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CAS No. : | 28165-50-6 | MDL No. : | MFCD08277300 |
Formula : | C6H6BrNO | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | LOBRHADLNRMHOO-UHFFFAOYSA-N |
M.W : | 188.02 | Pubchem ID : | 15531506 |
Synonyms : |
|
Num. heavy atoms : | 9 |
Num. arom. heavy atoms : | 6 |
Fraction Csp3 : | 0.0 |
Num. rotatable bonds : | 0 |
Num. H-bond acceptors : | 1.0 |
Num. H-bond donors : | 2.0 |
Molar Refractivity : | 40.57 |
TPSA : | 46.25 Ų |
GI absorption : | High |
BBB permeant : | Yes |
P-gp substrate : | No |
CYP1A2 inhibitor : | No |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | Yes |
Log Kp (skin permeation) : | -6.03 cm/s |
Log Po/w (iLOGP) : | 1.49 |
Log Po/w (XLOGP3) : | 1.99 |
Log Po/w (WLOGP) : | 1.74 |
Log Po/w (MLOGP) : | 1.58 |
Log Po/w (SILICOS-IT) : | 1.34 |
Consensus Log Po/w : | 1.63 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 1.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -2.75 |
Solubility : | 0.332 mg/ml ; 0.00177 mol/l |
Class : | Soluble |
Log S (Ali) : | -2.59 |
Solubility : | 0.486 mg/ml ; 0.00259 mol/l |
Class : | Soluble |
Log S (SILICOS-IT) : | -2.32 |
Solubility : | 0.906 mg/ml ; 0.00482 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 2.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.28 |
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 |
---|---|---|
55% | With di-isopropyl azodicarboxylate; triphenylphosphine In tetrahydrofuran at 20 - 25℃; for 1.08333 h; | Preparation 22Stepl[00236j To a slurry of 2-amino-6-bromophenol (4.00 g, 21.27 mmol) in methanol (2.152 mL, 53.2 mmol) and THF (10 mL) at room temperature was added triphenylphosphine (11.16 g, 42.5 mmol). After stirring for a few minutes, diisopropylazodicarboxylate (DIAD, 12.41 mL, 63.8 mmol) was then added dropwise via syringe over 5 minutes. After the addition was complete, the reaction was allowed to stir at room temperature for 1 h. The resulting mixture was then concentrated to remove the volatiles and the resulting residue was purified by silica gel flash chromatography using hexanes/ethyl acetate as the eluent. Fractions containing the major UV-active productwere combined and concentrated under vacuum to afford 2.35 g (55percent) of a dark brown oil as the desired product. HPLC (Method N) RT = 1.33 minutes. LCMS MH+ 202/204 (observed bromide isotope pattern). |
55% | With di-isopropyl azodicarboxylate; triphenylphosphine In tetrahydrofuran at 20℃; for 1 h; | Step 4 To a slurry of 2-amino-6-bromophenol (4.00 g, 21.27 mmol) in methanol (2.152 mL, 53.2 mmol) and THF (10 mL) at rt was added triphenylphosphine (11.16 g, 42.5 mmol). After stirring for a few minutes, DIAD (12.41 mL, 63.8 mmol) was then added dropwise via syringe over ~5 min. (exothermic). After the addition was complete, the reaction which had warmed due to the exothermic reaction was allowed to stir at rt for ~1 h. The resulting mixture was then concentrated to remove the volatiles and the resulting residue was purified by silica gel flash chromatography using hexanes/ethyl acetate as the eluant. Fractions containing the major uv active product were combined and concentrated under vacuum to afford 2.35 g (55percent) of a dark brown oil as the desired product. HPLC (method N) RT = 1.33 min. LCMS MH+ 202/204 (observed bromide isotope pattern). |
55% | Stage #1: With triphenylphosphine In tetrahydrofuran at 20℃; Stage #2: With di-isopropyl azodicarboxylate In tetrahydrofuran at 20℃; for 1 h; |
To a slurry of 2-amine-6-bromophenol (4.00 g, 21.27 mmol) in methanol (2.152 mL, 53.2 mmol) and THF (10 mL) at rt was added triphenylphosphine (11.16 g, 42.5 Mmol).After stirring for several minutes, DIAD (12.41 mL, 63.8 mmol) (exotherm) was added dropwise via the syringe over about 5 minutes. After the addition was complete, the reaction, which had been heated by the exothermic reaction, was stirred for about 1 h at rt. The resulting mixture was then concentrated to remove the volatiles and the resulting residue was purified by flash chromatography on silica gel using hexane / ethyl acetate as the eluent. The fractions containing the major product of uv activity were combined and concentrated in vacuo to afford 2.35 g (55percent) of the desired product as a dark brown oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
67% | With caesium carbonate In acetonitrile at 20℃; for 2.5h; | 1; A2 A mixture of A1a (2.59 g, 13.8 mmol), A2a (4.10 g, 15.2 mmol) and Cs2CO3 (4.49 g, 13.8 mmol) in CH3CN (40 mL) was stirred at room temperature for 2.5 h. The solid was filtered and washed with THF and CH2Cl2. The filtrate was concentrated and purified by column chromatography to give 3.87 g (67%) of A2b as a brownish oil: 1H NMR (300 MHz, CDCl3) δ 7.84 (s, 1H), 7.76 (d, J=7.8 Hz, 1H), 7.51 (t, J=8.0 Hz, 1H), 7.41-7.36 (m, 3H), 6.93 (t, J=7.9 Hz, 1H), 5.95 (mt, J=53.0 Hz, 1H), 5.17 (s, 2H); MS (ES) m/z: 404 (M-H2O). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
52% | With potassium carbonate In 1,4-dioxane; water at 100℃; for 17.3333h; | 7; D A mixture of 2-amino-6-bromo-phenol (255 mg, 1.36 mmol), m-trifluoromethoxy-phenyl boronic acid (560 mg, 2.72 mmol), K2CO3 (2.0 M, 2.0 mL, 4.0 mmol) in 1,4-dioxane (8 mL) was degassed under N2 for 10 min, and PdCl2(PPh3)2 (95 mg, 0.14 mmol) was added. The mixture was purged with N2 for another 10 min then heated at 100° C. for 17 h. After cooling to room temperature, the organic layer was separated and the aqueous layer was extracted with CH2Cl2. The combined organic layers were dried (Na2SO4), concentrated and purified by column chromatography to give 191 mg (52%) of D2 as a yellow oil: 1H NMR (300 MHz, CDCl3) δ 7.54-7.40 (m, 2H), 7.35 (s, 1H), 7.24 (m, 1H), 6.88-6.77 (m, 2H), 6.70-6.62 (m, 1H), 5.20 (brs, 1H), 3.78 (brs, 2H); MS (ES) m/z: 270 (M+H+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With potassium carbonate In water; butanone at 20 - 80℃; | 50; FF Example 50 To a solution of A1a (1.30 g, 6.91 mmol) in 2-butanone (35 mL) was added a solution of K2CO3 (3.34 g, 24.2 mmol) in water (5 mL) followed by chloro acetyl chloride (0.8 mL, 10 mmol). After stirring at room temperature for 2 h and then 80° C. for another 2 h, the mixture was cooled down and was let standing at room temperature overnight. The precipitated crystals were filtered, washed with Et2O and dried under vacuum to give 1.58 g (100%) of compound FF1 as a pink crystal: 1H NMR (400 MHz, CDCl3) δ 8.21 (brs, 1H), 7.22 (m, 1H), 6.85 (t, J=8.0 Hz, 1H), 6.76 (d, J=7.9 Hz, 1H), 4.73 (s, 2H). |
100% | With potassium carbonate | |
94% | With sodium hydrogencarbonate In water; acetonitrile at 0℃; Reflux; | 10.A Example 10 3-((4-(4-(4-(2,3-Dimethylphenoxy)butanoyl)-3,4-dihydro-2H-benzo[ ?][l,4]oxazin-8-yl)- lH-pyrazol- 1 -yl)methyl)benzoic acidStep A. 8-Bromo-2H-benzo[ ?][l,4]oxazin-3(4H)-one[00158] To a solution of 2-amino-6-bromophenol (1 g, 5.32 mmol) in acetonitrile (10 mL) and water (10 mL) was added sodium bicarbonate (1.028 g, 12.23 mmol). The mixture was cooled to 0 °C and chloroacetyl chloride (0.554 mL, 6.91 mmol) was added dropwise. The reaction was refluxed overnight. After cooling to room temperature, the mixture was diluted with EtOAc, washed with water, dried over anhydrous MgS04, filtered, and concentrated to afford the title compound (1.14 g, 94% yield) as a dark brown solid. ¾ NMR (400 MHz, CDC13) δ 8.22 (br. s, 1H), 7.23 (dd, J= 8.0, 1.4 Hz, 1H), 6.86 (t, J= 8.0 Hz, 1H), 6.76 (dd, J= 7.9, 1.3 Hz, 1H), 4.74 (s, 2H). |
91% | With potassium carbonate In N,N-dimethyl-formamide at 20℃; | 32.1 Step 1 8-bromo-4H-benzoxazin-3-one 2-Amino-6-bromophenol (1.0 g, 5.32 mmol) was dissolved in DMF (20 mL), and potassium carbonate (1.6 g, 11.7 mmol) and chloroacetyl chloride (0.466 mL), 5.85 mmol) were added thereto, and stirred at room temperature overnight. After diluted with ethyl acetate, the resultant was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled away, and the residue washed with an ethyl acetate -hexane mixture solvent to thus obtain the title compound. Yield: 1.1 mg (4.85 mmol), percentage yield: 91% MS (ESI, m/z) 228 [M+H]+ |
39% | With potassium carbonate In N,N-dimethyl-formamide at 80℃; for 3h; | |
With sodium hydrogencarbonate In water; acetonitrile at 0℃; for 3h; Reflux; | To a mixture of 2-amino-6-bromophenol (10.0 g, 53.2 mmol) and NaHCO3(13.4 g, 159.5 mmol) in CH3CN (260 mL) /H2O (130 mL), 2-chloroacetyl chloride (5.5 mL, 69.1 mmol) was added dropwise at 0oC. The mixture was refluxed for 3 h. After which period, the mixture was diluted with ethyl acetate and washed by brine, dried over Na2SO4, filtered and concentrated under reduced pressure to give the desired product A (11.7 g, 96.4%) as a pink solid, which was used in next step without purification. | |
Stage #1: 2-amino-6-bromophenol; chloroacetyl chloride With N-ethyl-N,N-diisopropylamine In Dimethyl ether at 85℃; for 6h; Stage #2: With potassium carbonate In Dimethyl ether at 85℃; for 6h; | 4.1 Step 1: 8-bromo-4H-1,4-benzoxazin-3-one To a solution of 2-amino-6-bromophenol (0.8 g, 4.25 mmol) in DME (125 mL), was added 2-chloroacetyl chloride (0.54 mL, 6.81 mmol) and DIPEA (2.11 mL, 12.76 mmol). The mixture was stirred at 85 °C for 6 h. Then K2CO3 (2.38 mL, 12.76 mmol) was added, the mixture was stirred anther 6 h at 85 °C. The result mixture was concentrated and diluted with water (50 mL), extracted with EA (50 mL). The organic phase was washed with brine, dried over sodium sulfate, concentrated to afford crude 8-bromo-4H-1,4-benzoxazin-3-one (730 mg, 2.72 mmol, 64% yield), which was used in the next step without further purification. LCMS calculated for C8H7BrNO2 (M+H)+ m/z =228.0/230.0; found: 228.0/230.0. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With sodium hydrogencarbonate In water; ethyl acetate at 0℃; for 3h; | 10 2-Bromopropionyl chloride (1.47 ml, 14.6 mmol) was added dropwise to a vigorously stirred and ice- cooling mixture of 2-amino-6-bromophenol (2.74 g, 14.6 mmol) and sodium bicarbonate (3.06 g, 36.4 mmol) in ethyl acetate (50 ml)/ water (15 ml). The mixture was stirred at 0 °C for 3 h and diluted with water. The aqueous layer was extracted with ethyl acetate. The extract was washed with. brine, dried over magnesium sulfate and concentrated under vacuum. The residue used for the following step without further purification to afford 4.71 g (99%) of the title coxnpound. |
73% | With sodium hydrogencarbonate In water; ethyl acetate at 0℃; for 3h; | 11.A Example 113-((4-(4-(4-(2,3-Dimethylphenoxy)butanoyl)-2-methyl-3,4-dihydro-2H- benzo[&] [ 1 ,4]oxazin-8-yl)- lH-pyrazol- 1 -yl)methyl)benzoic acid Step A. 2-Bromo-N-(3-bromo-2-hydroxyphenyl)propanamide[00162] To a mixture of 2-amino-6-bromophenol (3 g, 15.96 mmol) and sodium bicarbonate (3.35 g, 39.9 mmol) in ethyl acetate (30 mL) and water (10 mL) at 0 °C was added 2-bromopropionyl chloride (1.61 ml, 15.96 mmol) dropwise. The reaction mixture was stirred at 0 °C for 3 h and then diluted with water. The resulting mixture was extracted with EtOAc and the organic layer was washed with brine, dried over anhydrous MgS04, filtered, and concentrated to afford the title compound (4.7 g, 73% yield). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In tetrahydrofuran at 20℃; for 20h; | 1.b A mixture of 0.376g (2.0mmol) 2-amino-6-bromo-phenol and 0.46g (2.0mmol) 3,4,5-trimethoxy-isothiocyanate in 10ml THF is stirred at room temperature for ca. 20h. The reaction mixture is concentrated in vacuo, followed by the addition of toluene and concentration. The toluene addition and evaporation is repeated one more time to afford the title compound as a brown solid. | |
In tetrahydrofuran |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | With ammonium chloride; zinc In methanol at 0 - 20℃; for 0.583333h; | B. Synthesis of 2-amino-6-bromophenol (29) To a solution of 2-bromo-6-nitrophenol (5.57 g, 25.5 mmol) in MeOH (128 mL) was added zinc (dust) (16.71 g, 255 mmol). Reaction mixture was cooled to 0 C in a ice/water bath followed by the addition of ammonium chloride (13.67 g, 255 mmol) portion wise over 5 min. The heterogeneous reaction mixture allowed to warm to RT and was stirred at RT for 30 min. Reaction was filtered through a plug of celite and concentrated to a dark brown solid. Solid partitioned between water and EtOAc. Aqueous phase extracted with EtOAc. Organic phases combined, washed with water, brine, dried (Na2SO4), filtered and concentrated to a dark solid of 2-amino-6-bromophenol (4.66 g, 24.78 mmol, 97 % yield). LCMS m/z 187.8 (MH+), Rt 0.34 min. |
97.4% | With palladium 10% on activated carbon; hydrogen In methanol at 20 - 30℃; for 6h; Autoclave; | 1.1 1. Preparation of a compound of formula II Add 1000 ml of methanol to a 2 L autoclave,100 g (0.46 mol) of 2-bromo-6-nitrophenol,5g of 10% palladium on carbon,Closed reactor,Replaced three times with nitrogen,Replaced with hydrogen three times,Keep the hydrogen pressure 0.1~0.2MPa,The reaction temperature is between 20 and 30 ° C, and the reaction is carried out for 6 hours.At the end of the reaction, the hydrogen was replaced with nitrogen three times, evacuated, the reaction vessel was opened, and the reaction solution was filtered.The filtrate was concentrated to dryness to give a brown solid (yield: 2-amino-6-bromophenol (II) 84 g, yield 97.4%, purity 92.265%. |
