Structure of 767-00-0
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CAS No. : | 767-00-0 |
Formula : | C7H5NO |
M.W : | 119.12 |
SMILES Code : | OC1=CC=C(C=C1)C#N |
MDL No. : | MFCD00002312 |
InChI Key : | CVNOWLNNPYYEOH-UHFFFAOYSA-N |
Pubchem ID : | 13019 |
GHS Pictogram: |
![]() |
Signal Word: | Warning |
Hazard Statements: | H302-H315-H319-H335-H402 |
Precautionary Statements: | P261-P273-P305+P351+P338 |
Num. heavy atoms | 9 |
Num. arom. heavy atoms | 6 |
Fraction Csp3 | 0.0 |
Num. rotatable bonds | 0 |
Num. H-bond acceptors | 2.0 |
Num. H-bond donors | 1.0 |
Molar Refractivity | 33.18 |
TPSA ? Topological Polar Surface Area: Calculated from |
44.02 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
1.17 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
1.6 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
1.26 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
0.79 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
1.34 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
1.23 |
Log S (ESOL):? ESOL: Topological method implemented from |
-2.08 |
Solubility | 0.991 mg/ml ; 0.00832 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (Ali)? Ali: Topological method implemented from |
-2.14 |
Solubility | 0.871 mg/ml ; 0.00731 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-1.86 |
Solubility | 1.65 mg/ml ; 0.0139 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 |
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) |
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) |
Yes |
Log Kp (skin permeation)? Skin permeation: QSPR model implemented from |
-5.89 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 |
0.0 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) |
1.03 |
* 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 |
---|---|---|
94.52% | Weigh 20.36gNa was added to a 250ml three-necked flask containing 25ml of ethanol until Na was completely dissolved.To this, 200 ml of an ethanol solution containing 51.0 g of p-cyanophenol was added dropwise to control the feeding rate so that the reaction temperature was maintained at 25 to 30,After the addition was completed, the mixture was slowly heated to reflux. After 1 hour of reaction, 40.4 g of 1,6-dibromohexane was added dropwise to the reaction system to control the feeding rate. After completion of the addition, the reaction was carried out for 3 hours.After the reaction was completed, the temperature was lowered to below 10 , stirred for 2 hours, filtered and the filter cake was dried to give 55.4g of white powder. Yield: 94.52%. | |
81% | In with stirring, thermometer, a reflux condenser of the dropping funnel and 2L in three-mouth bottle, to which in turn is added to sodium hydroxide 23.3g (0.56mol) and water 240 ml, after stirring to make it dissolve completely, cooling to room temperature; the instillment contains 66.7g (0.56mol) 4-cyano phenol 267 ml ethanol solution, control drop of acceleration, keeping the temperature at the 25-30 C; after dripping slowly increase, 80 C reaction 2h, cooling to room temperature; dropwise 65.3g (0.27mol) 1,6- two hexyl bromides, reflux (80-85 C) 8-10h, cooling to 0 C, stirring 2-3h, filtered, white solid product I shall be intermediate 98g, to the wet product 417 ml in ethanol, heating and stirring to 75 C reflux reaction 2-3h, cooling, about 50 C the left and right filter, drying filter cake, weighing more 70.01g, yield 81%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | With ammonium hydroxide; iodine; potassium iodide; In water; at 20℃; for 16h;Inert atmosphere; | To a solution of 4-hydroxy-benzonitrile (5 g, CAS: 767-00-0) in NH4OH (225 mL) was added a solution of KI (34.14 g, CAS: 7681-11-0) and ?2(10.65 g, CAS: 7553-56-2) in H20 (50 mL). The reaction mixture was stirred at rt for 16 hours. The reaction mixture was filtered andthe filtrate was evaporated. The residue was dissolved in DCM (250 mL) and was washed with H20 (2x150 mL), saturated aqueous Na5203 solution (100 mL) and brine (100 mL). The organic layer was dried over anhydrous Na2504, filtered and concentrated under reduced pressure to give the title compound (8.44 g, 82%) that was used in the next step without further purification. LC-MS: (ESI): mlz = 244.0 [M-H] |
