Structure of 3-Bromoisothiazole
CAS No.: 55512-82-8
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CAS No. : | 55512-82-8 |
Formula : | C3H2BrNS |
M.W : | 164.02 |
SMILES Code : | BrC1=NSC=C1 |
MDL No. : | MFCD07778378 |
InChI Key : | OTNWEAKNUYQUKP-UHFFFAOYSA-N |
Pubchem ID : | 15323364 |
GHS Pictogram: |
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Signal Word: | Warning |
Hazard Statements: | H302-H315-H319-H335 |
Precautionary Statements: | P261-P305+P351+P338 |
Num. heavy atoms | 6 |
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 | 29.81 |
TPSA ? Topological Polar Surface Area: Calculated from |
41.13 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
1.69 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
2.01 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
1.91 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
0.53 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
3.07 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
1.84 |
Log S (ESOL):? ESOL: Topological method implemented from |
-2.74 |
Solubility | 0.299 mg/ml ; 0.00182 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (Ali)? Ali: Topological method implemented from |
-2.5 |
Solubility | 0.518 mg/ml ; 0.00316 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-2.14 |
Solubility | 1.2 mg/ml ; 0.00729 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 |
-5.87 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) |
2.62 |
* 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 |
---|---|---|
1% | General procedure: N-(4-Bromo-3-[(d imethylam ino)methylene]su lfamoyl}phenyl)-2-(2-chlorophenyl)acetamide (amount as indicated in examples) was dissolved in methanol (3 mL in case of 0.59 mmol scale) and degassed with nitrogen. Bis(pinacolato)diboron (2.5 eq), mesylate[(di(1 -adamantyl)-n-butylphosphine)-2-(2?-amino-1 ,1 ?-biphenyl)]palladium(l I) (cataCXium A Pd G3, 0.05 eq) and N,N-diisoproyplethylamine (2.5 eq) were added andit was stirred for 1 hour at 50C. The catalyst was removed by filtration and the filtrate was reduced in vacuo.The crude was redissolved in n-propanol (3 mL in case of 0.59 mmol scale), followed by degassing with nitrogen. The corresponding hetarylbromide (2 eq), potassium fluoride (0.23 eq), bis(tri-tert-butylphosphine)palladium(0) (0.05 eq) and triphenylphosphine (0.05 eq) were added. It was again degassed with nitrogen and potassium phosphate (2.5 eq) was added, followed by irradiating for 1 hour at 10000 in the microwave.Any precipitate was removed by filtration and the filtrate was concentrated in vacuo andredissolved in methanol (2 mL in case of 0.59 mmol scale). Aqueous ammoniumhydroxide solution (33%, 2 mL) was added. It was stirred until UPLC-MS showed completion of deprotection. In most cases stirring overnight was sufficient, in certain cases longer stirring and addition of further aqueous ammonium hydroxide solution was necessary. The reaction mixture was then concentrated in vacuo and purified as indicatedintheexamples. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
37.2% | With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; sodium carbonate; In N,N-dimethyl-formamide; at 90℃; for 0.5h;Inert atmosphere; Sealed tube; Microwave irradiation; | Intermediate I-1 (15 mg, 0.045 mmol) and <strong>[55512-82-8]3-bromoisothiazole</strong> (10.98 mg, 0.067 mmol) were dissolved in DMF (446 muL). PdCl2(dppf)-CH2Cl2 (2.187 mg, 2.68 mumol) was added and the reaction mixture was degassed by bubbling with argon for 15 minutes. Sodium carbonate (2 M, 26.8 muL, 0.054 mmol) was added and the reaction mixture was degassed for 5 minutes, then sealed