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CAS No. : | 105655-01-4 | MDL No. : | MFCD08544341 |
Formula : | C8H8BrNO | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | RWKBNMSHIJBNAO-UHFFFAOYSA-N |
M.W : | 214.06 | Pubchem ID : | 10727336 |
Synonyms : |
|
Num. heavy atoms : | 11 |
Num. arom. heavy atoms : | 6 |
Fraction Csp3 : | 0.25 |
Num. rotatable bonds : | 0 |
Num. H-bond acceptors : | 1.0 |
Num. H-bond donors : | 1.0 |
Molar Refractivity : | 50.76 |
TPSA : | 21.26 Ų |
GI absorption : | High |
BBB permeant : | Yes |
P-gp substrate : | No |
CYP1A2 inhibitor : | Yes |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -5.94 cm/s |
Log Po/w (iLOGP) : | 2.08 |
Log Po/w (XLOGP3) : | 2.34 |
Log Po/w (WLOGP) : | 1.68 |
Log Po/w (MLOGP) : | 1.83 |
Log Po/w (SILICOS-IT) : | 2.53 |
Consensus Log Po/w : | 2.09 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 0.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -3.05 |
Solubility : | 0.193 mg/ml ; 0.000902 mol/l |
Class : | Soluble |
Log S (Ali) : | -2.43 |
Solubility : | 0.803 mg/ml ; 0.00375 mol/l |
Class : | Soluble |
Log S (SILICOS-IT) : | -3.6 |
Solubility : | 0.0539 mg/ml ; 0.000252 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 2.13 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H302-H315-H319-H335 | Packing Group: | N/A |
GHS Pictogram: |
* 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 |
---|---|---|
100% | Stage #1: With borane-THF In tetrahydrofuran at 20℃; for 1.16667 h; Heating / reflux Stage #2: With sodium hydroxide; water In tetrahydrofuran |
INTERMEDIATE 13; 6-Bromo-3,4-dihydro-2H-benzo[l.,4]oxazine; Borane-TηF ( 13.2 mL of a 1 M solution in TηF, 13.2 mmol) was added portionwise to Intermediate 6 (2.0 g, 8.0 mmol) in TηF (50 mL) at r.t. The resulting solution was stirred at r.t. for 10 min, heated to reflux for 1 h and then allowed to cool to r.t. The reaction was cooled in an ice bath and quenched with water (20 mL) and 2N aqueous sodium hydroxide solution (2OmL). The solvent was removed in vacuo and the resulting mixture diluted with water (100 mL). It was extracted with EtOAc (10OmL), washed with brine (10OmL), dried (MgSO4), filtered and concentrated in vacuo to yield the title compound as a brown oil (2 g, quant). δη (DMSO-d6) 3.36-3.44 (2H, m), 3.81 (IH, br s), 4.18-4.25 (2H, m), 6.68 (3H, m). |
100% | With borane-THF In tetrahydrofuran at 20℃; for 1.16667 h; Heating / reflux | Borane-TηF (13.2 mL, IM solution in TηF, 13.2 mmol) was added portionwise to Intermediate 37 (2.0 g, 8.0 mmol) in TηF (50 mL) at r.t. The resulting mixture was stirred at r.t. for 10 minutes, heated to reflux for 1 h and then allowed to cool to r.t. The reaction mixture was cooled to 00C and quenched with water (20 mL) and aqueous 2N NaOH (20 mL). The solvent was removed in vacuo and the resulting mixture diluted with water (100 mL). The aqueous fraction was extracted with EtOAc (100 mL), washed with brine (100 mL), dried (MgSO4), filtered and concentrated in vacuo to yield the title <n="52"/>compound (2 g, quantitative) as a brown oil. δH (DMSOd6) 6.68 (3H, m), 4.25-4.18 (2H, m), 3.81 (IH, br. s), 3.44-3.36 (2H, m). |
100% | Stage #1: With borane-THF In tetrahydrofuran at 20℃; for 1.16667 h; Heating / reflux Stage #2: With sodium hydroxide; water In tetrahydrofuran at 0℃; |