80% | With ammonium hydroxide; iodine; potassium iodide; In water; for 6h; | To a solution of A- hydroxybenzonitrile (0.5 g; 4.18 mmol) in 25% NH4OH (22 ml) a solution of I2 (1.06 g; 4.18 mmol) and Kl (3.41 g; 20.54 mmol) in H2O (5 ml) was added at once with stirring. The stirring was continued for 6 h, during which time the mixture turn from black into colourless. The precipitate formed was filtered off and filtrate was evaporated to dryness under reduced pressure. The residue was treated with H2O (3 ml). The precipitate formed was filtered off, washed with cold H2O (3 x 2 ml), and dried in vacuo to give the title compound (0.82 g; 80%), as colourless solid. 1H-NMR (CDCI3) 7.96 (d, 1 H, 1 .9 Hz); 7. 53 (dd, 1 H, J = 1 .9 Hz, 8.5 Hz); 7.03 (d, 1 H, J = 8.5 Hz); 6.03 (s, 1 H); |
80% | With ammonia; iodine; potassium iodide; In water; for 6h; | To a solution of 4- hydroxybenzonitrile (0.5 g; 4.18 mmol) in 25% NH4OH (22 ml) a solution of I2 (1.06 g; 4.18 mmol) and Kl (3.41 g; 20.54 mmol) in H2O (5 ml) was added at once with stirring. The stirring was continued for 6 h, during which time the mixture turn from black into colourless. The precipitate formed was filtered off and filtrate was evaporated to dryness under reduced pressure. The residue was treated with H2O (3 ml). The precipitate formed was filtered off, washed with cold H2O (3 x 2 ml), and dried in vacuo to give the title compound (0.82 g; 80%), as colourless solid. 1 H-NMR (CDCI3 ) 6.03 (s, 1 H); 7.03 (d, 1 H, J = 8.5 Hz); 7. 53 (dd, 1 H, J = 1 .9 Hz, 8.5 Hz); 7.96 (d, 1 H, 1 .9 Hz). |
80% | With ammonium hydroxide; iodine; potassium iodide; In water; for 6h; | To a solution of 4- hydroxybenzonitrile (0.5 g; 4.18 mmol) in 25% NH4OH (22 ml) a solution of l2 (1 .06 g; 4.18 mmol) and Kl (3.41 g; 20.54 mmol) in H20 (5 ml) was added at once with stirring. The stirring was continued for 6 h, during which time the mixture turn from black into colourless. The precipitate formed was filtered off and filtrate was evaporated to dryness under reduced pressure. The residue was treated with H20 (3 ml). The precipitate formed was filtered off, washed with cold H20 (3 x 2 ml), and dried in vacuo to give the title compound (0.82 g; 80%), as colourless solid. 1 H-NMR (CDCI3) 7.96 (d, 1 H, 1 .9 Hz) ; 7. 53 (dd, 1 H, J = 1 .9 Hz, 8.5 Hz) ; 7.03 (d, 1 H, J = 8.5 Hz); 6.03 (s, 1 H) ; |
With ammonia; iodine; In methanol; water; at 20℃; for 2h; | A. 3-Iodo-4-hydroxybenzonitrile 11.9 g (0.1 mol) of 4-hydroxybenzonitrile are dissolved in 250 ml of methanol and 250 ml of 20% aqueous ammonia are added. A solution of 31.75 g of iodine in 250 ml of methanol is then added dropwise, with care, due to the explosive nature of the reaction. After addition, the mixture is stirred for 2 hours at ambient temperature. The methanol is evaporated off, dilution is carried out in water and acidification with a hydrochloric acid solution is performed until pH=2 to 3 is obtained. Extraction with ethyl acetate and washing with water, a sodium thiosulfate solution and a saturated sodium chloride solution are subsequently carried out. In this way, 24.73 g of desired compound are obtained. M.p.: 144-146 C. The compound below was prepared using the same process as above: |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
