Structure of 5198-86-7
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The BI-3802 was designed by Boehringer Ingelheim and could be obtained free of charge through the Boehringer Ingelheim open innovation portal opnMe.com, associated with its negative control.
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CAS No. : | 5198-86-7 |
Formula : | C4H4BrNOS |
M.W : | 194.05 |
SMILES Code : | C1=C(N=C(S1)Br)CO |
MDL No. : | MFCD04115727 |
InChI Key : | FRPHIGOLOLSXAI-UHFFFAOYSA-N |
Pubchem ID : | 2763211 |
GHS Pictogram: |
![]() |
Signal Word: | Warning |
Hazard Statements: | H302-H315-H319-H335 |
Precautionary Statements: | P261-P305+P351+P338 |
Num. heavy atoms | 8 |
Num. arom. heavy atoms | 5 |
Fraction Csp3 | 0.25 |
Num. rotatable bonds | 1 |
Num. H-bond acceptors | 2.0 |
Num. H-bond donors | 1.0 |
Molar Refractivity | 35.94 |
TPSA ? Topological Polar Surface Area: Calculated from |
61.36 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
1.56 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
1.13 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
1.25 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
-0.01 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
2.69 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
1.32 |
Log S (ESOL):? ESOL: Topological method implemented from |
-2.15 |
Solubility | 1.37 mg/ml ; 0.00705 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (Ali)? Ali: Topological method implemented from |
-2.01 |
Solubility | 1.89 mg/ml ; 0.00972 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-1.98 |
Solubility | 2.04 mg/ml ; 0.0105 mol/l |
Class? Solubility class: Log S scale |
Soluble |
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) |
No |
CYP1A2 inhibitor? Cytochrome P450 1A2 inhibitor: SVM model built on 9145 molecules (training set) |
No |
CYP2C19 inhibitor? Cytochrome P450 2C19 inhibitor: SVM model built on 9272 molecules (training set) |
No |
CYP2C9 inhibitor? Cytochrome P450 2C9 inhibitor: SVM model built on 5940 molecules (training set) |
No |
CYP2D6 inhibitor? Cytochrome P450 2D6 inhibitor: SVM model built on 3664 molecules (training set) |
No |
CYP3A4 inhibitor? Cytochrome P450 3A4 inhibitor: SVM model built on 7518 molecules (training set) |
No |
Log Kp (skin permeation)? Skin permeation: QSPR model implemented from |
-6.68 cm/s |
Lipinski? Lipinski (Pfizer) filter: implemented from |
0.0 |
Ghose? Ghose filter: implemented from |
None |
Veber? Veber (GSK) filter: implemented from |
0.0 |
Egan? Egan (Pharmacia) filter: implemented from |
0.0 |
Muegge? Muegge (Bayer) filter: implemented from |
2.0 |
Bioavailability Score? Abbott Bioavailability Score: Probability of F > 10% in rat |
0.55 |
PAINS? Pan Assay Interference Structures: implemented from |
0.0 alert |
Brenk? Structural Alert: implemented from |
0.0 alert: heavy_metal |
Leadlikeness? Leadlikeness: implemented from |
No; 1 violation:MW<1.0 |
Synthetic accessibility? Synthetic accessibility score: from 1 (very easy) to 10 (very difficult) |
2.79 |
* 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.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With sodium tetrahydroborate; water; lithium chloride In tetrahydrofuran for 2 h; | Preparation of (2-bromothiazol-4-yl)methanol (5) To a solution of ester 4 (10.0 g, 42.4 mmol, 1 equiv) in THF (200 mL) was added NaBH4 (4.81 g, 127 mmol, 3 equiv), LiCl (5.4 g, 130 mmol, 3 equiv) and H2O (40 mL). The resulting biphasic mixture was vigorously stirred for 2 h, after which TLC (20percent EtOAc:hexanes) showed complete consumption of starting material. The reaction was quenched with saturated aqueous NH4Cl (200 mL), diluted with EtOAc (200 mL), and the layers were separated. The aqueous layer was extracted with EtOAc (100 mL), and the organic layers were combined, dried (Na2SO4), filtered, and concentrated under reduced pressure to give the title compound as a yellow semi-solid (7.82 g, 95percent). Rf= 0.2 (SiO2, 20percent EtOAcrhexanes); 1H and 13C NMR of the product matched those previously reported (Wipf and Wang 2007). |
91% | at 20 - 70℃; for 8 h; | 2-Bromothiazol-4-Carboxylic acid ethyl ester (11.8g, 50.0mmol)Was dissolved in absolute ethanol (100 mL)Sodium borohydride (3.8 g, 100 mmol) was added, stirred at room temperature for 4 hours, and then heated to 70 ° C for 4 hours.The solvent was evaporated under reduced pressure and the crude product was purified by column chromatography (ethyl acetate / petroleum ether (v / v) = 1/5) to give a pale yellow oil (8.85 g, 91percent). |