93% | Stage #1: 2-bromo-6-nitro-phenol With tin(II) chloride dihdyrate; water In tetrahydrofuran at 80℃; for 1h; Stage #2: With sodium hydrogencarbonate In tetrahydrofuran; water | 159.1 Step 1. 2-amino-6-bromophenol2-Bromo-6-nitrophenol (Aldrich, 0.25 g, 1.1 mmol) was dissolved in THF (6.4 mL), water (6.4 mL) and stannous chloride dihydrate (1.3 g, 5.7 mmol) were added. The mixture was heated to 80° C. for 1 h. Upon cooling to RT, sat'd sodium bicarbonate was added, followed by ethyl acetate. Insoluble material was filtered off. The layers were separated and the aqueous phase was extracted with two further portions of ethyl acetate. The combined organic extracts were washed with brine, dried over sodium sulfate and concentrated to provide the desired product as an off-white crystalline solid, used without further purification (200 mg, 93%). LCMS (M+H)+: 188.0/190.0. |
93% | With hydrogen In methanol at 0 - 10℃; for 2h; | 4 Example 4 Preparation of 2-bromo-6-aminophenol 2-bromo-6-nitro-phenol, 15g (68.8mmol), 200 mL of methanol, Raney nickel 0.15g, stirring to dissolve, cooled to 0 ~ 10 , substituted with hydrogen, the reaction 2h, TLC the reaction was complete, filtered, and the filtrate was The solvent was evaporated to give 6-amino-2-bromo-phenol (compound I) 12.03g, yield 93%. |
90% | With sodium dithionite; water In ethanol | |
86% | With sodium dithionite; ethanol; water at 60℃; | 1; A1 To a mixture of 2-bromo-6-nitro-phenol (15.0 g, 68.8 mmol) in EtOH (200 mL) at 60° C. was added a warm solution of Na2S2O4 (50.0 g, 287 mmol) in water (180 mL) dropwise. Upon the addition of Na2S2O4 solution the reaction mixture turned to deep orange. After addition of about half of the Na2S2O4 solution, the deep orange changed to light yellow. The reaction mixture was allowed to cool to room temperature and EtOH was removed in vacuo. The residue was filtered, and the solid washed with water and dried under vacuum. The filtrate was extracted with CH2Cl2. The combined organic layers were dried (Na2SO4) and concentrated. The solids were combined to give 11.1 g (86%) of Ala as a white crystalline material: 1H NMR (300 MHz, CDCl3) δ 6.87-6.83 (m, 1H), 6.66-6.63 (m, 2H), 5.39 (brs, 1H), 3.85 (brs, 2H); MS (ES) m/z: 188 (M+H+). |
86% | Stage #1: 2-bromo-6-nitro-phenol With hydrogenchloride; tin(ll) chloride In methanol; water at 20℃; Stage #2: With sodium hydroxide In methanol; water | 2-Amino-6-bromophenol: To a solution of 2-bromo-6-nitrophenol (1.0 g, 4.6 mmol) in methanol (20 mL) and concentrated hydrogen chloride (20 mL) was added SnCl2-H2O (4.9 g, 18.4 mmol) at room temperature in one portion. The mixture was stirred at room temperature overnight. Then the mixture was quenched with 2 N sodium hydroxide. The resulting mixture was filtered through a pad of celite. The filtrate was extracted with methylene chloride. The solvent was removed under vacuum afforded 0.69 g (86%) of the title product as a white solid. MS (ES) m/z 186.0 [M - H]". |
83% | With iron; acetic acid at 90℃; for 0.5h; | 37 5.1.37 2-Amino-6-bromophenol (56) To a solution of reduced iron (7.17 g, 128 mmol) in AcOH (30 mL) was added dropwise a solution of 2-bromo-6-nitrophenol (4.00 g, 18.3 mmol) in AcOH (20 mL) at 90 °C. The reaction mixture was stirred at 90 °C for 30 min and cooled to room temperature. The reaction mixture was filtered through Celite, and the filtrate was concentrated. The residue was diluted with EtOAc and aqueous saturated NaHCO3. The organic layer was separated, washed with brine, and dried over anhydrous sodium sulfate. After filtration, the solvent was removed in vacuo, and the residue was purified by silica gel column chromatography using hexane/EtOAc (5:1, v/v) as eluent to give 56 (2.84 g, 83%) as a brown solid: mp 84-86 °C; 1H NMR (400 MHz, CDCl3) δ: 6.87-6.83 (1H, m), 6.65-6.63 (2H, m), 5.41 (1H, br s), 3.85 (2H, br s); IR (ATR) 3032, 1578, 1473, 1456, 1227 cm-1; HRMS (ESI) m/z calcd for C6H7BrNO [M+H]+ 187.9706; found 187.9704. |
79% | With tin(ll) chloride In ethanol at 70℃; for 1h; | 10 A mixture of 2-bromo-6-nitrophenol (4.00 g, 18.4 mmol) and tin (II) dihydrate (20.7 g, 91.7 rnmol) in ethanol (80 ml) was heated at 70 °C for 1 h. The mixture was poured into ice and the pH was made slightly basic (pH 7-8) by addition of IN sodium hydroxide solution in water. The aqueous solution was extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate and concentrated under vacuum to afford 2.74 g (79%) of the title compound. ¹H-NMR (CDC13) No.: 3.85 (m, 2H), 5.39 (m, 1H), 6.60-6.70 (m, 2H), 6.80-6.90 (m, 1H). MS Calcd. : 187; Found: 188 (M+H), 190. |
40% | With tin(II) chloride dihdyrate In ethanol at 70℃; for 1h; | |
25% | Stage #1: 2-bromo-6-nitro-phenol With tin(ll) chloride In ethanol at 70℃; for 0.0833333h; Inert atmosphere; Stage #2: In ethanol for 0.5h; Inert atmosphere; Cooling with ice; | |
With sodium dithionite In ethanol; water | ||
With hydrogen In tetrahydrofuran; methanol for 4h; | 1.c 5g (22.9mmol) 2-nitro-6-bromo-phenol (Fluka 67211) is hydrogenated in the presence of 0.1g Ra-Ni (B113W EtOH, Degussa) in 100ml of THF:MeOH = 1:1. for 4h. The reaction mixture is filtered (2 glass fiber filters used) and the filtrate is concentrated in vacuo. The residue is purified by chromatography (silicagel, hexane: EtOAc = 2:1) to afford the title compound as a reddish oil which slowly solidifies. | |
With Raney-Ni In tetrahydrofuran; methanol | ||
With Raney-Ni In tetrahydrofuran; methanol | ||
Stage #1: 2-bromo-6-nitro-phenol With acetic acid; zinc In methanol at 20℃; for 0.25h; Stage #2: With sodium hydrogencarbonate In dichloromethane; water | A Intermediate 1 : 2-Amino-6-bromophenolMethod A To a solution of 2-bromo-6-nitrophenol (5g; Aldrich) in MeOH (459ml) and acetic acid (115ml) was added portionwise with stirring zinc powder (7.5Og), and the reaction mixture stirred at room temperature for fifteen minutes. The reaction mixture was filtered through a pad of celite and washed with water (500ml) and the filtrate evaporated to remove the methanol. The aqueous layer was extracted with DCM (2x 500ml) and the combined organic layers washed with saturated sodium bicarbonate (2x 500ml) and brine (500ml), then dried and evaporated to afford the title compound (3.45g) as a dark brown solid, m/z [M+H]+: 188.0 /190.0. Retention time 0.51 min (LC/MS method 3). | |
With sodium dithionite; water In ethanol at 60℃; | B Method BTo a solution of 2-bromo-6-nitrophenol (25g) in ethanol (250ml) was added dropwise with stirring a solution of sodium hydrosulfite (8Og) in water (500ml), and the reaction mixture stirred at 6O0C for three hours then cooled overnight. The reaction mixture was evaporated to remove the ethanol. The aqueous was extracted with DCM (500ml and 250ml) and the combined organic layers washed with brine (300ml), then dried and evaporated to afford the title compound (13.2g) as a brown solid. | |
Stage #1: 2-bromo-6-nitro-phenol With acetic acid; zinc In methanol at 20℃; for 0.25h; Stage #2: With sodium hydrogencarbonate In dichloromethane | 1.A To a solution of 2-bromo-6-nitrophenol (5g; Aldrich) in MeOH (459ml) and acetic acid(115ml) was added portionwise with stirring zinc powder (7.5Og), and the reaction mixture stirred at room temperature for fifteen minutes. The reaction mixture was filtered through a pad of celite and washed with water (500ml) and the filtrate evaporated to remove the methanol. The aqueous layer was extracted with DCM (2x 500ml) and the combined organic layers washed with saturated sodium bicarbonate (2x 500ml) and brine (500ml), then dried and evaporated to afford the title compound (3.45g) as a dark brown solid, m/z [M+H]+: 188.0 /190.0. Retention time 0.51 min (LC/MS method 3). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With pyridine In dichloromethane at 0 - 20℃; for 1h; | 1.1 Pyridine (1.8 ml, 22.3 mmol) was added to a solution of 2-amino-6-bromo-phenol (4.198 g, 22.3 mmol) in dry CH2Cl2 (200 ml). The mixture was cooled in ice and then a solution of 2-bromo-2-methyl-propionylbromide (2.8 ml, 22.6 mmol) was added slowly. The mixture was stirred at the room temperature for an hour and was poured into CH2Cl2. and water. The organic layer was washed with water, dried and concentrated in vacuo to yield crude 2-bromo-N-(3-bromo-2-hydroxy-phenyl)-2-methyl-propionamide, which was used directly in step 2 without further purification. | |
With pyridine In dichloromethane at 0 - 20℃; for 1h; | 3.1 Example 3;4-Benzyl-2.2-dimethyl-8-piperazin-1-yl-4H-benzo[1,4]oxazin-3-one; [0230] Step 1; [0231] 2-Bromo-N-(3-bromo-2-hydroxy-phenyl)-2-methyl-propionamide [0232] Pyridine (1.8 ml, 22.3 mmol) was added to a solution of 2-Amino-6-bromo-phenol (4.198 g, 22.3 mmol) in dry CH2Cl2 (200 ml). The mixture was cooled in ice and then a solution of 2-bromo-2-methyl-propionylbromide (2.8 ml, 22.6 mmol) was added slowly. The mixture was stirred at the room temperature for an hour and was poured into CH2Cl2 and water. The organic layer was washed with water, dried and concentrated in vacuo to yield crude 2-bromo-N-(3-bromo-2-hydroxy-phenyl)-2-methyl-propionamide, which was used directly in step 2. | |
Stage #1: 2-bromoisobutyric acid bromide; 2-amino-6-bromophenol With sodium hydrogencarbonate In N,N-dimethyl-formamide for 1h; Stage #2: With potassium carbonate In N,N-dimethyl-formamide at 70℃; for 2h; | 3.3.2 Step 2: Sodium bicarbonate (2.23 g, 26.6 mmol) was added to a solution of 2- bromo-6-aminophenol (5 g, 26.6 mmol) in THF (95 mL), followed by dropwise addition of 2- bromo-isobutyryl bromide (3.62 mL, 29.3 mmol). After 1 hour, potassium carbonate (7.35 g, 53.2 mmol) and DMF (95 mL) were added and the mixture was heated to 70 °C for 2 hours. After cooling to room temperature, the mixture was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate. The layers were separated and the organic phase was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (ethyl acetate/hexanes) to afford 2-bromo-N-(3-bromo-2-hydroxyphenyl)-2- methylpropanamide. MS ESI calcd. for Ci0H12Br2NO2 [M + H]+ 338 found 338. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | With potassium carbonate In acetone for 19h; Heating / reflux; | Ethyl 8-bromo-3,4-dihydro-2H-benzo[] [l,4]oxazine-2-carboxylate: To a solution of 2- amino-6-bromophenol (1.5 g, 8.0 mmol) in acetone (50 mL) was added ethyl 2,3- dibromopropanoate (1.4 mL, 8.1 mmol) and potassium carbonate (3.3 g, 24 mmol) at room temperature. The resulting mixture was refluxed for 19 h. The reaction was quenched with water, and extracted with methylene chloride. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under vacuum. ISCO CombiFlash chromatography with 10-30% ethyl acetate in hexanes afforded the title product 2.15 g (94%) as an off-white solid. MS (ES) m/z 286.0 [M + H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
68% | With sodium tris(acetoxy)borohydride In dichloromethane at 20℃; for 1h; | 1.A Example IA. tert-Butyl 4-(3-bromo-2-hydroxyphenylamino)piperidine-l- carboxylate[00143] To a solution of 2-amino-6-bromophenol (4.18 g, 22.35 mmol) and t- butyl-4-oxo-l-piperidinecarboxylate (4.45 g, 22.35 mmol) in 120 mL of methylene chloride was added sodium triacetoxyborohydride (5.19 g, 24.59 mmol) portionwise. Upon completion of addition, the reaction mixture was allowed to stir at ambient temperature for 60 min. After this time, the reaction mixture was filtered through a pad of CELITE 545 filter aid and concentrated to yield a crude product. The crude product was purified by flash chromatography on silica gel (elution with 0-50% EtOAc/hexane) to afford 5.60 g (68%) of Example IA as a solid. 1H NMR (500 MHz, CDCl3) δ 1.40 (m, 2H), 1.47 (s, 9H), 2.05 (m, 2H)1 2.93 (m, 2H), 3.42 (m, IH), 4.11 (m, 2H), 6.60 (d, J = 8.3 Hz, IH), 6.70 (dd, J = 7.7, 8.3 Hz, IH), 6.81 (d, J = 7.7 Hz, IH). LRMS (ESI): 315.2./317.2 [M + H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
56% | With triethylamine In tetrahydrofuran at 0 - 20℃; | |
Stage #1: 2-amino-6-bromophenol; 2-Fluorobenzoyl chloride With triethylamine In tetrahydrofuran at 0℃; Stage #2: With hydrogenchloride In tetrahydrofuran; water | A.12.a Example A.12; a) Preparation of intermediate (45); 2-Fluoro-benzoyl chloride(15.6 mmol) in THF (25 mL) was added dropwise to a mixture of 2-amino-6-bromo-phenol (15.6 mmol) and triethylamine (31.1 mmol) in THF (75 mL) at 00C. The reaction mixture was allowed to warm to room temperature and stirred overnight. The reaction mixture was poured into water (400 mL) and acidifed to pH 4-5 with IN aqueous HCl. The aqueous layer was extracted twice with 200 mL of DCM. The organic layer was dried on MgSO4 and concentrated in vacuo. The residue was purified using purification method A, yielding 2.8 g of intermediate(45). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine In ethyl acetate at 90℃; for 2h; Inert atmosphere; | Intermediate 2: 2-Bromo-N-(3-bromo-2-hydroxyphenyl)-2,2-difluoroacetamideA mixture of 2-amino-6-bromophenol (13.2g, may be prepared as described in intermediate 1 ), ethyl bromo(difluoro)acetate (15.7g; Aldrich) and triethylamine (10.8ml) in ethyl acetate (80ml) was refluxed (9O0C) under argon for two hours. The reaction mixture was diluted with EtOAc (400ml) and washed with water (3x 200ml).The combined aqueous was extracted with EtOAc (200ml) and the combined organic layers dried and evaporated. The residue was dissolved in DCM and loaded onto four Biotage Si 40+M columns and purified using the Biotage SP4 eluting with 0-20% EtOAc/isohexane over twenty column volumes to afford the title compound (12.5g) as an orange oil. m/z [M-H]": 343.8 / 345.7. Retention time 1.01 min (LC/MS method 3). | |