and heated to 90 °C in the microwave for 30 minutes. The reaction mixture was diluted with DMF, filtered, and purified by preparative HPLC (Method D, 35 to 80percent B in 10 minutes) to give Example 5 (5.0 mg, 0.017 mmol, 37.2percent): 1H NMR (500MHz, METHANOL-d4) delta 8.89 (d, J=4.7 Hz, 1H), 8.59 (s, 1H), 8.13 (d, J=1.9 Hz, 1H), 8.10 (d, J=4.7 Hz, 1H), 7.84-7.52 (m, 2H), 2.64 (s, 3H); LC^MS: Method H, RT = 1.08 min, MS (ESI) m/z: 293.9 (M+H)+; Analytical HPLC Method B: 97.4percent purity |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
46% | Intermediate 123d was reacted with <strong>[55512-82-8]3-bromoisothiazole</strong> in a method analogous to Example 122 to give Example 123 (5.9 mg, 11.5 muiotaetaomicron, 46percent). LC-MS (Method Al) RT = 1.39 min, MS (ESI) m/z: 512.4 (M+H)+. H NMR (500 MHz, DMSO-cfe) delta 9.18 (d, 7=4.6 Hz, 1H), 8.12 (br d, 7=7.9 Hz, 1H), 8.09 - 8.01 (m, 2H), 7.75 (br d, 7=7.9 Hz, 1H), 7.17 (br d, 7=7.9 Hz, 2H), 7.07 (br d, 7=7.9 Hz, 2H), 4.68 (s, 2H), 2.32 (t, 7=7.6 Hz, 2H), 1.90 - 1.77 (m, 6H), 1.67 (br d, 7=6.7 Hz, 2H), 1.49 (quin, 7=7.5 Hz, 2H), 1.27 (dq, 7=14.9, 7.4 Hz, 2H), 0.81 (t, 7=7.3 Hz, 3H) (1 exchangeable proton not observed). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
49.28% | With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In 1,4-dioxane; water; at 80℃; for 4h;Inert atmosphere; | In a 50-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed [4-[3-(benzyloxy)propyljquinolin-7-yljboronic acid (904 mg, 2.81 mmol, 1 equiv), Na2CO3 (596.6 mg, 5.63 mmol, 2 equiv), <strong>[55512-82-8]3-bromo-1,2-thiazole</strong> (923.3 mg, 5.63 mmol, 2 equiv), and Pd(PPh3)4 (325.2 mg, 0.28 mmol, 0.1 equiv) in dioxane (20 mL) and H20 (5 mL). The resulting solution was stirred for 4 hours at 80 °C in an oil bath. The resulting mixture was cooled to room temperature and concentrated. Theresidue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:1). This resulted in 500 mg (49.28percent) of 4- [3 -(benzyloxy)propylj -7-( 1 ,2-thiazol-3-yl)quinoline as a light brow solid. LC-MS: (ES, m/z): [M+Hj = 361.1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
46% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; sodium carbonate; In 1,2-dimethoxyethane; water; at 120℃; for 0.5h;Inert atmosphere; Microwave irradiation; | To a reaction flask were added compound 5 (200 mg, 0.392 mmol), <strong>[55512-82-8]3-bromoisothiazole</strong> (96 mg, 0.588 mmol), Pd(dppf)Cl2 (32 mg, 0.02 mmol) and sodium carbonate (126 mg, 1.18 mmol), 2 mL glycol dimethyl ether and 0.4 mL water were added, bubbled with nitrogen gas for 10 minutes, heated to 120 C in microwave and reacted for 0.5 hour. After TLC detected the reaction was complete, the reaction was concentrated, purified by silica gel column chromatography to afford 84 mg of a product, yield: 46%. LC-MS(APCI): m/z = 467.3(M+1)+; 1H NMR (400 MHz, DMSO) delta 10.17 (s, 1H), 9.04 (s, 1H), 8.90 (s, 1H),8.76 (d, J = 2.3 Hz, 1H), 8.05 (d, J = 2.3 Hz, 1H), 7.86 (d, J = 9.1 Hz, 2H), 7.33 (d, J = 8.8 Hz, 2H), 4.86 (d, J = 3.4 Hz, 1H), 4.21 (s, 1H), 3.41 (dd, J = 17.0, 9.3 Hz, 1H), 3.29 - 3.18 (m, 2H), 2.90 (d, J = 11.1 Hz, 1H), 1.89 - 1.80 (m, 1H), 1.75 (s, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