20% | With copper(l) iodide; potassium carbonate; dimethylbiguanide; In acetonitrile; at 20 - 60℃; for 24.1667h; | General procedure: To a 25 mL flask containing a mixture of CuI (19.2 mg,0.1 mmol), metformin (0.1 mmol), phenol (1.0 mmol), and K2CO3(2 mmol, 276 mg) in CH3CN (5 mL) was added an aryl halide(1.1 mmol). The mixture was stirred for 10 min at room temperature, and then heated to 60∘C for the appropriate amount of time(see Table 4). The progress of the reaction was monitored by TLC. After completion of the reaction, the mixture was extracted with EtOAc (5 1 mL) and the organic phase separated and evaporated. Further purification by column chromatography gave the desired coupled product. |
7% | With tetrabutylammomium bromide; caesium carbonate; In dimethyl sulfoxide; at 120℃; for 20h; | General procedure: Polymer supported Cu(II) catalyst (0.05 g, 0.0098 mmol) in DMSO (5 mL) was taken in a 100 ml R.B flask and stirred at room temperature for 10 min. Then aryl halide (1 mmol), phenol(1 mmol), tetrabutylammonium bromide (tBu4NBr) (0.1 mmol),Cs2CO3 (1 mmol) and DMSO (5 mL) were added to it. The final reaction mixture was refluxed at 120 C under an open air condition.The reaction mixtures were collected at different time intervals and identified by GCMS and quantified by GC. After the completion of the reaction, the catalyst was filtered off and washed with water followed by acetone and dried in oven. The filtrate was extracted with ethyl acetate (3 x 20 ml) and the combined organic layers were dried with anhydrous Na2SO4 by vacuum. The filtrate was concentrated by vacuum and the resulting residue was purified by column chromatography on silica gel to provide the desired product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78.3 mol% | With potassium fluoride; In acetone; | SYNTHESIS EXAMPLE 4 Synthesis of 3-(2,6-dibutyl-4-methylphenoxy)-4,5-bis(4-cyanophenoxy)-6-fluorophthalonitrile In a four-neck separable flask having an inner volume of 500 ml, 60 g (0.30 mol) of <strong>[1835-65-0]tetrafluorophthalonitrile</strong>, 41.8 g (0.72 mol) of potassium fluoride, and 160 ml of acetone. Further, to a dropping funnel attached thereto, 71.5 g (0.60 mol) of 4-cyanophenol and 110 ml of acetone were placed. The 4-cyalophenol/acetone mixed solution was added dropwise from the dropping funnel to the flask over a period of about two hours while kept stirred at -1° C. The stirring was subsequently continued for about two hours. Thereafter, the contents of the flask were stirred overnight, with the reaction temperature thereof slowly raised to room temperature. Then, to this flask, 79.8 g (0.30 mol) of 2,6-dibutyl-4-methylphenol, 20.9 g (0.36 mol) of potassium fluoride, and 15.0 mol of acetone were charged and the mixture was kept stirred at 40° C. for 10 hours. The reaction solution was cooled and filtered. The filtrate was distilled by a rotary evaporator to expel the acetone and was recrystallized from methanol. The produced crystals were separated by filtration and vacuum dried to afford 151.3 g of 3-(2,6-dibutyl-4-methylphenoxy)-4,5-bis(4-cyanophenoxy)-6-fluorophthalonitrile (yield: 78.3 mol percent). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