With triethylamine In ethyl acetate at 90℃; for 2h; Reflux; Inert atmosphere; | 2 mixture of 2-amino-6-bromophenol (13.2g, may be prepared as described in intermediate 1 ), ethyl bromo(difluoro)acetate (15.7g; Aldrich) and triethylamine (10.8ml) in ethyl acetate (80ml) was refluxed (9O0C) under argon for two hours. The reaction mixture was diluted with EtOAc (400ml) and washed with water (3x 200ml).The combined aqueous was extracted with EtOAc (200ml) and the combined organic layers dried and evaporated. The residue was dissolved in DCM and loaded onto four Biotage Si 40+M columns and purified using the Biotage SP4 eluting with 0-20% EtOAc/isohexane over twenty column volumes to afford the title compound (12.5g) as an orange oil. m/z [M-H]": 343.8 / 345.7. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: 2-amino-6-bromophenol With sodium hydride In N,N-dimethyl-formamide at 0℃; for 0.5h; Inert atmosphere; Stage #2: Ethyl bromodifluoroacetate In N,N-dimethyl-formamide at 0 - 30℃; for 3.5h; | B Method BTo a solution of 2-amino-6-bromophenol (2.00 g, 10.70 mmol, may be prepared as described in intermediate 1 ) in DMF (20 ml) was added sodium hydride (60%, 560 mg, 13.90 mmol) at 00C under nitrogen. The mixture was stirred for 30 min then ethyl bromo(difluoro)acetate (2.61 g, 12.84 mmol, Aldrich) was added dropwise at 00C and stirred for 30 min at 00C, then stirred for 3 hr at 300C. The mixture was diluted with EtOAc (50 ml), washed with water three times, then washed with brine, dried over sodium sulfate, filtered and concentrated. It was purified via column chromatography on silica gel (eluting with petroleum ether / ethyl acetate 10:1 ) to give the title compound (1.18 g) as a brown solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
for 10.0h;Reflux; | Preparation Example 21 A mixture of 2-amino-6-bromophenol (1 g) and trimethylorthoacetate (3.5 g) was stirred under refluxing with heating for 10 hours. The reaction mixture was concentrated under reduced pressure and the resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain 7-bromo-2-methyl-1,3-benzoxadiazole (873 mg). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
71% | With 1,8-diazabicyclo[5.4.0]undec-7-ene In 1-methyl-pyrrolidin-2-one | PI8-bromo-2-ethyl-2H-benzo[b][l,4]oxazin-3(4H)-one PROCEDURE & NMR DATA : 1.5g (7.9mmol) of 2-bromo-6-aminophenol, 1.08mL (0,9eq, 7.11mmol) of l,8-diazabicyclo[5.4.0]undec-7-ene and 3.5mL of DL-Ethyl 2-bromobutyrate (3eq, 23.7mmol)) in 30mL of l-Methyl-2-pyrrolidinone were mixed. 1.447g of PI were obtained, yield 71%.*H NMR (400 MHz, CDCI3) δ 7.84 (s, 1H), 7.14 (dd, J = 8.1, 1.4 Hz, 1H), 6.76 (dd, J = 8.1, 7.9 Hz, 1H), 6.65 (dd, J = 7.9, 1.4 Hz, 1H), 4.54 (dd, J = 9.1, 4.2 Hz, 1H), 2.00 - 1.71 (m, 2H), 1.08 (t, J = 7.4 Hz, 3H). 13C NMR (101 MHz, CDCI3) δ 167.20, 139.69, 127.75, 127.27, 123.17, 114.43, 111.37, 79.04, 23.95, 9.61. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | In tetrahydrofuran for 2h; Reflux; | 38 5.1.1. 5-Phenyl-1,3-benzoxazol-2(3H)-one (11) General procedure: To a solution of 2-amino-4-phenylphenol (6.10 g, 32.9 mmol) in THF (150 mL) was added 1,1'-carbonyldiimidaziole (6.41 g, 39.5 mml) at room temperature. The mixture was stirred at reflux for 2 h and cooled to room temperature. The reaction was then quenched by adding 2 M HCl solution, and the mixture was extracted with EtOAc. The organic layer was washed with brine and dried over anhydrous sodium sulfate. After filtration, the solvent was removed in vacuo to give 11 (6.89 g, 99%) as a white solid |
90% | In tetrahydrofuran for 2h; Reflux; | 5 Example 5; Preparation of compound II Bromo-6-aminophenol 12g (63.8mmol), 240 mL of tetrahydrofuran, stirred to dissolve, 1,1'-carbonyl-diimidazole was added 12.42g (76.6mmol), warmed to reflux, the reaction 2h, TLC the reaction was complete, reduced at room temperature, the reaction mixture was added 240 mL of water, 2N HCl adjusting the pH = 6 ~ 7, 240 mL of ethyl acetate was added, with stirring, phases were separated, the organic phase was washed with a saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and spin dry solvent, recrystallized from toluene to give compound II12.3g, yield 90%. |
89% | In N,N-dimethyl-formamide at 60℃; for 2h; |
86% | In N,N-dimethyl-formamide at 60℃; for 2h; | Intermediate 1. 7-bromo-3 H-1,3-benzoxazol-2-one General procedure: 1,1’-Carbonyldiimidazole (1.2 eq.) was added to a solution of the optionally substituted aminophenol IX (1 eq.) in DMF (2.0 mL per mmol IX), and the solution was heated to 60 °C for 2 h. After cooling to rt, the reaction mixture was poured into water (15 mL per mmcl V) and extractedwith EtOAc (3 x 15 mL per mmclix). The combined organic phases were washed with brine (15 mL per mmcl IX), dried over Na2SO4, and evaporated on silica. The compound was purified by column chromatography using the Teledyne ISCO apparatus (cyclohexane:EtOAc). The title compound was obtained according to the General Procedure V, starting from 2-amino- 6-bromo-phenol (1.88 g, 10.0 mmol) and 1,1’-carbonyldiimidazole (1.95 g, 12.0 mmcl). Orange solid (1.85 g, 86%). 1H NMR (DMSO-d6) 7.06 -7.14 (m, 2H), 7.25-7.32 (m, 1H), 11.93 (s, 1H). MS(ESI) m/z: 212 [M-H]-. |
73% | With triethylamine In tetrahydrofuran at 60℃; for 18h; | 25 To a solution of 2-amino-6-bromophenol (3 g, 15 mmol) in THF (20 mL)was added CDI (5.2 g, 32 mmol), TEA (4.5 mL, 32 mmol). Then the mixture was stirred at60°C for 18h. The reaction was concentrated under reduced pressure to remove solvent. rhO(15 mL) and EA (20 mL) were added to the reaction and the organic layer was separated.T11e aqueous layer was extracted with EA (15 mL), the combined organic layer was washedwith HCl(lM, 20 mL x 2), brine ( 20mL), dried over anhydrous Na2S04, filtered andconcentrated under reduced pressure to afford compound 114A (2.5 g, yield 73%) as brownsolid, which was used directly in next step. 1B NMR (DMSO-d6, 400MHz): ()I 1.96 (br s,lH), 7.30- 7.23 (m, lH), 7.13- 7.04 (m, 2H). |
70% | In tetrahydrofuran Reflux; | [0958] To a solution of XXXV-lc (200 mg, 1.08 mmol) in dry THF(15 ml) was added CDI (262 mg, 1.62mmol). The reaction mixture was heated to reflux overnight, then quenched with water, extracted with EA, the organic layer was washed with brine, dried over anhydrous Na2SO4,and concentrated in vacuo. The residue was purified by chromatography on silica gel (PE:EA=10: 1) to afford XXXV-2c (160 mg, yield 70%). |
46% | In N,N-dimethyl-formamide at 60℃; for 2h; | 1 Example 1: Methyl (E)-2-(7-(4-hydroxy-3-methoxystyryl)-2-benzoxazolone-3(2H)-alkyl)acetic acid (Compound 1) Add 1,1'-carbonyldiimidazole (1.6mmol) to the DMF (3mL) solution containing 2-amino-6-bromophenol (1.0mmol), and heat at 60 °C for 2h,The reaction mixture was poured into water (15ml) and extracted with EtOAc (3x15ml).The organic layer was collected, washed with brine (15 mL), dried by adding MgSO4, and then rotary evaporated. Recrystallization from ethyl ethoxyacetate gave the desired product 7-bromo-2-benzoxazolone.(Yellow crystals, yield 46%, 115mg) |
In N,N-dimethyl-formamide at 60℃; for 2h; | 4.1.2. General procedure for synthesis of benzo[d]oxazol-2(3H)-onederivatives (2) General procedure: 1,10-Carbonyldiimidazole (1.6 mmol) was added to a solution ofthe 2-amino-6-bromophenol (1.0 mol) in DMF (3 mL), and the solutionwas heated to 60 C for 2 h [43]. Then, the reaction mixturewas poured into water (15 mL) and extracted with ethyl acetate(3 15 mL). The organic layer was collected, dried, filtered, andevaporated in vacuo. The residue was recrystallized from ethylacetate to give desired product 2. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
28 g | With pyridine In dichloromethane at 0 - 20℃; for 2.5h; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With pyridine In chloroform at 20℃; for 16h; | D52terf-butyl (3-bromo-2-hydroxyphenyl)carbamateTo a stirred suspension of 2-amino-6-bromophenol (2 g, 10.64 mmol) in chloroform (15 mL) at RT was added pyridine (2.58 mL, 31.9 mmol) followed by the dropwise addition of Boc- anhydride (2.96 mL, 12.76 mmol) in chloroform (5 mL). The mixture was stirred at RT for 16 hours. The reaction mixture was then quenched using 1M HCl aqueous solution (10.64 mL, 10.64 mmol), extracted with DCM, organic phase separated, dried and volatiles removed by evaporation. The residue was then purified on silica eluting with a gradient of 0-30% ethyl acetate in cyclohexane to afford the title compound (3 g). LCMS (A): m/z (M+H)+ 288/290, Cl lH14BrN03 requires 287/289 (acidic). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | In 1-methyl-pyrrolidin-2-one | Procedure & NMR Data: 8-bromo-2-methyl-2H-benzo[b][1,4]oxazin-3(4H)-one Procedure & NMR Data: 1.51 g (8 mmol) of 2-bromo-6-aminophenol, 1.1 ml (0.9 eq, 7.2 mmol) of 1,8-diazabicyclo[5.4.0]undec-7-ene and 2.1 mL (2 eq, 1.6 mmol) of Methyl 2-bromopropionate in 1-Methyl-2-pyrrolidinone (25 ml) were mixed. 1.55 g of P10 were obtained, yield 80%. 1H NMR (400 MHz, CDCl3) δ 8.09 (s broad, 1H), 7.23 (dd, J=8.1, 1.5 Hz, 1H), 6.86 (dd, J=8.1, 7.9 Hz, 1H), 6.76 (dd, J=7.9, 1.5 Hz, 1H), 4.78 (q, J=6.9 Hz, 1H), 1.64 (d, J=6.9 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 168.4, 140.4, 127.8, 127.4, 123.3, 114.9, 111.1, 73.9, 16.3. |
80% | In 1-methyl-pyrrolidin-2-one | 8-bromo-2-methyl-2H-benzo[b][1,4]oxazin-3(4H)-one 8-bromo-2-methyl-2H-benzo[b][1,4]oxazin-3(4H)-one Procedure & NMR Data: 1.51 g (8 mmol) of 2-bromo-6-aminophenol, 1.1 ml (0.9 eq, 7.2 mmol) of 1,8-diazabicyclo[5.4.0]undec-7-ene and 2.1 mL (2 eq, 1.6 mmol) of Methyl 2-bromopropionate in 1-Methyl-2-pyrrolidinone (25 ml) were mixed. 1.55 g of P10 were obtained, yield 80%. 1H NMR (400 MHz, CDCl3) δ 8.09 (s broad, 1H), 7.23 (dd, J=8.1, 1.5 Hz, 1H), 6.86 (dd, J=8.1, 7.9 Hz, 1H), 6.76 (dd, J=7.9, 1.5 Hz, 1H), 4.78 (q, J=6.9 Hz, 1H), 1.64 (d, J=6.9 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 168.4, 140.4, 127.8, 127.4, 123.3, 114.9, 111.1, 73.9, 16.3. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
50% | In 1-methyl-pyrrolidin-2-one | Procedure & NMR Data: 8-bromo-2-isopropyl-2H-benzo[b][1,4]oxazin-3(4H)-one Procedure & NMR Data: 1.52 g (8 mmol) of 2-bromo-6-aminophenol, 1.1 mL (7.2 mmol, 0.9 eq) of 1,8-diazabicyclo[5.4.0]undec-7-ene and 3.35 g (2 eq, 16 mmol) of ethyl 2-bromo-3-methylbutyrate in 1-methyl-2-pyrrolidinone (20 mL) were mixed. 1.1 g of P16 were obtained, yield 50%. 1H NMR (400 MHz, CDCl3) δ 8.78 (s, 1H), 7.12 (dd, J=8.0, 1.5 Hz, 1H), 6.74 (dd, J=8.0, 7.9 Hz, 1H), 6.67 (dd, J=7.9, 1.5 Hz, 1H), 4.39 (d, J=6.2 Hz, 1H), 2.19 (qq, J=6.9, 6.7 Hz, 1H), 1.07 (d, J=6.9 Hz, 3H), 1.00 (d, J=6.7 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 166.90, 140.59, 127.78, 126.96, 122.95, 114.59, 110.84, 82.49, 29.98, 18.62, 17.58. |
50% | In 1-methyl-pyrrolidin-2-one | 8-bromo-2-isopropyl-2H-benzo[b][1,4]oxazin-3(4H)-one 8-bromo-2-isopropyl-2H-benzo[b][1,4]oxazin-3(4H)-one Procedure & NMR Data: 1.52 g (8 mmol) of 2-bromo-6-aminophenol, 1.1 mL (7.2 mmol, 0.9 eq) of 1,8-diazabicyclo[5.4.0]undec-7-ene and 3.35 g (2 eq, 16 mmol) of ethyl 2-bromo-3-methylbutyrate in 1-methyl-2-pyrrolidinone (20 mL) were mixed. 1.1 g of P16 were obtained, yield 50%. 1H NMR (400 MHz, CDCl3) δ 8.78 (s, 1H), 7.12 (dd, J=8.0, 1.5 Hz, 1H), 6.74 (dd, J=8.0, 7.9 Hz, 1H), 6.67 (dd, J=7.9, 1.5 Hz, 1H), 4.39 (d, J=6.2 Hz, 1H), 2.19 (qq, J=6.9, 6.7 Hz, 1H), 1.07 (d, J=6.9 Hz, 3H), 1.00 (d, J=6.7 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 166.90, 140.59, 127.78, 126.96, 122.95, 114.59, 110.84, 82.49, 29.98, 18.62, 17.58. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
71% | In 1-methyl-pyrrolidin-2-one | Procedure & NMR Data: 8-bromo-2-ethyl-2H-benzo[b][1,4]oxazin-3(4H)-one Procedure & NMR Data: 1.5 g (7.9 mmol) of 2-bromo-6-aminophenol, 1.08 ml (0.9 eq, 7.11 mmol) of 1,8-diazabicyclo[5.4.0]undec-7-ene and 3.5 mL of DL-Ethyl 2-bromobutyrate (3 eq, 23.7 mmol)) in 30 mL of 1-Methyl-2-pyrrolidinone were mixed. 1.447 g of P1 were obtained, yield 71%. 1H NMR (400 MHz, CDCl3) δ 7.84 (s, 1H), 7.14 (dd, J=8.1, 1.4 Hz, 1H), 6.76 (dd, J=8.1, 7.9 Hz, 1H), 6.65 (dd, J=7.9, 1.4 Hz, 1H), 4.54 (dd, J=9.1, 4.2 Hz, 1H), 2.00-1.71 (m, 2H), 1.08 (t, J=7.4 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 167.20, 139.69, 127.75, 127.27, 123.17, 114.43, 111.37, 79.04, 23.95, 9.61. |
71% | In 1-methyl-pyrrolidin-2-one | 8-bromo-2-ethyl-2H-benzo[b][1,4]oxazin-3(4H)-one 8-bromo-2-ethyl-2H-benzo[b][1,4]oxazin-3(4H)-one Procedure & NMR Data: 1.5 g (7.9 mmol) of 2-bromo-6-aminophenol, 1.08 ml (0.9 eq, 7.11 mmol) of 1.8-diazabicyclo[5.4.0]undec-7-ene and 3.5 mL of DL-Ethyl 2-bromobutyrate (3 eq, 23.7 mmol)) in 30 mL of 1-Methyl-2-pyrrolidinone were mixed. 1.447 g of P1 were obtained, yield 71%. 1H NMR (400 MHz, CDCl3) δ 7.84 (s, 1H), 7.14 (dd, J=8.1, 1.4 Hz, 1H), 6.76 (dd, J=8.1, 7.9 Hz, 1H), 6.65 (dd, J=7.9, 1.4 Hz, 1H), 4.54 (dd, J=9.1, 4.2 Hz, 1H), 2.00-1.71 (m, 2H), 1.08 (t, J=7.4 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 167.20, 139.69, 127.75, 127.27, 123.17, 114.43, 111.37, 79.04, 23.95, 9.61. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | In ethanol for 6h; Reflux; | |