44% | With copper(l) iodide; (1R,2R)-1,2-diaminocyclohexane; potassium carbonate; In 1,4-dioxane; at 120℃; for 12h; | To a solution of 3-bromo-4-methylbenzamide (78.30 mg, 365.80 pmol) in dioxane (2 mL) were added <strong>[55512-82-8]3-bromoisothiazole</strong> (50 mg, 304.83 pmol), Cul (11.61 mg, 60.97 pmol), (li?,2i?)-cyclohexane-l,2-diamine (6.96 mg, 60.97 pmol) and K2CO3 (84.26 mg, 609.67 pmol). The reaction mixture was stirred at 120C for 12 hours, then poured into water extracted with EtOAc. The organic layer was washed with brine, dried over Na2S04, and concentrated under reduce pressure. The crude product was purified by column chromatography (S1O2) eluting with a gradient of 5-10% EtOAc in petroleum ether to give the title compound as a yellow solid (40 mg, 44%). NMR (400 MHz, DMSO-Tis) d ppm 2.43 (s, 3 H) 7.51 (d, 7=8.0 Hz, 1 H) 7.87 (d, 7=4.8 Hz, 1 H) 7.96 (dd, Ji = 8.0, J2 = 2.0 Hz, 1 H) 8.18 - 8.38 (m, 1 H) 9.07 (d, 7=4.8 Hz, 1 H) 11.55 (s, 1 H); ESI-MS m/z [M+H]+ =297.0. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
37% | With copper(l) iodide; (1R,2R)-1,2-diaminocyclohexane; potassium carbonate; In 1,4-dioxane; at 120℃; under 760.051 Torr; for 16h;Inert atmosphere; | A mixture of 5-bromo-2-fluoro-4-methylbenzamide (300 mg, 1.29 mmol), 3- bromoisothiazole (212.05 mg, 1.29 mmol), Cul (49.24 mg, 258.57 pmol), K2CO3 (357.35 mg, 2.59 mmol) and ( 17?, 2i?)-cyclohexane- 1,2-diamine (29.53 mg, 258.57 pmol) in dioxane (4 mL) was degassed and purged with N2 (3 x). The reaction mixture was stirred at 120C for 16 hours under N2 atmosphere and then diluted with water and extracted with EtOAc. The organic layers were combined, washed with brine, dried over Na2S04 and concentrated under reduced pressure. The resulting residue was purified by column chromatography (S1O2) eluting with a gradient of 0-20% EtOAc in petroleum ether to give the title compound as a white solid (150 mg, 37%). NMR (400 MHz, DMSO-r/e) d ppm 2.47 (s, 3 H) 7.12 (d, =12.4 Hz, 1 H) 8.03 (d, J= 4.8 Hz, 1 H) 8.34 (d, =7.6 Hz, 1 H) 8.67 (d, =4.8 Hz, 1 H) 9.32 (d, .7=13.6 Hz, 1 H); ESI-MS m/z [M+H]+ = 314.8. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
35% | With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In 1,4-dioxane; water; at 100℃; for 16h; | To a stirred solution of tert-butyl (R)-3-((5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1- ((2-(trimethylsilyl) ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidine-1- carboxylate (0.72 g, 1.25 mmol) and <strong>[55512-82-8]3-bromoisothiazole</strong> (0.3 g, 1.63 mmol) in 1,4-dioxane (20 mL) was added tetrakis(triphenyl phosphine)palladium(0) (0.18 g, 0.25 mmol) followed by 2M aqueous solution of sodium carbonate (0.4 g, 3.77 mmol) and the reaction mixture heated at 100 C for16 hours. After cooling the reaction mixture was diluted with ethyl acetate and filtered through celite. The filtrate was washed with water, brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The crude material was purified by flash chromatography (25% ethyl acetate/hexane) to provide tert-butyl (R)-3-((5- (isothiazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-4- yl)amino)piperidine-1-carboxylate as a pale yellow liquid (0.23 g, 35% yield): MS (ES) m/z 529.9 (M+H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium phosphate; methanesulfonic acid(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II); In 1,4-dioxane; water; at 80℃; for 1h;Inert atmosphere; | To a reaction vessel containing 3- bromoisothiazole (114 mg, 0.697 mmol), the product from Example 128 Step 1 (250 mg, 0.697 mmol), 1 M KsP04(aq) (1.20 ml, 1.20 mmol) and dioxane (4.80 ml) was added XPhos Pd G3 (29.5 mg, 0.035 mmol). The resultant reaction mixture was degassed with N2 for 10 min and then heated to 80 C for 1 h. The reaction mixture was concentrated in vacuo. The crude product was purified by chromatography on silica gel (12 g cartridge, 0-15%EtOAc/isohexane) to afford the title compound (154 mg, 0.580 mmol, 83% yield, 92% purity) as a light brown solid. UPLC-MS (Method 