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CAS No. : | 57653-35-7 | MDL No. : | MFCD09954934 |
Formula : | C14H17NO5 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | VVKAGQHUUDRPOI-RYUDHWBXSA-N |
M.W : | 279.29 | Pubchem ID : | 688413 |
Synonyms : |
|
Num. heavy atoms : | 20 |
Num. arom. heavy atoms : | 6 |
Fraction Csp3 : | 0.43 |
Num. rotatable bonds : | 6 |
Num. H-bond acceptors : | 5.0 |
Num. H-bond donors : | 1.0 |
Molar Refractivity : | 73.87 |
TPSA : | 76.07 Ų |
GI absorption : | High |
BBB permeant : | No |
P-gp substrate : | No |
CYP1A2 inhibitor : | No |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -7.23 cm/s |
Log Po/w (iLOGP) : | 2.26 |
Log Po/w (XLOGP3) : | 1.09 |
Log Po/w (WLOGP) : | 0.4 |
Log Po/w (MLOGP) : | 0.76 |
Log Po/w (SILICOS-IT) : | 0.66 |
Consensus Log Po/w : | 1.03 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 0.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -2.08 |
Solubility : | 2.3 mg/ml ; 0.00824 mol/l |
Class : | Soluble |
Log S (Ali) : | -2.28 |
Solubility : | 1.47 mg/ml ; 0.00525 mol/l |
Class : | Soluble |
Log S (SILICOS-IT) : | -1.98 |
Solubility : | 2.96 mg/ml ; 0.0106 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 1.0 alert |
Leadlikeness : | 0.0 |
Synthetic accessibility : | 3.33 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H319 | Packing Group: | N/A |
GHS Pictogram: |
* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79.5% | With Dess-Martin periodane In dichloromethane at 0 - 20℃; for 1 h; Inert atmosphere; Sealed tube | To a solution of compound 20-3 (1.0 g, 3.6 mmol) in DCM (20 mL) was added Dess-Martin periodinane (3.0 g, 7.1 mmol) in a portionwise manner at 0 °C. When the addition was completed, the mixture was stirred at rt for 1.0 hr. After the reaction was completed, the mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v) = 5/1) to give the title compound as yellow oil (0.79 g, 79.5percent). The compound was characterized by the following spectroscopic data: H NMR (400 Hz, CDC13) δ (ppm): 7.47 (d, 2H, J = 8.24 Hz), 7.38 (d, 2H, J = 8.24 Hz), 7.24 (m, 1H), 5.09 (s, 2H), 4.18 (t, 1H), 3.68 (s, 3H), 3.38 (m, 1H), 3.32 (m, 1H), 2.21 (m, 1H), 1.96 (m, 1H). |
79.5% | With Dess-Martin periodane In dichloromethane at 20℃; for 1 h; Cooling with ice | To a mixture of compound Q-1 (2 g, 15.3 mmol) in CH3OH (25 mL) was added thionyl chloride (3.4 mL, 46.9 mmol) slowly at 0 °C. The reaction mixture was refluxed at 80 °C for 3.5 hours and concentrated in vacuo to give compound Q-2 as a white solid (2.76 g, 99.5percent). The crude product was used for the next step without further purification. The compound was characterized by the following spectroscopic data: 1H NMR (400 MHz, CD3Cl): δ 3.68 (s, 3H), 3.58 (t, 1H), 3.56 (s, 1H), 3.32 (m, 1H), 3.02 (m, 1H), 2.77 (m, 1H), 2.52 (s, 1H), 2.21 (m, 1H), 1.96 (m, 1H). [0707] To a solution of benzyl chloroformate (3.7 mL, 26.3 mmol) and K2CO3 (10.6 g, 76.7 mmol) in mixed solvents of THF (20 mL) and H2O (10 mL) was added compound Q-2 (3.1 g, 17.1 mmol) in one portion while the mixture was stirred vigorously. At the end of the addition, the mixture was stirred at rt overnight, adjusted to pH 3 with diluted hydrochloric acid and extracted with EtOAc (50 mL x 3). The combined organic phases were dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated in vacuo and the residue was purified by silica gel column