77.5 mol% | With potassium fluoride; In acetone; | SYNTHESIS EXAMPLE 5 Synthesis of 3-(2,6-dimethylphenoxy)-4,5-bis(4-cyanophenoxy)-6-fluorophthalonitrile In a four-neck separable flask having an inner volume of 500 ml, 60 g (0.30 mol) of <strong>[1835-65-0]tetrafluorophthalonitrile</strong>, 41.8 g (0.72 mol) of potassium fluoride, and 160 ml of acetone. Further, in a dropping funnel attached thereto, 71.5 g (0.60 mol) of 4-cyanophenol and 110 ml of acetone were placed. The 4-cyalophenol/acetone mixed solution was added dropwise from the dropping funnel to the flask over a period of about two hours while kept stirred at -1° C. The stirring was subsequently continued for about two hours. Thereafter, the contents of the flask were stirred overnight, with the reaction temperature thereof slowly raised to room temperature. Then, to this flask, 36.7 g (0.30 mol) of 2,6-dimethylphenol, 20.9 g (0.36 mol) of potassium fluoride, and 15.0 ml of acetone were charged and the mixture was kept stirred at 40° C. for 10 hours. The reaction solution was cooled and filtered. The filtrate was distilled by a rotary evaporator to expel the acetone and was recrystallized from methanol. The produced crystals were separated by filtration and vacuum dried to afford 116.3 g of 3-(2,6-dimethylphenoxy)-4,5-bis(4-cyanophenoxy)-6-fluorophthalonitrile (yield: 77.5 mol percent). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
64% | With potassium tert-butylate; In dimethyl sulfoxide; at 40 - 45℃; | General procedure: Phenol (94mg, 1mmol) and bromobenzene (314mg, 2.0mmol) were added to a single necked flask containing DMSO (1mL) and resulted reaction mixture was stirred for 5min. After this potassium tert-butoxide (280mg, 2.5mmol) was added portion wise and stirring continued for 6-8h at 40-45C. The progress of reaction was monitored by TLC. Upon completion of the reaction, mixture poured into water, and extracted four times with 20mL of ethyl acetate. The combined organic layer was dried over Na2SO4, and filtered. The solvent was removed in vacuo and the residue was purified by column chromatography (silica gel, eluent: hexane/ethyl acetate) to afford the coupling product. |
19% | With potassium phosphate; 2-((o-toluidino)methyl)phenol; copper(l) chloride; In acetonitrile; at 81℃; for 24h;Schlenk technique; Inert atmosphere;Catalytic behavior; | General procedure: Aminophenol (5 mol %), CuCl (5 mol %), phenol (1.5 mmol), aryl halide (if solid, 1 mmol), and K3PO4 (425 mg, 2.0 mmol) were added to a screwcapped Schlenk tube under argon. The tube was then evacuated and backfilled with argon (three cycles). Aryl halide (if liquid, 1.0 mmol) and dry CH3CN (0.5 mL) were added by syringe at room temperature. The reaction mixture was stirred at needed temperature (110 oC) for 24 h. The reaction mixture was allowed to reach room temperature and then diluted with dichloromethane (10 mL). The slurry was filtered, and filter cake was washed with 10 mL of dichloromethane. The solvent was removed in vacuo, and the residue was purified by column chromatography on silica gel to afford the desired product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | With caesium carbonate; In N,N-dimethyl-formamide; at 20℃; for 4h; | EXAMPLE 474-((6-(2-(2,4-Difluorophenyl)-l,l-difluoro-2-hydroxy-3-(lH-tetrazol-l- yl)propyl)pyridin-3-yl)methoxy)benzonitrile (79) and 4-((6-(2-(2,4-difluorophenyl)-l,l- difluoro-2-hydroxy-3-(2H-tetrazol-2-yl)propyl)pyridin-3-yl)methoxy)benzonitrile (80)To a stirred solution of compound J (prepared as in the first step of Example 17; 2.0 g, 10.75 mmol) in CH3OH (30 mL) was added NaBH4 (0.53 g, 13.97 mmol) portionwise at 0 C and the reaction mixture was stirred at 0 C for 1 h. After completion of the reaction (by TLC), CH3OH was removed under reduced pressure, and the reaction mixture was diluted with ice- cold water (75 mL) and extracted with EtOAc (2 x 75 mL). The combined organic layers were washed with water (75 mL) and brine (75 mL), dried over anhydrous Na2S04 and concentrated under reduced pressure to obtain the crude material. Purification by silica gel column chromatography (eluting with 40% EtOAc/hexanes) afforded compound AV (1.4 g, 7.44 mmol, 69%) as a yellow solid. 