Structure of 54151-74-5
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CAS No. : | 54151-74-5 |
Formula : | C11H8BrN |
M.W : | 234.09 |
SMILES Code : | BrC1=NC=CC(C2=CC=CC=C2)=C1 |
MDL No. : | MFCD00235159 |
InChI Key : | KRIILKQTJUOQCJ-UHFFFAOYSA-N |
Pubchem ID : | 104700 |
GHS Pictogram: |
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Signal Word: | Warning |
Hazard Statements: | H302-H315-H319-H335 |
Precautionary Statements: | P261-P305+P351+P338 |
Num. heavy atoms | 13 |
Num. arom. heavy atoms | 12 |
Fraction Csp3 | 0.0 |
Num. rotatable bonds | 1 |
Num. H-bond acceptors | 1.0 |
Num. H-bond donors | 0.0 |
Molar Refractivity | 57.37 |
TPSA ? Topological Polar Surface Area: Calculated from |
12.89 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
2.34 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
3.5 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
3.51 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
2.82 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
3.7 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
3.17 |
Log S (ESOL):? ESOL: Topological method implemented from |
-4.11 |
Solubility | 0.018 mg/ml ; 0.000077 mol/l |
Class? Solubility class: Log S scale |
Moderately soluble |
Log S (Ali)? Ali: Topological method implemented from |
-3.45 |
Solubility | 0.0823 mg/ml ; 0.000352 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-5.4 |
Solubility | 0.00093 mg/ml ; 0.00000397 mol/l |
Class? Solubility class: Log S scale |
Moderately soluble |
GI absorption? Gatrointestinal absorption: according to the white of the BOILED-Egg |
High |
BBB permeant? BBB permeation: according to the yolk of the BOILED-Egg |
Yes |
P-gp substrate? P-glycoprotein substrate: SVM model built on 1033 molecules (training set) |
No |
CYP1A2 inhibitor? Cytochrome P450 1A2 inhibitor: SVM model built on 9145 molecules (training set) |
Yes |
CYP2C19 inhibitor? Cytochrome P450 2C19 inhibitor: SVM model built on 9272 molecules (training set) |
Yes |
CYP2C9 inhibitor? Cytochrome P450 2C9 inhibitor: SVM model built on 5940 molecules (training set) |
No |
CYP2D6 inhibitor? Cytochrome P450 2D6 inhibitor: SVM model built on 3664 molecules (training set) |
No |
CYP3A4 inhibitor? Cytochrome P450 3A4 inhibitor: SVM model built on 7518 molecules (training set) |
No |
Log Kp (skin permeation)? Skin permeation: QSPR model implemented from |
-5.24 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) |
1.85 |
* 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 |
---|---|---|
55.1% | Dimethylaminoethanol (DMAE, 1.50 mL, 15.0 mmol) was dissolved in hexane (20.0 mL) stirred at ice-cooling. A small amount of n-butyllithium (2.5 mol / L hexane solution, 12.0 mL, 30.0 mmol) was successively dropped under ice-cooling, and the mixture was stirred for 30 minutes. A small amount of 4-phenylpyridine (776 mg, 5.00 mmol) in hexane (30.0 mL) was added dropwise under ice-cooling, and the mixture was stirred for 1 hour in this state.After the reaction solution was cooled to -78 C, a small amount of the solution (15.0 mL) of carbon tetrafromide (6.30 g, 18.0 mmol) was successively dropped, and the mixture was stirred for 50 minutes. The purified water was added under ice cooling to stop the reaction, followed by extraction with ethyl acetate (100 mL × 2). The organic layer was washed with saturated brine, then dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography using ethyl acetate / hexane (1/4 (volume ratio)) as an elution solvent to obtain Compound 7 in a yield of 645 mg (yield 55.1%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With trimethylsilyl bromide; In propiononitrile; at 150℃; for 0.166667h;Microwave; | 