1): m/z 245.2 (M+H)+(ES+), at 1.57 min.1H NMR (500 MHz, DMSO-cfe) d 9.16 (d, J = 4.8 Hz, 1 H), 8.00 (d, = 4.9 Hz, 1 H), 7.95 (d, J = 8.2 Hz, 1 H), 7.16 (d, J = 1.9 Hz, 1 H), 7.12 (br s, 2H), 6.86 (dd, J = 8.4, 1.9 Hz, 1 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | With potassium phosphate; methanesulfonic acid(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II); In 1,4-dioxane; water; at 80℃; for 2h;Inert atmosphere; | To a reaction vessel containing the product from Example 152 Step 1 (236 mg, 0.706 mmol), <strong>[55512-82-8]3-bromoisothiazole</strong> (127 mg, 0.776 mmol), 1 M KsP04(aq) (1.24 ml, 1.24 mmol) and dioxane (4.96 ml) was added XPhos Pd G3 (30 mg, 0.035 mmol). The resultant reaction mixture was degassed with N2 for 10 min and then heated to 80 C for 2 h. The reaction mixture was allowed to cool to RT, filtered through Celite, washed with MeOH (10 ml) and then concentrated in vacuo. The crude product was purified by chromatography on silica gel (12 g cartridge, 0-25% EtOAc/isohexane) to afford the title compound (104 mg, 0.511 mmol, 72% yield, 99% purity) as a yellow solid. UPLC- MS (Method 1): m/z 202.2 (M+H)+(ES+), at 1.26 min.1H NMR (500 MHz, DMSO-cfe) d 9.17 (d, J = 4.8 Hz, 1 H), 8.02 (d, = 4.8 Hz, 1 H), 7.94 (d, = 8.1 Hz, 1 H), 7.19 (d, = 1.7 Hz,1 H), 7.14 (br s, 2H), 6.97 (dd, J = 8.1 , 1.7 Hz, 1 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium phosphate; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In 1,4-dioxane; water; at 80℃; for 1h;Inert atmosphere; | A mixture of the product from Example 178 Step 1 (100 mg, 322 pmol, 90% purity), <strong>[55512-82-8]3-bromoisothiazole</strong> (31 pi, 352 pmol), 1 M K3PC>4(aq) (550 mI, 550 pmol) and dioxane (3 ml) was treated with Pd(dppf)Cl2- DCM complex (13 mg, 15.9 pmol). The resultant solution was degassed with N2 for 10 min, then heated at 80 C for 1 h. The reaction mixture was concentrated onto silica and purified by chromatography on silica gel (24 g cartridge, 0-40% EtOAc/isohexane) to afford the title compound (57 mg, 227 pmol, 70% yield, 94% purity) as a yellow solid. UPLC-MS (Method 1) m/z 236.1 (M+H)+at 1.43 min |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
50% | With potassium phosphate; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In 1,4-dioxane; water; at 80℃; for 1h;Inert atmosphere; | A mixture of the product from Step 1 above (200 mg, 736 pmol, 96% purity), <strong>[55512-82-8]3-bromoisothiazole</strong> (65 pi, 0.74 mmol), 1M K3PC>4(aq) (1.30 ml, 1.30 mmol) and dioxane (6 ml) was treated with Pd(dppf)CI2-DCM complex (30 mg, 37 pmol). The resultant solution was degassed with N2for 10 min, then heated at 80 C for 1 h. The reaction mixture was concentrated onto silica and purified by chromatography on silica gel (40 g cartridge, 0-40% EtOAc/isohexane) to afford the title compound (81 mg, 364 pmol, 50% yield, 99% purity) as a yellow solid. UPLC-MS (Method 1) m/z 220.2 (M+H)+at 1.32 min. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With n-butyllithium; In tetrahydrofuran; at -70℃; for 1h;Inert atmosphere; | To a mixture of 88a (0.30 g, 1.83 mmol, 1.00 eq) and triisopropyl borate (482 mg, 2.56 mmol, 589 uL, 1.40 eq) in THF (4 mL) n-BuLi (2.5 M, 1.02 mL, 1.40 eq) was added drop- wise at -70C under N2. The reaction mixture was stirred at -70C for 1 hr. LCMS showed the starting material was consumed completely. Water (8 mL) was added to the reaction mixture at 0C, and then extracted with ethyl acetate (20 mL x 2). The combined organic layers were dried over Na2S04, filtered and concentrated under reduced pressure to give 88b (0.34 g, crude) as a brown oil. |