208264-53-3|1-(4-Bromothiazol-2-yl)ethanone| Ambeed

CAS No. :	208264-53-3
Formula :	C₅H₄BrNOS
M.W :	206.06
SMILES Code :	CC(C1=NC(Br)=CS1)=O
MDL No. :	MFCD10697512
InChI Key :	YQJROTDRGHSQNZ-UHFFFAOYSA-N
Pubchem ID :	11171754

Safety of [ 208264-53-3 ]

GHS Pictogram:
Signal Word:	Warning
Hazard Statements:	H302
Precautionary Statements:	P264-P270-P301+P312-P330-P501

Computational Chemistry of [ 208264-53-3 ] Show Less

Physicochemical Properties

Num. heavy atoms	9
Num. arom. heavy atoms	5
Fraction Csp3	0.2
Num. rotatable bonds	1
Num. H-bond acceptors	2.0
Num. H-bond donors	0.0
Molar Refractivity	40.01
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	58.2 Å²

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	1.97
Log P_o/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by XLOGP program, version 3.2.2, courtesy of CCBG, Shanghai Institute of Organic Chemistry	1.99
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	2.11
Log P_o/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.	0.27
Log P_o/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	3.06
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	1.88

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-2.72
Solubility	0.396 mg/ml ; 0.00192 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.	-2.84
Solubility	0.299 mg/ml ; 0.00145 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	-2.49
Solubility	0.67 mg/ml ; 0.00325 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.	-6.14 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)	2.51

Application In Synthesis of [ 208264-53-3 ]

* 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 [ 208264-53-3 ]

[ 208264-53-3 ] Synthesis Path-Downstream 1~54

1
[ 1696-20-4 ]
[ 4175-77-3 ]
[ 208264-53-3 ]

Yield	Reaction Conditions	Operation 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)+.

References: [1]Organic and Biomolecular Chemistry,2018,vol. 16,p. 526 - 530.
[2]Organic Letters,2007,vol. 9,p. 3425 - 3427.
[3]Patent: WO2009/158011,2009,A1 .Location in patent: Page/Page column 172-173.
[4]Tetrahedron Letters,2011,vol. 52,p. 5435 - 5437.
[5]Bioorganic and Medicinal Chemistry Letters,2011,vol. 21,p. 5849 - 5853.
[6]Patent: US9138427,2015,B2 .Location in patent: Page/Page column 299.
[7]Patent: WO2018/160878,2018,A1 .Location in patent: Page/Page column 255-256.
[8]Tetrahedron Asymmetry,1998,vol. 9,p. 1395 - 1407.
[9]Organic Letters,2009,vol. 11,p. 3690 - 3693.

2
[ 208264-53-3 ]
[ 149-73-5 ]
[ 208264-54-4 ]

Yield	Reaction Conditions	Operation in experiment
90%		To a solution of 1 -(4-bromothiazol-2-yl)ethanone B.32 (3.383 g, 16.42 mmol) in dry methanol (55 mL) was added trimethyl orthoformate (9 mL, 82.27 mmol) andp-TsOH (2.8103 g, 14.77 mmol). The mixture was heated at reflux for 21.5 hours. The mixture was poured into saturated aqueous NaHCO3 (100 mL). The aqueous layer was extracted with ethyl acetate (100 mL x T). The combined organic layers were washed with 1 N aqueous NaOH (100 mL x 1), brine (100 mL x 1), dried over MgSO4, filtered, and concentrated under reduced pressure to give a white solid. The product was purified by silica gel column chromatography using 10% ethyl acetate in hexane as eluent to give 4-bromo-2-(l,l-dimethoxyethyl)thiazole B.33 (3.753 g, 90% yield) as a light yellow solid: 1H NMR (400 MHz, CHLOROFORM-d) delta ppm 7.24 (1 H, s), 3.26 (6 H, s), 1.73 (3 H, s); Mass Spectrum (ESI) m/e = 219.9 [M+l (79Br)] and 221.9 [M+l (81Br)].

References: [1]Tetrahedron Asymmetry,1998,vol. 9,p. 1395 - 1407.
[2]Patent: WO2009/158011,2009,A1 .Location in patent: Page/Page column 173.

