Structure of 612845-44-0
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CAS No. : | 612845-44-0 |
Formula : | C7H10BNO3 |
M.W : | 166.97 |
SMILES Code : | C(C)OC1=NC=C(C=C1)B(O)O |
MDL No. : | MFCD06201032 |
InChI Key : | UONCERAQKBPLML-UHFFFAOYSA-N |
Pubchem ID : | 12012237 |
GHS Pictogram: |
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Signal Word: | Warning |
Hazard Statements: | H315-H319-H335 |
Precautionary Statements: | P261-P305+P351+P338 |
Num. heavy atoms | 12 |
Num. arom. heavy atoms | 6 |
Fraction Csp3 | 0.29 |
Num. rotatable bonds | 3 |
Num. H-bond acceptors | 4.0 |
Num. H-bond donors | 2.0 |
Molar Refractivity | 45.36 |
TPSA ? Topological Polar Surface Area: Calculated from |
62.58 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
0.0 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
0.43 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
-0.84 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
-0.84 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
-0.92 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
-0.43 |
Log S (ESOL):? ESOL: Topological method implemented from |
-1.32 |
Solubility | 8.03 mg/ml ; 0.0481 mol/l |
Class? Solubility class: Log S scale |
Very soluble |
Log S (Ali)? Ali: Topological method implemented from |
-1.31 |
Solubility | 8.15 mg/ml ; 0.0488 mol/l |
Class? Solubility class: Log S scale |
Very soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-1.44 |
Solubility | 6.05 mg/ml ; 0.0362 mol/l |
Class? Solubility class: Log S scale |
Soluble |
GI absorption? Gatrointestinal absorption: according to the white of the BOILED-Egg |
High |
BBB permeant? BBB permeation: according to the yolk of the BOILED-Egg |
No |
P-gp substrate? P-glycoprotein substrate: SVM model built on 1033 molecules (training set) |
No |
CYP1A2 inhibitor? Cytochrome P450 1A2 inhibitor: SVM model built on 9145 molecules (training set) |
No |
CYP2C19 inhibitor? Cytochrome P450 2C19 inhibitor: SVM model built on 9272 molecules (training set) |
No |
CYP2C9 inhibitor? Cytochrome P450 2C9 inhibitor: SVM model built on 5940 molecules (training set) |
No |
CYP2D6 inhibitor? Cytochrome P450 2D6 inhibitor: SVM model built on 3664 molecules (training set) |
No |
CYP3A4 inhibitor? Cytochrome P450 3A4 inhibitor: SVM model built on 7518 molecules (training set) |
No |
Log Kp (skin permeation)? Skin permeation: QSPR model implemented from |
-7.01 cm/s |
Lipinski? Lipinski (Pfizer) filter: implemented from |
0.0 |
Ghose? Ghose filter: implemented from |
None |
Veber? Veber (GSK) filter: implemented from |
0.0 |
Egan? Egan (Pharmacia) filter: implemented from |
0.0 |
Muegge? Muegge (Bayer) filter: implemented from |
1.0 |
Bioavailability Score? Abbott Bioavailability Score: Probability of F > 10% in rat |
0.55 |
PAINS? Pan Assay Interference Structures: implemented from |
0.0 alert |
Brenk? Structural Alert: implemented from |
1.0 alert: heavy_metal |
Leadlikeness? Leadlikeness: implemented from |
No; 1 violation:MW<1.0 |
Synthetic accessibility? Synthetic accessibility score: from 1 (very easy) to 10 (very difficult) |
2.23 |
* 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 |
---|---|---|