84% | In ethanol at 90℃; for 2h; | |
In ethanol at 90℃; for 2h; | 1. To a round bottom flask with stir bar equipped with a bubbler was added 2-amino-6-bromophenol (4.66 g, 24.78 mmol) and EtOH (24.78 mL). To this solution was added ethylxanthic acid, K+ salt (5.96 g, 37.2 mmol). Mixture was heated to 90 °C in a preheated oil bath for 2 hr. Reaction mixture was diluted with water and the pH adjusted to 4 with acetic acid. A solid develops and is collected. Solids washed with water, air dried then placed under vacuum for 18 hr to yield a grey crystalline of 7-bromobenzo[d]oxazole-2-thiol (4.59 g, 19.95 mmol, 80 % yield). LCMS m/z 229.9 (MH+), Rt 0.79 min. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
55% | With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 20 - 25℃; for 1.08333h; | Preparation 22Stepl[00236j To a slurry of 2-amino-6-bromophenol (4.00 g, 21.27 mmol) in methanol (2.152 mL, 53.2 mmol) and THF (10 mL) at room temperature was added triphenylphosphine (11.16 g, 42.5 mmol). After stirring for a few minutes, diisopropylazodicarboxylate (DIAD, 12.41 mL, 63.8 mmol) was then added dropwise via syringe over 5 minutes. After the addition was complete, the reaction was allowed to stir at room temperature for 1 h. The resulting mixture was then concentrated to remove the volatiles and the resulting residue was purified by silica gel flash chromatography using hexanes/ethyl acetate as the eluent. Fractions containing the major UV-active productwere combined and concentrated under vacuum to afford 2.35 g (55%) of a dark brown oil as the desired product. HPLC (Method N) RT = 1.33 minutes. LCMS MH+ 202/204 (observed bromide isotope pattern). |
55% | With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 20℃; for 1h; | Step 4 To a slurry of 2-amino-6-bromophenol (4.00 g, 21.27 mmol) in methanol (2.152 mL, 53.2 mmol) and THF (10 mL) at rt was added triphenylphosphine (11.16 g, 42.5 mmol). After stirring for a few minutes, DIAD (12.41 mL, 63.8 mmol) was then added dropwise via syringe over ~5 min. (exothermic). After the addition was complete, the reaction which had warmed due to the exothermic reaction was allowed to stir at rt for ~1 h. The resulting mixture was then concentrated to remove the volatiles and the resulting residue was purified by silica gel flash chromatography using hexanes/ethyl acetate as the eluant. Fractions containing the major uv active product were combined and concentrated under vacuum to afford 2.35 g (55%) of a dark brown oil as the desired product. HPLC (method N) RT = 1.33 min. LCMS MH+ 202/204 (observed bromide isotope pattern). |
55% | To a slurry of 2-amine-6-bromophenol (4.00 g, 21.27 mmol) in methanol (2.152 mL, 53.2 mmol) and THF (10 mL) at rt was added triphenylphosphine (11.16 g, 42.5 Mmol).After stirring for several minutes, DIAD (12.41 mL, 63.8 mmol) (exotherm) was added dropwise via the syringe over about 5 minutes. After the addition was complete, the reaction, which had been heated by the exothermic reaction, was stirred for about 1 h at rt. The resulting mixture was then concentrated to remove the volatiles and the resulting residue was purified by flash chromatography on silica gel using hexane / ethyl acetate as the eluent. The fractions containing the major product of uv activity were combined and concentrated in vacuo to afford 2.35 g (55%) of the desired product as a dark brown oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | With sodium tris(acetoxy)borohydride; acetic acid In 1,2-dichloro-ethane at 20℃; for 16h; | [0127] Step 1. To a solution of 2,4-dimethoxybenzaldehyde (6.64 g, 40.0 mmol) and 2-bromo-6-aminophenol (7.52 g, 40.0 mmol) in 1,2-dichloroethane (120 mL) was added sodium triacetoxyborohydride (10.0 g, 47.1 mmol) in several portions. Acetic acid (300 μΚ) was added and the mixture stirred at room temperature for 16 h. The mixture was diluted with water (200 mL) and extracted with 1,2-dichloroethane (2 x 80 mL). The combined organic layers were washed with 5% aqueous sodium bicarbonate (1 x 40 mL). The organic layer was dried over sodium sulfate and evaporated to give 2-bromo-6-(2,4-dimethoxybenzylamino)- phenol (9.4 g, 27.8 mmol, 70%) as a tan solid. LCMS: 97%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: triphenylphosphine; di-isopropyl azodicarboxylate / tetrahydrofuran / 1 h / 20 °C 2: dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium acetate / 1,4-dioxane / 100 °C | ||
Multi-step reaction with 2 steps 1.1: triphenylphosphine / tetrahydrofuran / 20 °C 1.2: 1 h / 20 °C 2.1: potassium acetate; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2 / 1,4-dioxane / 100 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With 1,8-diazabicyclo[5.4.0]undec-7-ene In 1-methyl-pyrrolidin-2-one at 140℃; for 0.166667h; Microwave irradiation; | 5.2 Step 2. 8-bromo-2-pyridin-2-yl-2H-l,4-benzoxazin-3(4H)-one Step 2. 8-bromo-2-pyridin-2-yl-2H-l,4-benzoxazin-3(4H)-one A mixture of 2-amino-6-bromophenol (100 mg, 0.5 mmol), methyl bromo(pyridin-2- yl)acetate (100 mg, 0.5 mmol) and l,8-diazabicyclo[5.4.0]undec-7-ene (80 μ,, 0.5 mmol) in N-methylpyrrolidinone (3 mL) was heated in microwave at 140 °C for 10 min. The reaction was allowed to cool, was diluted with ethyl acetate and washed with water. The combined organic layers were washed with brine, dried over MgSC , filtered, and concentrated to afford 8-bromo-2-pyridin-2-yl-2H-l,4-benzoxazin-3(4H)-one (0.15 g, 90%) as a crude product. LCMS calculated for Ci3HioBrN202 (M+H)+: m/z = 304.9 306.9; found= 305.0, 307.0. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60% | With 1,8-diazabicyclo[5.4.0]undec-7-ene In 1-methyl-pyrrolidin-2-one at 140℃; for 0.0833333h; Sealed tube; Microwave irradiation; | 1.1 Step 1. 8-bromo-2-phenyl-2H-l,4-benzoxazin-3(4H)-one Step 1. 8-bromo-2-phenyl-2H-l,4-benzoxazin-3(4H)-one 2-Amino-6-bromophenol (0.10 g, 0.53 mmol) (Frinton cat FR-2404) and a-bromo- benzeneacetic acid methyl ester (0.084 mL, 0.53 mmol) (Aldrich cat 365270) were combined with N-methylpyrrolidinone (2.0 mL) and l,8-diazabicyclo[5.4.0]undec-7-ene (0.080 mL, 0.53 mmol) in a sealed tube. The mixture was heated to 140 °C in the microwave for 5 minutes. The reaction mixture was then cooled, dissolved in ethyl acetate, and washed with 1 Ν HC1, brine, dried over magnesium sulfate, and concentrated to give a dark oil. The product was purified by FCC on silica gel eluting a hexane: ethyl acetate gradient to afford 8- bromo-2-phenyl-2H-l,44oenzoxazin-3(4H)-one as a semisolid (0.1 g, 60%). LCMS calculated for Ci4HnBrN02 (M+H)+: m/z = 304.0, 306.0; found: 303.8, 305.8. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 20h; Cooling with ice; | 20.21.A Step A: 8-bromo-2-(4-(trifluoromethyl)phenyl)-2H-benzo[b][l,4]oxazin-3(4H)-one Step A: 8-bromo-2-(4-(trifluoromethyl)phenyl)-2H-benzo[b][l,4]oxazin-3(4H)-one To a solution of 2-amino-6-bromophenol (2.5 g, 13.34 mmol) in DMF (50 mL) was added K2CO3 (4.61 g, 33.4 mmol). The reaction mixture was cooled by ice-water bath, and 2- bromo-2-(4-(trifluoromethyl)phenyl)acetyl chloride (5.0 g, 16.7 mmol) was added dropwise. The reaction mixture was stirred at room temperature for 20 h. TLC (petroleum ether: EtOAc= 5: 1) showed that the reaction was complete. The resulting mixture was diluted with H2O (40 mL) and extracted with DCM (30 mL*3). The combined organic layers were washed with brine (100 mL*3), dried over a2S04, filtered and concentrated in vacuo to give the crude product, which was further purified by silica gel column chromatography (EtOAc in petroleum ether: 0-20%) to give 8-bromo-2-(4-(trifluoromethyl)phenyl)-2H-benzo[b][l,4]oxazin-3(4H)-one as a solid. FontWeight="Bold" FontSize="10" H NMR (CDC13, 400 MHz): δ 8.31 (s, 1H), 7.62-7.67 (m, 4H), 7.24 (d, J=0.4 Hz, 1H), 6.86 (t, J= 8.0Hz, 1H), 6.73(d, J=7.2Hz, 1H), 5.91 (s, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 5h; | 56.A Step A: 8-bromo-2-(4-bromophenyl)-2H-benzo[b][l,4]oxazin-3(4H)-one Step A: 8-bromo-2-(4-bromophenyl)-2H-benzo[b][l,4]oxazin-3(4H)-one A suspension of 2-amino-6-bromophenol (0.37 g, 1.2 mmol), 2-bromo-2-(4- bromophenyl)acetyl chloride (0.19 g, 1.0 mmol) and K2CO3 (0.28 g, 2.0 mmol) in DMF (15 m was stirred at room temperature for 5 h. TLC (petroleum ether: EtOAc= 5: 1) showed that the starting material was consumed. Water (150 mL) was added. This mixture was extracted with EtOAc (30 mL*3), washed by brine, dried over Na2S04. A solution of the crude product in DCM (20 mL) was stirred at room temperature for 30 min. The soild precipitate was collected to give 8-bromo-2-(4-bromophenyl)-2H-benzo[b][l,4]oxazin-3(4H)-one as a solid. NMR (CDC13, 400 MHz): δ 8.07 (s, 1H), 7.50 (d, J=8.4 Hz, 2H), 7.381 (d, J=8.4 Hz, 2H), 7.23 (d, J=8.0 Hz, 1H), 6.85 (t, J=8.0 Hz, 1H), 6.72 (d, J=7.6 Hz, 1H), 5.82 (s, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate In N,N-dimethyl-formamide at 125℃; for 16h; | A Step A: 8-bromo-3,4-dihydro-2H-benzo[b][l,4]oxazine Step A: 8-bromo-3,4-dihydro-2H-benzo[b][l,4]oxazine A suspension of 2-amino-6-bromophenol (1 g, 5.32 mmol), 1,2-dibromoethane (1.199 g, 6.38 mmol) and K2C03 (2.205 g, 15.96 mmol) in DMF (10 mL) was heated at 125 °C for 16 h. LCMS showed that the reaction completed. The mixture was cooled to room temperature. The resulting mixture was diluted with aqueous NaCl (50 mL) and extracted with EtOAc (50 mL*3). The combined organic layers were washed with aqueous NaCl (50 mL*3), dried over a2S04, filtered and evaporate to give 8-bromo-3,4-dihydro-2H-benzo[b][l,4]oxazine as an oil. NMR (CDC13, 400 MHz): δ 6.89 (d, J= 8.0 Hz, 1H), 6.63 (t, J= 8.0 Hz, 1H), 6.53 (d, J= 8.0 Hz, 1H), 4.36 (t, J= 4.0 Hz, 2H), 3.85 (brs, 1H), 3.44-3.46 (m, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With tetra(n-butyl)ammonium hydrogensulfate; potassium carbonate In dichloromethane; water at 20℃; | A Step A: 8-bromo-2-(4-(trifluoromethyl)phenyl)-2H-benzo[b][l,4]oxazine Step A: 8-bromo-2-(4-(trifluoromethyl)phenyl)-2H-benzo[b][l,4]oxazine Into a 3-L 3-necked round-bottom flask were placed a solution of 2-amino-6- bromophenol (56.3 g, 299.43 mmol, 1.00 equiv) in dichloromethane (600 mL), BU4NSO4H (5 g, 1.05 equiv), aq K2CO3 (207 mL, 1.00 equiv, 20%). This was followed by the addition of a solution of 2-bromo-l-[4-(trifluoromethyl)phenyl]ethan-l-one (80 g, 299.58 mmol, 1.00 equiv) in dichloromethane (200 mL) dropwise with stirring at room temperature. The resulting solution was stirred overnight at room temperature. Then it was diluted with 500 mL of water and extracted with 3x500 mL of dichloromethane. The organic layers were combined, dried and concentrated under vacuum. The crude product was re-crystallized from EA/Hexane (1 : 10) to give 8-bromo-3-[4-(trifluoromethyl)phenyl]-2H-l,4-benzoxazine as a solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With tetra(n-butyl)ammonium hydrogensulfate; potassium carbonate In dichloromethane; water at 20℃; for 20h; | 27.A Step A: 8-bromo-3-(4-(trifluoromethyl)benzyl)-2H-benzo[b][l,4]oxazine Step A: 8-bromo-3-(4-(trifluoromethyl)benzyl)-2H-benzo[b][l,4]oxazine To a solution of 2-amino-6-bromophenol (5 g, 26.6 mmol) in DCM (120 mL) were added aqueous K2CO3 (120 mL, 26.6 mmol) and tetrabutylammonium hydrogen sulfate (0.090 g, 0.266 mmol), then l-bromo-3-(4-(trifluoromethyl)phenyl)propan-2-one (7.47 g, 26.6 mmol) in DCM (20 mL) was added dropwise to the reaction mixture. The reaction was stirred at room temperature for 20 h. LCMS showed that the reaction completed. The resulting mixture was extracted with DCM (50 mL*3). The combined organic layers were washed with brine (50 mL*3), dried over Na2S04, filtered and concentrated in vacuo to give 8-bromo-3-(4- (trifluoromethyl)benzyl)-2H-benzo[b][l,4]oxazine as an oil, which was used directly in the next step. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
543 mg | With pyridine; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In N,N-dimethyl-formamide at 20℃; for 15h; | 142 N-(3-bromo-2-hydroxyphenyl)-2-[4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetamide General procedure: 600 mg of N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride and 550 mg of 2-amino-6-bromophenol are added to a solution of 500 mg of sodium [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate prepared in stage 2 of example 1, in 4 ml of pyridine. The reaction mixture is stirred at ambient temperature for 20 hours, and then concentrated under reduced pressure. Water and ethyl acetate are added and the resulting mixture is thus stirred for 30 minutes. The precipitate formed is filtered off, and rinsed with water, ethyl ether and petroleum ether. The solid obtained is dried under vacuum. 543 mg of N-(3-bromo-2-hydroxyphenyl)-2-[4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetamide are obtained in the form of a beige solid |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
