) was cooled to -78 0C. To the cooled solution was added n-BuLi (1.6 M sol. in hexane, 14.2 mL, 22.72 mmol) and the mixture was stirred at -78 0C for 30 minutes. To the cooled mixture was then added dropwise N-acetylmorpholine (3.1 mL, 26.83 mmol). The mixture was stirred at -78 0C for 1.5 hours and then room temperature for 18 hours. The mixture was diluted with ether (200 mL), washed with saturated aqueous NaHCO3 (100 mL x 1), dried over MgSO4, filtered, and concentrated under reduced pressure. The product was purified by silica gel column chromatography using 0% to 50% gradient of ethyl acetate in hexane as eluent to give 1 -(4- bromothiazol-2-yl)ethanone B.32 (3.383 g, 79.5% yield): 1H NMR (500 MHz, CHLOROFORM-d) 5 ppm 7.59 (1 H, s), 2.73 (3 H, s); Mass Spectrum (ESI) m/e = 205.9 [M+l (79Br)] and 207.9 [M+l (81Br)].
50% To a solution of compound 21-2 (3.0 g, 12.35 mmol) in THF (25 ml) was added dropwise n-BuLi (2.5 M in hexane, 2.5 ml) at -78 C. After addition, the reaction mixture was stirred at -78 C for 30 min. N-acetyl morpholine (1.9 ml, 16.06 mmol) was added dropwise during 15 min at -78 C. After addition, the reaction mixture was stirred at -78 C for 4 h, quenched with saturated NaHCO3 (15 ml) and extracted with ethyl acetate (25 ml x 4). The combined organic layers were washed with brine (30 ml), dried over Na2SO4, filtered, concentrated and purified by silica gel column chromatography (PE : EA = 50 : 1 to 10 : 1) to afford 21-3 as a white solid (1.28 g, yield 50%).
50% Compound 22-3 (0435) To a solution of compound 22-2 (3.0 g, 12.35 mmol) in THF (25 mL) was added dropwise n-BuLi (2.5 M in hexane, 2.5 mL) at -78 C. After addition, the reaction mixture was stirred at -78 C. for 30 min. N-acetyl morpholine (1.9 mL, 16.06 mmol) was added dropwise during 15 min at -78 C. After addition, the reaction mixture was stirred at -78 C. for 4 h, then quenched with sat. NaHCO3 (15 mL) and extracted with ethyl acetate (25 mL×4). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, filtered, concentrated and purified by silica gel column chromatography (PE:EA=50:1 to 10:1) to afford 22-3-3 as a white solid (1.28 g, yield 50%).
33% To a stirring solution of 2, 4-dibromothiazole 84 (50 g, 205.82 mmol) in anhydrous THF (500 mL) under inert atmosphere was added n-butyllithium (193 mL, 308.74 mmol) dropwise for 30 min at -40 oC and stirred for 1 h at the same temperature. To this was added 1- morpholinoethan-1-one (32 g, 248 mmol) in anhydrous THF (100 mL) dropwise for 20 min at -40 oC and stirred for 3 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was quenched with saturated ammonium chloride solution and extracted using EtOAc. The combined organic extracts were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 1-2% EtOAc/ hexanes to afford compound 85 (14 g, 33%) as an off-white solid. TLC: 10% EtOAc/ hexanes (Rf: 0.8); 1H NMR (DMSO-d6, 400 MHz): delta 8.33 (s, 1H), 2.62 (s, 3H); LCMS Calculated for C5H4BrNOS: 204.92; LCMS observed: 208.0 (M+2)+.