1B. 4-Phenyl-pyridine-2-carbaldehyde: To a clear, colorless solution of lA (0.850 g, 4.5 mmol) in propionitrile (4.5 mmol) was added trimethylsilyl bromide (2.95 mL, 22.4 mmol). The resulting orange suspension was microwaved in a sealed tube at 150 °C for 10 min. The reaction was cooled to rt and poured into 1.0 N NaOH containing ice. The aqueous layer was extracted with diethyl ether (2x). The combined organic layers were washed with sat. NaHC03, brine, dried over Na2S04, filtered and concentrated to give 1.07 g of 2-bromo-4-phenyl pyridine as an off-white solid. MS 233.9 (M+H) + and 235.9 (M+2+H)+. [00337] To a cooled (-78 °C) clear, slightly yellow solution of 2-bromo-4- phenyl-pyridine (0.500 g, 2.14 mmol) in THF (8.6 mL) was added dropwise 2.5 M n-BuLi in hexane (0.86 mL, 2.14 mmol). The resulting red solution was stirred at-78 °C for 1h, then 1-formylpiperidine (0.48 mL, 4.28 mmol) was added dropwise. The reaction was allowed to warm to 0 °C over 1h and then stirred at 0 °C for 1h. The reaction was quenched with 1.0 N HCl. The reaction was extracted with ethyl acetate. The combined organic layers were washed with sat. NaHC03, brine, dried over Na2S04, filtered, and concentrated to give 0.555 gas a golden oil. Column chromatography (40 g silica gel; gradient elution; 0-40percent ethyl acetate/hexane) provided 1B (0.194 g, 49percent) as a yellow solid. 1H-NMR (400 MHz, CDCI3) No.: 10.16 (s, 1H), 8.84 (d, J = 5.3 Hz, 1H), 8.21 (d, J = 1.3 Hz, 1H), 7.75 (dd, J = 5.3, 1.8 Hz, 1H), 7.71-7.69 (m, 2H), 7.55-7.48 (m, 3H). MS 184.1 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Besides making 2-bromopyridine, the process of the present invention may be suitable to the preparation of various substituted 2-bromopyridines that could be made by the general Craig procedure. Such substituted 2-bromopyridines would include: 2-bromo-3-picoline 6-bromo-3-picoline 2-bromo-4-picoline 2-bromo-4-ethylpyridine 2-bromo-4-phenylpyridine 2-bromo-2-phenylpyridine 2,5-dibromopyridine | ||
With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In tetrahydrofuran; water; for 12h;Inert atmosphere; Reflux; | General procedure: In a 1 L reaction vessel Intermediate A-3 (25 g), Phenylboronic acid (10.74 g), & lt; RTI ID = 0.0 & gt; Pd (PPh3) 4 (3.05 g), K2CO3 (24.3 g) , THF (333 mL) and distilled water (166 mL) were put together, And refluxed under nitrogen for 12 hours. After completion of the reaction, the reaction mixture was cooled to room temperature, and the aqueous layer was removed. The organic layer was washed with 5% brine (500 mL) And once with distilled water (500 mL). The organic layer obtained was dried over MgSO4, the solvent was removed, and ethyl acetate: n-hexane (= 3: 97) The residue was purified by silica gel column chromatography Purification yielded intermediate A-2 (12.4 g). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
57% | With bis-triphenylphosphine-palladium(II) chloride; potassium carbonate; In 1,2-dimethoxyethane; water; at 80℃; for 14h;Inert atmosphere; | General procedure: Reactions were carried out with Phenylboronic acid (146 mg,1.2 mmol), 2-bromo-pyridine derivatives (234 mg, 1.0 mmol, <strong>[54151-74-5]2-bromo-4-phenylpyridine</strong> for 18a; 172 mg, 1.0 mmol, 2-bromo-4-methylpyridine for 18b; 192 mg, 1.0 mmol, 2-bromo-4-chloropyridine for 18c; 183 mg, 1.0 mmol, 2-bromoisonicotinonitrilefor 18d; 186 mg, 1.0 mmol, 2-bromoisonicotinaldehyde for 18e;176 mg, 1.0 mmol, 2-bromo-5-fluoropyridine for 18j; 192 mg,1.0 mmol, 2-bromo-5-chloropyridine for 18k; 183 mg, 1.0 mmol, 6-bromonicotinonitrile for 18m; 186 mg, 1.0 mmol, 6-bromonicotinaldehyde for 18n; 236 mg, 1.0 mmol, 2-bromo-5-(methylsulfonyl)pyridine