Structure of 525362-07-6
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CAS No. : | 525362-07-6 |
Formula : | C15H21BO4 |
M.W : | 276.14 |
SMILES Code : | O=C(OC)C1=CC=C(B2OC(C)(C)C(C)(C)O2)C=C1C |
MDL No. : | MFCD16996354 |
InChI Key : | GUHFNSOJOCZHQO-UHFFFAOYSA-N |
Pubchem ID : | 24824346 |
GHS Pictogram: |
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Signal Word: | Warning |
Hazard Statements: | H302-H315-H319-H335 |
Precautionary Statements: | P261-P305+P351+P338 |
* 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 |
---|---|---|
99% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate; In 1,4-dioxane; at 80℃; for 16h;Inert atmosphere; | To a solution of methyl 4-bromo-2-methyl-benzoate (10 g, 44 mmol, 1 eq), KOAc (13 g, 0.13 mol, 3 eq), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l,3,2- dioxaborolane (12 g, 48 mmol, 1.1 eq) in dioxane (100 mL) was added Pd(dppf)Ch (1.6 g, 2.2 mmol, 0.05 eq). The reaction mixture was stirred at 80 C for 16 h under N2 atmosphere. The reaction mixture was filtrated. The filtrate was concentrated in vacuo to give a residue. The residue was purified by column chromatography (S1O2, PE : EA = 1 :0 to 20: 1) to give 1 (12 g, 99% yield) as a yellow solid. LCMS: tR = 1.034 min, (ES+) m/z (M+H)+ = 277.2. |
66.4% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate; In 1,4-dioxane; at 110℃; for 4h;Inert atmosphere; | A mixture of potassium acetate (649.2 mg, 6.55 mmol), 1,1’- bis(diphenylphosphino)ferrocene palladium dichloride (159.7 mg, 0.22 mmol),bis(pinacolato)diboron (1108.5 mg, 4.37 mmol) and methyl 4-bromo-2-methylbenzoate (500.0 mg, 2.18 mmol) in 1,4-dioxane (20 mL) was stirred at 110 C for 4 h under N2 protection, and evaporated to dryness. The residue was taken up in EtOAc (30 mL), washed with water (20 mL x 2) and brine (20 mL), dried over Mg504 and concentrated. The residue was purified by flash column chromatography (10% ethyl acetate in petroleum ether, Rf = 0.6) to afford methyl 2-methyl-4-(4,4,5 ,5-tetramethyl- 1,3 ,2-dioxaborolan-2-yl)benzoate (400 mg, 66.4% yield) as a yellow oil. |
With potassium acetate;1,1'-bis-(diphenylphosphino)ferrocene; (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In 1,4-dioxane; at 95℃; for 16h; | Preparation 35: 2-Methyl-4-(4,4,5,5-tetramethyl-[l,3,2]dioxaborolan-2-yl)benzoic acid methyl ester <n="26"/>4-Bromo-2-methylbenzoic acid methyl ester (0.028 mmol), 4,4,5, 5,4',4',5',5'- octamethyl-[2,2']bi[[l,3,2]dioxaborolanyl] (0.028 mmol) and potassium acetate (0.064 mmol) were combined in dioxane (65 mL) and de-gassed with argon. [l,l'-bis(diphenylphosphino)- ferrocene]dichloropalladium (5.62xlO~4 mmol) and l,l'-bis(diphenylphosphino)ferrocene (5.62xlO~4 mmol) were added and the mixture stirred at 950C under argon for 16 h. The mixture was cooled then partitioned between water and ethyl acetate. The water was separated and washed with ethyl acetate. The organic extracts were combined, dried over MgSO4, concentrated and purified by dry-flash chromatography to afford the title compound: RT = 4.07 min; m/z (ES+)=277.24 [M+H]+. |
With potassium acetate;1,1'-bis-(diphenylphosphino)ferrocene; (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In 1,4-dioxane; at 95℃; for 16h; | Preparation 17: 2-Methyl-4-(4,4,5,5-tetramethyl-[l,3,2]dioxaborolan-2-yl)benzoic acid methyl ester4-Bromo-2-methylbenzoic acid methyl ester (0.028 mmol), ), 4,4,5,5,4',4',5',5'- octamethyl-[2,2']bi[[l,3,2]dioxaborolanyl] (0.028 mmol) and potassium acetate (0.064 mmol) were combined in dioxane (65 mL) and de-gassed with argon. [l,l'-Bis(diphenylphosphino)- ferrocene]dichloropalladium (5.62xlO~4 mmol) and l,l'-bis(diphenylphosphino)ferrocene (5.62xlO~4 mmol) were added and the mixture stirred at 950C under argon for 16 h. The mixture was cooled then partitioned between water and ethyl acetate. The water was separated and washed with ethyl acetate. The organic extracts were combined, dried (MgSO4), concentrated and purified by dry-flash chromatography to afford the title compound: RT = 4.07 min; m/z(ES+) = 277.24 [M+H]+ (LCMS protocol 3). | |