chromatography (PE/EtOAc (v/v) = 4/1) to give compound Q-3 as pale yellow oil (3 g, 62.8percent). The compound was characterized by the following spectroscopic data: 1H NMR (400 MHz, CD3Cl): δ 7.47 (d, J = 8.24 Hz, 2H), 7.38 (d, J = 8.24 Hz, 2H), 7.24 (m, 1H), 5.09 (s, 2H), 4.18 (t, 1H), 3.68 (s, 3H), 3.63 (m, 1H), 3.58 (s, 1H), 3.38 (m, 1H), 3.32 (m, 1H), 2.21 (m, 1H), 1.96 (m, 1H). [0708] To a solution of compound Q-3 (1.0 g, 3.6 mmol) in DCM (20 mL) was added Dess-Martin (3.0 g, 7.1 mmol) slowly in an ice bath. The reaction mixture was stirred at rt for 1 hour and filtered. The filtrate was concentrated in vacuo and the residue was purified by silica gel column chromatography (PE/EA (v/v) = 5/1) to give compound Q-4 as yellow oil (0.79 g, 79.5percent). The compound was characterized by the following spectroscopic data: 1H NMR (400 MHz, CD3Cl): δ 7.47 (d, J = 8.24 Hz, 2H), 7.38 (d, J = 8.24 Hz, 2H), 7.24 (m, 1H), 5.09 (s, 2H), 4.18 (t, 1H), 3.68 (s, 3H), 3.38 (m, 1H), 3.32 (m, 1H), 2.21 (m, 1H), 1.96 (m, 1H). [0709] To a solution of compound Q-4 (1.0 g, 3.6 mmol) in toluene (20 mL) in a flask equipped with Dean-Stock trap were added ethylene glycol (0.8 mL, 15.7 mmol) and TsOH (0.14 g, 0.8 mmol) in turn. The reaction mixture was refluxed overnight. After the reaction was complete, the mixture was diluted with EtOAc (10 mL), and washed with saturated NaHCO3 aqueous solution (10 mL) and brine (15 mL) separately. The organic phase was dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated in vacuo and the residue was purified by silica gel column chromatography (PE/EtOAc (v/v) = 6/1) to give compound Q-5 as colorless and sticky liquid (0.54 g, 46.7percent). The compound was characterized by the following spectroscopic data: 1H NMR (400 MHz, CD3Cl): δ 7.47 (d, 2H, J = 8.24 Hz), 7.38 (d, 2H, J = 8.24 Hz), 7.24 (m, 1H), 5.09 (s, 2H), 4.18 (t, 1H), 4.05 (m, 2H), 3.95 (m, 2H), 3.68 (s, 3H), 3.38 (m, 1H), 3.32 (m, 1H), 2.21 (m, 1H), 1.96 (m, 1H). [0710] To a solution of compound Q-5 (0.59 g, 1.8 mmol) in CH3OH (150 mL) was added Pd/C (0.5 g). The reaction mixture was stirred at rt under H2 overnight and filtered. The filtrate was concentrated in vacuo to give compound Q-6 (0.34 g, 98.9percent). The crude product was used for the next step without further purification. The compound was characterized by the following spectroscopic data: 1H NMR (400 MHz, CD3Cl): δ 4.18 (t, 1H), 4.05 (m, 2H), 3.95 (m, 2H), 3.68 (s, 3H), 3.38 (m, 1H), 3.32 (m, 1H), 2.21 (m, 1H), 1.96 (m, 1H). [0711] To a solution of compound Q-6 (3.48 g, 18.6 mmol) in DCM (50 mL) in an ice bath were added compound Q-7 (3.26 g, 18.6 mmol), DIPEA (12.3 mL, 74.4 mmol) and EDCI (7.1 g, 37.0 mmol) in turn. The reaction mixture was stirred at rt overnight, washed with H2O (20 mL), dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated in vacuo and the residue was purified by silica gel column chromatography (PE/EtOAc (v/v) = 3/1) to give compound Q-8 as pale yellow oil (2.5 g, 39.1percent). The compound was characterized by the following spectroscopic data: 1H NMR (400 MHz, CD3Cl): δ 9.80 (s, 1H), 4.54 (d, 1H, J = 7.25 Hz), 4.28 (m, 1H), 4.06 (m, 4H), 3.76 (m, 2H), 3.50 (s, 3H), 3.45 (s, 3H), 2.71 (m, 2H), 2.65 (m, 1H), 0.87 (m, 3H), 0.81 (m, 3H). [0712] To a solution of compound Q-8 (0.9 g, 2.6 mmol) in mixed solvents of THF (5 mL) and H2O (5 mL) was added LiOH (0.12 g, 5.0 mmol). The