INTERMEDIATE 106-Bromo-3,4-dihvdro-2H-benzo[ 1 ,4]oxazineBorane-THF (13.2 mL of a IM solution in THF, 13.2 mmol) was added portionwise to Intermediate 8 (2.0 g, 8.0 mmol) in THF (50 mL) at r.t. The resulting solution was stirred at r.t. for 10 minutes, heated to reflux for 1 h and then allowed to cool to r.t. The reaction was cooled in an ice bath and quenched with water (20 mL) and 2N aqueous sodium hydroxide solution (20 mL). The solvent was removed in vacuo and the resulting mixture diluted with water (100 mL). It was extracted with EtOAc (100 mL), <n="99"/>washed with brine (100 mL), dried (MgSO4), filtered and concentrated in vacuo to yield the title compound (2 g, quantitative) as a brown oil. δH (DMSO-d6) 6.68 (3H, m), 4.18- 4.25 (2H, m), 3.81 (IH, br s), 3.36-3.44 (2H, m). |
100% | Stage #1: With borane-THF In tetrahydrofuran at 20℃; for 1.16667 h; Heating / reflux Stage #2: With sodium hydroxide In tetrahydrofuran; water at 0℃; |
Borane-THF (13.2 mL, IM solution in THF, 13.2 mmol) was added portionwise to Intermediate 5 (2.0 g, 8.0 mmol) in THF (50 mL) at r.t. The resulting solution was stirred at r.t. for 10 minutes, heated to reflux for 1 h and then allowed to cool to r.t. The reaction mixture was cooled to 00C and quenched with water (20 mL) and aqueous 2N NaOH (20 mL). The solvent was removed in vacuo and the resulting mixture diluted with water (100 mL). The aqueous fraction was extracted with EtOAc (100 mL), washed with brine (100 mL), dried (MgSO4), filtered and concentrated in vacuo to yield the title compound (2 g, quantitative) as a brown oil. δH (DMSO-d6) 6.68 (3H, m), 4.25-4.18 (2H, m), 3.81 (IH, br. s), 3.44-3.36 (2H, m). |
100% | Stage #1: With borane-THF In tetrahydrofuran at 20℃; for 1.16667 h; Heating / reflux Stage #2: With sodium hydroxide In tetrahydrofuran; water |
To a stirred solution of Intermediate 32 (2.0 g, 8.0 mmol) in TηF (50 mL) was added borane-TηF (13.2 mL, IM solution in TηF, 13.2 mmol) portionwise. The reaction mixture was stirred at r.t. for 10 minutes, then heated to reflux for 1 h and allowed to cool to r.t. The reaction mixture was cooled to 00C and quenched with water (20 mL), then 2M aqueous NaOH (20 mL), and concentrated in vacuo. Water (100 mL) and EtOAc (100 mL) were added and the layers separated. The organic fraction was washed with <n="105"/>brine (100 mL), dried (MgSO4), filtered and concentrated in vacuo to give the title compound (2 g, quantitative) as a brown oil. δH (DMSOd6) 6.68 (3 H, m), 4.25-4.18 (2H, m), 3.81 (IH, br. s), 3.44-3.36 (2H, m). |
93% | With dimethylsulfide borane complex In tetrahydrofuran for 3 h; Inert atmosphere; Reflux | To a solution of 6-bromo-2H-benzo[b][1,4]oxazin-3(4H)-one (400 mg, 1.75 mmol) in anhydrous tetrahydrofuran (3 mL) under a nitrogen atmosphere was added a 1M solution of borane dimethyl sulfide complex in tetrahydrofuran (7.0 mL, 7.0 mmol) slowly. The resulting solution was refluxed for 3 hours. Then, the reaction mixture was cooled to ambient temperature and carefully quenched with the addition of methanol (10 mL). Next, the reaction mixture was heated to reflux for 10 minutes, and then the reaction mixture was cooled and concentrated in vacuo to provide a residue. The residue was redissolved in ethyl acetate, washed with water, brine, dried with sodium sulfate, filtered and concentrated in vacuo to yield title compound. The title compound was used in Part IV below without purification. (350 mg, 93percent yield) ESI m/z 214.03, 216.0 (M+H). |