With potassium acetate;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In dimethyl sulfoxide; at 80℃; for 2h; | Step A. Methyl 2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate; A round bottomed flask was charged with methyl 4-bromo-2-methylbenzoate (3.98 g, 17.37 mmol), bis(pinacolato)diboron (4.85 g, 19.11 mmol), potassium acetate (5.12 g, 52.1 mmol), and dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium (II) dichloromethane adduct (0.426 g, 0.521 mmol). The flask was purged with nitrogen. Anhydrous DMSO (100 mL) was added, and the resulting suspension was degassed via nitrogen sparge. The mixture was then placed in a pre-heated oil bath (80 C.), and was held at this temperature for 2 h, whereupon it was allowed to cool to ambient temperature, then was poured into water. The aqueous phase was extracted with ether, and the organic phase was washed with brine. The organic phase was then separated, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. Purification by flash chromatography on silica gel (0 to 10% EtOAc in hexanes, then 10 to 100% EtOAc in hexanes) provided the title compound: LCMS m/z 277.6 [M+H]+; 1H NMR (500 MHz, CDCl3) δ 7.87 (d, J=7.5 Hz, 1H), 7.68 (s, 1H), 7.66 (d, J=7.5 Hz, 1H), 3.89 (s, 3H), 2.59 (s, 3H), 1.35 (s, 12H). | |
With potassium acetate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In dichloromethane; dimethyl sulfoxide; at 80℃; for 3h; | Methyl 4-bromo-2-methylbenzoate (9.16 g) obtained in Step 2 was dissolved in dimethyl sulfoxide (120 ml), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane(1:1) (1.46 g), potassium acetate (11.8 g) and bis(pinacolato)diboron (11.2 g) were added at 80 C. The mixture was stirred for 3 hrs. The reaction mixture was cooled to room temperature, water was added and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=9:1) and the resulting compound was dissolved in toluene (80 ml) and ethanol (80 ml). Thereto was added a solution of [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II),complex with dichloromethane (1:1) (1.17 g) and (2R)-2-[((1R)-(2-bromophenyl)ethoxy)methyl]oxirane (10.5 g) obtained in Step 1 in ethanol (80 ml) and 2M aqueous sodium carbonate solution (80 ml) was added. The mixture was heated under reflux for 3 hrs. The reaction mixture was allowed to return to room temperature, and extracted with diethyl ether. The organic layer was washed successively with water and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=5:1) to give the title compound (8.93 g). 1H-NMR (300 MHz, δppm, CDCl3) 7.96(1H, d, J=8.6 Hz), 7.60(1H, d, J=6.7 Hz), 7.43-7.28(4H, m), 7.18-7.13(1H, m), 4.55(1H, q, J=6.4 Hz), 3.92(3H, s), 3.44-3.40(1H, m), 3.18-3.12(1H, m), 3.07-3.02(1H, m), 2.73-2.70(1H, m), 2.65(3H, s), 2.47-2.45(1H, m), 1.37(3H, d, J=6.4 Hz | |