reaction mixture was stirred at rt overnight, then adjusted to pH 2 with diluted hydrochloric acid and extracted with EtOAc (50 mL x 3). The combined organic phases were dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated in vacuo to give compound Q-9 as a white solid (0.85 g, 99.0percent). The crude product was used for the next step without further purification. The compound was characterized by the following spectroscopic data: 1H NMR (400 MHz, CD3Cl): δ 9.80 (s, 1H), 4.54 (d, 1H, J = 7.25 Hz), 4.28 (m, 1H), 4.06 (m, 4H), 3.76 (m, 2H), 3.50 (s, 3H), 2.71 (m, 2H), 2.65 (m, 1H), 0.87 (m, 3H), 0.81 (m, 3H). [0713] To a solution of compound Q-9 (1.78 g, 5.4 mmol) in CH3CN (30 mL) was added compound Q-10 (1.65 g, 5.9 mmol). Then to the mixture was added DIPEA (1.1 mL, 6.7 mmol) slowly at 0 °C. The reaction mixture was stirred at rt overnight and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v) = 3/1) to give compound Q-11 as a pale yellow solid (2.76 g, 97.3percent). The compound was characterized by the following spectroscopic data: 1H NMR (400 MHz, CD3Cl): δ 9.30 (s, 1H), 7.95 (d, 2H, J = 8.27 Hz), 7.71 (d, 2H, J = 8.25 Hz), 5.34-5.72 (m, 2H), 4.52 (d, 1H), 4.29 (m, 1H), 4.19 (m, 4H), 3.77 (m, 2H), 3.69 (s, 3H), 2.71 (m, 1H), 2.65 (m, 2H), 0.91 (m, 3H), 0.89 (m, 3H). [0714] A suspension of compound Q-11 (3.0 g, 5.7 mmol) and ammonium acetate (4.4 g, 57.1 mmol) in xylene (20 mL) was heated at 130 °C overnight in a sealed tube. The resulting mixture was diluted with EtOAc (40 mL), washed with brine, dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated in vacuo and the residue was purified by silica gel column chromatography (PE/EtOAc (v/v) = 3/1) to give compound Q-12 as a claybank solid (2.6 g, 89.9percent). The compound was characterized by the following spectroscopic data: 1H NMR (400 MHz, CD3Cl): δ 9.30 (s, 1H), 7.95 (d, 2H, J = 8.27 Hz), 7.71 (d, 2H, J = 8.25 Hz), 4.52 (d, 1H), 4.29 (m, 1H), 4.19 (m, 4H), 3.77 (m, 2H), 3.69 (s, 3H), 2.71 (m, 1H), 2.65 (m, 2H), 0.91 (m, 3H), 0.89 (m, 3H). [0715] A mixture of compound Q-12 (4.0 g, 7.9 mmol), PdCl2 (dppf)·CH2Cl2 (0.64 g, 0.8 mmol), anhydrous potassium acetate (1.94 g, 19.8 mmol) and bis(pinacolato)diboron (3.11 g, 12.2 mmol) in DMF (50 mL) was stirred at 90 °C for 4 hours under N2 and cooled to rt. To the resulting mixture was added H2O (100 mL). The mixture was extracted with EtOAc (100 mL x 3). The combined organic phases were washed with water and brine, dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated in vacuo and the residue was purified by silica gel column chromatography (PE/DCM (v/v) = 4/1) to give the title compound 51-6 as a white solid (4.15 g, 94.7percent, [0716] HPLC: 95percent). The compound was characterized by the following spectroscopic data: 1H NMR (400 MHz, CD3Cl): δ 9.30 (s, 1H), 7.95 (d, 2H, J = 8.27 Hz), 7.71 (d, 2H, J = 8.25 Hz), 4.52 (d, 1H), 4.29 (m, 1H), 4.19 (m, 4H), 3.77 (m, 2H), 3.69 (s, 3H), 2.71 (m, 1H), 2.65 (m, 2H), 1.35 (s, 12H), 0.91 (m, 3H), 0.89 (m, 3H). |