88% | Stage #1: With borane-THF In tetrahydrofuran for 1.25 h; Stage #2: With hydrogenchloride; water In tetrahydrofuran at 0℃; for 0.166667 h; Heating / reflux Stage #3: With sodium hydroxide In tetrahydrofuran; water |
Example 48; λ/-{2-chloro-5-[4-(phenylmethyl)-3,4-dihydro-2H-l,4-benzoxazin-6-yl]-3- pyridinyl}benzenesulfonamide; a) 6-bromo-3 ,4-dihy dro-2H- 1 ,4-benzoxazine; 6-Bromo-2H-l,4-benzoxazin-3(4H)-one (2.085 g, 9.143 mmol) was suspended in dry TηF (20 mL) and placed under nitrogen with stirring and to this was added 1 M BH3-THF complex (3.143 g, 36.572 mmol, 36.52 mL) over 5 minutes. Addition causes the reaction to become homogeneous. After 70 minutes, the reaction was cooled to O0C and made acidic by addition of 3N HCl (109 mL). Addition of acid causes vigorous bubbling. After the addition was completed, the reaction was refluxed for 10 minutes and then cooled and made basic by addition of 6N NaOH. The basified reaction was extracted with EtOAc (3 x 100 mL), dried over Na2SO4, filtered, and the concentrated filtrate was purified by flash chromatography on silica gel (.00percent CH2Cl2) to give the title compound (1.713 g, 88percent) as a pale yellow oil. MS(ES)+ m/e 214 [M+H]. |
87% | With borane-THF In tetrahydrofuranInert atmosphere; Cooling with ice; Reflux | [Synthesis of Compound E4] (0133) Compound E3 (1.0 g, 4.4 mmol, 1 Eq) was dissolved in THF (20 mL) in an argon atmosphere, and placed on an ice bath. A THF solution of 1 M borane-THF complex (7.0 mL, 7.0 mmol, 1.6 Eq) was added and the combination was stirred overnight while heating and refluxing. The reaction system was returned to room temperature, methanol was added in small amounts, and the solvent was removed under reduced pressure. The reaction system was then diluted by ethyl acetate, and the organic layer was washed by saturated sodium hydrogen carbonate aqueous solution and saturated saline, dried by anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The residue obtained was purified by medium-pressure silica gel chromatography (eluent: dichloromethane/methanol=98/2), and the target compound E4 (817 mg, 87percent) was obtained as a colorless liquid. (0134) 1H NMR (CDCl3): δ 6.71 (dd, J=2.3 Hz, 8.4 Hz, 1H), 6.68 (d, J=2.3 Hz, 1H), 6.62 (d, J=8.4 Hz, 1H), 4.20 (t, J=4.4 Hz, 2H), 3.80 (br s, 1H), 3.38 (t, J=4.4 Hz, 2H).; 13C NMR (CDCl3): δ 143.1 (C), 135.2 (C), 121.2 (CH), 118.1 (CH), 117.7 (CH), 113.2 (C), 65.1 (CH2), 40.6 (CH2).; HRMS-ESI (m/z): [M+H]+ calcd for C8H9BrNO: 213.98620. found: 213.98626 (−0.1 mDa, −0.3 ppm). |
3.2 g | With borane-THF In tetrahydrofuran at 0℃; for 3 h; Reflux | 6-bromo-3,4-dihydro-2H-benzo[6] [l,4]oxazine (2): To a stirred solution of 6- bromo-2H-benzo[6][l,4]oxazin-3(4H)-one (7 g, 30.8 mmol) in THF (20 mL) was added 1M borane in THF (15.41 mL) at 0 °C and stirred for 3 h at reflux temperature. After completion of the reaction, methanol (2 mL) was added to the reaction mixture at 0 °C and stirred for 2 h at reflux. After completion of the reaction, cone. HC1 (2 mL) was added to reaction mixture at 0 °C and again stirred for 2 h at reflux. The reaction mixture was then neutralized with 2N NaOH solution at 0 °C and extracted with ethyl acetate. The