With potassium acetate;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In dimethyl sulfoxide; at 80℃; for 2h;Inert atmosphere; | Example 3; Step A. Methyl 2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoateA round bottomed flask was charged with methyl 4-bromo-2-methylbenzoate (3.98 g, 17.37 mmol), bis(pinacolato)diboron (4.85 g, 19.11 mmol), potassium acetate (5.12 g, 52.1 mmol), and dichloro [1,1'-bis(diphenylphosphino) ferrocene] palladium (II) dichloromethane adduct (0.426 g, 0.521 mmol). The flask was purged with nitrogen. Anhydrous DMSO (100 mL) was added, and the resulting suspension was degassed via nitrogen sparge. The mixture was then placed in a pre-heated oil bath (80 C.), and was held at this temperature for 2 h, whereupon it was allowed to cool to ambient temperature, then was poured into water. The aqueous phase was extracted with ether, and the organic phase was washed with brine. The organic phase was then separated, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. Purification by flash chromatography on silica gel (0 to 10% EtOAc in hexanes, then 10 to 100% EtOAc in hexanes) provided the title compound: LCMS m/z 277.6 [M+H]+; 1H NMR (500 MHz, CDCl3) δ 7.87 (d, J=7.5 Hz, 1H), 7.68 (s, 1H), 7.66 (d, J=7.5 Hz, 1H), 3.89 (s, 3H), 2.59 (s, 3H), 1.35 (s, 12H). | |
With potassium acetate;palladium diacetate; In N,N-dimethyl-formamide; at 20 - 80℃; for 4.5h; | As shown in Reaction Scheme 6, a mixture of bis(pinacolato)diboron (0.55 g, 2.2 mmol), methyl 4-bromo-2-methylbenzoate (0.50 g, 2.2 mmol), palladium(II) acetate (0.01 g, 0.07 mmol), and KOAc (0.64 g, 6.6 mmol) in DMF (7.5 mL) was degassed with argon for 30 min at rt. The mixture was then heated at 800C for 4 h. After cooling the mixture to rt, N-(4-bromo-2-fluorophenyl)-6- fluoro-l,3-benzothiazol-2-amine (0.74 g, 2.2 mmol), tetrakis(triphenylphosphine)palladium(0) (0.08 g, 0.07 mmol), and saturated aqueous NaHCO3 (5 mL) were added. The mixture was heated at 850C overnight. The mixture was poured into ice water and extracted with EtOAc. The combined organic phases were dried over Na2SO4, concentrated in vacuo, and purified by column chromatography (20% EtOAc in hexanes). This yielded 0.345 g (39%) of the title compound. EPO <DP n="28"/>LC/MS m/z 411.3 (MH+); retention time 4.15 min. 1H NMR (400 MHz, CD2Cl2) δ 2.62 (s, 3H), 3.90 (s, 3H), 7.10 (t, IH), 7.39-7.53 (m, 5H), 7.62-7.70 (m, IH), 7.99 (d, IH), 8.58 (t, IH). | |
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate; In 1,4-dioxane; at 85℃; for 6h;Inert atmosphere; | Adding the compound 179a (500 mg, 2.18 mmol),Compound 179b (665.1 mg, 2.62 mmol), potassium acetate (427.8 mg, 4.36 mmol) and PdCl2 (dppf) (159.7 mg, 0.22 mmol) were dissolved in 1,4-dioxane (10 mL) and replaced with nitrogen three times. Then, it heated up to 85 C and stirred for 6 hours. Cool to room temperature,The reaction solution was directly used for feeding in the next step. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium carbonate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In ethanol; dichloromethane; water; toluene; for 3h;Heating / reflux; | Methyl 4-bromo-2-methylbenzoate (9.16 g) obtained in Step 2 was dissolved in dimethyl sulfoxide (120 ml), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane(1:1) (1.46 g), potassium acetate (11.8 g) and bis(pinacolato)diboron (11.2 g) were added at 80 C. The mixture was stirred for 3 hrs. The reaction mixture was cooled to room temperature, water was added and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=9:1) and the resulting compound was dissolved in toluene (80 ml) and ethanol (80 ml). Thereto was added a solution of [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II),complex with dichloromethane (1:1) (1.17 g) and (2R)-2-[((1R)-(2-bromophenyl)ethoxy)methyl]oxirane (10.5 g) obtained in Step 1 in ethanol (80 ml) and 2M aqueous sodium carbonate solution (80 ml) was added. The mixture was heated under reflux for 3 hrs. The reaction mixture was allowed to return to room temperature, and extracted with diethyl ether. The organic layer was washed successively with water and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=5:1) to give the title compound (8.93 g). 