1H NMR (400 MHz, CDC13): δ 8.35 (s, 1H), 7.59 (dd, J = 8.0, 2.4 Hz, 1H), 7.48 (d, J = 8.0 Hz, 1H), 4.71 (d, J = 6.0 Hz, 2H), 2.03 (t, J = 6.0 Hz, OH). MS (ESI): m/z 188 [M+] .To a stirred solution of compound AV (1.0 g, 5.31 mmol) in Et20 (20 mL) was added phosphorus tribromide (PBr3; 1.5 mL, 15.95 mmol) at 0 C, and the mixture was stirred for 1 h at RT. After complete consumption of the starting material (by TLC), the reaction mixture was quenched with ice-cold water (30 mL), adjusted to pH~8 using satd NaHC03 and extracted with EtOAc (2 x 100 mL). The combined orgainc extracts were washed with water (100 mL) and brine (100 mL), dried over anhydrous Na2S04 and concentrated under reduced pressure to obtain the crude material. Purification by silica gel column chromatography (10% EtOAc/hexanes) afforded compound AW (0.83 g, 3.30 mmol, 62%) as a colorless liquid. 1H NMR (400 MHz, CDC13): δ 8.38 (d, J = 2.4 Hz, 1H), 7.59 (dd, J = 8.0, 2.4 Hz, 1H), 7.48 (d, J = 8.0 Hz, 1H), 4.41 (s, 2H).To a stirred suspension of 4-hydroxybenzonitrile (0.39 g, 3.30 mmol) and Cs2C03 (1.62 g, 4.96 mmol) in DMF (10 mL) was added compound AW (0.83 g, 3.30 mmol) at RT, and the mixture was stirred for 4 h. After completion of the reaction (by TLC), the reaction mixture was quenched with ice-cold water (25 mL) and extracted with EtOAc (4 x 50 mL). The combined organic extracts were washed with water (50 mL) and brine (50 mL), dried over anhydrous Na2S04 and concentrated under reduced pressure to obtain the crude material. Purification by silica gel column chromatography (eluting with 10% EtOAc/hexanes) afforded compound AX (0.90 g, 3.11 mmol, 94%) as a pale yellow solid. 1H NMR (500 MHz, CDC13): δ 8.44 (d, J = 2.0 Hz, 1H), 7.64-7.61 (m, 3H), 7.54 (d, J = 8.5 Hz, 1H), 7.01 (d, J = 8.5 Hz, 2H), 5.08 (s, 2H). MS (ESI): m/z 291 [M+2]+.To a stirred suspension of copper powder (1.55 g, 6.22 mmol) in DMSO (10 mL) was added ethyl 2-bromo-2,2-difluoroacetate (0.63 g, 3.11 mmol) at RT and the mixture was stirred for 1 h. A solution of compound AX (0.9 g, 3.11 mmol) in DMSO (5 mL) was added to the reaction mixture and stirring was continued for another 16 h at RT. After complete consumption of the starting material (by TLC), the reaction mixture was quenched with satd NH4C1 solution (100 mL) and extracted with EtOAc (2 x 100 mL). The combined organic extracts were washed with water (100 mL) and brine (100 mL), dried over anhydrous Na2S04 and concentrated under reduced pressure to obtain the crude material. Purification by silica gel column chromatography (eluting with 25% EtOAc/hexane) afforded compound AY (0.5 g, 1.5 mmol, 49%) as a pale yellow solid. 1H NMR (500 MHz, CDC13): δ 8.71 (s, 1H), 7.94 (d, J = 8.0 Hz, 1H), 7.80 (d, J = 8.0 Hz, 1H), 7.63 (d, J = 9.0 Hz, 2H), 7.03 (d, J = 9.0 Hz, 2H), 5.18 (s, 2H), 4.38 (q, J = 7.0 Hz, 2H), 1.34 (t, J = 7.0 Hz, 3H). MS (ESI): m/z 334 [M+2]+.To a stirred solution of l-bromo-2,4-difluorobenzene (348 mg, 1.80 mmol) in Et20 (10 mL) was added w-BuLi (1.6 M in hexane; 0.7 mL, 1.80 mmol) at -78 C, and the mixture was stirred for 30 min under inert atmosphere. A solution of compound AY (500 mg, 1.50 mmol) in Et20 (30 mL) was added to the reaction mixture at -78 C and stirring was continued for another 2 h. After completion of the reaction (by TLC), the reaction mixture was quenched with satd NH4C1 solution (100 mL) and extracted with EtOAc (2 x 100 mL). The combined organic extracts were washed with water (100 mL) and brine (100 mL), dried over anhydrous Na2S04 and concentrated under reduced pressure to afford the crude AZ (1.5 g) as a brownish liquid. This crude material was used in the next step without any further purification. MS (ESI): m/z 401 [M+H]+.To a stirred solution of crude AZ (650 mg, crude) in Et20 (100 mL) was added freshly prepared diazomethane [prepared by dissolving NMU (1.67 g, 16.25 mmol) in a 1 : 