* 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.
With silver nitrate; acetyl chloride In water; acetonitrile at 0 - 20℃; for 5 h;
Silver nitrate (1.41 g, 8.32 mmol) and coumaran 3 (0.59 mL, 8.32 mmol) were dissolved in acetonitrile (10 mL) and placed in a 100 mL three-necked flask equipped with a dropping funnel, condenser and drying tube, and thermometer. 0.59 mL (8.32 mmol) of acetyl chloride was added to the reaction mixture at 0°C. As the quantity of silver chloride increased, further dilution with acetonitrile and more vigorous stirring were used to help maintain reactant contact for 1 h at 0–5°C and for 4 h at room temperature. 20 mL of water was added to the reaction flask at 0°C and then an additional 10 mL of water was added when the mixture was at room temperature. Exhaustive treatments of solid and liquid materials with ethyl acetate were used to extract the products. The organic layer was concentrated, dried over MgSO4, and then purified by column chromatography(EA/n-hexane) to give 740 mg of 5 (54percent) as a yellow solid.
44.4%
at 65 - 75℃; for 0.5 h;
Example 14: Preparation of (R)-2-[[[4-(3-methoxylpropoxy)-3-methyl-2-pyridyl]methyl]-sulfinyl]-6,7-dihydro-3H-benzofuro[5,6-d]imidazole sodium (sodium salt of Compound 30) Step 1: Preparation of 5-nitro-2,3-dihydrobenzofuran [Show Image] 2,3-Dihydrobenzofuran (36 g, 0.3 mol) was added to glacial acetic acid (100 mL), heated to 65°C, then concentrated nitric acid (25 mL, 0.36 mol) was added dropwise into the reaction solution, the temperature of the reaction solution was controlled at 65-75°C. After the end of dropwise addition, the agitation was kept for 0.5 h. It was then cooled to room temperature, filtered, washed with water, and dried to obtain a product (22 g, 44.4percent).
29%
With nitric acid; acetic acid In water at 70℃; for 0.5 h;
To a solution of 25.5 g (0.212 mol) of 2, 3-dihydrobenzofuran in 175 mL of acetic acid was added about one quarter of 4.5 mL (0.227 mol) of 70percent aqueous nitric acid dropwise. The reaction was monitored by TLC (EtOAc-hexanes (15: 85) ). The mixture was warmed to 70°C where the reaction began. The remainder of the nitric acid was then added while maintaining the reaction at 70°C. After 30 minutes, the reaction was cooled and poured into 1.5 L of ice water. The black solid was collected by filtration washing with water. The solid was partitioned between 500 mL of saturated aqueous sodium bicarbonate and 150 mL of EtOAc. The aqueous layer was separated and extracted with three 150 mL portions of EtOAc. The combined organic layers were washed with three 100 mL portions of saturated aqueous sodium bicarbonate, 100 mL of saturated aqueous ammonium chloride, 100 mL of brine, dried over magnesium sulfate, filtered, and concentrated to afford a red oil/solid. The mixture was dissolved in dichloromethane and passed through a pad of silica gel eluting with dichloromethane and concentrated. The resulting red mixture was triturated with ether-hexanes (1: 1) and filtered to afford 10.5 g (29percent) of 5-nitro-2, 3-dihydrobenzofuran as a tan solid.
17%
at 0 - 20℃; for 2 h;
To a solution of 20 (27.1 g, 226 mmol) in acetic acid (100 mL) was slowly added nitric acid (11.2 mL, 249 mmol) at 0 °C. After stirring at room temperature for 2 h, the reaction mixture was poured into a mixture of ice and 12 N NaOH (100 mL). The mixture was extracted with EtOAc. The extract was washed with aqueous NH4Cl and brine, dried and concentrated. The residue was purified by flash chromatography on SiO2 with an eluent of 20percent EtOAc/hexane to provide 21 (6.4 g, 17percent) as a pale brown powder; 1H NMR (CDCl3) δ: 3.30 (2H, t, J = 8.7 Hz), 4.74 (2H, t, J = 8.7 Hz), 6.81 (1H, d, J = 9.6 Hz), 8.07-8.12 (2H, m); Anal. Calcd for C8H7NO: C, 58.18; H, 4.27; N, 8.48. Found: C, 57.93; H, 4.19; N, 8.27.