89% | With potassium carbonate;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In 1,4-dioxane; water; at 90℃; for 18h;Inert atmosphere; | Example 11Synthesis of 3-Methoxy-1 -(2-f 4-r°-d -methyl-1 H-F1 ,2,41triazol-3-yl)-phenv?-3.6- dihvdro-2H-pyridin-1 -yl)-2-oxo-ethyl)-pyrrolidine-3-carboxylic acid r3-(6-ethoxy- pyridin-3-yl)-1 H-indazol-5-yll-amide (Example 1) Step 1 : A mixture of <strong>[612845-44-0]6-ethoxypyridine-3-boronic acid</strong> (2.5 g, 14.97 mmol), bromoindazole 3Bl (7.25 g, 14.97 mmol), potassium carbonate (6.2 g, 44.91 mmol), PdCI2(dppf)2.CH2Cl2 (1.22 g, 1.497 mmol), 1 ,4-dioxane (40 ml_) and water (10 rriL), was purged with nitrogen for 15 min at r.t. and then heated at 90 0C for 18 hrs and cooled to r.t. Water (100 ml_) and ethyl acetate (300 ml_) were added. Solids were filtered through Celite. Layers were separated and the separated organic layer was washed with water (100 ml_). The combined organic layers were dried (Na2SO4), filtered and solvents were removed in vacuum. Column purification [Hexanes-ethyl acetate = 9:1 (Wv)] gave Compound 2BU (7 g, 89%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
67% | With triethylamine;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; XPhos; In 1,4-dioxane; at 100℃;Inert atmosphere; | Step 1. In a 100 mL round-bottomed flask, 1-acetyl-6-bromo-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile (250 mg, 947 mumol, Eq: 1.00), triethylamine (575 mg, 792 mul, 5.68 mmol, Eq: 6) and X-PHOS (181 mg, 379 mumol, Eq: 0.40) were combined with dioxane (25 ml) to give a colorless solution. [1,1'-bis(diphenylphosphino)ferrocene]dichloropaladium(II) (173 mg, 237 mumol, Eq: 0.25) and <strong>[612845-44-0]2-ethoxy-5-pyridineboronic acid</strong> (205 mg, 1.23 mmol, Eq: 1.3) were added and the resultant mixture was degassed for 5 minutes under Nitrogen. The reaction mixture was heated to 100 C. and stirred for O/N h. The reaction mixture was poured into 50 mL H2O and extracted with EtOAc (3×50 mL). The organic layers were dried over MgSO4 and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 40 g, 20% to 30% EtOAc in hexanes) to give 6-(6-ethoxypyridin-3-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile (167 mg, 67%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Intermediate 62-(6-Ethoxy-pyridin-3-yl)-pyrimidine-5-carboxylic acid cvclopropyl-piperidin-4-yl-annideAqueous Na2CO3 solution (2 M, 1 .05 ml_) and Pd(PPh3)2CI2 (22 mg) are added to a mixture of 4-[(2-chloro-pyrimidine-5-carbonyl)-cyclopropyl-amino]-piperidine-1 - carboxylic acid tert-butyl ester (400 mg) and <strong>[612845-44-0]2-ethoxy-5-pyridineboronic acid</strong> (351 mg) in 1 ,4-dioxane (20 ml_) and methanol (10 ml_) under argon atmosphere. The reaction mixture is stirred over night at 80 C. After cooling to room temperature, the solvents are evaporated and the residue is mixed with dichloromethane and water. The aqueous phase is extracted with dichloromethane and the combined organic phases are dried and concentrated in vacuo. The crude product is dissolved in dichloromethane and trifluoroacetic acid is added. The mixture is stirred for 1 h at room temperature and concentrated in vacuo. The crude product is purified by HPLC (MeOH/H2O/TFA) to give the title compound as trifluoroacetic acid salt. LC (method 4): tR = 0.99 min; Mass spectrum (ESI+): m/z = 368 [M+H]+. | ||
2-(6-Ethoxy-pyridin-3-yl)-pyrimidine-5-carboxylic acid cyclopropyl-piperidin-4-yl-amide Aqueous Na2CO3 solution (2 M, 1.05 mL) and Pd(PPh3)2Cl2 (22 mg) are added to a mixture of 4-[(2-chloro-pyrimidine-5-carbonyl)-cyclopropyl-amino]-piperidine-1-carboxylic acid tert-butyl ester (400 mg) and <strong>[612845-44-0]2-ethoxy-5-pyridineboronic acid</strong> (351 mg) in 1,4-dioxane (20 mL) and methanol (10 mL) under argon atmosphere. The reaction mixture is stirred over night at 80 C. After cooling to room temperature, the solvents are evaporated and the residue is mixed with dichloromethane and water. The aqueous phase is extracted with dichloromethane and the combined organic phases are dried and concentrated in vacuo. The crude product is dissolved in dichloromethane and trifluoroacetic acid is added. The mixture is stirred for 1 h at room temperature and concentrated in vacuo. The crude product is purified by HPLC (MeOH/H2O/TFA) to give the title compound as trifluoroacetic acid salt. LC (method 4): tR=0.99 min; Mass spectrum (ESI+): m/z=368 [M+H]+. | ||