combined organic layer was washed with water and brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude compound was purified by column chromatography (100-200 mesh silica gel, 15percent ethyl acetate in pet. ether as eluent) to afford 2 (3.2 g, 49percent yield) as a brown solid. MS m/z (M+H): 214.4 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | With potassium carbonate In N,N-dimethyl-formamide at 60℃; for 4 h; | A mixture of the product 5-bromo-2-(2-bromoethoxy)benzenamine (250 mg, 0.848 mmol) and K2C03 (234 mg, 1.695 mmol) in DMF (5 mL) was stirred at 60 °C for 4 h. The mixture was diluted with water (100 mL) and extracted with ethyl acetate (100 mL). The organic layer was washed with water (3 x 50 mL) and brine (50 mL), concentrated to give 6-bromo-3,4-dihydro-2H-benzo[6][l,4]oxazine (170 mg, 94percent) as a yellow oil. LCMS: 214 [M+l]+. 1H NMR (400 MHz, DMSO-<3/4) δ 3.26 (m, 2H), 4.08 (t, J= 4.8 Hz, 2H), 6.06 (s, 1H), 6.56 (m, 2H), 6.69 (d, J= 1.6 Hz, 1H). |
94% | With potassium carbonate In N,N-dimethyl-formamide at 60℃; for 4 h; | A mixture of the product 5-bromo-2-(2-bromoethoxy)benzenamine (250 mg, 0.848 mmol) and K2CO3 (234 mg, 1.695 mmol) in DMF (5 mL) was stirred at 60° C. for 4 h. The mixture was diluted with water (100 mL) and extracted with ethyl acetate (100 mL). The organic layer was washed with water (3×50 mL) and brine (50 mL), concentrated to give 6-bromo-3,4-dihydro-2H-benzo[b][1,4]oxazine (170 mg, 94percent) as a yellow oil. LCMS: 214 [M+1]+. 1H NMR (400 MHz, DMSO-d6) δ 3.26 (m, 2H), 4.08 (t, J=4.8 Hz, 2H), 6.06 (s, 1H), 6.56 (m, 2H), 6.69 (d, J=1.6 Hz, 1H) |
94% | With potassium carbonate In N,N-dimethyl-formamide at 60℃; for 4 h; | The product 5-bromo-2- (2-bromoethoxy) benzene amine (250mg, 0.848mmol) and K2CO3 (234mg, 1.695mmol) A mixture of in DMF (5 mL), and stirred for 4 hours at 60 ° C.. The mixture was diluted with water (100 mL), and extracted with ethyl acetate (100 mL). The organic layer was washed with water (3 × 50 mL) and brine (50 mL), concentrated to give 6-bromo-3,4-dihydro -2H- benzo [b] [1,4] oxazine as a yellow oil (170 mg , 94percent). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
19% | With potassium carbonate In N,N-dimethyl-formamide at 125℃; for 15 h; Inert atmosphere | To a solution of 2-amino-4-bromophenol (4e) (200.0 mg, 1.06 mmol) and K2C03 (735.3 mg, 5.32 mmol) in anhydrous DMF (3 mL) was added 1,2-dibromoethane (0.14 mL, 1.60 mmol) under argon. The resulting mixture was stirred at 125 °C for 15 h. After being quenched with H20 (5 mL), the aqueous layer was extracted with EtOAc (2 x 15 mL). The combined organic extracts were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by column chromatography on silica gel (EtOAc/hexane, 10:90 to 20:80) to afford 3e (44.0 mg, 19percent) as a brown oil; ‘H NMR (CDC13, 400 MHz) 6.74—6.69 (2 H, m), 6.64 (1 H, d, J = 8.7 Hz), 4.22—4.20 (2 H, m), 3.89 (2 H, br),3.04—3.38 (2 H, m); ‘3C NMR (CDC13, 100 MHz) 142.9, 135.0, 121.0, 118.0, 117.6, 113.1,64.9, 40.5. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65% | With dmap; triethylamine In tetrahydrofuran at 20℃; | A mixture of the product 6-bromo-3,4-dihydro-2H-benzo[.pound.][l,4]oxazine (1.37 g, 6.4 mmol), Boc20 (1.676 g, 7.68 mmol), Et3N (970 mg, 9.6 mmol), DMAP (78 mg, 0.64 mmol) in THF (27 mL) was stirred at room temperature overnight. The reaction mixture was diluted with water (200 mL) and extracted with ethyl acetate (100 mL). The organic layer was washed with water (50 mL) and brine, dried over Na2S04 and concentrated to give compound 0601-182 (1.3 g, 65percent) as a yellow oil. LCMS: 258 [M-55]+. 1H NMR (400 MHz, OMSO-de) δ 1.49 (s, 9H), 3.78 (t, J= 4.8 Hz, 2H), 4.21 (t, J= 4.4 Hz, 2H), 6.83 (d, J = 4.4 Hz, 1H), 7.12 (dd, J; = 2.0 Hz, J2 = 8.4 Hz, 2H), 8.01 (s, 1H). |