1H-NMR (300 MHz, δppm, CDCl3) 7.96(1H, d, J=8.6 Hz), 7.60(1H, d, J=6.7 Hz), 7.43-7.28(4H, m), 7.18-7.13(1H, m), 4.55(1H, q, J=6.4 Hz), 3.92(3H, s), 3.44-3.40(1H, m), 3.18-3.12(1H, m), 3.07-3.02(1H, m), 2.73-2.70(1H, m), 2.65(3H, s), 2.47-2.45(1H, m), 1.37(3H, d, J=6.4 Hz |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hydrogencarbonate;tetrakis(triphenylphosphine) palladium(0); In water; N,N-dimethyl-formamide; at 85℃; | As shown in Reaction Scheme 6, a mixture of bis(pinacolato)diboron (0.55 g, 2.2 mmol), methyl 4-bromo-2-methylbenzoate (0.50 g, 2.2 mmol), palladium(II) acetate (0.01 g, 0.07 mmol), and KOAc (0.64 g, 6.6 mmol) in DMF (7.5 mL) was degassed with argon for 30 min at rt. The mixture was then heated at 800C for 4 h. After cooling the mixture to rt, N-(4-bromo-2-fluorophenyl)-6- fluoro-l,3-benzothiazol-2-amine (0.74 g, 2.2 mmol), tetrakis(triphenylphosphine)palladium(0) (0.08 g, 0.07 mmol), and saturated aqueous NaHCO3 (5 mL) were added. The mixture was heated at 850C overnight. The mixture was poured into ice water and extracted with EtOAc. The combined organic phases were dried over Na2SO4, concentrated in vacuo, and purified by column chromatography (20% EtOAc in hexanes). This yielded 0.345 g (39%) of the title compound. EPO <DP n="28"/>LC/MS m/z 411.3 (MH+); retention time 4.15 min. 1H NMR (400 MHz, CD2Cl2) δ 2.62 (s, 3H), 3.90 (s, 3H), 7.10 (t, IH), 7.39-7.53 (m, 5H), 7.62-7.70 (m, IH), 7.99 (d, IH), 8.58 (t, IH). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
71.2% | With sodium periodate; ammonium acetate; In water; acetone; at 20℃; for 16h; | A mixture of methyl 2-methyl-4-(4,4,5 ,5-tetramethyl- 1,3 ,2-dioxaborolan-2- yl)benzoate (400.0 mg, 1.45 mmol) , sodium periodate (309.8 mg, 1.45 mmol) and ammoniumacetate (800.0 mg, 10.38 mmol) in acetone (8 mL) and water (4 mL) was stirred at 20 C for 16 h, and evaporated to dryness. The residue was taken up in EtOAc (20 mL), washed with water (20 mL x 2) and brine (20 mL), dried over Mg504 and concentrated. The residue was purified by flash column chromatography (33% ethyl acetate in petroleum ether) to afford (4- methoxycarbonyl-3-methyl-phenyl)boronic acid (200 mg, 71.2% yield) as a white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With caesium carbonate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In 1,4-dioxane; water; at 90℃; for 16h; | Preparation 36: 3-[6-(4-Methoxycarbonyl-3-methylphenyl)pyridin-3-yloxy]azetidine-l- carboxylic acid tert-butyl ester3-(6-Bromopyridin-3-yloxy)azetidine-l-carboxylic acid tert-butyl ester (17.79 mmol), 2-Methyl-4-(4,4,5,5-tetramethyl-[l,3,2]dioxaborolan-2-yl)-benzoic acid methyl ester (19.57 mmol) and cesium carbonate (26.69 mmol) were combined in 4:1 dioxane:H2O (65 mL) and degassed with argon. Bis(diphenylphosphino)ferrocene]dichloropalladium (1.78 mmol) was added and the mixture stirred at 9O0C under argon for 16 h. The reaction mixture was cooled and partitioned between ethyl acetate and sat. Na2CO3 (aq). The aqueous layer was separated and extracted with further ethyl acetate. The organics were combined, dried over MgSO4 and concentrated. The crude mixture was purified by flash column chromatography followed by trituration to afford the title compound: RT = 4.07 min; m/z (ES+)=399.33 [M+H]+. | |