Intermediate 892-(6-Ethoxy-ryridin-3-yl)-ryrimidine-5-carboxylic acid cyclororyl-rireridin-4-yl-amide: Under an argon atmosphere an aqueous solution of Na2003 (2 M, 1 .0 mL) andbis(triphenylphosphine)-palladium(II) chloride (22 mg) are added to a mixture of <strong>[612845-44-0]2-ethoxy-5-pyridineboronic acid</strong> (0.35 g) and 4-[(2-chloro-pyrimidine-5-carbonyl)- cyclopropyl-amino]-piperidine-1-carboxylic acid tert-butyl ester (0.4 g) in 1 ,4-dioxane (20 mL) and methanol (10 mL). The mixture is stirred for 12 h at 80C and concentrated in vacuo. To the residue is added dichloromethane and water. Theorganic phase is separated and the aqueous phase is extracted with dichloromethane. The combined extracts are dried over MgSO4 and concentrated in vacuo and treated with dichloromethane/ trifluoroacetic acid (1:1 +5% H20). The mixture is stirred at room temperature for 1 h, concentrated and purified by HPLC (018 RP Sunfire, MeOH/H20 +0.1% TEA) to give the desired product as atrifluoroacetic acid salt. LC (method 12): tR = 0.99 mm; Mass spectrum (ESI): mlz =368 [M+H] |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
45% | With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In N,N-dimethyl-formamide; at 80℃; for 22h;Inert atmosphere; Sealed tube; | Example 7 6-(4-(6-Ethoxypyridin-3-yl)phenyl)-2-oxo-4-p-tolyl-6-(trifluoromethyl)-1,2,5,6-tetrahydropyridine-3-carbonitrile To a solution of Example 3 (20 mg, 0.046 mmol), <strong>[612845-44-0]6-ethoxypyridin-3-yl boronic acid</strong> (11 mg, 0.07 mmol) and tetrakis(triphenylphosphine) palladium(0) (5 mg, 10 mol %) in DMF (0.6 mL) sparged with Ar was added 2 N aq K2CO3 (46 mL, 0.096 mmol). The vessel was sealed and the reaction heated to 80 C. for 22 h. The reaction was cooled to rt and the product was purified twice by preparative HPLC (CH3CN/H2O/TFA and CH3OH/H2O/TFA sequentially) to provide Example 7 (10 mg, 45%) as a light brown solid. LCMS Anal. Calc'd for C27H22F3N3O2 477.48. found [M+H] 478.3. 1H NMR (500 MHz, CD3OD) delta 1.40 (t, J=6.87 Hz, 3H), 2.40 (s, 3H), 3.71-3.88 (m, 2H), 4.37 (q, J=7.15 Hz, 2H), 6.94 (d, J=8.25 Hz, 1H), 7.33 (d, J=7.70 Hz, 2H), 7.54 (d, J=8.25 Hz, 2H), 7.66-7.78 (m, 4H), 8.05 (dd, J=8.80, 2.20 Hz, 1H), 8.42 (d, J=2.20 Hz, 1 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
2-(6-Ethoxy-pyridin-3-yl)-pyrimidine-5-carboxylic acid cyclopropyl-piperidin-4-yl-amide Under an argon atmosphere an aqueous solution of Na2CO3 (2 M, 1.0 mL) and bis(triphenylphosphine)-palladium(II) chloride (22 mg) are added to a mixture of <strong>[612845-44-0]2-ethoxy-5-pyridineboronic acid</strong> (0.35 g) and 4-[(2-chloro-pyrimidine-5-carbonyl)-cyclopropyl-amino]-piperidine-1-carboxylic acid tert-butyl ester (0.4 g) in 1,4-dioxane (20 mL) and methanol (10 mL). The mixture is stirred for 12 h at 80 C. and concentrated in vacuo. To the residue is added dichloromethane and water. The organic phase is separated and the aqueous phase is extracted with dichloromethane. The combined extracts are dried over MgSO4 and concentrated in vacuo and treated with dichloromethane/trifluoroacetic acid (1:1+5% H2O). The mixture is stirred at room temperature for 1 h, concentrated and purified by HPLC (C18 RP Sunfire, MeOH/H2O+0.1% TFA) to give the desired product as a trifluoroacetic acid salt. LC (method 12): tR=0.99 min; Mass spectrum (ESI+): m/z=368 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