Reference：
[1] Journal of Medicinal Chemistry, 2014, vol. 57, # 13, p. 5579 - 5601
[2] Bioorganic and Medicinal Chemistry, 2013, vol. 21, # 13, p. 3821 - 3830
[3] Patent: EP2532665, 2012, A1, . Location in patent: Page/Page column 41
[4] Patent: WO2003/82787, 2003, A1, . Location in patent: Page/Page column 138-139
[5] Journal of Medicinal Chemistry, 2010, vol. 53, # 18, p. 6681 - 6698
[6] Bioorganic and Medicinal Chemistry, 2011, vol. 19, # 21, p. 6430 - 6446
2
[ 7169-34-8 ]
[ 17403-47-3 ]
Reference：
[1] Bioorganic and Medicinal Chemistry, 2013, vol. 21, # 13, p. 3821 - 3830
3
[ 17403-47-3 ]
[ 42933-43-7 ]
Yield
Reaction Conditions
Operation in experiment
97.2%
With hydrogen In methanol at 20℃;
Step 2: Preparation of 5-amino-2,3-dihydrobenzofuran [Show Image] The product (1 g, 6.1 mmol) obtained in Step 1, Raney Ni (0.1 g) and MeOH(10 mL) were used for hydrogenation at room temperature and hydrogen pressure of 50 PSI, until the reaction was finished. The catalyst was removed by filtration, the fitrate was concentrated under vacuum to obtain a product (800 mg, 97.2percent).
90%
With palladium 10% on activated carbon; hydrogen In ethanol; water for 13 h;
A mixture of 21 (6.3 g, 38.1 mmol) and 10percent palladium on carbon (1.0 g) in EtOH (50 mL) and THF (50 mL) was stirred under an atmosphere of H2 (1 atm) at room temperature for 13 h. The catalyst was removed by filtration, and then the filtrate was concentrated. The residue was purified by flash chromatography on SiO2 with a gradient eluent of 0-10percent MeOH/EtOAc to provide 22 (4.63 g, 90percent) as a pale brown powder; 1H NMR (CDCl3) δ: 3.12 (2H, t, J = 8.6 Hz), 3.37 (2H, s), 4.49 (2H, t, J = 8.6 Hz), 6.43-6.47 (1H, m) 6.57-6.61 (2H, m); Anal. Calcd for C8H9NO: C, 71.09; H, 6.71; N, 10.36. Found: C, 70.92; H, 6.60; N, 10.09.
Reference：
[1] Journal of Medicinal Chemistry, 2010, vol. 53, # 18, p. 6681 - 6698
[2] Patent: EP2532665, 2012, A1, . Location in patent: Page/Page column 21
[3] Bioorganic and Medicinal Chemistry, 2011, vol. 19, # 21, p. 6430 - 6446
[4] Journal of Medicinal Chemistry, 2014, vol. 57, # 13, p. 5579 - 5601
[5] Journal of Medicinal Chemistry, 2009, vol. 52, # 14, p. 4161 - 4172
[6] Patent: WO2003/82787, 2003, A1, . Location in patent: Page/Page column 139
[7] Bioorganic and Medicinal Chemistry, 2013, vol. 21, # 13, p. 3821 - 3830
EXAMPLE A 2,3-Dihydro-5-benzofuranamine: A mixture of 10 g. of <strong>[17403-47-3]5-nitro-2,3-dihydrobenzofuran</strong>, 2.5 g. of Raney Nickel and 50 ml. of ethanol is hydrogenated in a Parr apparatus at a hydrogen pressure of 50 p.s.i. and room temperature until the uptake of hydrogen ceases. The resulting mixture is filtered to remove catalyst and the filtrate evaporated in vacuo to obtain an oil of 2,3-dihydro-5-benzofuranamine.