for 18o, 200 mg, 1.0 mmol, 1-(6-bromopyridin-3-yl)ethan-1-one for 18p, 234 mg, 1.0 mmol, 2-bromo-5-phenylpyridine for 18r; 263 mg, 1.0 mmol, N-benzyl-6-bromopyridin-3-amine for 18s), Pd(PPh3)2Cl2 (3.5 mg, 0.5 mol %),K2CO3 (387 mg, 2.8 mmol) in DME/H2O (8 mL, 3:1) under nitrogenatmosphere. The mixture was stirred at 80 C for about 14 h and thecompletion of the reaction was monitored by TLC. After cooling toroomtemperature, themixturewas extracted with ethyl acetate. Thecombined organic layers were washed with brine and the organicphase was dried with anhydrous sodium sulfate and concentrated invacuo. The crude compound was purified by silica gel column chromatographyto give corresponding intermediates. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
A solution of <strong>[54151-74-5]2-bromo-4-phenylpyridine</strong> (1 eq.) in THF was cooled to -78 C. and treated dropwise with n-BuLi (1.1 eq.). After 30 min, a solution of the imine (O1) (1.2 eq.) in THF was added. The reaction mixture was stirred for 2 h at -78 C. and than slowly warmed to RT. The reaction was quenched with H2O and the aqueous phase was extracted with EtOAc. The combined organic phase was dried (MgSO4) and solvent was removed under reduced pressure. The crude amine was used without further purification |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1B. 4-Phenyl-pyridine-2-carbaldehyde: To a clear, colorless solution of lA (0.850 g, 4.5 mmol) in propionitrile (4.5 mmol) was added trimethylsilyl bromide (2.95 mL, 22.4 mmol). The resulting orange suspension was microwaved in a sealed tube at 150 C for 10 min. The reaction was cooled to rt and poured into 1.0 N NaOH containing ice. The aqueous layer was extracted with diethyl ether (2x). The combined organic layers were washed with sat. NaHC03, brine, dried over Na2S04, filtered and concentrated to give 1.07 g of 2-bromo-4-phenyl pyridine as an off-white solid. MS 233.9 (M+H) + and 235.9 (M+2+H)+. [00337] To a cooled (-78 C) clear, slightly yellow solution of 2-bromo-4- phenyl-pyridine (0.500 g, 2.14 mmol) in THF (8.6 mL) was added dropwise 2.5 M n-BuLi in hexane (0.86 mL, 2.14 mmol). The resulting red solution was stirred at-78 C for 1h, then 1-formylpiperidine (0.48 mL, 4.28 mmol) was added dropwise. The reaction was allowed to warm to 0 C over 1h and then stirred at 0 C for 1h. The reaction was quenched with 1.0 N HCl. The reaction was extracted with ethyl acetate. The combined organic layers were washed with sat. NaHC03, brine, dried over Na2S04, filtered, and concentrated to give 0.555 gas a golden oil. Column chromatography (40 g silica gel; gradient elution; 0-40% ethyl acetate/hexane) provided 1B (0.194 g, 49%) as a yellow solid. ¹H-NMR (400 MHz, CDCI3) No.: 10.16 (s, 1H), 8.84 (d, J = 5.3 Hz, 1H), 8.21 (d, J = 1.3 Hz, 1H), 7.75 (dd, J = 5.3, 1.8 Hz, 1H), 7.71-7.69 (m, 2H), 7.55-7.48 (m, 3H). MS 184.1 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
62% | With potassium tert-butylate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl;tris-(dibenzylideneacetone)dipalladium(0); In toluene; at 90℃; for 17h;Inert atmosphere; | (4-Phenyl-pyridin-2-yl)-pyridin-2-yl-amine (I) 2-Bromo-4-phenylpyridine (280 mg, 1.19 mmol), 2-aminopyridine (124 mg, 1.31 mmol), potassium terf-butoxide (201 mg, 1.79 mmol), (+/-)-BINAP (3 mg, 0.05 mmol) and Pd2(dba)3 (2.7 mg, 0.03 mmol) were stirred in toluene (2.5 ml_) at 9O0C under Ar(g). After 17h stirring, the reaction mixture was diluted with CH2CI2 (2.5 mL) and silica was added. The solvent was removed under reduced pressure and the resulting dry loaded material purified by silica gel column chromatography, eluting with CH2CI2/Me0H (100:2), to furnish I as a yellow solid (183 mg, 62%).1H NMR (400MHz, CDCI3) δH: 8.29 (t, J=5.8Hz, 2H), 7.91-7.78 (m, 1H), 7.72- 7.58 (m, 4H), 7.54-7.39 (m, 3H), 7.12 (d, J=4.5Hz, 1 H), 6.94-6.85 (m, 1 H). MW: 247.29 LCMS (ES): found 248.1. [MH]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