1 mixture of 10% KOH solution (100 mL) and Et20 (100 mL) at 0 C followed by separation and drying of the organic layer usin... |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | With potassium carbonate; In ethanol; water; at 80℃; for 16h; | A mixture of 1-chloro-2-methyl-propan-2-ol (10 mL ), 4-hydroxybenzonitrile (2 g, 16.8 mmol), K2CO3 (9.3 g, 67.3 mmol) in water (6 mL) and ethanol (60 mL) was heated at 80 °C for 16 hours. The reaction mixture was cooled and the solvent was concentrated in vacuo. The residue was diluted with ether (200 mL) and filtered and the filtrate was washed sequentially with water (50 mL) and brine solution (50 mL). The organics were separated and dried over MgSO4 and solvent was removed in vacuo to give a residue which was purified by silica gel column chromatography using (0-100percent) EtOAc/DCM as eluent to give 4-(2-hydroxy- 2-methyl-propoxy)benzonitrile (3.0 g, 94 percent) as a yellow solid. ESI-MS m/z calc. 191.1, found 192.3 (M+1)+; Retention time: 1.05 minutes (3 min run). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
45% | With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 20℃; for 12h; | Methyl 4-(l-(4-cyanophenoxy)ethyl)benzoate. Methyl 4-(l -hydroxy ethyl)benzoate (540 mg, 3 mmol), 3-hydroxybenzonitrile (360 mg, 3 mmol), triphenylphosphine (1.04 mg, 4 mmol), azodicarboxylic acid diisopropyl ester (800 mg, 4 mmol) in tetrahydrofuran (130 mL) were stirred at 20C for 12 hours. Water was added and the mixture was extracted with ethyl acetate (150 mL x 3), the combined organic phase was dried by sodium sulfate, then filtered. The filtrate was evaporated in vacuum and the residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate = 3: 1) to give methyl 4-(l-(4- cyanophenoxy)ethyl)benzoate (370 mg, 45%) as colorless oil. LRMS (M + H+) m/z: calcd 281.11; found 281.). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
14% | With potassium carbonate; In N,N-dimethyl-formamide; at 130℃; under 2400.24 Torr; for 0.5h;Microwave irradiation; | Tert-butyl 4-(4-cyanophenoxy)benzoate. To a solution of tert-butyl 4- fluorobenzoate (392 mg, 2 mmol) in dimethyl formamide (20 mL) was added 4- hydroxybenzonitrile (240 mg, 2 mmol) and potassium carbonate (552 mg, 4 mmol), the mixture was heated to 130C for 0.5 hour by microwave (pressure: 3.2 bar, equipment power : 150W). The solvent was evaporated in vacuo and purified by column chromatography (silica gel, dichloromethane/methanol = 20: 1) to give tert-butyl 4-(4-cyanophenoxy)benzoate (80 mg, 14%). LRMS (M + H+) m/z: calcd 295.12; found 295. |
14% | With potassium carbonate; In N,N-dimethyl-formamide; at 130℃; under 2400.24 Torr; for 0.5h;Microwave irradiation; | To a solution of <strong>[58656-98-7]ter<strong>[58656-98-7]t-butyl 4-fluorobenzoate</strong></strong> (392 mg, 2 mmol) in dimethyl formamide (20 mL) was added 4-hydroxybenzonitrile (240 mg, 2 mmol) and potassium carbonate (552 mg, 4 mmol), the mixture was heated to 130 C. for 0.5 hour by microwave (pressure: 3.2 bar, equipment power: 150 W). The solvent was evaporated in vacuo and purified by column chromatography (silica gel, dichloromethane/methanol=20:1) to give tert-butyl 4-(4-cyanophenoxy)benzoate (80 mg, 14%). LRMS (M+H+) m/z: calcd 295.12. found 295. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