With silver nitrate; acetyl chloride; In water; acetonitrile; at 0 - 20℃; for 5.0h;
Silver nitrate (1.41 g, 8.32 mmol) and coumaran 3 (0.59 mL, 8.32 mmol) were dissolved in acetonitrile (10 mL) and placed in a 100 mL three-necked flask equipped with a dropping funnel, condenser and drying tube, and thermometer. 0.59 mL (8.32 mmol) of acetyl chloride was added to the reaction mixture at 0C. As the quantity of silver chloride increased, further dilution with acetonitrile and more vigorous stirring were used to help maintain reactant contact for 1 h at 0-5C and for 4 h at room temperature. 20 mL of water was added to the reaction flask at 0C and then an additional 10 mL of water was added when the mixture was at room temperature. Exhaustive treatments of solid and liquid materials with ethyl acetate were used to extract the products. The organic layer was concentrated, dried over MgSO4, and then purified by column chromatography(EA/n-hexane) to give 740 mg of 5 (54%) as a yellow solid.
44.4%
With nitric acid; acetic acid; at 65 - 75℃; for 0.5h;Product distribution / selectivity;
Example 14: Preparation of (R)-2-[[[4-(3-methoxylpropoxy)-3-methyl-2-pyridyl]methyl]-sulfinyl]-6,7-dihydro-3H-benzofuro[5,6-d]imidazole sodium (sodium salt of Compound 30) Step 1: Preparation of 5-nitro-2,3-dihydrobenzofuran [Show Image] 2,3-Dihydrobenzofuran (36 g, 0.3 mol) was added to glacial acetic acid (100 mL), heated to 65C, then concentrated nitric acid (25 mL, 0.36 mol) was added dropwise into the reaction solution, the temperature of the reaction solution was controlled at 65-75C. After the end of dropwise addition, the agitation was kept for 0.5 h. It was then cooled to room temperature, filtered, washed with water, and dried to obtain a product (22 g, 44.4%).
35%
With silver nitrate; acetyl chloride; In acetonitrile; at 0℃; for 1.0h;
General procedure: A solution of 29 (1.0mmol) in CH3CN was cooled to 0C and was added with silver nitrate (1.0mmol) and acetyl chloride (1.0mmol). The reaction mixture was stirred at 0C for 1h. After completion, the reaction mixture was diluted with water and extracted with EtOAc several times. The combined organic layer was washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography to afford the desire product.
29%
With nitric acid; acetic acid; In water; at 70℃; for 0.5h;
To a solution of 25.5 g (0.212 mol) of 2, 3-dihydrobenzofuran in 175 mL of acetic acid was added about one quarter of 4.5 mL (0.227 mol) of 70% aqueous nitric acid dropwise. The reaction was monitored by TLC (EtOAc-hexanes (15: 85) ). The mixture was warmed to 70C where the reaction began. The remainder of the nitric acid was then added while maintaining the reaction at 70C. After 30 minutes, the reaction was cooled and poured into 1.5 L of ice water. The black solid was collected by filtration washing with water. The solid was partitioned between 500 mL of saturated aqueous sodium bicarbonate and 150 mL of EtOAc. The aqueous layer was separated and extracted with three 150 mL portions of EtOAc. The combined organic layers were washed with three 100 mL portions of saturated aqueous sodium bicarbonate, 100 mL of saturated aqueous ammonium chloride, 100 mL of brine, dried over magnesium sulfate, filtered, and concentrated to afford a red oil/solid. The mixture was dissolved in dichloromethane and passed through a pad of silica gel eluting with dichloromethane and concentrated. The resulting red mixture was triturated with ether-hexanes (1: 1) and filtered to afford 10.5 g (29%) of 5-nitro-2, 3-dihydrobenzofuran as a tan solid.