6% | Example 65 (S)-2-(tert-Butoxy)-2-(7-(4,4-dimethylpiperidin-1-yl)-5-methyl-2-(4-phenylpyridin-2-yl)pyrazolo[1,5-a]pyrimidin-6-yl)acetic acid To a solution of (S)-methyl 2-(2-bromo-7-(4,4-dimethylpiperidin-1-yl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate (0.050 g, 0.107 mmol, 1 equiv) in dioxane (1.0 mL) was added <strong>[54151-74-5]2-bromo-4-phenylpyridine</strong> (0.030 g, 0.128 mmol, 1.2 equiv), hexabutyldistannane (0.12 mL, 0.235 mmol, 2.2 equiv), and Pd(PPh3)4 (0.012 g, 0.011 mmol, 0.1 equiv). The reaction was heated at 85 C. for 72 h. The reaction temperature was then lowered to 60 C. Methanol (1 mL), water (0.3 mL), and LiOH.H2O (26 mg, 1.07 mmol, 10 equiv) added and heating was continued for 2 h. Upon completion of the saponification, the reaction was removed from heat and filtered through a syringe filter. The crude reaction mixture was purified via preparative LC/MS with the following conditions: Column: Waters XBridge C18, 19*200 mm, 5-μm particles; Guard Column. Waters XBridge C18, 19*10 mm, 5-μm particles; Mobile Phase A: water with 20-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 20-mM ammonium acetate; Gradient: 45-85% B over 20 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min, to provide (S)-2-(tert-butoxy)-2-(7-(4,4-dimethylpiperidin-1-yl)-5-methyl-2-(4-phenylpyridin-2-yl)pyrazolo[1,5-a]pyrimidin-6-yl)acetic acid (3.5 mg, 6%). 1H NMR (500 MHz, DMSO-d6) δ 8.73 (d, J=4.9 Hz, 1H), 8.48 (s, 1H), 7.83 (d, J=7.6 Hz, 2H), 7.75 (d, J=4.0 Hz, 1H), 7.60-7.49 (m, 3H), 7.06 (s, 1H), 5.72 (br. s., 1H), 3.61-3.55 (m, 4H), 2.53 (s, 3H), 1.65 (br. s., 2H), 1.50 (br. s., 2H), 1.18 (s, 9H), 1.11 (br. s., 6H). LCMS (ESI, M+1): 528.3. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
6%; 89% | With palladium diacetate; triphenylphosphine; potassium hydroxide; In acetonitrile; for 24h;Inert atmosphere; Reflux; | General procedure: 2,4-dibromopyridine (0.12 g, 0.50 mmol), phenylboronic acid pinacol ester (0.11 g, 0.55 mmol), KOH (56 mg, 1.0 mmol), Pd(OAc)2 (11 mg, 5 mol %), PPh3 (52 mg, 20 mol %) were dissolved in CH3CN (6 mL). The reaction was stirred at 70 C under nitrogen atmosphere for 24 h and then cooled. The solid was filtrated off and the filtrate was concentrated. The crude product was then dissolved in CH2Cl2 (10 mL) and the solution was washed with water (10 mL*3) and brine (10 mL), and dried over sodium sulfate. Upon evaporation, the resulting residue was subjected to column chromatography (petroleum ether/AcOEt, 400:1) to give 3w (104 mg, 89%) as a colorless liquid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
13%; 9%; 37% | With palladium(II) trifluoroacetate; triphenylphosphine; potassium hydroxide; In acetonitrile; at 30℃; for 24h;Inert atmosphere; | General procedure: 2,5-dibromopyridine (0.12 g, 0.50 mmol), phenylboronic acid (67 mg, 0.55 mmol), K2CO3 (0.14 g, 1.0 mmol), Pd(OAc)2 (11 mg, 5 mol %), PPh3 (26 mg, 10 mol %) were dissolved in CH3CN/CH3OH (2:1, 6 mL). The solution was stirred at 50 C under nitrogen atmosphere for 24 h and then cooled and the solid was filtered off. The filtrate was then concentrated and the resulting crude product was dissolved in CH2Cl2 (10 mL). The solution was washed with water (10 mL*3) and brine (10 mL), and dried over sodium sulfate. Upon removal of the solvent with a rotavapor, the resulting residue was subjected to column chromatography (petroleum ether/AcOEt, 400:1) to give the desired product 3a (114 mg, 97%) as a white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