79.5% | With Dess-Martin periodane In dichloromethane at 0 - 20℃; for 1 h; | To a solution of compound 19-4 (1.0 g, 3.6 mmol) in DCM (20 mL) at 0 °C was added Dess-Martin periodinane (3.0 g, 7.1 mmol) in portions. At the end of the addition, the mixture was stirred at rt for 1 hour. After the reaction was completed, the mixture was concentrated in vacuo and the residue was purified by silica gel column chromatography (PE/EtOAc (v/v) = 5/1) to give the title compound as pale yellow oil (0.79 g, 79.5 percent). The compound was characterized by the following spectroscopic data: lH NMR (400 Hz, CDCI3): δ 7.47 (d, 2H, J = 8.24 Hz), 7.38 (d, 2H, J = 8.24 Hz), 7.24 (m, 1H), 5.09 (s, 2H), 4.18 (t, 1H), 3.68 (s, 3H), 3.38 (m, 1H), 3.32 (m, 1H), 2.21 (m, 1H), 1.96 (m, 1H) ppm. |
79.5% | With Dess-Martin periodane In dichloromethane at 20℃; for 1 h; Cooling with ice | To a solution of compound Q-3 (1.0 g, 3.6 mmol) in DCM (20 mL) was added Dess-Martin (3.0 g, 7.1 mmol)slowly in an ice bath. The reaction mixture was stirred at rt for 1 hour and filtered. The filtrate was concentrated in vacuoand the residue was purified by silica gel column chromatography (PE/EA (v/v) = 5/1) to give compound Q-4 as yellowoil (0.79 g, 79.5percent). The compound was characterized by the following spectroscopic data:1H NMR (400 MHz, CD3Cl): δ 7.47 (d, J = 8.24 Hz, 2H), 7.38 (d, J = 8.24 Hz, 2H), 7.24 (m, 1H), 5.09 (s, 2H), 4.18(t, 1H), 3.68 (s, 3H), 3.38 (m, 1H), 3.32 (m, 1H), 2.21 (m, 1H), 1.96 (m, 1H). |
79.5% | With Dess-Martin periodane In dichloromethane at 0 - 20℃; for 1 h; | Compound 15-3 (1.0 g, 3.6 mmol) was dissolved in DCM (20 mL) and Dess-Martinperiodinane (3.0 g, 7.1 mmol) was added portionwise at 0 ° C. After the reaction wascompleted, the reaction solution was concentrated and purified by column chromatography(eluent: PE / EtOAc (v / v) = 5/1) to give 0.79 g of a yellow oily liquid. Yield: 79.5percent. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
62.8% | With potassium carbonate In tetrahydrofuran; water at 20℃; | To a mixture of benzyl chloroformate (3.7 mL, 26.3 mmol) and potassium carbonate (10.6 g, 76.7 mmol) in a mixed solvent of THF and H20 (THF/H20 (v/v) = 20 mL/10 mL) was added compound 19-3 (3.1 g, 17.1 mmol) in one portion with vigorous stirring. At the end of the addition, the mixuture was stirred at rt overnight. After the reaction was completed, the mixture was acidified with aqueous HC1 (1 M) till pH = 1 and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with a saturated aqueous solution of NaCl, dried over anhydrous Na2S04 and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v) = 4/1) to give the title compound as pale yellow oil (3 g, 62.8percent). The compound was characterized by the following spectroscopic data: lli NMR (400 Hz, CDCI3): δ 7.47 (d, 2H, J = 8.24 Hz), 7.38 (d, 2H, J= 8.24 Hz), 7.24 (m, 1H), 5.09 (s, 2H), 4.18 (t, 1H), 3.68 (s, 3H), 3.63 (m, 1H), 3.58 (s, 1H), 3.38 (m, 1H), 3.32 (m, 1H), 2.21 (m, 1H), 1.96 (m, 1H) ppm |
62.8% | With potassium carbonate In tetrahydrofuran; water at 20℃; | Compound 15-2 (3.1 g, 17.1 mmol) was added in one portion to a vigorouslystirred mixture of benzyl chloroformate (3.7 mL, 26.3 mmol) and potassium carbonate(10.6 g, 76.7 mmol) in THF / H 2O (20 mL / 10 mL). After the addition was complete,react at room temperature overnight. After the reaction was completed, the reactionmixture was adjusted to pH 3 with dilute hydrochloric acid (1 M) and extracted withEtOAc (50 mL x 3). The organic phases were combined, washed with brine, dried overanhydrous sodium sulfate and concentrated. Separation and purification (eluent: PE /EtOAc (v / v) = 4/1) gave 3.0 g of a pale yellow oily liquid, yield: 62.8percent. |