With caesium carbonate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In 1,4-dioxane; water; at 90℃; for 16h; | Preparation 18: 3-[6-(4-Methoxycarbonyl-3-methylphenyl)pyridin-3-yloxy]azetidine-l- carboxylic acid tert-butyl ester3-(6-Bromopyridin-3-yloxy)azetidine-l-carboxylic acid tert-butyl ester (17.79 mmol), 2-methyl-4-(4,4,5,5-tetramethyl-[l,3,2]dioxaborolan-2-yl)benzoic acid methyl ester (19.57 mmol) and cesium carbonate (26.69 mmol) were combined in 4:1 dioxane:H2O (65 mL) and degassed with argon. Bis(diphenylphosphino)ferrocene]dichloropalladium (1.78 mmol) was added and the mixture stirred at 9O0C under argon for 16 h. The reaction mixture was cooled and partitioned between ethyl acetate and sat. Na2CO3 (aq). The aqueous layer was separated and extracted with further ethyl acetate. The organics were combined, dried (MgSO4) and concentrated. The crude mixture was purified by flash column chromatography followed by trituration to afford the title compound: RT = 4.07 min; m/z (ES+) = 399.33 [M+H]+ (LCMS protocol 3). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium carbonate;trans-bis(triphenylphosphine)palladium dichloride; In water; acetonitrile; at 70℃; for 15h; | Step B. Methyl 4-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)-2-methylbenzoate; To a flask containing the enol triflate synthesized according to Example 10 Step A (1.10 g, 3.82 mmol) were added the title compound from Example 13 Step A (1.16 g, 4.20 mmol) and trans-dichlorobis(triphenylphosphine) palladium (II) (134 mg, 0.191 mmol). Acetonitrile (15 mL) and sodium carbonate (9.54 mL, 1.0 M aqueous, 9.54 mmol) were added, and the resulting mixture was degassed via nitrogen sparge. The reaction mixture was stirred at 70 C. for 15 h, then was allowed to cool to ambient temperature and was poured into water. The mixture was extracted with EtOAc, and the organic phase was concentrated in vacuo.Purification by chromatography on silica gel (0 to 30% EtOAc in hexanes, then 30 to 100% EtOAc in hexanes) provided the title compound: LCMS m/z 289.4 [M+H]+; 1H NMR (500 MHz, CDCl3) δ 7.87 (d, J=8.5 Hz, 1H), 7.27-7.25 (m, 2H), 6.09-6.07 (m, 1H), 4.03 (s, 4H), 3.88 (s, 3H), 2.68-2.65 (m, 2H), 2.60 (3, H), 2.49-2.47 (m, 2H), 1.94-1.91 (m, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium carbonate;trans-bis(triphenylphosphine)palladium dichloride; In water; acetonitrile; at 70℃; for 3h;Inert atmosphere; | Step B. tert-Butyl-4-(4-(methoxycarbonyl)-3-methylphenyl)-3,6-dihydropyridine-1(2H)-carboxylateTo a flask containing 1,1-dimethylethyl 4-(((trifluoromethyl)sulfonyl)oxy)-3,6-dihydropyridine-1(2H)-carboxylate (3.80 g, 11.5 mmol, prepared according to Heterocycles, 1996, 43, 2131-2138) were added the title compound from Example 3 Step A (3.80 g, 13.8 mmol) and trans-dichlorobis(triphenylphosphine)palladium (II) (804 mg, 1.15 mmol). Acetonitrile (57 mL) and sodium carbonate (28.7 mL, 1.0 M aqueous, 28.7 mmol) were added, and the resulting mixture was degassed via nitrogen sparge. The reaction mixture was stirred at 70 C. for 3 h, then was allowed to cool to ambient temperature and was poured into water. The mixture was extracted with EtOAc, and the organic phase was concentrated in vacuo. Purification by chromatography on silica gel (0 to 10% EtOAc in hexanes, then 10 to 100% EtOAc in hexanes) provided the title compound: LCMS m/z 276.0 [M-C4H9]+; 1H NMR (500 MHz, CDCl3) δ 7.89 (d, J=9.0 Hz, 1H), 7.24-7.22 (m, 2H), 6.12 (br s, 1H), 4.09 (br m, 2H), 3.88 (s, 3H), 3.65-3.62 (m, 2H), 2.61 (s, 3H), 2.52 (br m, 2H), 1.49 (s, 9H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate; In 1,4-dioxane; at 80℃; for 20h; | General procedure: Procedure G: To a mixture of 1-(5-bromoindolin-1-yl) propan-1-one (1.5 g, 5.9 mmol) in dioxane (15 mL), were added B2Pin2 (1.65 g, 6.5 mmol), Pd(dppf)Cl2 (240 mg, 0.3 mmol), and KOAc (1.7 g, 17.7 mmol). The reaction mixture was stirred at 80 C for 20 h. It was then diluted with DCM, and washed with water and brine. The organic layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography over silica gel (PE/EA 4:1, v/v) to give 1-(5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) indolin-1-yl) propan-1-one as a yellow solid (800 mg, 45%). LC-MS (ESI): m/z (M-56)+ = 254.20. |