8.80% | With copper(l) iodide; 1,10-Phenanthroline; caesium carbonate; In 5,5-dimethyl-1,3-cyclohexadiene; for 24h;Reflux; | Compound 7 (645 mg, 2.75 mmol) was dissolved in xylene (30.0 mL) Copper iodide (I) (105 mg, 0.550 mmol), cesium carbonate (2.67 g, 8.26 mmol) and 1,10-phenanthroline (198 mg, 1.10 mmol) were added to a solution of 4-dibromoaniline (690 mg, 2.75 mmol) And the mixture was heated under reflux for 24 hours with stirring. The reaction solution was returned to room temperature and extracted with ethyl acetate (100 mL × 2). The organic layer was washed with saturated brine, then dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography using ethyl acetate / hexane (1/4 (volume ratio)) as an elution solvent to obtain Compound 8 in a yield of 78.4 mg (yield 8.80%) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | With methanol; magnesium; at 20℃; | General procedure: The aryl halide was dissolved in 5mL of methanol per mmol of (hetero)arylhalide, magnesium (5 equiv.) added and the mixture was stirred at room temperature. After completion of the reaction (between 6-12h), the reaction mixture was poured into water, acidified with dilute HCl, and extracted with ethyl acetate. The organic phase was dried over MgSO4 and concentrated under reduced pressure. The product was purified if necessary by column chromatography on silica gel. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In tetrahydrofuran; ethanol; water; for 17h;Reflux; | 5 grams (g) (17.9 millimoles, mmol, 1.2 equivalents, equiv.) of Intermediate A, 3.5 g (14.9 mmol, 1 equiv.) of <strong>[54151-74-5]2-bromo-4-phenylpyridine</strong>, 1.2 g (1.05 mmol, 0.07 equiv.) of tetrakis(triphenylphosphine)palladium(0), and 5.2 g (37.4 mmol, 2.5 equiv.) of potassium carbonate were mixed with 50 milliliters (mL) (concentration 0.6 molar, M) of a solvent in which tetrahydrofuran (THF), distilled water (H2O), and ethanol (EtOH) were mixed at a ratio of 3:1:1, and the mixture was refluxed for 17 hours. The resultant mixture was cooled to room temperature and a precipitate was filtered. Then, a filtrate obtained therefrom was washed by using ethyl acetate (EA)/H2O and purified by column chromatography (while increasing a rate of MC/Hex to between 25% and 50%) to obtain 4.2 g (yield: 72%) of Intermediate B. The obtained product was confirmed by Mass Spectrometry and HPLC analysis.HRMS (MALDI) calcd for C23H16BrN: m/z 385.0466, Found: 385.0465. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In ethanol; water; toluene; for 18h;Reflux; | 4.00 g (17.1 mmol, 1.0 equiv.) of Intermediate b1, 4.12 g (20.51 mmol, 1.2 equiv.) of (2-bromophenyl)boronic acid, 1.38 g (1.20 mmol, 0.07 equiv.) of tetrakis(triphenylphosphine)palladium(0), and 4.53 g (42.72 mmol, 2.5 equiv.) of sodium carbonate were mixed with a solvent (0.6 M) in which toluene, ethanol, and distilled water (H2O) were mixed at a ratio of 3:1:1, and the resulting mixture was refluxed for 18 hours. The mixture obtained therefrom was cooled to room temperature, and a precipitate was filtered therefrom to obtain a solid. The obtained solid was washed with EA/H2O and purified by column chromatography (while increasing a rate of EA/Hex to between 5% and 10%) to obtain 4.24 g (yield: 80%) of Intermediate B1. The obtained product was identified by Mass and HPLC analysis. HRMS (MALDI) calcd for C17H12BrN: m/z 309.0153, Found: 309.0154. |
A148172 [50488-34-1]
2-Bromo-4-(tert-butyl)pyridine
Similarity: 0.87
A148172 [50488-34-1]
2-Bromo-4-(tert-butyl)pyridine
Similarity: 0.87