3 g | With potassium carbonate In tetrahydrofuran; water at 20℃; Inert atmosphere; Sealed tube | To a vigorously stirred solution of benzyl chloroformate (3.7 mL, 26.3 mmol) and K2C03 (10.6 g, 76.7 mmol) in a mixed solvent of THF (20 mL) and H2O (10 mL) was added compound 20-2 (3.1 g, 17.1 mmol) in one portion. The reaction mixture was stirred at rt overnight. After the reaction was completed, the mixture was adjusted to pH 3 with diluted hydrochloric acid (1 M) and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine, dried over anhydrous Na2S04 and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v) = 4/1) to give the title compound as pale yellow oil (3.0 g, 62.8percent). The compound was characterized by the following spectroscopic data: H NMR (400 Hz, CDC13) δ (ppm): 7.47 (d, 2H, J = 8.24 Hz), 7.38 (d, 2H, J = 8.24 Hz), 7.24 (m, 1H), 5.09 (s, 2H), 4.18 (t, 1H), 3.68 (s, 3H), 3.63 (m, 1H), 3.58 (s, 1H), 3.38 (m, 1H), 3.32 (m, 1H), 2.21 (m, 1H), 1.96 (m, 1H). |
3 g | With potassium carbonate In tetrahydrofuran; water at 20℃; | To a mixture of compound Q-1 (2 g, 15.3 mmol) in CH3OH (25 mL) was added thionyl chloride (3.4 mL, 46.9 mmol) slowly at 0 °C. The reaction mixture was refluxed at 80 °C for 3.5 hours and concentrated in vacuo to give compound Q-2 as a white solid (2.76 g, 99.5percent). The crude product was used for the next step without further purification. The compound was characterized by the following spectroscopic data: 1H NMR (400 MHz, CD3Cl): δ 3.68 (s, 3H), 3.58 (t, 1H), 3.56 (s, 1H), 3.32 (m, 1H), 3.02 (m, 1H), 2.77 (m, 1H), 2.52 (s, 1H), 2.21 (m, 1H), 1.96 (m, 1H). [0707] To a solution of benzyl chloroformate (3.7 mL, 26.3 mmol) and K2CO3 (10.6 g, 76.7 mmol) in mixed solvents of THF (20 mL) and H2O (10 mL) was added compound Q-2 (3.1 g, 17.1 mmol) in one portion while the mixture was stirred vigorously. At the end of the addition, the mixture was stirred at rt overnight, adjusted to pH 3 with diluted hydrochloric acid and extracted with EtOAc (50 mL x 3). The combined organic phases were dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated in vacuo and the residue was purified by silica gel column chromatography (PE/EtOAc (v/v) = 4/1) to give compound Q-3 as pale yellow oil (3 g, 62.8percent). The compound was characterized by the following spectroscopic data: 1H NMR (400 MHz, CD3Cl): δ 7.47 (d, J = 8.24 Hz, 2H), 7.38 (d, J = 8.24 Hz, 2H), 7.24 (m, 1H), 5.09 (s, 2H), 4.18 (t, 1H), 3.68 (s, 3H), 3.63 (m, 1H), 3.58 (s, 1H), 3.38 (m, 1H), 3.32 (m, 1H), 2.21 (m, 1H), 1.96 (m, 1H). [0708] To a solution of compound Q-3 (1.0 g, 3.6 mmol) in DCM (20 mL) was added Dess-Martin (3.0 g, 7.1 mmol) slowly in an ice bath. The reaction mixture was stirred at rt for 1 hour and filtered. The filtrate was concentrated in vacuo and the residue was purified by silica gel column chromatography (PE/EA (v/v) = 5/1) to give compound Q-4 as yellow oil (0.79 g, 79.5percent). The compound was characterized by the following spectroscopic data: 1H NMR (400 MHz, CD3Cl): δ 7.47 (d, J = 8.24 Hz, 2H), 7.38 (d, J = 8.24 Hz, 2H), 7.24 (m, 1H), 5.09 (s, 2H), 4.18 (t, 1H), 3.68 (s, 3H), 3.38 (m, 1H), 3.32 (m, 1H), 2.21 (m, 1H), 1.96 (m, 1H). [0709] To a solution of compound Q-4 (1.0 g, 3.6 mmol) in toluene (20 mL) in a flask equipped with Dean-Stock trap were added ethylene glycol (0.8 mL, 15.7 mmol) and TsOH (0.14 g, 0.8 mmol) in turn. The reaction mixture was refluxed overnight. After the reaction was