80% | With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium acetate; In 1,4-dioxane; at 90℃;Inert atmosphere; | General procedure: General procedure A: Potassium acetate (2.94 g, 30.0 mmol), bis-(pinacolato)-diboron (3.05 g, 12.0 mmol) and bis(diphenylphosphine) ferrocene dichloropalladium (II) complex with (0355) dichloromethane (0.36 g, 0.5 mmol) was added to an anhydrous solution of 4-bromo-2-methylphenol (1.87 g, 10.0 mmol) in dioxane (180 mL) under anhydrous conditions in an atmosphere of nitrogen. The mixture was stirred at 90 C overnight. The reaction was then quenched with water and extracted with ethyl acetate The combined organic layers were dried over magnesium sulfate, filtered and concentrated. The residue was purified by flash column chromatography on silica gel (eluent: dichloromethane/ethyl acetate, 10-100%) to give the title compound (12) as a white solid (1.75 g, 75%). ESI-MS m/z: 235.1508 [M+H]+; 1H NMR (400 MHz, CDC13) δ 7.60 (s, 1H), 7.55 (d, J= 7.9 Hz, 1H), 6.76 (d, J= 7.9 Hz, 1H), 4.97 (s, 1H), 2.25 (s, 3H), 1.33 (s, 12H); 13C NMR (101 MHz, CDC13) δ 156.77, 138.04, 134.46, 123.20, 114.56, 83.71, 24.99, 15.56. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
62% | With tetrakis(triphenylphosphine) palladium(0); sodium hydrogencarbonate; In 1,4-dioxane; water; at 140℃; for 0.5h;Microwave irradiation; | To 3-bromo-l-(4-(trifluoromethoxy)phenyl)-lH-l,2,4-triazole (0.496 g, 1.609 mmol), methyl 2-methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)benzoate (0.466 g, 1.689 mmol), sodium bicarbonate (0.405 g, 4.83 mmol) and tetrakis(triphenylphosphine)palladium (0.186 g, 0.161 mmol) in a 2.0 mL microwave vial was added dioxane (6 mL) and water (1.5 mL). The reaction was capped and placed on a Biotage Initiator microwave reactor for 30 min at 140 C. The reaction mixture was then diluted with EtOAc and washed with water. The aqueous layer was extracted with EtOAc. The combined organic layers were dried over MgS04, filtered and concentrated. Purification by flash column chromatography provided the title compound as a white solid (0.376 g, 0.997 mmol, 62%): ]H NMR (400 MHz, CDC13) δ 8.59 (s, 1H), 8.10 (dt, / = 1.6, 0.7 Hz, 1H), 8.09 - 8.00 (m, 2H), 7.84 - 7.78 (m, 2H), 7.44 - 7.37 (m, 2H), 3.93 (s, 3H), 2.70 (s, 3H); 19F NMR (376 MHz, CDC13) δ -58.02; ESIMS m/z 378 ([M+H]+) |
62% | With tetrakis(triphenylphosphine) palladium(0); sodium hydrogencarbonate; In 1,4-dioxane; water; at 140℃; for 0.5h;Microwave irradiation; | Example 60. Preparation of methyl 2-methyl-4-(l-(4-(trifluoromethoxy)phenyl)-lH- l,2,4-triazol-3-yl) benzoate To 3-bromo-l-(4-(trifluoromethoxy)phenyl)-lH-l,2,4-triazole (0.496 g, 1.609 mmol), methyl 2-methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)benzoate (0.466 g, 1.689 mmol), sodium bicarbonate (0.405 g, 4.83 mmol) and tetrakis(triphenylphosphine)palladium (0.186 g, 0.161 mmol) in a 2.0 mL microwave vial was added dioxane (6 mL) and water (1.5 mL). The reaction was capped and placed on a Biotage Initiator microwave reactor for 30 min at 140 C. The reaction mixture was then diluted with EtOAc and washed with water. The aqueous layer was extracted with EtOAc. The combined organic layers were dried over MgS04, filtered and concentrated. Purification by flash column chromatography provided the title compound as a white solid (0.376 g, 0.997 mmol, 62%): ]H NMR (400 MHz, CDC13) δ 8.59 (s, 1H), 8.10 (dt, / = 1.6, 0.7 Hz, 1H), 8.09 - 8.00 (m, 2H), 7.84 - 7.78 (m, 2H), 7.44 - 7.37 (m, 2H), 3.93 (s, 3H), 2.70 (s, 3H); 19F NMR (376 MHz, CDC13) δ -58.02; ESIMS m/z 378 ([M+H]+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1.51g | With potassium carbonate; palladium; In ethanol;Inert atmosphere; Heating; | In a reaction vessel Compound 2.00g of the formula (I-4-1), the compound represented by formula (the I-4-2) 2.08g with potassium carbonate 1.56g, the ethanol 40mL were added. After nitrogen substitution, it was added a palladium catalyst. After heating was stirred and washed diluted with toluene hydrochloric acid, water, brine. This was purified by column chromatography and recrystallization to give the compound 1.51g of formula (I-4-3). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88.6% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; caesium carbonate; In water; toluene; at 110℃; for 16h;Inert atmosphere; | : A mixture of 2-chloro-5-isobutylpyridine (50.0 mg, 0.29 mmol), 1,1’- bis(diphenylphosphino)ferrocene palladium dichloride (21.6 mg, 0.03 mmol), methyl 2-methyl- 4-(4,4,5 ,5-tetramethyl- 1,3 ,2-dioxaborolan-2-yl)benzoate (122.1 mg, 0.44 mmol) and cesium carbonate (288.1 mg, 0.88 mmol) in toluene (5 mL) and water (1 mL) was stirred at 110Cfor 16 h under nitrogen. The mixture was diluted with H20 (10 mL) and extracted with EtOAc (10 mL x 2). The combined organic layers were washed with water (20 mL x 4) and brine (20 mL), dried over Na2504 and concentrated. The residue was purified by prep-TLC (7.5% EtOAc in petroleum) to obtain methyl 4-(5-isobutylpyridin-2-yl)-2-methylbenzoate (74 mg, 88.6% yield) as a yellow oil. LCMS (Method 5-95 AB, ESI): tR = 0.8 16 mi [M+Hj = 283.9. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
58.1% | With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In water; toluene; at 80℃; for 16h; | To a solution of 2,5-dibromopyrazine (200.0 mg, 0.84 mmol) in toluene (5 mL) andwater (1 mL) were added potassium carbonate (348.6 mg, 2.52 mmol), methyl 2-methyl-4-(4,4,5 ,5-tetramethyl- 1,3 ,2-dioxaborolan-2-yl)benzoate (232.2 mg, 0.84 mmol) and tetrakis(triphenylphosphine)palladium(0) (97.2 mg, 0.08 mmol). The reaction mixture was stirred at 80 C for 16 h and filtered. The filtrate was diluted with H20 (20 mL) and extracted with EtOAc (40 mL x 2). The combined organic layers were washed with water (80 mL x 3) andbrine (80 mL), dried over Na2SO4 and concentrated. The residue was purified by prep-TLC (7.5% EtOAc in petroleum ether) to obtain methyl 4-(5-bromopyrazin-2-yl)-2-methylbenzoate(150 mg, 58.1% yield) as a white solid. ‘H NMR (400 MHz, CDC13): 8.81 (s, 1H), 8.75 (d, I =1.2 Hz, 1H), 8.04 (d, I = 8.4 Hz, 1H), 7.88 (s, 1H), 7.85 (d, I = 8.4 Hz, 1H), 3.93 (s, 3H), 2.70(s, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; sodium carbonate; In 1,4-dioxane; water; at 85℃; for 16h;Inert atmosphere; | The compound 179d (380.8 mg, 1.81 mmol), compound 179c (601.8 mg, 2.18 mmol), Na2CO3 (385.1 mg, 3.63 mmol), PdCl2 (dppf) (132.9 mg, 0.18 mmol) were added to 1,4-bis In a mixed solution of oxane (20 mL) and water (5 mL).Nitrogen was replaced three times, and then the reaction solution was stirred at 85 C for 16 hours. Cool to room temperature, filter, and wash the filter cake with ethyl acetate (15 mL x 2). The filtrate was concentrated. The concentrate was purified by silica gel chromatography (ethyl acetate: petroleum ether = 0-80%) to obtain the yellow solid compound 179e, which is 2- Methyl-4- (2-((1-methyl-1H-pyrazol-4-yl) amino) pyrimidin-4-yl) benzoic acid methyl ester (420 mg, 78.0% yield). |
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