26% | With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In 1-methyl-pyrrolidin-2-one; at 20℃; for 36h; | General procedure: To a mixture of 1H-indole-2-carboxylic acid (84 mg, 0.52 mmol, 1.0 eq.) and HBTU (237 mg, 0.62 mmol, 1.0 eq.) in NMP (6 mL) were added5-bromo-1,3-benzothiazol-2-amine (120 mg, 0.52 mmol, 1.0 eq.) andDIPEA (180 muL, 1.04 mmol, 2.0 eq.).The reaction mixture was stirred at room temperature during 24 hours, quenched with water and extracted with ethyl acetate. The organic layer was washed with 1M hydrochloric acid and 1M sodium hydroxide aqueous solutions, and then was dried over Na2SO4. The solvent was evaporated under reduced pressure and the residue purified by silica gel flash-column chromatography (eluent: heptane/EtOAc, 90/10 to 70/30) to afford26cas a white solid (25 mg, 13 %). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium cyanide In N,N-dimethyl-formamide at 100℃; for 3h; | 4.1 Preparation of compound 3-1 After introducing compound E (CAS: 9 13835-76-4, 40 g, 212.7 mmol), benzaldehyde (27 g, 255.29 mmol), sodium cyanide (10.4 g, 212.7 mmol), and N,N-dimethylformamide (DMF) (1000 mL) into a reaction vessel, the mixture was stilTed for 3 hours at 100°C. The reaction solution cooled to room temperature was extracted with ethyl acetate. The obtained compound 3-1 was used in the next reaction without any further purification. | |
With sodium cyanide In N,N-dimethyl-formamide at 100℃; for 3h; | 4.1 1’) Preparation of compound 3-1 After adding compound E (CAS: 9 13835-76-4, 40 g, 212.7 mmol), benzaldehyde (27 g, 255.29 mmol), sodium cyanide (10.4 g, 212.7 mmol), and N,N-dimethylformamide(DMF) (1000 mL) into a reaction vessel, the mixture was stirred at 100°C for 3 hours. After the reaction solution was cooled to room temperature, the solution was extracted with ethyl acetate. The obtained compound 3-1 was used in the next reaction without further purification. | |
With sodium cyanide In N,N-dimethyl-formamide at 100℃; for 3h; | 4.1 1) Preparation of compound 3-1 After adding compound E (CAS: 913835-76-4, 40 g, 212.7 mmol), benzaldehyde (27 g, 255.29 mmol), sodium cyanide (10.4 g, 212.7 mmol), and N,N-dimethylformamide (DMF) (1000 mL) into a reaction vessel, the mixture was stirred at 100°C for 3 hours. After the reaction solution was cooled to room temperature, the solution was extracted with ethyl acetate. The obtained compound 3-1 was used in the next reaction without further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In methanol; dichloromethane; at 20.0℃; for 4.0h; | A mixture of 2-amino-6-bromophenol (5 g, 26.6 mmol) and cyanogen bromide (1.67 ml, 31.9 mmol) in Dichloromethane (25 ml) and MeOH (50 ml) was stirred at rt for 4 hr. The resulting mixture was quenched with aqueous sodium hydrogen carbonate (200 mL), then diluted with water (200 mL). The precipitated yellow solid was collected and dried under vacuumto give the title compound as a solid. LCMS (ESI) calc?d for C7H5BrN2O [M + H]: 213, found 213; ?H NMR (DMSO-d6, 400 MHZ): oe7.69 (s, 2H), 7.19-7.10 (m, 2H), 7.07-7.03 (m, |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With boric acid In diphenylether at 180℃; for 8h; | 1.2 Step 2: Preparation of Intermediate Int.-3 20g (0.106mol) of 2-hydroxy-3-bromoaniline was dissolved in 80ml of diphenyl ether, and 13g (0.106mol) of benzoic acid and 0.66g of boric acid were added. The temperature was raised to 180°C and the reaction was stirred for 8 hours. The water produced by the reaction was taken out, cooled to room temperature, separated and purified with a silica gel column, and concentrated under reduced pressure to dryness, to obtain 26.2 g of white solid, with a yield of 90% |
70.7% | With polyphosphoric acid at 160℃; for 6h; | 1 Intermediate 1 - 1 synthesis of In the 250 ml flask in a single port, adding 2 - amino -6 - bromophenol (25 g, 0.13 µM), benzoic acid (16.25 g, 0 . 13 µM) and 50 ml poly phosphoric acid, 160 °C reaction under 6 hours. After the reaction, to the reaction mixture cooled to room temperature, water washing, filtering to get the crude product, the crude product by column chromatography purification, to obtain white solid 25.75 g, yield is 70.7%. |
70.7% | With polyphosphoric acid at 160℃; for 6h; | 1 Synthesis of Intermediate 6-1 In a 250 mL single-necked flask, 2-amino-6-bromophenol (25 g, 0.13 mol), benzoic acid (16.25 g, 0.13 mol) and 50 mL of polyphosphoric acid were added and reacted at 160 ° C for 6 hours.After the reaction was completed, the reaction mixture was cooled to room temperature, washed with water and filtered to obtain a crude product. The crude product was purified by column chromatography to obtain 25.75 g of a white solid in a yield of 70.7%. |
70.7% | With polyphosphoric acid at 160℃; for 6h; | 1 Synthesis of Intermediate 8-1 In a 250 mL one-necked flask, 2-amino-6-bromophenol (25 g, 0.13 mol), benzoic acid (16.25g,0.13 mol) and 50 mL of polyphosphoric acid were added, and themixturewas reacted at 160 ° C for 6 hours.After completion of the reaction, the reaction mixture was cooled to room temperature,washedwith water, and then filtered to give a crude product. by column chromatographypurification, to obtain white solid 25.75 g,yield is 70.7% |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With toluene-4-sulfonic acid at 80℃; for 1h; Inert atmosphere; | 1 A mixture of 2-amino-6-bromophenol (500 mg, 2.67 mmol), p-TsOH (50 mg, 0.29 mmol) and trimethoxymethane (4 mL) was stirred at 80 oC under N2 for 1 h, and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/EA = 9:1) to afford 7-bromobenzo[d]oxazole (481 mg, 92%) as a white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | With polyphosphoric acid at 150℃; for 3h; | 1 Synthesis of Intermediate 1-1 In a three-necked flask, p-chlorobenzoic acid (20 g, 128 mmol),Amino-6-bromophenol (23.8 g, 128 mmol) and 60 g of polyphosphoric acid,Heated to 150 ° C for 3 hours, cooled, water, filtered,Cake with methanol beating,Filtration and drying gave 28 g of product, 72% yield. |
72% | With polyphosphoric acid at 150℃; for 3h; | 1 Synthesis of Intermediate 4-1 In a three-necked flask, p-chlorobenzoic acid (20 g, 128 mmol),2-Amino-6-bromophenol (23.8 g, 128 mmol) and 60 g of polyphosphoric acid,Heated to 150 ° C, the reaction 3 hours, cooled, water, filtered,The filter cake was beaten with methanol, filtered and dried to give the product 28g in 72% yield. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | Stage #1: 2-amino-6-bromophenol With sodium hydride In N,N-dimethyl-formamide; mineral oil at 0℃; for 2h; Stage #2: benzyl bromide In N,N-dimethyl-formamide; mineral oil at 20℃; for 18h; | 38 Preparation of compound 38-h Sodium hydrogen (289 mg, 7.22 mmol) was slowly added to a solution of 2-hydroxy-3-bromoaniline (300 mg,1.60 mmol) in N,N-dimethylformamide (3 mL) at 0°C. After the mixed solution was stirred for 2 hours, benzyl bromide(1.23 g, 7.22 mmol) was added and the reaction mixture was stirred at room temperature for 18 hours. The reactionmixture was poured into water (50 mL) and extracted with ethyl acetate (50 mL 3 3). The combined organic phaseswere washed successively with water (20 mL 3 3) and brine (20 mL),dried over sodium, filtered, and the filtrate wasconcentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 100: 1) to deliver a pale brown solid 38-h (690 mg, yield: 94%). LC-MS (ESI): m/z = 458 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | 200 ml of 2 mol/L hydrochloric acid was added to the reaction vessel.750ml of ethanol,50 g (0.26 mol) of 2-amino-6-bromophenol,Stir well,Cool down to 0 ~ 10 C,Slowly add sodium nitrite solution [18g (0.26mol) sodium nitrite dissolved in 50ml water],Temperature control does not exceed 10 C,Completion of the dropwise addition, the reaction at 5 ~ 10 1.5 ~ 2h,The reaction solution was allowed to rise to room temperature.Add triethylamine to adjust the pH of the reaction solution to 7-8.Further, 54 g (0.26 mol) of the compound of the formula (III) is added.The reaction was continued at 20 to 30 C for 2 hours.At the end of the reaction, the pH of the reaction solution was adjusted to 1-2 with 2 mol/L hydrochloric acid, the solid was precipitated, filtered, and the filter cake was washed with a mixture of ethanol/water (1:1), and the filter cake was dried under vacuum at 45 C.A dark red solid was obtained in 104.5 g (IV), yield 98%, and purity 99.562%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | With sulfur; 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; sodium t-butanolate In N,N-dimethyl-formamide at 70℃; for 3h; Molecular sieve; Inert atmosphere; | |
84% | With sulfur; sodium t-butanolate In N,N-dimethyl-formamide at 70℃; for 3h; Molecular sieve; | 6 Example 6 Place one PTFE magnet in a 25 mL reaction tube.Add 0.4 mmol of 2-amino-6-bromophenol,2 mmol S8, 2 mmol sodium difluorochloroacetate,1.6 mmol sodium tert-butoxide,60 mg molecular sieve and 6 mL N,N-dimethylformamide,After stirring for 3 h in a 70 ° C closed system,Extract three times with ethyl acetate, combine the organic phases, add saturated sodium chloride solutionAfter washing, drying over anhydrous magnesium sulfate, the organic solvent was removed by rotary evaporation; the crude product was eluted with n-pentane and ethyl acetate.Separation by silica gel column chromatography to give 2-mercapto-3-difluoromethyl-7-bromo-benzoxazole (yield 84%) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
71% | With N-ethyl-N,N-diisopropylamine; HATU In N,N-dimethyl-formamide at 20℃; for 4h; | Synthesis of Compounds 5a-c General procedure: To a solution of benzoic acid (37 mg, 0.30 mmol) and HATU(138 mg, 0.36 mmol) in N,N-dimethylformamide (DMF)(4 mL) was added DIPEA (63 μL, 0.36 mmol) and 4-amino-2-bromophenol (56 mg, 0.30 mmol) separately. The reactionmixture was stirred at room temperature for 4 h. After water(20 mL) was added, the mixture was extracted with EtOAc(10 mL × 2). The combined organic layer was dried over anhydrousNa2SO4 and concentrated under vacuum. The residuewas purified by flash chromatography over silica gel (petroleum-EtOAc = 10 : 1 to 5 : 1) to give the compound 5a. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | With sulfur; 2,2'-azobis-(2,4-dimethylvaleronitrile); sodium hydrogencarbonate; bis(pinacol)diborane In N,N-dimethyl-formamide at 100℃; for 15h; Inert atmosphere; | 20 Example 20 In a 10 mL reaction tube, a PTFE magnet is placed in a nitrogen atmosphere.Add 0.3 mmol of 2-amino-6-bromophenol, 2.4 mmol of S8, 2.1 mmol2-bromo-3,3,3-trifluoropropene, 0.9 mmol sodium bicarbonate,0.2 mmol of azobisisoheptanenitrile, 0.2 mmol of pinacol borate,4.5 mL of N,N-dimethylformamide, stirred for 15 h in a 100 ° C closed system,Extract three times with ethyl acetate, combine the organic phases, and wash with saturated sodium chloride solution.After drying over anhydrous magnesium sulfate, the organic solvent is removed by rotary evaporation;The obtained crude product was eluted with n-pentane and ethyl acetate.Separated by silica gel column chromatography7-Bromo-2-(2,2,2-trifluoroethyl)benzoxazole (yield 78%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
38.6% | Stage #1: tert-butyl 4-(4-isothiocyanatophenyl)piperazine-1-carboxylate; 2-amino-6-bromophenol In N,N-dimethyl-formamide at 20℃; for 14h; Stage #2: With potassium carbonate; copper dichloride In N,N-dimethyl-formamide at 20℃; for 14h; | 4.1.24. Step 4 Tert-butyl 4-(4-((7-bromobenzo[d]oxazol-2-yl)amino)phenyl)piperazine-1-carboxylate (4a) General procedure: To a solution of 3a (1.0 g, 3.1 mmol) in DMF (30 mL) was added 2-amino-6-bromophenol (0.6 g, 3.4 mmol) at room temperature. The reactionmixture was stirred at room temperature for 14 h. Then, to thereaction mixture was added CuCl2 (0.01 g, 0.074 mmol) and K2CO3(1.2 g, 8.7 mmol). The reaction mixture was stirred at room temperaturefor another 14 h. Water (100 mL) was added to quench the reaction,and the mixture was extracted with ethyl acetate (30 mL×3). Thecombined organic layer was dried over MgSO4. The solvent was removedin vacuo. The residue was purified by silica gel chromatography(Developing solvent: PE/EA=5/1) to give 4a (0.55 g, yield 38.6%). 