complete, the mixture was diluted with EtOAc (10 mL), and washed with saturated NaHCO3 aqueous solution (10 mL) and brine (15 mL) separately. The organic phase was dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated in vacuo and the residue was purified by silica gel column chromatography (PE/EtOAc (v/v) = 6/1) to give compound Q-5 as colorless and sticky liquid (0.54 g, 46.7percent). The compound was characterized by the following spectroscopic data: 1H NMR (400 MHz, CD3Cl): δ 7.47 (d, 2H, J = 8.24 Hz), 7.38 (d, 2H, J = 8.24 Hz), 7.24 (m, 1H), 5.09 (s, 2H), 4.18 (t, 1H), 4.05 (m, 2H), 3.95 (m, 2H), 3.68 (s, 3H), 3.38 (m, 1H), 3.32 (m, 1H), 2.21 (m, 1H), 1.96 (m, 1H). [0710] To a solution of compound Q-5 (0.59 g, 1.8 mmol) in CH3OH (150 mL) was added Pd/C (0.5 g). The reaction mixture was stirred at rt under H2 overnight and filtered. The filtrate was concentrated in vacuo to give compound Q-6 (0.34 g, 98.9percent). The crude product was used for the next step without further purification. The compound was characterized by the following spectroscopic data: 1H NMR (400 MHz, CD3Cl): δ 4.18 (t, 1H), 4.05 (m, 2H), 3.95 (m, 2H), 3.68 (s, 3H), 3.38 (m, 1H), 3.32 (m, 1H), 2.21 (m, 1H), 1.96 (m, 1H). [0711] To a solution of compound Q-6 (3.48 g, 18.6 mmol) in DCM (50 mL) in an ice bath were added compound Q-7 (3.26 g, 18.6 mmol), DIPEA (12.3 mL, 74.4 mmol) and EDCI (7.1 g, 37.0 mmol) in turn. The reaction mixture was stirred at rt overnight, washed with H2O (20 mL), dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated in vacuo and the residue was purified by silica gel column chromatography (PE/EtOAc (v/v) = 3/1) to give compound Q-8 as pale yellow oil (2.5 g, 39.1percent). The compound was characterized by the following spectroscopic data: 1H NMR (400 MHz, CD3Cl): δ 9.80 (s, 1H), 4.54 (d, 1H, J = 7.25 Hz), 4.28 (m, 1H), 4.06 (m, 4H), 3.76 (m, 2H), 3.50 (s, 3H), 3.45 (s, 3H), 2.71 (m, 2H), 2.65 (m, 1H), 0.87 (m, 3H), 0.81 (m, 3H). [0712] To a solution of compound Q-8 (0.9 g, 2.6 mmol) in mixed solvents of THF (5 mL) and H2O (5 mL) was added LiOH (0.12 g, 5.0 mmol). The reaction mixture was stirred at rt overnight, then adjusted to pH 2 with diluted hydrochloric acid and extracted with EtOAc (50 mL x 3). The combined organic phases were dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated in vacuo to give compound Q-9 as a white solid (0.85 g, 99.0percent). The crude product was used for the next step without further purification. The compound was characterized by the following spectroscopic data: 1H NMR (400 MHz, CD3Cl): δ 9.80 (s, 1H), 4.54 (d, 1H, J = 7.25 Hz), 4.28 (m, 1H), 4.06 (m, 4H), 3.76 (m, 2H), 3.50 (s, 3H), 2.71 (m, 2H), 2.65 (m, 1H), 0.87 (m, 3H), 0.81 (m, 3H). [0713] To a solution of compound Q-9 (1.78 g, 5.4 mmol) in CH3CN (30 mL) was added compound Q-10 (1.65 g, 5.9 mmol). Then to the mixture was added DIPEA (1.1 mL, 6.7 mmol) slowly at 0 °C. The reaction mixture was stirred at rt overnight and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v) = 3/1) to give compound Q-11 as a pale yellow solid (2.76 g, 97.3percent). The compound was characterized by the following spectroscopic data: 1H NMR (400 MHz, CD3Cl): δ 9.30 (s, 1H), 7.95 (d, 2H, J = 8.27 Hz), 7.71 (d, 2H, J = 8.25 Hz), 5.34-5.72 (m, 2H), 4.52 (d, 1H), 4.29 (m, 1H), 4.19 (m, 4H), 3.77 (m, 2H), 3.69 (s, 3H), 2.71 (m, 1H), 2.65 (m, 2H), 0.91 (m, 3H), 0.89 (m, 3H). [0714] A suspension of compound Q-11 (3.0 g, 5.7 mmol) and ammonium acetate (4.4 g, 57.1 mmol) in xylene (20 mL) was heated at 130 °C overnight in a sealed tube. The resulting mixture was diluted with EtOAc (40 mL), washed with brine, dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated in vacuo and the residue was purified by silica gel column chromatography (PE/EtOAc (v/v) = 3/1) to give compound Q-12 as a claybank solid (2.6 g, 89.9percent). The compound was characterized by the following spectroscopic data: 1H NMR (400 MHz, CD3Cl): δ 9.30 (s, 1H), 7.95 (d, 2H, J = 8.27 Hz), 7.71 (d, 2H, J = 8.25 Hz), 4.52 (d, 1H), 4.29 (m, 1H), 4.19 (m, 4H), 3.77 (m, 2H), 3.69 (s, 3H), 2.71 (m, 1H), 2.65 (m, 2H), 0.91 (m, 3H), 0.89 (m, 3H). [0715] A mixture of compound Q-12 (4.0 g, 7.9 mmol), PdCl2 (dppf)·CH2Cl2 (0.64 g, 0.8 mmol), anhydrous potassium acetate (1.94 g, 19.8 mmol) and bis(pinacolato)diboron (3.11 g, 12.2 mmol) in DMF (50 mL) was stirred at 90 °C for 4 hours under N2 and cooled to rt. To the resulting mixture was added H2O (100 mL). The mixture was extracted with EtOAc (100 mL x 3). The combined organic phases were washed with water and brine, dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated in vacuo and the residue was purified by silica gel column chromatography (PE/DCM (v/v) = 4/1) to give the title compound 51-6 as a white solid (4.15 g, 94.7percent, [0716] HPLC: 95percent). The compound was characterized by the following spectroscopic data: 1H NMR (400 MHz, CD3Cl): δ 9.30 (s, 1H), 7.95 (d, 2H, J = 8.27 Hz), 7.71 (d, 2H, J = 8.25 Hz), 4.52 (d, 1H), 4.29 (m, 1H), 4.19 (m, 4H), 3.77 (m, 2H), 3.69 (s, 3H), 2.71 (m, 1H), 2.65 (m, 2H), 1.35 (s, 12H), 0.91 (m, 3H), 0.89 (m, 3H). |
3 g | With potassium carbonate In tetrahydrofuran; water at 20℃; | To a solution of benzyl chloroformate (3.7 mL, 26.3 mmol) and K2CO3 (10.6 g, 76.7 mmol) in mixed solventsof THF (20 mL) and H2O (10 mL) was added compound Q-2 (3.1 g, 17.1 mmol) in one portion while the mixture wasstirred vigorously. At the end of the addition, the mixture was stirred at rt overnight, adjusted to pH 3 with dilutedhydrochloric acid and extracted with EtOAc (50 mL x 3). The combined organic phases were dried over anhydrousNa2SO4 and filtered. The filtrate was concentrated in vacuo and the residue was purified by silica gel column chromatography(PE/EtOAc (v/v) = 4/1) to give compound Q-3 as pale yellow oil (3 g, 62.8percent). The compound was characterizedby the following spectroscopic data:1H NMR (400 MHz, CD3Cl): δ 7.47 (d, J = 8.24 Hz, 2H), 7.38 (d, J = 8.24 Hz, 2H), 7.24 (m, 1H), 5.09 (s, 2H), 4.18(t, 1H), 3.68 (s, 3H), 3.63 (m, 1H), 3.58 (s, 1H), 3.38 (m, 1H), 3.32 (m, 1H), 2.21 (m, 1H), 1.96 (m, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | at 0 - 20℃; for 1 h; | To a solution of D (23 g, 65.8 mmol) in MeOH (100 mL) was added K2C03 (9.1 g, 65.8mmol) at 0 °C , and the mixture was stirred at room temperature for 1 h. TLC showed the reaction was complete. The mixture was filtered, the filtrate was concentrated in vacuo to remove MeOH, the residue was dissolved in EtOAc, washed with water, brine, dried (MgS0 ) filtered and concentrated to give crude product which was purified by chromatography on silica gel (Pet Ether/EtOAc=4/1 -1/1) to get the desired product (12.6 g, 70percent) as light yellow oil. |
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