44% | With magnesium(II) perchlorate; In dichloromethane; for 3h;Inert atmosphere; Reflux; | 3.75 g of Mg(ClO4)2 (16.8 mmol, 0.1 equiv) in a 500 mL round-bottom flask was heated under vacuum at 130 C for 2 h and cooled to room temperature under argon. Then, 20 g of 4-cyanophenol (168 mmol, 1 equiv) in 200 mL of DCM was added, followed by 88.8 mL of Boc2O (387 mmol, 2.3 equiv). The resulting mixture was refluxed for at least 3 h and the reaction was monitored by TLC (20 % Et2O/hexanes). Once no more progression observed, the mixture was diluted in 300 mL of water and extracted twice with DCM. The organic layers were combined, dried with MgSO4, filtered and concentrated under vacuum. Purification with flash chromatography (20 % Et2O/hexanes) afforded 12.82g (73.2 mmol, 44 % yield) of 4-tert-butoxybenzonitrile. 1H NMR (400 MHz, CDCl3) δ 7.54 (dq, J = 9.1, 2.3 Hz, 2H, Ar), 7.02 (m, 2H, Ar), 1.40 (s, 9H, tBu-CH3). 12.82 g of 4-tert-butoxybenzonitrile (73.2 mmol) was dissolved in 110 mL of Et2O and 72.8 mL of a solution of 1M LiAlH4 in THF added dropwise. After refluxing for 3 h, the mixture was brought back to room temperature and quenched slowly with 10 mL of water, 10 mL of aqueous 1M NaOH and finally 50 mL of water. The resulting slurry was filtered, the residue washed with Et2O and the filtrate concentrated under vacuum. Afterward, 50 mL of water was added to the crude and the pH adjusted to 2.7 using aqueous 1M KHSO4. The aqueous phase was washed with Et2O, the pH readjusted to 9-10 with aqueous 1M NaOH and extracted twice with DCM. Combined organic layers were washed with brine, dried with MgSO4, filtered and evaporated to dryness under vacuum to afford 12.53 g (69.9 mmol, 95 % yield) of 4-tert-butoxybenzylamine. 1H NMR (400 MHz, CDCl3) δ 7.13 (m, 2H, Ar), 6.89 (m, 2H, Ar), 3.75 (s, 2H, CH2), 1.28 (s, 9H, tBu-CH3). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | With potassium carbonate; In N,N-dimethyl-formamide; at 80℃; for 15h; | [0608] Procedure: To a stirred solution of <strong>[13790-39-1]4-chloro-6,7-dimethoxyquinazoline</strong> (0.5 g, 2.2257 mmol) in DMF (5 mL) was added 4-hydroxybenzonitrile (0.29 g, 2.44 mmol) followed by K2CO3 (0.92 g, 6.677 mmol) and heated at 80 C for 15 h. The progress of the reaction was monitored by TLC. The reaction mixture was quenched with ice-water and filtered. The solid was washed with water followed by hexane to afford 4-((6,7-dimethoxyquinazolin-4-yl)oxy) benzonitrile as off-white solid (0.68 g, 88%).1H NMR (400 MHz, DMSO-d6): δ 8.57(s, 1H), 7.97(d, J =8.4 Hz, 2H), 7.58-7.55 (m, 3H), 7.40(s, 1H), 3.98(s, 3 H), 3.96(s, 3H); LC-MS (ES) m/z =308.0 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With uranyl(VI) nitrate monohydrate; water; trichloroacetic acid; at -78 - 25℃; for 72h;Irradiation; Inert atmosphere; | In a 25mL reaction tube, add 1ah (0.2mmol, 39.0mg), uranyl nitrate hydrate (4mol%/0.008mmol, 4mg), the source of water is the same as in Example 1, and the ratio of 1ah to the water effectively participating in the reaction is 1 : 0.99, trichloroacetic acid (0.4mmol, 65.3mg), acetone (2mL), evacuate and change nitrogen 3 times at -78C, stir for 72 hours under the irradiation of 9W blue LED lamp (wavelength 460nm) at 25C, and react After the completion, it is concentrated and separated by column chromatography (VPE/VEA10/1) to obtain brown liquid 2a (13.2mg, 70%), which is separated by column chromatography (VPE/VEA5/1) White solid for 2h (23.4mg, 99%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 20℃;Inert atmosphere; | B2 (1472 mg, 6 mmol), 4-cyanophenol (B3, 858 mg, 7.2 mmol) and triphenylphosphine (2518 mg, 9.6 mmol) were dissolved in tetrahydrofuran (25 mL), and DIAD (1941 mg, 9.6 mmol) was added dropwise under N2 atmosphere. ) in tetrahydrofuran (5 mL) and stirred at room temperature overnight. The solvent was evaporated to dryness, and the residue was subjected to column chromatography (eluent: petroleum ether/ethyl acetate/triethylamine=20:5:1) to obtain crude B4 (white solid, 1093 mg). |
Tags: 767-00-0 synthesis path| 767-00-0 SDS| 767-00-0 COA| 767-00-0 purity| 767-00-0 application| 767-00-0 NMR| 767-00-0 COA| 767-00-0 structure
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