87% | With sodium tetrahydroborate In ethanol at 0 - 70℃; for 7.5 h; | At 0 , 2-bromo-thiazole-4-carboxylate (13.30g, 56.33mmol)In ethanol (150 mL) was added portionwiseSodium borohydride (4.263 g, 112.7 mmol),Stirring was continued at 0 0.5 hours.The mixture was stirred at room temperature for 3 hours,And heated to 70 ° C for 4 hours.The solvent was distilled off under reduced pressure,Slowly add water (100 mL)Extracted with ethyl acetate (100 mL x 3).Combine organic phase,Washed with saturated brine (50 mL)Dried over anhydrous sodium sulfate.Filtration, evaporation of the solvent under reduced pressure,The crude product was purified by column chromatography (petroleum ether / ethyl acetate (v / v) = 5/1)To give a colorless oil (9.5 g, 87percent). |
87% | With sodium tetrahydroborate In ethanol at 0 - 20℃; for 3 h; | Into a 500-mL round-bottom flask, was placed ethyl 2-bromothiazole-4-carboxylate (14 g, 59.30 mmol) and EtOH (200 mL). This was followed by the addition of NaBH4 (2.3 g, 60.53 mmol) in portions at 0oC. The resulting solution was stirred for 3 h at RT and then was quenched by the addition of 100 mL of water. The resulting solution was extracted with 2x200 mL of DCM and the organic layers combined and dried over anhydrous Na2SO4, then concentrated under vacuum. This resulted in 10 g (87percent) of the title compound as colorless oil. MS-ESI: 195.9, 193.9 (M+1). |
87% | at 0 - 20℃; for 3 h; | Into a 500-mL round-bottom flask was placed a solution of ethyl 2-bromothiazole-4-carboxylate(14 g, 59.3 mmol), EtOH (200 mL). This was followed by the addition of NaBH4(2.3 g, 60.5 mmol) in portions at 0°C. The resulting solution was stirred for 3 h at RT and then was quenched by the addition of 100 mL of water. The resulting solution was extracted with 2x200 mL of DCM.The organic layers were combined, dried over anhydrous Na2S04 and then concentrated under vacuum. This resulted in 10.0 g (87percent) of the title compound as colorless oil. MS-ESI: 195.9, 193.9(M+l). |
81% | at 20℃; for 3 h; Cooling | Into a 100-mL round-bottom flask was placed a solution of ethyl 2-bromo-1,3-thiazole-4- carboxylate (3 g, 12.71 mmol) in EtOH (30 mL). NaBH4 (1.0 g, 25.41 mmol) was added in portions with an ice/water bath. The resulting solution was stirred for 3 hr at room temperature. The reaction was then quenched by the addition of 100 mL of water in an ice/water bath. The resulting solution was extracted with 3x100 ml of ethyl acetate, and the combined organic layers were concentrated. This resulted in 2 g (81percent) of the title compound as yellow oil. MS-ESI: 196.2, 194.2 (M+1). |
68% | With sodium tetrahydroborate; lithium chloride In tetrahydrofuran; water at 0 - 20℃; for 16 h; | NaBH4 (2.49 g, 0.066 mol, 3 equiv), LiCl (2.79 g, 0.066 mol, 3 equiv) and H20 (30 mL) were added to a stirred solution ethyl 2-bromothiazole-4-carboxylate (1) (5.0 g, 0.022 mol, 1 equiv) in THF (50 mL) at 0 °C. The reaction mixture was allowed to warm to ambient temperature and stirred for 16 h. The reaction mixture was quenched with 1.5 M hydrochloric acid and the resulting mixture was extracted with ethyl acetate (2X150 mL). The combined organic layers were washed with water (150 mL), brine (150 mL), dried over Na2S04, filtered through celite bed and concentrated to provide compound 2 as a pale brown liquid (3.0 g, 68percent). LC-MS (ESI+): m/z 195.9 (M+H)+ 1H-NMR (300 MHz, DMSO-d6): δ 7.48 (s, 1H), 5.43 (t, J = 5.7 Hz, 1H), 4.52 (d, J = 5.7 Hz, 2H). |
67% | Stage #1: With lithium borohydride In tetrahydrofuran for 1 h; Cooling with an ice bath Stage #2: With methanol In tetrahydrofuran for 3.5 h; |
Step 3 : (2-bromothiazol-4-yl)methanolA solution of ethyl 2-bromothiazole-4-carboxylate (7.821 g, 33.13 mmol) in THF (100 mL) was cooled in an ice-bath and treated portionwise with lithium borohydride (1.083 g, 49.70 mmol). After 1 hour MeOH (1.614 g, 2.040 mL, 50.36 mmol) was added over a period of half an hour. The reaction was allowed to stir for 3 hours and then the solvent was concentrated in vacuo and the resultant residue was dissolved in EtOAc, washed with HCl (2x), saturated sodium bicarbonate, followed by brine, dried (Na2SO4), concentrated and purified by column chromatography (EtOAc/Petroleum ether 1: 1) to give the required product as a colorless oil (4.3Og, 67percent Yield). 1H NMR (CDCl3, 400 MHz) δ 2.51 (IH, m), 4.75 (2H, m), 7.19 (IH, s); MS (ES+) 195.96 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
49% | at 0 - 90℃; for 1.33 h; Inert atmosphere | A solution of methyl 2-bromothiazole-4-carboxylate (0.500 g, 2.25 mmol) in EtOH (10 mL) in a 50 mL flask under a nitrogen atmosphere was cooled to 0 °C and treated with NaBH4 (170 mg, 4.50 mmol) portion- wise over 5 min. After stirring for 15 min at 0 °C, the reaction mixture was heated at 90 °C for 1 h. The cooled mixture was then quenched with saturated aqueous NH4C1 (15 mL) and stirring was continued for 20 min. Ethyl acetate (50 mL) was then added and the organic phase was separated, washed with brine, dried over MgS04 and concentrated to give the title compound (0.212 g, 49percent) which was used as such in the next step. 1H NMR (CDCl3, 400 MHz) δ ppm: 7.18 (s, 1H), 4.76 (s, 2H), 2.21 (br s, 1H). |
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