1HNMR (300 MHz, DMSO-d6): δ 1.42 (s, 9H), 3.03 (s, 4H), 3.47 (s, 4H),7.00 (d, J=8.6 Hz, 2H), 7.15 (t, J=8.7 Hz, 1H), 7.28 (d, J=7.8 Hz,1H), 7.40 (d, J=7.6 Hz, 1H), 7.60 (d, J=8.6 Hz, 2H), 10.69 (s, 1H).MS m/z: 473.2 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: (4-diethylaminophenyl)isothiocyanate; 2-amino-6-bromophenol In N,N-dimethyl-formamide at 20℃; for 14h; Stage #2: With potassium carbonate; copper dichloride In N,N-dimethyl-formamide at 20℃; for 14h; | 4.1.24. Step 4 Tert-butyl 4-(4-((7-bromobenzo[d]oxazol-2-yl)amino)phenyl)piperazine-1-carboxylate (4a) General procedure: To a solution of 3a (1.0 g, 3.1 mmol) in DMF (30 mL) was added 2-amino-6-bromophenol (0.6 g, 3.4 mmol) at room temperature. The reactionmixture was stirred at room temperature for 14 h. Then, to thereaction mixture was added CuCl2 (0.01 g, 0.074 mmol) and K2CO3(1.2 g, 8.7 mmol). The reaction mixture was stirred at room temperaturefor another 14 h. Water (100 mL) was added to quench the reaction,and the mixture was extracted with ethyl acetate (30 mL×3). Thecombined organic layer was dried over MgSO4. The solvent was removedin vacuo. The residue was purified by silica gel chromatography(Developing solvent: PE/EA=5/1) to give 4a (0.55 g, yield 38.6%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: 1-(4-isothiocyanatophenyl)piperidine; 2-amino-6-bromophenol In N,N-dimethyl-formamide at 20℃; for 14h; Stage #2: With potassium carbonate; copper dichloride In N,N-dimethyl-formamide at 20℃; for 14h; | 4.1.24. Step 4 Tert-butyl 4-(4-((7-bromobenzo[d]oxazol-2-yl)amino)phenyl)piperazine-1-carboxylate (4a) General procedure: To a solution of 3a (1.0 g, 3.1 mmol) in DMF (30 mL) was added 2-amino-6-bromophenol (0.6 g, 3.4 mmol) at room temperature. The reactionmixture was stirred at room temperature for 14 h. Then, to thereaction mixture was added CuCl2 (0.01 g, 0.074 mmol) and K2CO3(1.2 g, 8.7 mmol). The reaction mixture was stirred at room temperaturefor another 14 h. Water (100 mL) was added to quench the reaction,and the mixture was extracted with ethyl acetate (30 mL×3). Thecombined organic layer was dried over MgSO4. The solvent was removedin vacuo. The residue was purified by silica gel chromatography(Developing solvent: PE/EA=5/1) to give 4a (0.55 g, yield 38.6%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: 4-(4-isothiocyanato-phenyl)morpholine; 2-amino-6-bromophenol In N,N-dimethyl-formamide at 20℃; for 14h; Stage #2: With potassium carbonate; copper dichloride In N,N-dimethyl-formamide at 20℃; for 14h; | 4.1.24. Step 4 Tert-butyl 4-(4-((7-bromobenzo[d]oxazol-2-yl)amino)phenyl)piperazine-1-carboxylate (4a) General procedure: To a solution of 3a (1.0 g, 3.1 mmol) in DMF (30 mL) was added 2-amino-6-bromophenol (0.6 g, 3.4 mmol) at room temperature. The reactionmixture was stirred at room temperature for 14 h. Then, to thereaction mixture was added CuCl2 (0.01 g, 0.074 mmol) and K2CO3(1.2 g, 8.7 mmol). The reaction mixture was stirred at room temperaturefor another 14 h. Water (100 mL) was added to quench the reaction,and the mixture was extracted with ethyl acetate (30 mL×3). Thecombined organic layer was dried over MgSO4. The solvent was removedin vacuo. The residue was purified by silica gel chromatography(Developing solvent: PE/EA=5/1) to give 4a (0.55 g, yield 38.6%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: 2-amino-6-bromophenol; 1-(4-isothiocyanato-phenyl)-4-methyl-piperazine In N,N-dimethyl-formamide at 20℃; for 14h; Stage #2: With potassium carbonate; copper dichloride In N,N-dimethyl-formamide at 20℃; for 14h; | 4.1.24. Step 4 Tert-butyl 4-(4-((7-bromobenzo[d]oxazol-2-yl)amino)phenyl)piperazine-1-carboxylate (4a) General procedure: To a solution of 3a (1.0 g, 3.1 mmol) in DMF (30 mL) was added 2-amino-6-bromophenol (0.6 g, 3.4 mmol) at room temperature. The reactionmixture was stirred at room temperature for 14 h. Then, to thereaction mixture was added CuCl2 (0.01 g, 0.074 mmol) and K2CO3(1.2 g, 8.7 mmol). The reaction mixture was stirred at room temperaturefor another 14 h. Water (100 mL) was added to quench the reaction,and the mixture was extracted with ethyl acetate (30 mL×3). Thecombined organic layer was dried over MgSO4. The solvent was removedin vacuo. The residue was purified by silica gel chromatography(Developing solvent: PE/EA=5/1) to give 4a (0.55 g, yield 38.6%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: 2-amino-6-bromophenol; 4-(2-fluoro-4-isothiocyanophenyl)piperazine-1-carboxylic acid tert-butyl ester In N,N-dimethyl-formamide at 20℃; for 14h; Stage #2: With potassium carbonate; copper dichloride In N,N-dimethyl-formamide at 20℃; for 14h; | 4.1.24. Step 4 Tert-butyl 4-(4-((7-bromobenzo[d]oxazol-2-yl)amino)phenyl)piperazine-1-carboxylate (4a) General procedure: To a solution of 3a (1.0 g, 3.1 mmol) in DMF (30 mL) was added 2-amino-6-bromophenol (0.6 g, 3.4 mmol) at room temperature. The reactionmixture was stirred at room temperature for 14 h. Then, to thereaction mixture was added CuCl2 (0.01 g, 0.074 mmol) and K2CO3(1.2 g, 8.7 mmol). The reaction mixture was stirred at room temperaturefor another 14 h. Water (100 mL) was added to quench the reaction,and the mixture was extracted with ethyl acetate (30 mL×3). Thecombined organic layer was dried over MgSO4. The solvent was removedin vacuo. The residue was purified by silica gel chromatography(Developing solvent: PE/EA=5/1) to give 4a (0.55 g, yield 38.6%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: tert-butyl 4-(4-isothiocyanato-2-methylphenyl)piperazine-1-carboxylate; 2-amino-6-bromophenol In N,N-dimethyl-formamide at 20℃; for 14h; Stage #2: With potassium carbonate; copper dichloride In N,N-dimethyl-formamide at 20℃; for 14h; | 4.1.24. Step 4 Tert-butyl 4-(4-((7-bromobenzo[d]oxazol-2-yl)amino)phenyl)piperazine-1-carboxylate (4a) General procedure: To a solution of 3a (1.0 g, 3.1 mmol) in DMF (30 mL) was added 2-amino-6-bromophenol (0.6 g, 3.4 mmol) at room temperature. The reactionmixture was stirred at room temperature for 14 h. Then, to thereaction mixture was added CuCl2 (0.01 g, 0.074 mmol) and K2CO3(1.2 g, 8.7 mmol). The reaction mixture was stirred at room temperaturefor another 14 h. Water (100 mL) was added to quench the reaction,and the mixture was extracted with ethyl acetate (30 mL×3). Thecombined organic layer was dried over MgSO4. The solvent was removedin vacuo. The residue was purified by silica gel chromatography(Developing solvent: PE/EA=5/1) to give 4a (0.55 g, yield 38.6%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: tert-butyl 4-(4-isothiocyanato-2-methoxyphenyl)piperazine-1-carboxylate; 2-amino-6-bromophenol In N,N-dimethyl-formamide at 20℃; for 14h; Stage #2: With potassium carbonate; copper dichloride In N,N-dimethyl-formamide at 20℃; for 14h; | 4.1.24. Step 4 Tert-butyl 4-(4-((7-bromobenzo[d]oxazol-2-yl)amino)phenyl)piperazine-1-carboxylate (4a) General procedure: To a solution of 3a (1.0 g, 3.1 mmol) in DMF (30 mL) was added 2-amino-6-bromophenol (0.6 g, 3.4 mmol) at room temperature. The reactionmixture was stirred at room temperature for 14 h. Then, to thereaction mixture was added CuCl2 (0.01 g, 0.074 mmol) and K2CO3(1.2 g, 8.7 mmol). The reaction mixture was stirred at room temperaturefor another 14 h. Water (100 mL) was added to quench the reaction,and the mixture was extracted with ethyl acetate (30 mL×3). Thecombined organic layer was dried over MgSO4. The solvent was removedin vacuo. The residue was purified by silica gel chromatography(Developing solvent: PE/EA=5/1) to give 4a (0.55 g, yield 38.6%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
30% | In ethanol at 20 - 140℃; for 0.416667h; | 1 Step 1-3-(3-bromo-2-hydroxyphenylamino)-1-(4-methoxybenzyl)piperidine-2,6-dione To a solution of 3-bromo-1-(4-methoxybenzyl)piperidine-2,6-dione (145 mg, 0.77 mmol, Intermediate LJ) in EtOH (10 mL) was added 2-amino-6-bromophenol (200 mg, 0.64 mmol) and at r.t. The reaction mixture was heated and stirred under microwave irradiation at 140° C. for 25 mins. The reaction mixture was concentrated under reduced pressure. The residue was purified via reverse phase column chromatography (ACN/H2O with 0.1% TFA) to give title compound (80 mg, 30% yield) as a colorless oil. 1H NMR (400 MHz, DMSO-d6) δ 8.94 (s, 1H), 7.18 (d, J=8.6 Hz, 2H), 6.85 (d, J=8.7 Hz, 2H), 6.75 (dd, J=6.9, 2.6 Hz, 1H), 6.67-6.59 (m, 2H), 5.48 (d, J=7.1 Hz, 1H), 4.76 (q, J=14.3 Hz, 2H), 4.58-4.40 (m, 1H), 3.71 (s, 3H), 3.05-2.89 (m, 1H), 2.83-2.61 (m, 1H), 2.25-2.10 (m, 1H), 2.02-1.97 (m, 1H). LC-MS (ESI+): m/z 421.1 (M+H)+. |
30% | In ethanol at 140℃; for 0.416667h; Inert atmosphere; Microwave irradiation; | 1 Step 1 - 3-(3-bromo-2-hydroxyphenylamino)-1-(4-methoxybenzyl)piperidine-2,6- dione To a solution of 3-bromo-1-(4-methoxybenzyl)piperidine-2,6-dione (145 mg, 0.77 mmol, Intermediate LJ) in EtOH (10 mL) was added 2-amino-6-bromophenol (200 mg, 0.64 mmol) and at r.t.. The reaction mixture was heated and stirred under microwave irradiation at 140oC for 25 mins. The reaction mixture was concentrated under reduced pressure. The residue was purified via reverse phase column chromatography (ACN/H2O with 0.1%TFA) to give title compound (80 mg, 30% yield) as a colorless oil.1H NMR (400 MHz, DMSO-d6) d 8.94 (s, 1H), 7.18 (d, J = 8.6 Hz, 2H), 6.85 (d, J = 8.7 Hz, 2H), 6.75 (dd, J = 6.9, 2.6 Hz, 1H), 6.67- 6.59 (m, 2H), 5.48 (d, J = 7.1 Hz, 1H), 4.76 (q, J = 14.3 Hz, 2H), 4.58- 4.40 (m, 1H), 3.71 (s, 3H), 3.05- 2.89 (m, 1H), 2.83- 2.61 (m, 1H), 2.25- 2.10 (m, 1H), 2.02-1.97 (m, 1H). LC-MS (ESI+): m/z 421.1 (M+H)+. |
30% | In ethanol at 20 - 140℃; for 0.416667h; Microwave irradiation; | 1 Step 1 - 3-(3-bromo-2-hydroxyphenylamino)-1-(4-methoxybenzyl)piperidine-2,6-dione To a solution of 3-bromo-1-(4-methoxybenzyl)piperidine-2,6-dione (145 mg, 0.77 mmol) in EtOH (10 mL) was added 2-amino-6-bromophenol (200 mg, 0.64 mmol) and at r.t.. The reaction mixture was heated and stirred under microwave irradiation at 140 °C for 25 mins. The reaction mixture was concentrated under reduced pressure. The residue was purified via reverse phase column chromatography (ACN/H2O with 0.1%TFA) to give title compound (80 mg, 30% yield) as a colorless oil. 1H NMR (400 MHz, DMSO-d6) δ 8.94 (s, 1H), 7.18 (d, J= 8.6 Hz, 2H), 6.85 (d, J= 8.7 Hz, 2H), 6.75 (dd, J= 6.9, 2.6 Hz, 1H), 6.67 - 6.59 (m, 2H), 5.48 (d, J= 7.1 Hz, 1H), 4.76 (q, J= 14.3 Hz, 2H), 4.58 - 4.40 (m, 1H), 3.71 (s, 3H), 3.05 - 2.89 (m, 1H), 2.83 - 2.61 (m, 1H), 2.25 - 2.10 (m, 1H), 2.02-1.97 (m, 1H). LC-MS (ESI+): m/z 421.1 (M+H)+. |
30% | In ethanol at 20 - 140℃; for 0.416667h; Microwave irradiation; | 1 Step 1 - 3-(3-bromo-2-hydroxyphenylamino)-1-(4-methoxybenzyl)piperidine-2,6-dione To a solution of 3-bromo-1-(4-methoxybenzyl)piperidine-2,6-dione (145 mg, 0.77 mmol) in EtOH (10 mL) was added 2-amino-6-bromophenol (200 mg, 0.64 mmol) and at r.t.. The reaction mixture was heated and stirred under microwave irradiation at 140 °C for 25 mins. The reaction mixture was concentrated under reduced pressure. The residue was purified via reverse phase column chromatography (ACN/H2O with 0.1%TFA) to give title compound (80 mg, 30% yield) as a colorless oil. 1H NMR (400 MHz, DMSO-d6) δ 8.94 (s, 1H), 7.18 (d, J= 8.6 Hz, 2H), 6.85 (d, J= 8.7 Hz, 2H), 6.75 (dd, J= 6.9, 2.6 Hz, 1H), 6.67 - 6.59 (m, 2H), 5.48 (d, J= 7.1 Hz, 1H), 4.76 (q, J= 14.3 Hz, 2H), 4.58 - 4.40 (m, 1H), 3.71 (s, 3H), 3.05 - 2.89 (m, 1H), 2.83 - 2.61 (m, 1H), 2.25 - 2.10 (m, 1H), 2.02-1.97 (m, 1H). LC-MS (ESI+): m/z 421.1 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With cyclopentyl methyl ether; dihydrogen peroxide; oxygen In water at 50℃; Sealed tube; | |
95% | With dihydrogen peroxide; oxygen In ethanol at 27℃; for 2h; | |
71% | With 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; tetrabutylammonium tetrafluoroborate In N,N-dimethyl-formamide at 20℃; for 5h; Electrochemical reaction; Green chemistry; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In ethanol at 30 - 80℃; for 3h; | 49 The synthesis of intermediate I-453: To a solution of 2-amino-6-bromo-phenol (5.00 g, 26.6 mmol) in EtOH (10 mL) was added dropwise 2-chloro-1,1,1-trimethoxyethane (4.32 g, 27.9 mmol) at 30 °C. The mixture was stirred at 80 °C for 3 hr and concentrated to give a residue. The residue was purified by silica gel chromatography to give 7-bromo-2-(chloromethyl)benzo[d]oxazole (I- 446) (6.10 g, 93% yield) as a yellow oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
42% | With sodium hydroxide In water at 100℃; for 4h; Inert atmosphere; | 4.2. Procedure for preparation of (8-Bromo-2-oxo-2,3-dihydro-benzo[1,4]oxazin -4-yl)-acetic acid (2a) General procedure: A mixture of 6-bromo-2-aminophenol (8.82 g, 0.049 mol), chloroaceticacid (9.8 g, 0.1 mol), NaOH (6 g, 0.15 mol), in 100 mL waterwas stirred at 100 °C for 4 h under argon. A solution of NaOH (6 M, aq)was added dropwise to the reaction in order to maintain pH at 7-8. Thereaction mixture was cooled and concentrated HCl was added until thepH of the solution was strongly acidic. Solid brown deposits were filteredand purified by silica gel column chromatography with petroleumether/ethyl acetate (3:1) to give the desired compound 2a, yield 42%. 4.2.1. (8-Bromo-2-oxo-2,3-dihydro-benzo[1,4]oxazin-4-yl)-acetic acid(2a)Yield: 5.86 g (42%); brown solid, 1H NMR (400 MHz, DMSO-d6) δ12.91 (s, 1H), 7.51 (s, 1H), 6.93 (m, 1H), 6.86 (d,J = 7.8 Hz, 1H), 4.20(s, 2H), 4.16 (s, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With palladium diacetate; sodium carbonate In N,N-dimethyl-formamide at 80℃; for 2h; | 4.1 Step 1: Preparation of Intermediate Int.-9 10g (31.8mmol) Intermediate Int.