3
[ 7486-35-3 ]
[ 208264-53-3 ]
1-(4-vinylthiazol-2-yl)ethanone [ No CAS ]

References: [1]Organic Letters,2007,vol. 9,p. 3425 - 3427.

4
[ 208264-53-3 ]
[ 214420-47-0 ]

References: [1]Organic Letters,2007,vol. 9,p. 3425 - 3427.

5
[ 208264-53-3 ]
(3aR,4R,6aR)-4-[2-(1,1-Dimethoxy-ethyl)-thiazol-4-yl]-2,2-dimethyl-tetrahydro-furo[3,4-d][1,3]dioxol-4-ol [ No CAS ]

References: [1]Tetrahedron Asymmetry,1998,vol. 9,p. 1395 - 1407.

6
[ 208264-53-3 ]
(3aR,4S,6aR)-4-[2-(1,1-Dimethoxy-ethyl)-thiazol-4-yl]-2,2-dimethyl-tetrahydro-furo[3,4-d][1,3]dioxol-4-ol [ No CAS ]

References: [1]Tetrahedron Asymmetry,1998,vol. 9,p. 1395 - 1407.

7
[ 107-21-1 ]
[ 208264-53-3 ]
[ 1037747-43-5 ]

References: [1]Organic Letters,2008,vol. 10,p. 2909 - 2912.

8
[ 73183-34-3 ]
[ 208264-53-3 ]
C₁₁H₁₆BNO₃S [ No CAS ]

References: [1]Organic Letters,2009,vol. 11,p. 3690 - 3693.

9
[ 208264-53-3 ]
[ 1338605-39-2 ]

References: [1]Tetrahedron Letters,2011,vol. 52,p. 5435 - 5437.

10
[ 208264-53-3 ]
[ 1338605-39-2 ]
(R)-tert-butyl 2-(4-bromo-2,4'-bithiazol-2'-yl)pyrrolidine-1-carboxylate [ No CAS ]

References: [1]Tetrahedron Letters,2011,vol. 52,p. 5435 - 5437.

11
[ 208264-53-3 ]
[ 1338605-44-9 ]

Yield	Reaction Conditions	Operation in experiment
80%	With hydrogen bromide; bromine; acetic acid; at 20℃; for 5h;Inert atmosphere;	33% HBr solution in AcOH (680 muL, 3.88 mmol), and bromine (200 muL, 3.88 mmol) were added to a solution of <strong>[208264-53-3]2-acetyl-4-bromothiazole</strong> (800 mg, 3.88 mmol) in AcOH (43 mL) and the mixture was stirred at rt under N2. After 5 h the mixture was poured over a suspension of ice in EtOAc (100 mL) and then solid Na2CO3 was added stepwise until basic pH was reached. The aqueous phase was extracted with EtOAc (2 × 100 mL) and the combined organic extracts dried over Na2SO4 and then concentrated in vacuo. The crude product was purified by automated silica column chromatography (0-40% CH2Cl2 in hexanes), which yielded the product as a yellowish solid (887 mg, 80%). IR (KBr) 3113, 1704, 1454, 1379, 1191, 954, 640 cm-1. 1H NMR (400 MHz, CDCl3) delta = 4.69 (s, 2 H), 7.67 (s, 1 H) ppm. 13C NMR (100 MHz, CDCl3) delta = 30.6 (t), 126.4 (d), 127.8 (s), 163.8 (s), 183.9 (s) ppm. HRMS(ESI) m/z calcd for C5H4Br2NOS (M+H) 283.8375, found 283.8375.

References: [1]Organic and Biomolecular Chemistry,2018,vol. 16,p. 526 - 530.
[2]Tetrahedron Letters,2011,vol. 52,p. 5435 - 5437.

12
[ 208264-53-3 ]
tert-butyl [(5S)-5-(4-bromo-1,3-thiazol-2-yl)-2,5-dimethyl-1,1-dioxido-5,6-dihydro-2H-1,2,4-thiadiazin-3-yl]carbamate [ No CAS ]