65% | With dmap; triethylamine In tetrahydrofuran at 20℃; | A mixture of the product 6-bromo-3,4-dihydro-2H-benzo[b][1,4]oxazine (1.37 g, 6.4 mmol), Boc2O (1.676 g, 7.68 mmol), Et3N (970 mg, 9.6 mmol), DMAP (78 mg, 0.64 mmol) in THF (27 mL) was stirred at room temperature overnight. The reaction mixture was diluted with water (200 mL) and extracted with ethyl acetate (100 mL). The organic layer was washed with water (50 mL) and brine, dried over Na2SO4 and concentrated to give compound 0601-182 (1.3 g, 65percent) as a yellow oil. LCMS: 258 [M-55]+. 1H NMR (400 MHz, DMSO-d6) δ 1.49 (s, 9H), 3.78 (t, J=4.8 Hz, 2H), 4.21 (t, J=4.4 Hz, 2H), 6.83 (d, J=4.4 Hz, 1H), 7.12 (dd, J1=2.0 Hz, J2=8.4 Hz, 2H), 8.01 (s, 1H). |
65% | With dmap; triethylamine In tetrahydrofuran at 20℃; | The product 6-bromo-3,4-dihydro--2H- benzo [b] [1,4] oxazine (1.37g, 6.4mmol), Boc2O (1.676g, 7.68mmol), Et3N (970mg, 9.6mmol), DMAP (78mg, 0.64mmol) a mixture of in THF (27mL), and stirred at room temperature overnight. The reaction mixture was diluted with water (200 mL), and extracted with ethyl acetate (100 mL). The organic layer was washed with water (50 mL) and brine, dried and concentrated in Na2SO4, to give the compound 0601-182 as a yellow oil (1.3g, 65percent). |
60% | With triethylamine In tetrahydrofuranHeating / reflux | INTERMEDIATE 25; 6-Bromo-2,3-dihvdrobenzo[l,41oxazine-4-carboxylic acid fe/t-butyl ester; A mixture of Intermediate 13 (4.0 g, 18.6 mmol), di-fert-butyl dicarbonate (4.9 g, 22.4 mmol), 4-(dimethylamino)pyridine (50 mg, catalytic) and triethylamine (2.6 mL, 18.6 mmol) in THF (50 mL) was heated to reflux overnight. After cooling to r.t. the reaction mixture was concentrated in vacuo. The crude material was purified by column chromatography (SiO2, linear gradient elution: 0-100percent EtOAc in heptane) to give the title compound as an off-white solid (3.5g, 60percent). δH (DMSO-d6) 1.56 (9H, s), 3.80-3.89 (2H, m), 4.19-4.26 (2H, m), 6.77 (IH, d, J 8.9 Hz), 7.08 (IH, dd, J8.7, 2.4 Hz), 8.02 (IH, s). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | Stage #1: at 130 - 150℃; Stage #2: With sodium hydroxide In water; ethyl acetate for 1 h; Sonographic reaction |
A mixture of 6-bromo-3,4-dihydro-2H-benzo[1,4]oxazine (9D, 1.5 g, 7.05 mmol) and CuCN (1.58 g, 17.61 mmol) in anhydrous DMF (15 mL) was stirred at 130° C. for 3 h and then at 150° C. overnight. Then the mixture was cooled to RT, quenched with water and concentrated under vacuum. The residue was taken up in 2N NaOH and EtOAc (100 mL) and then agitated in a sonicator for 1 h. The precipitate was filtered off and washed with EtOAc. The filtrate and washings were combined and extracted with EtOAc (2.x.80 mL). The organic layer was dried (MgSO4), filtered and concentrated under vacuum to give compound 12A (1.062 g, 94percent). |
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