-8, 5.0g (26.5mmol)The raw material 3-bromo-2-hydroxyaniline and 6.7g (63.6mmol) of sodium carbonate are mixed,Then add 30mg (0.13mmol) of palladium acetate catalyst and 60mL of N,N-dimethylformamide, heat up to 80°C and stir for 2 hours, cool to room temperature, pour the reaction solution into 600mL of ice water, filter, and filter The cake was washed with water and ethanol to obtain 9.2g off-white solid, the yield was 92% |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95.18% | Stage #1: 2-amino-6-bromophenol With hydrogenchloride In water at 0 - 5℃; for 0.5h; Stage #2: With sodium nitrite In water at 0 - 10℃; for 1h; Stage #3: ethyl acetoacetate In water for 0.5h; | 1-3 Preparation of Compound III At room temperature, add 15.00g (79.78mmol) 2-amino-6bromophenol to a 1L three-necked flask, and cool the system to 0-5°C.Add 200 mL of 1N hydrochloric acid dropwise to the system for 30 minutes and control the temperature to 0-10°C.55.04g (79.78mmol) of 10% NaNO2 aqueous solution was added dropwise for 30 minutes, and the reaction was stirred at 5°C for 30 minutes.Add 10.37g (79.78mmol) ethyl acetoacetate to the system, continue to stir for 30min, add triethylamine to adjust the pH to 6-8, add 165mL H2O, 165mL EtOH, warm the system to room temperature and stir to react, TLC click the plate until the reaction When complete, 2N hydrochloric acid was added to the reaction flask to adjust the pH to 2-3, a yellow solid was precipitated, filtered under reduced pressure, washed with water, and dried to obtain 24.99 g of formula III compound with a yield of 95.18% and a purity of 97.03%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | Stage #1: 2-amino-6-bromophenol; 4-chlorobenzoyl chloride With pyridine In 5,5-dimethyl-1,3-cyclohexadiene at 20℃; for 1h; Stage #2: With toluene-4-sulfonic acid In 5,5-dimethyl-1,3-cyclohexadiene at 120℃; for 18h; | 4.1.1. General procedures for the synthesis of bromobenzo[d]oxazole analogs General procedure: General procedure A: Aryl chloride (1 mmol) and pyridine (81 μL) were added sequentially to a solution of 2-amino-6-bromophenol (1 mmol, 188 mg) in xylene (3.5 mL) at room temperature. The mixture was stirred for 1 h at room temperature.Then, p-toluenesulfonic acid (3 mmol) was added to the mixture.The reaction mixture was stirred at 120 °C for 18 h, and monitored by thin-layer chromatography. After the reaction was completed,the reaction mixturewas cooled to room temperature, dumped into the water (50 mL), and extracted using ethyl acetate (2 x 20 mL).The combined organic phases were dried with anhydrous sodiumsulfate. After filtration and evaporation, the pure product was obtainedby chromatography (n-hexane: ethyl acetate 25: 1, vv). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | Stage #1: m-Chlorobenzoyl chloride; 2-amino-6-bromophenol With pyridine In 5,5-dimethyl-1,3-cyclohexadiene at 20℃; for 1h; Stage #2: With toluene-4-sulfonic acid In 5,5-dimethyl-1,3-cyclohexadiene at 120℃; for 18h; | 4.1.1. General procedures for the synthesis of bromobenzo[d]oxazole analogs General procedure: General procedure A: Aryl chloride (1 mmol) and pyridine (81 μL) were added sequentially to a solution of 2-amino-6-bromophenol (1 mmol, 188 mg) in xylene (3.5 mL) at room temperature. The mixture was stirred for 1 h at room temperature.Then, p-toluenesulfonic acid (3 mmol) was added to the mixture.The reaction mixture was stirred at 120 °C for 18 h, and monitored by thin-layer chromatography. After the reaction was completed,the reaction mixturewas cooled to room temperature, dumped into the water (50 mL), and extracted using ethyl acetate (2 x 20 mL).The combined organic phases were dried with anhydrous sodiumsulfate. After filtration and evaporation, the pure product was obtainedby chromatography (n-hexane: ethyl acetate 25: 1, vv). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
73% | Stage #1: 4-chloro-benzoyl chloride; 2-amino-6-bromophenol With pyridine In 5,5-dimethyl-1,3-cyclohexadiene at 20℃; for 1h; Stage #2: With toluene-4-sulfonic acid In 5,5-dimethyl-1,3-cyclohexadiene at 120℃; for 18h; | 4.1.1. General procedures for the synthesis of bromobenzo[d]oxazole analogs General procedure: General procedure A: Aryl chloride (1 mmol) and pyridine (81 μL) were added sequentially to a solution of 2-amino-6-bromophenol (1 mmol, 188 mg) in xylene (3.5 mL) at room temperature. The mixture was stirred for 1 h at room temperature.Then, p-toluenesulfonic acid (3 mmol) was added to the mixture.The reaction mixture was stirred at 120 °C for 18 h, and monitored by thin-layer chromatography. After the reaction was completed,the reaction mixturewas cooled to room temperature, dumped into the water (50 mL), and extracted using ethyl acetate (2 x 20 mL).The combined organic phases were dried with anhydrous sodiumsulfate. After filtration and evaporation, the pure product was obtainedby chromatography (n-hexane: ethyl acetate 25: 1, vv). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | Stage #1: 4-methyl-benzoyl chloride; 2-amino-6-bromophenol With pyridine In 5,5-dimethyl-1,3-cyclohexadiene at 20℃; for 1h; Stage #2: With toluene-4-sulfonic acid In 5,5-dimethyl-1,3-cyclohexadiene at 120℃; for 18h; | 4.1.1. General procedures for the synthesis of bromobenzo[d]oxazole analogs General procedure: General procedure A: Aryl chloride (1 mmol) and pyridine (81 μL) were added sequentially to a solution of 2-amino-6-bromophenol (1 mmol, 188 mg) in xylene (3.5 mL) at room temperature. The mixture was stirred for 1 h at room temperature.Then, p-toluenesulfonic acid (3 mmol) was added to the mixture.The reaction mixture was stirred at 120 °C for 18 h, and monitored by thin-layer chromatography. After the reaction was completed,the reaction mixturewas cooled to room temperature, dumped into the water (50 mL), and extracted using ethyl acetate (2 x 20 mL).The combined organic phases were dried with anhydrous sodiumsulfate. After filtration and evaporation, the pure product was obtainedby chromatography (n-hexane: ethyl acetate 25: 1, vv). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
57% | Stage #1: 2-amino-6-bromophenol; 3-Methylbenzoyl chloride With pyridine In 5,5-dimethyl-1,3-cyclohexadiene at 20℃; for 1h; Stage #2: With toluene-4-sulfonic acid In 5,5-dimethyl-1,3-cyclohexadiene at 120℃; for 18h; | 4.1.1. General procedures for the synthesis of bromobenzo[d]oxazole analogs General procedure: General procedure A: Aryl chloride (1 mmol) and pyridine (81 μL) were added sequentially to a solution of 2-amino-6-bromophenol (1 mmol, 188 mg) in xylene (3.5 mL) at room temperature. The mixture was stirred for 1 h at room temperature.Then, p-toluenesulfonic acid (3 mmol) was added to the mixture.The reaction mixture was stirred at 120 °C for 18 h, and monitored by thin-layer chromatography. After the reaction was completed,the reaction mixturewas cooled to room temperature, dumped into the water (50 mL), and extracted using ethyl acetate (2 x 20 mL).The combined organic phases were dried with anhydrous sodiumsulfate. After filtration and evaporation, the pure product was obtainedby chromatography (n-hexane: ethyl acetate 25: 1, vv). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | Stage #1: 4-nitrobenzaldehdye; 2-amino-6-bromophenol With oxygen In 5,5-dimethyl-1,3-cyclohexadiene at 120℃; for 0.5h; Stage #2: With 4-methoxy-2,2,6,6-tetramethylpiperidin-1-oxyl radical In 5,5-dimethyl-1,3-cyclohexadiene at 120℃; for 5h; | 4.1.1. General procedures for the synthesis of bromobenzo[d]oxazole analogs General procedure: General procedure B: 2-amino-6-bromophenol (1 mmol,188 mg) and the corresponding aldehyde were deposited inside asealed pressure tube. The tube was vacuumed using an oil pump,and then gently flushed with an ordinary purity oxygen balloon.After exchanging oxygen and air three times, xylene (5 mL) wasadded. Then, the mixture was stirred at room temperature. Afterdissolving the solids, the reaction mixture was stirred at 120 °C.After 0.5 h, a solution of xylene (0.3 mL) containing 4-methoxy-TEMPO (0.05 mmol, 9.3 mg) was added to the mixture, which was then stirred at 120 °C for 5 h, and monitored by thin-layer chromatography.After the reaction was completed, the reaction mixture was cooled to room temperature, and concentrated under reduced pressure. The purified compound was obtained by columnchromatography (n-hexane: ethyl acetate 15:1, vv) of the acquiredresidue from the previous step. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | Stage #1: 3-nitro-benzaldehyde; 2-amino-6-bromophenol With oxygen In 5,5-dimethyl-1,3-cyclohexadiene at 120℃; for 0.5h; Stage #2: With 4-methoxy-2,2,6,6-tetramethylpiperidin-1-oxyl radical In 5,5-dimethyl-1,3-cyclohexadiene at 120℃; for 5h; | 4.1.1. General procedures for the synthesis of bromobenzo[d]oxazole analogs General procedure: General procedure B: 2-amino-6-bromophenol (1 mmol,188 mg) and the corresponding aldehyde were deposited inside asealed pressure tube. The tube was vacuumed using an oil pump,and then gently flushed with an ordinary purity oxygen balloon.After exchanging oxygen and air three times, xylene (5 mL) wasadded. Then, the mixture was stirred at room temperature. Afterdissolving the solids, the reaction mixture was stirred at 120 °C.After 0.5 h, a solution of xylene (0.3 mL) containing 4-methoxy-TEMPO (0.05 mmol, 9.3 mg) was added to the mixture, which was then stirred at 120 °C for 5 h, and monitored by thin-layer chromatography.After the reaction was completed, the reaction mixture was cooled to room temperature, and concentrated under reduced pressure. The purified compound was obtained by columnchromatography (n-hexane: ethyl acetate 15:1, vv) of the acquiredresidue from the previous step. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | Stage #1: 1H-indole-5-carboxaldehyde; 2-amino-6-bromophenol With oxygen In 5,5-dimethyl-1,3-cyclohexadiene at 120℃; for 0.5h; Stage #2: With 4-methoxy-2,2,6,6-tetramethylpiperidin-1-oxyl radical In 5,5-dimethyl-1,3-cyclohexadiene at 120℃; for 5h; | 4.1.1. General procedures for the synthesis of bromobenzo[d]oxazole analogs General procedure: General procedure B: 2-amino-6-bromophenol (1 mmol,188 mg) and the corresponding aldehyde were deposited inside asealed pressure tube. The tube was vacuumed using an oil pump,and then gently flushed with an ordinary purity oxygen balloon.After exchanging oxygen and air three times, xylene (5 mL) wasadded. Then, the mixture was stirred at room temperature. Afterdissolving the solids, the reaction mixture was stirred at 120 °C.After 0.5 h, a solution of xylene (0.3 mL) containing 4-methoxy-TEMPO (0.05 mmol, 9.3 mg) was added to the mixture, which was then stirred at 120 °C for 5 h, and monitored by thin-layer chromatography.After the reaction was completed, the reaction mixture was cooled to room temperature, and concentrated under reduced pressure. The purified compound was obtained by columnchromatography (n-hexane: ethyl acetate 15:1, vv) of the acquiredresidue from the previous step. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65% | Stage #1: 2-furancarbonyl chloride; 2-amino-6-bromophenol With pyridine In 5,5-dimethyl-1,3-cyclohexadiene at 20℃; for 1h; Stage #2: With toluene-4-sulfonic acid In 5,5-dimethyl-1,3-cyclohexadiene at 120℃; for 18h; | 4.1.1. General procedures for the synthesis of bromobenzo[d]oxazole analogs General procedure: General procedure A: Aryl chloride (1 mmol) and pyridine (81 μL) were added sequentially to a solution of 2-amino-6-bromophenol (1 mmol, 188 mg) in xylene (3.5 mL) at room temperature. The mixture was stirred for 1 h at room temperature.Then, p-toluenesulfonic acid (3 mmol) was added to the mixture.The reaction mixture was stirred at 120 °C for 18 h, and monitored by thin-layer chromatography. After the reaction was completed,the reaction mixturewas cooled to room temperature, dumped into the water (50 mL), and extracted using ethyl acetate (2 x 20 mL).The combined organic phases were dried with anhydrous sodiumsulfate. After filtration and evaporation, the pure product was obtainedby chromatography (n-hexane: ethyl acetate 25: 1, vv). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
53% | Stage #1: 2-Thiophenecarbonyl chloride; 2-amino-6-bromophenol With pyridine In 5,5-dimethyl-1,3-cyclohexadiene at 20℃; for 1h; Stage #2: With toluene-4-sulfonic acid In 5,5-dimethyl-1,3-cyclohexadiene at 120℃; for 18h; | 4.1.1. General procedures for the synthesis of bromobenzo[d]oxazole analogs General procedure: General procedure A: Aryl chloride (1 mmol) and pyridine (81 μL) were added sequentially to a solution of 2-amino-6-bromophenol (1 mmol, 188 mg) in xylene (3.5 mL) at room temperature. The mixture was stirred for 1 h at room temperature.Then, p-toluenesulfonic acid (3 mmol) was added to the mixture.The reaction mixture was stirred at 120 °C for 18 h, and monitored by thin-layer chromatography. After the reaction was completed,the reaction mixturewas cooled to room temperature, dumped into the water (50 mL), and extracted using ethyl acetate (2 x 20 mL).The combined organic phases were dried with anhydrous sodiumsulfate. After filtration and evaporation, the pure product was obtainedby chromatography (n-hexane: ethyl acetate 25: 1, vv). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | Stage #1: benzoyl chloride; 2-amino-6-bromophenol With pyridine In 5,5-dimethyl-1,3-cyclohexadiene at 20℃; for 1h; Stage #2: With toluene-4-sulfonic acid In 5,5-dimethyl-1,3-cyclohexadiene at 120℃; for 18h; | 4.1.1. General procedures for the synthesis of bromobenzo[d]oxazole analogs General procedure A: Aryl chloride (1 mmol) and pyridine (81 μL) were added sequentially to a solution of 2-amino-6-bromophenol (1 mmol, 188 mg) in xylene (3.5 mL) at room temperature. The mixture was stirred for 1 h at room temperature.Then, p-toluenesulfonic acid (3 mmol) was added to the mixture.The reaction mixture was stirred at 120 °C for 18 h, and monitoredby thin-layer chromatography. After the reaction was completed,the reaction mixturewas cooled to room temperature, dumped into the water (50 mL), and extracted using ethyl acetate (2 x 20 mL).The combined organic phases were dried with anhydrous sodiumsulfate. After filtration and evaporation, the pure product was obtainedby chromatography (n-hexane: ethyl acetate 25: 1, vv). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | Stage #1: 4-methoxy-benzoyl chloride; 2-amino-6-bromophenol With pyridine In 5,5-dimethyl-1,3-cyclohexadiene at 20℃; for 1h; Stage #2: With toluene-4-sulfonic acid In 5,5-dimethyl-1,3-cyclohexadiene at 120℃; for 18h; | 4.1.1. General procedures for the synthesis of bromobenzo[d]oxazole analogs General procedure: General procedure A: Aryl chloride (1 mmol) and pyridine (81 μL) were added sequentially to a solution of 2-amino-6-bromophenol (1 mmol, 188 mg) in xylene (3.5 mL) at room temperature. The mixture was stirred for 1 h at room temperature.Then, p-toluenesulfonic acid (3 mmol) was added to the mixture.The reaction mixture was stirred at 120 °C for 18 h, and monitored by thin-layer chromatography. After the reaction was completed,the reaction mixturewas cooled to room temperature, dumped into the water (50 mL), and extracted using ethyl acetate (2 x 20 mL).The combined organic phases were dried with anhydrous sodiumsulfate. After filtration and evaporation, the pure product was obtainedby chromatography (n-hexane: ethyl acetate 25: 1, vv). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