29 mg | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; tetrakis(triphenylphosphine) palladium(0); potassium carbonate; tricyclohexylphosphine; In 1,4-dioxane; at 140℃; for 0.5h;Inert atmosphere; Microwave irradiation; | Example 14 4-(6-Ethoxypyridin-3-yl)-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5,5-dimethyl-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one Under an atmosphere of argon, 150 mg (0.18 mmol) of 2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-4-iodo-5,5-dimethyl-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one (Example 47A) were suspended in 4 ml of absolute dioxane, 91 mg (0.54 mmol) of 6-ethoxypyridin-3-yl)boronic acid, 10 mg (0.04 mmol) of tricyclohexylphosphine and 0.72 ml (0.72 mmol) of 1 N aqueous potassium carbonate solution were added and the mixture was stirred in a stream of argon for 10 min. 20 mg (0.03 mmol) of 1,1'-bis(diphenylphosphino)ferrocenepalladium(II) chloride and 31 mg (0.03 mmol) of tetrakis(triphenylphosphine)palladium(0) were added and the mixture was stirred at 140 C. in a microwave for 30 min. After cooling, the reaction mixture was filtered through an Extrelut cartridge, the cartridge was rinsed with dichloromethane/methanol (v/v=2:1) and the filtrate was concentrated on a rotary evaporator. The residue was purified by preparative HPLC (mobile phase: acetonitrile/water, gradient 20:80?100:0). 29 mg of the target compound were obtained (30% of theory). LC-MS (Method 1) Rt=1.22 min; MS (ESIpos): m/z=510 (M+H)+ 1H NMR (400 MHz, DMSO-d6): delta [ppm]=1.25 (s, 6H), 1.38 (t, 3H), 4.42 (q, 2H), 5.87 (s, 2H), 7.01 (d, 1H), 7.12-7.25 (m, 3H), 7.33-7.39 (m, 1H), 7.42 (dd, 1H), 7.98 (dd, 1H), 8.44 (d, 1H), 8.66 (dd, 1H), 8.79 (dd, 1H), 11.79 (s, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
48% | With bis-triphenylphosphine-palladium(II) chloride; potassium carbonate; In tetrahydrofuran; water; at 70℃; for 12h;Inert atmosphere; | General procedure: A mixture of compound 4 (100 mg, 0.29 mmol), aryl boronic acid (0.35 mmol), bis(triphenylphosphine)palladium(II) dichloride (9 mg, 0.013 mmol) and K2CO3 (71 mg, 0.52 mmol) was placed in a mixed solvent of THF and water (4:1, v/v, 10 mL). N2 gas was bubbled into this mixture for 10 min, and then the mixture was heated at 70 C while stirring under N2 for 12 h. The reaction mixture was left to cool at room temperature, and extracted with ethyl acetate (100 mL × 3). The combined organic extracts were dried over anhydrous MgSO4 and evaporated under vacuum. The target compounds 5a-j were separated in pure form by column chromatography (silica gel) using the proper ratio of ethyl acetate and n-hexane. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
69% | With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium carbonate; In water; acetonitrile; at 80℃; for 1h;Inert atmosphere; | A mixture of (6-ethoxy py rid in-3-yl) bo ran ic acid (121 mg, 0.722 mmol), (2R)-4-(6-bromo-4- fluoro-1 -oxoisoquinolin-2(1 H)-yl)-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2 H-pyran-2- yl)oxy)butanamide (250 mg, 0.481 mmol), PdCI2(dppf)-CH2Cl2 adduct (59.0 mg, 0.072 mmol) and K2C03 (133 mg, 0.963 mmol) in acetonitrile (6 ml_) and water (1 ml_) was stirred at room temperature under a nitrogen atomsphere. The reaction mixture was heated to 80 C for 1 hr. when the acetonitrile was removed by evaporation. The aqueous layer was extracted with DCM (50 ml_ x 2) and the combined organic layers were dried over Na2S04, filtered and concentrated. The crude product was purified by silica gel column chromatography (MeOH/DCM: 0-5%) to afford (2R)-4-(6-(6-ethoxypyridin-3-yl)-4- fluoro-1 -oxoisoquinolin-2(1 H)-yl)-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2- yl)oxy)butanamide (250 mg, 0.401 mmol, 69 % yield) as an off-white solid. LCMS: [M+H] 562.2. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