  • 4
  • [ 4175-77-3 ]
  • [ 68-12-2 ]
  • [ 167366-05-4 ]
YieldReaction ConditionsOperation in experiment
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of commercially available 2,4-dibromo-thiazole (3.50 g, 14.41 mmol) in dry Et2O (120 ml.) was treated with n-BuLi (5.9 ml. of a 2.5M solution in hexanes, 14.72 mmol) at -78 0C. The reaction mixture was stirred at this temperature for 30 min. lambda/,lambda/-Dimethylformamide (1.35 ml_, 14.47 mmol) was then added and the mixture allowed to warm to rt over a period of 1 h. The reaction was quenched by the addition of sat. aq. NH4CI (50 ml_). The layers were separated and the aq. layer extracted with Et2O (3 x 50 ml_). The combined org. extracts dried over Na2SO4, filtered, and the solvents were removed under reduced pressure. Purification of the residue by FC (10:1 -> 3:1 hept-EA) gave the title compound as a pale yellow solid. TLC: rf (1 :1 hept-EA) = 0.21. LC-MS-conditions 02: tR = 0.81 min.
With n-butyllithium; In diethyl ether; at -78 - 20℃; for 1.25h; To a solution of 2,4-dibromothiazole (2.50 g, 10.28 mmol) in diethyl ether (50 ml) cooled to -78 C. was added n-butyl lithium (1.40 M, 8.80 ml, 12.38 mmol) and the resulting reaction mixture was stirred for 15 min at the same temperature followed by addition of DMF (5.0 ml, 64.30 mmol). The reaction mass was then allowed to come to room temperature and stirred for 1 h. After the completion of the reaction (TLC monitoring), the reaction mass was cooled to 0 C. and quenched with saturated NH4Cl solution (aqueous). Water was then added to the reaction mass and extracted with diethyl ether (3×100 ml). The combined organics was then dried over anhydrous Na2SO4, filtered and concentrated to get the desired product (2.10 g, quantitative crude yield) that was carried forward to the next step without further purification.
4-Bromo-thiazole-2-carbaldehyde:; In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of commercially available 2,4-dibromo-thiazole (3.50 g, 14.41 mmol) in dry Et2O (120 mL) was treated with n-BuLi (5.9 mL of a 2.5M solution in hexanes, 14.72 mmol) at -78 0C. The reaction mixture was stirred at this temperature for 30 min. Lambda/,Lambda/-Dimethylformamide (1.35 mL, 14.47 mmol) was then added and the mixture allowed to warm to rt over a period of 1 h. The reaction was quenched by the addition of sat. aq. NH4CI (50 mL). The layers were separated and the aq. layer extracted with Et2O (3 x 50 mL). The combined org. extracts dried over Na2SO4, filtered, and the solvents were removed under reduced pressure. Purification of the residue by FC (10:1 ->; 3:1 hept-EA) gave the title compound as a pale yellow solid. TLC: rf (1 :1 hept-EA) = 0.21. LC-MS-conditions 02: tR = 0.81 min.
(Example 30a) (4-bromo-1,3-thiazol-2-yl)methanol [Show Image] Under a nitrogen atmosphere at -78C, to a solution (20 mL) of 2,4-dibromothiazole (5 g, 20.6 mmol) in diethyl ether was added n-butyllithium (1.6 M hexane solution, 15.4 mL, 24.7 mmol), and the mixture was stirred at the same temperature for 30 min. N,N-Dimethylformamide (2.3 g, 30.9 mmol) was added to the reaction mixture at -78C, and the mixture was gradually warmed to room temperature. After confirmation of the termination of the reaction by TLC, hexane was added. The resulting salt was filtered and the solvent was evaporated under reduced pressure to give 4-bromo-1,3-thiazole-2-carbaldehyde as a crude product. 1H NMR (400 MHz, CHLOROFORM-d) delta ppm 7.68 (1 H, d, J=1.0 Hz), 9.95 (1 H, d, J=1.2 Hz)

  • 5
  • [ 4394-85-8 ]
  • [ 4175-77-3 ]
  • [ 167366-05-4 ]
YieldReaction ConditionsOperation in experiment
61% General procedure: The reaction was carried out in a sealed tube under N2 using THF (4 mL) as the solvent. To the solution of tert-butyl 2-bromothiazole-4-carboxylate 1a (0.397 mmol), iPrMgCl·LiCl (1.3 M, 0.52 mmol) was added dropwise at -78 C. After 15 min the corresponding aldehyde (0.79-0.99 mmol) or N-formyl-morpholine (in the case of 2-formylthiazoles 3a-b) was added dropwise under stirring and the reaction mixture was stirred at -78 C for 10 min, then 1.5 h at 0 C. Saturated aqueous NH4Cl was added and the aqueous layer was extracted with Et2O (3 × 10 mL). The combined organic layers were washed with 5% aqueous HCl (10 mL), brine (10 mL), dried over MgSO4 and concentrated in vacuo. The crude product was purified by flash column chromatography on silica gel using a mixture of EtOAc:P (petroleum ether) as eluent (see below) to give tert-butyl 2-(1-hydroxymethyl)thiazole-4-carboxylate derivatives rac-2a-h.
 

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Technical Information

Categories

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[ 4175-77-3 ]

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