64% | Stage #1: m-anisoyl chloride; 2-amino-6-bromophenol With pyridine In 5,5-dimethyl-1,3-cyclohexadiene at 20℃; for 1h; Stage #2: With toluene-4-sulfonic acid In 5,5-dimethyl-1,3-cyclohexadiene at 120℃; for 18h; | 4.1.1. General procedures for the synthesis of bromobenzo[d]oxazole analogs General procedure: General procedure A: Aryl chloride (1 mmol) and pyridine (81 μL) were added sequentially to a solution of 2-amino-6-bromophenol (1 mmol, 188 mg) in xylene (3.5 mL) at room temperature. The mixture was stirred for 1 h at room temperature.Then, p-toluenesulfonic acid (3 mmol) was added to the mixture.The reaction mixture was stirred at 120 °C for 18 h, and monitored by thin-layer chromatography. After the reaction was completed,the reaction mixturewas cooled to room temperature, dumped into the water (50 mL), and extracted using ethyl acetate (2 x 20 mL).The combined organic phases were dried with anhydrous sodiumsulfate. After filtration and evaporation, the pure product was obtainedby chromatography (n-hexane: ethyl acetate 25: 1, vv). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
61% | Stage #1: 2-amino-6-bromophenol; 3,4-dimethoxybenzoic acid chloride With pyridine In 5,5-dimethyl-1,3-cyclohexadiene at 20℃; for 1h; Stage #2: With toluene-4-sulfonic acid In 5,5-dimethyl-1,3-cyclohexadiene at 120℃; for 18h; | 4.1.1. General procedures for the synthesis of bromobenzo[d]oxazole analogs General procedure: General procedure A: Aryl chloride (1 mmol) and pyridine (81 μL) were added sequentially to a solution of 2-amino-6-bromophenol (1 mmol, 188 mg) in xylene (3.5 mL) at room temperature. The mixture was stirred for 1 h at room temperature.Then, p-toluenesulfonic acid (3 mmol) was added to the mixture.The reaction mixture was stirred at 120 °C for 18 h, and monitored by thin-layer chromatography. After the reaction was completed,the reaction mixturewas cooled to room temperature, dumped into the water (50 mL), and extracted using ethyl acetate (2 x 20 mL).The combined organic phases were dried with anhydrous sodiumsulfate. After filtration and evaporation, the pure product was obtainedby chromatography (n-hexane: ethyl acetate 25: 1, vv). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65% | Stage #1: 3-fluoro-4-methoxybenzoylchloride; 2-amino-6-bromophenol With pyridine In 5,5-dimethyl-1,3-cyclohexadiene at 20℃; for 1h; Stage #2: With toluene-4-sulfonic acid In 5,5-dimethyl-1,3-cyclohexadiene at 120℃; for 18h; | 4.1.1. General procedures for the synthesis of bromobenzo[d]oxazole analogs General procedure: General procedure A: Aryl chloride (1 mmol) and pyridine (81 μL) were added sequentially to a solution of 2-amino-6-bromophenol (1 mmol, 188 mg) in xylene (3.5 mL) at room temperature. The mixture was stirred for 1 h at room temperature.Then, p-toluenesulfonic acid (3 mmol) was added to the mixture.The reaction mixture was stirred at 120 °C for 18 h, and monitored by thin-layer chromatography. After the reaction was completed,the reaction mixturewas cooled to room temperature, dumped into the water (50 mL), and extracted using ethyl acetate (2 x 20 mL).The combined organic phases were dried with anhydrous sodiumsulfate. After filtration and evaporation, the pure product was obtainedby chromatography (n-hexane: ethyl acetate 25: 1, vv). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
69% | Stage #1: 2-amino-6-bromophenol; 3-fluorobenzoyl chloride With pyridine In 5,5-dimethyl-1,3-cyclohexadiene at 20℃; for 1h; Stage #2: With toluene-4-sulfonic acid In 5,5-dimethyl-1,3-cyclohexadiene at 120℃; for 18h; | 4.1.1. General procedures for the synthesis of bromobenzo[d]oxazole analogs General procedure: General procedure A: Aryl chloride (1 mmol) and pyridine (81 μL) were added sequentially to a solution of 2-amino-6-bromophenol (1 mmol, 188 mg) in xylene (3.5 mL) at room temperature. The mixture was stirred for 1 h at room temperature.Then, p-toluenesulfonic acid (3 mmol) was added to the mixture.The reaction mixture was stirred at 120 °C for 18 h, and monitored by thin-layer chromatography. After the reaction was completed,the reaction mixturewas cooled to room temperature, dumped into the water (50 mL), and extracted using ethyl acetate (2 x 20 mL).The combined organic phases were dried with anhydrous sodiumsulfate. After filtration and evaporation, the pure product was obtainedby chromatography (n-hexane: ethyl acetate 25: 1, vv). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
64% | Stage #1: 4-fluorobenzoyl chloride; 2-amino-6-bromophenol With pyridine In 5,5-dimethyl-1,3-cyclohexadiene at 20℃; for 1h; Stage #2: With toluene-4-sulfonic acid In 5,5-dimethyl-1,3-cyclohexadiene at 120℃; for 18h; | 4.1.1. General procedures for the synthesis of bromobenzo[d]oxazole analogs General procedure: General procedure A: Aryl chloride (1 mmol) and pyridine (81 μL) were added sequentially to a solution of 2-amino-6-bromophenol (1 mmol, 188 mg) in xylene (3.5 mL) at room temperature. The mixture was stirred for 1 h at room temperature.Then, p-toluenesulfonic acid (3 mmol) was added to the mixture.The reaction mixture was stirred at 120 °C for 18 h, and monitored by thin-layer chromatography. After the reaction was completed,the reaction mixturewas cooled to room temperature, dumped into the water (50 mL), and extracted using ethyl acetate (2 x 20 mL).The combined organic phases were dried with anhydrous sodiumsulfate. After filtration and evaporation, the pure product was obtainedby chromatography (n-hexane: ethyl acetate 25: 1, vv). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: meta-hydroxybenzaldehyde; 2-amino-6-bromophenol With oxygen In 5,5-dimethyl-1,3-cyclohexadiene at 120℃; for 0.5h; Stage #2: With 4-methoxy-2,2,6,6-tetramethylpiperidin-1-oxyl radical In 5,5-dimethyl-1,3-cyclohexadiene at 120℃; for 5h; | 4.1.1. General procedures for the synthesis of bromobenzo[d]oxazole analogs General procedure: General procedure B: 2-amino-6-bromophenol (1 mmol,188 mg) and the corresponding aldehyde were deposited inside asealed pressure tube. The tube was vacuumed using an oil pump,and then gently flushed with an ordinary purity oxygen balloon.After exchanging oxygen and air three times, xylene (5 mL) wasadded. Then, the mixture was stirred at room temperature. Afterdissolving the solids, the reaction mixture was stirred at 120 °C.After 0.5 h, a solution of xylene (0.3 mL) containing 4-methoxy-TEMPO (0.05 mmol, 9.3 mg) was added to the mixture, which was then stirred at 120 °C for 5 h, and monitored by thin-layer chromatography.After the reaction was completed, the reaction mixture was cooled to room temperature, and concentrated under reduced pressure. The purified compound was obtained by columnchromatography (n-hexane: ethyl acetate 15:1, vv) of the acquiredresidue from the previous step. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: vanillin; 2-amino-6-bromophenol With oxygen In 5,5-dimethyl-1,3-cyclohexadiene at 120℃; for 0.5h; Stage #2: With 4-methoxy-2,2,6,6-tetramethylpiperidin-1-oxyl radical In 5,5-dimethyl-1,3-cyclohexadiene at 120℃; for 5h; | 4.1.1. General procedures for the synthesis of bromobenzo[d]oxazole analogs General procedure: General procedure B: 2-amino-6-bromophenol (1 mmol,188 mg) and the corresponding aldehyde were deposited inside asealed pressure tube. The tube was vacuumed using an oil pump,and then gently flushed with an ordinary purity oxygen balloon.After exchanging oxygen and air three times, xylene (5 mL) wasadded. Then, the mixture was stirred at room temperature. Afterdissolving the solids, the reaction mixture was stirred at 120 °C.After 0.5 h, a solution of xylene (0.3 mL) containing 4-methoxy-TEMPO (0.05 mmol, 9.3 mg) was added to the mixture, which was then stirred at 120 °C for 5 h, and monitored by thin-layer chromatography.After the reaction was completed, the reaction mixture was cooled to room temperature, and concentrated under reduced pressure. The purified compound was obtained by columnchromatography (n-hexane: ethyl acetate 15:1, vv) of the acquiredresidue from the previous step. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
62% | Stage #1: 3-bromobenzoyl chloride; 2-amino-6-bromophenol With pyridine In 5,5-dimethyl-1,3-cyclohexadiene at 20℃; for 1h; Stage #2: With toluene-4-sulfonic acid In 5,5-dimethyl-1,3-cyclohexadiene at 120℃; for 18h; | 4.1.1. General procedures for the synthesis of bromobenzo[d]oxazole analogs General procedure: General procedure A: Aryl chloride (1 mmol) and pyridine (81 μL) were added sequentially to a solution of 2-amino-6-bromophenol (1 mmol, 188 mg) in xylene (3.5 mL) at room temperature. The mixture was stirred for 1 h at room temperature.Then, p-toluenesulfonic acid (3 mmol) was added to the mixture.The reaction mixture was stirred at 120 °C for 18 h, and monitored by thin-layer chromatography. After the reaction was completed,the reaction mixturewas cooled to room temperature, dumped into the water (50 mL), and extracted using ethyl acetate (2 x 20 mL).The combined organic phases were dried with anhydrous sodiumsulfate. After filtration and evaporation, the pure product was obtainedby chromatography (n-hexane: ethyl acetate 25: 1, vv). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
62% | With sodium hydrogencarbonate In tetrahydrofuran; water Inert atmosphere; Cooling with ice; | Propyl (3-bromo-2-hydroxyphenyl)carbamate (A11) Compound A11 was prepared from 2-amino-6-bromophenolfollowing the preparation method of A1. Flash column chromatographywas performed eluting the column with 8e15% EtOAc inPE. Off-white solid (900 mg, 62%). 1H NMR (400 MHz, DMSO-d6) d:9.47 (s, 1 H), 8.72 (brs, 1 H), 7.42 (d, J 7.6 Hz, 1 H), 7.27 (dd, J 1.6,8.0 Hz, 1 H), 6.76 (t, J 8.0 Hz, 1 H), 4.03 (t, J 6.8 Hz, 2 H),1.67e1.58 (m, 2 H), 0.92 (t, J 7.6 Hz, 3 H). HR-MS (ESI): m/z[M H]- calcd for C10H11BrNO3: 271.9917; found: 271.9923. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
20.84% | With triethylamine In dichloromethane at 0 - 25℃; for 1h; Inert atmosphere; | 1.1 Step 1: N-(3-Bromo-2-hydroxyphenyl)acetamide To a solution of 2-amino-6-bromo-phenol (1 g, 5.32 mmol) in DCM (10 ml_) was added AC2O (651 .56 mg, 6.38 mmol, 597.76 uL) and TEA (1 .61 g, 15.96 mmol, 2.22 ml_) at 0°C under N2. The mixture was heated to 25°C and stirred for 1 hr. Water was added (10 ml_) and the mixture extracted by dichloromethane (50 ml_ * 3). The combined organic phase was washed with brine (50 ml_ * 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (S1O2, Petroleum ether/Ethyl acetate=100/1 to 3/1) to give the title compound (300 mg, 1.11 mmol, 20.84% yield) as a light brown solid. LCMS (ESI) m/z: [79BrM+H]+ = 229.9. 1HNMR (400 MHz, CDCb) d = 7.96 (br s, 1 H), 7.90 (s, 1 H), 7.59 - 7.53 (m, 1 H), 7.32 - 7.28 (m, 1 H), 6.80 - 6.72 (m, 1 H), 2.24 (s, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With pyridine; at 50 - 90℃; for 20h;Sealed tube; | To a 40 mL vial was added 4-chloro-l-(4-chlorophenyl)butan-l-one (462 mg, 2.13 mmol) and 2-amino-6-bromophenol (400 mg, 2.13 mmol). The mixture was dissolved in pyridine (5 mL). The vial was sealed, stirred for 4 h at 50C, and then subsequently for 16 h at at 90 C. The mixture was concentrated under reduced pressure, and the crude material was purified by silica chromatography (eluent: EtO Ac/hexanes) to afford the desired product 1-4. ES/MS: 350.2 (M+). 1H NMR (400 MHz, Chloroform-d) δ 7.65 - 7.56 (m, 2H), 7.38 - 7.31 (m, 2H), 6.98 (dd, J = 8.1, 1.2 Hz, 1H), 6.78 (dd, J = 7.6, 1.2 Hz, 1H), 6.75 - 6.65 (m, 1H), 3.62 (ddd, J = 10.7, 8.6, 6.1 Hz, 1H), 3.33 (ddd, J = 10.9, 7.1, 4.3 Hz, 1H), 2.76 - 2.59 (m, 1H), 2.29 (ddd, J = 13.7, 9.0, 6.7 Hz, 1H), 2.07 - 1.88 (m, 2H). |
Tags: 28165-50-6 synthesis path| 28165-50-6 SDS| 28165-50-6 COA| 28165-50-6 purity| 28165-50-6 application| 28165-50-6 NMR| 28165-50-6 COA| 28165-50-6 structure
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