56% | With bis-triphenylphosphine-palladium(II) chloride; potassium carbonate; In 1,2-dimethoxyethane; water; at 100℃; for 2h;Inert atmosphere; | 2-Bromo-3-chloro-5-nitrobenzonitrile (3.84 g, 14.7 mmol), <strong>[612845-44-0](6-ethoxypyridin-3-yl)boronic acid</strong> (2.33 g, 14.0 mmol) and potassium carbonate (3.86 g, 28.0 mmol) were dissolved in DME (60 mL) and water (30 ml_). The reaction mixture was degassed under a stream of nitrogen before bis(triphenylphosphine)palladium(ll) dichloride (490 mg, 0.70 mmol) was added. The reaction mixture was stirred at 100 C for 2 hours. The reaction was allowed to cool to room temperature and water (50 mL) was added. The organics were extracted using DCM (3 x 8 mL) and the combined organics were dried over MgS04, filtered and concentrated under reduced pressure. The crude material was purified by Biotage Isolera chromatography (silica gel, eluting with heptanes-EtOAc, 1 :0 to 0:1 ) to afford 3.5 g (56% yield) as a yellow oil.1H NMR (250 MHz, DMSO-d6) delta 8.88 (d, J = 2.3 Hz, 1 H), 8.78 - 8.75 (m, 1 H), 8.32 (dd, J = 2.5, 0.6 Hz, 1 H), 7.90 (dd, J = 8.6, 2.5 Hz, 1 H), 7.02 (dd, J = 8.6, 0.6 Hz, 1 H), 4.41 (q, J = 7.0 Hz, 2H), 1.37 (t, J = 7.1 Hz, 3H).LCMS (Analytical Method A): Rt = 1.28 mins; MS (ESIpos) m/z = 303.9 (M+H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
25% | With bis-triphenylphosphine-palladium(II) chloride; potassium carbonate; In 1,2-dimethoxyethane; water; at 90℃; for 5h;Inert atmosphere; | Water (37 mL) and 1 ,2-dimethoxyethane (74 mL) were degassed with a stream of argon for 15 mins. Then 2-bromo-4-fluoro-5-nitrobenzonitrile (5.00 g, 20.4 mmol), 2-ethoxy-5- pyridine boronic acid (3.41 g, 20.4 mmol), potassium carbonate (9.31 g, 67.3 mmol) and dichlorobis(triphenylphosphine) palladium(ll) (172 mg, 0.245 mmol) were added, and the reaction heated at 90 C for 5 h. The mixture was cooled and put into water. Ethyl acetate was added and the layers separated. The aqueous layer was extracted 3x with EE. The combined organic layers were washed with brine, dried with sodium sulfate and concentrated under reduced pressure. The crude product was purified by chromatography (Si02, hexane/EE 0-100%-30% MeOH) to yield 1.63 g (25% yield) of the title compound (where the F atom is replaced by hydroxy).1H NMR (400 MHz, DMSO-d6) delta [ppm] 1.35 (t, 3H), 4.37 (q, 2H), 6.73 (s, 1 H), 6.92 (dd, 1 H), 7.87 (dd, 1 H), 8.29 (s, 1 H), 8.31 (d, 1 H).LCMS (method 1 ): Rt= 1.06 min; MS (ESIpos) m/z = 286 (M+H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With dichlorobis(triphenylphosphine)palladium(II); potassium carbonate; In 1,2-dimethoxyethane; water; at 90℃; | Under an atmosphere of nitrogen, methyl 5-amino-2-bromobenzoate (Int 1A, 1.0 g, 4.35 mmol), <strong>[612845-44-0](6-ethoxypyridin-3-yl)boronic acid</strong> (1.09 mg, 6.52 mmol) and potassium carbonate (1.98 g, 14.3 mmol) were dissolved in 1 ,2-dimethoxyethane (15.8 mL) and water (7.8 mL). Pd(PPh3)2Cl2 (36.7 mg, 0.052 mmol) was added and the reaction mixture heated at 90 C until completion. The reaction mixture was cooled to RT, diluted with water (30 mL) and extracted with ethyl acetate (20 mL). The organic layer was washed with water (15 mL), brine (15 mL), dried (Na2S04), filtered and concentrated at reduced pressure to give the title compound (1.37 g, 115% yield, approximately 87% purity) as a yellow solid. The material was used in the next step without further purification. LCMS (method 4): Rt = 1.03 min, MS (ESIpos) m/z = 273 (M+H) |
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