17%
With nitric acid; acetic acid; at 0 - 20℃; for 2.0h;
To a solution of 20 (27.1 g, 226 mmol) in acetic acid (100 mL) was slowly added nitric acid (11.2 mL, 249 mmol) at 0 C. After stirring at room temperature for 2 h, the reaction mixture was poured into a mixture of ice and 12 N NaOH (100 mL). The mixture was extracted with EtOAc. The extract was washed with aqueous NH4Cl and brine, dried and concentrated. The residue was purified by flash chromatography on SiO2 with an eluent of 20% EtOAc/hexane to provide 21 (6.4 g, 17%) as a pale brown powder; 1H NMR (CDCl3) delta: 3.30 (2H, t, J = 8.7 Hz), 4.74 (2H, t, J = 8.7 Hz), 6.81 (1H, d, J = 9.6 Hz), 8.07-8.12 (2H, m); Anal. Calcd for C8H7NO: C, 58.18; H, 4.27; N, 8.48. Found: C, 57.93; H, 4.19; N, 8.27.
With hydrogen;Raney Ni; In methanol; at 20℃; under 2585.81 Torr;Product distribution / selectivity;
Step 2: Preparation of 5-amino-2,3-dihydrobenzofuran [Show Image] The product (1 g, 6.1 mmol) obtained in Step 1, Raney Ni (0.1 g) and MeOH(10 mL) were used for hydrogenation at room temperature and hydrogen pressure of 50 PSI, until the reaction was finished. The catalyst was removed by filtration, the fitrate was concentrated under vacuum to obtain a product (800 mg, 97.2%).
90%
With palladium 10% on activated carbon; hydrogen; In ethanol; water; under 760.051 Torr; for 13h;
A mixture of 21 (6.3 g, 38.1 mmol) and 10% palladium on carbon (1.0 g) in EtOH (50 mL) and THF (50 mL) was stirred under an atmosphere of H2 (1 atm) at room temperature for 13 h. The catalyst was removed by filtration, and then the filtrate was concentrated. The residue was purified by flash chromatography on SiO2 with a gradient eluent of 0-10% MeOH/EtOAc to provide 22 (4.63 g, 90%) as a pale brown powder; 1H NMR (CDCl3) delta: 3.12 (2H, t, J = 8.6 Hz), 3.37 (2H, s), 4.49 (2H, t, J = 8.6 Hz), 6.43-6.47 (1H, m) 6.57-6.61 (2H, m); Anal. Calcd for C8H9NO: C, 71.09; H, 6.71; N, 10.36. Found: C, 70.92; H, 6.60; N, 10.09.
82%
With palladium 10% on activated carbon; hydrogen; In tetrahydrofuran; methanol; at 20℃; for 2h;
General procedure: To a solution of nitro compound (1.0mmol) in MeOH/THF (1:1) was added 10% Pd/C and charged with hydrogen gas. The mixture was stirred for 2hat room temperature. After completion, the mixture was filtered through Celite and the filtrate was concentrated in vacuo. The residue was puried by column chromatography on silica gel to afford the desired product.
With hydrogen;palladium 10% on activated carbon; In methanol; dichloromethane; under 2844.39 Torr; for 18.5h;
To a suspension of 10.3 g (62.37 mmol) of 5-nitro-2, 3-dihydrobenzofuran in 50 mL of MeOH and 10 mL of dichloromethane was added 350 mg of 10% palladium on carbon and the mixture was placed under 55 psi of hydrogen gas. Hydrogen gas uptake was evident during the first 30 minutes. After 18 hours, the mixture was then filtered through diatomaceous earth and concentrated to afford 8.2 g of 2,3-dihydrobenzofuran-5-ylamine as a gray solid which was used without further purification.
With palladium 10% on activated carbon; hydrogen; In tetrahydrofuran; methanol; at 20℃; for 2h;
General procedure: Procedure B: The nitro-group containing compound was dissolved in MeOH (or a mixture of MeOH and tetrahydrofuran) and then 10% Pd/C was added. The mixture was stirred at room temperature under hydrogen gas until the starting material had been consumed. The crude mixture was filtered through Celite, washed with methanol, and then concentrated. The product was carried on to the next step without further purification or was purified by column chromatography.
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