* 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 3-chloro-benzenecarboperoxoic acid In dichloromethane at 50℃; for 16 h;
To a solution of 2,3-dihydro-benzo[1,4]dioxin-6-carboxaldehyde (30.0 g, 183 mmol) in 500 ml CH2Cl2 was added mCPBA (37.85 g, 219 mmol). The suspension was heated to 50° C. After 16 h saturated NaHCO3 was added and the mixture was extracted with CH2Cl2 The combined organics were concentrated in vacuo and taken up in MeOH and 200 ml 4M NaOH was added. After 2 h the mixture was acidified with 4M HCl and extracted with ethyl acetate. The combined organics were washed with saturated NaHCO3, washed with brine, concentrated in vacuo, and taken up in CH2Cl2. The solution was filtered to remove the precipitate. The resulting solution was stirred with saturated NaHCO3 for 1 h, separated, dried over MgSO4, filtered and concentrated in vacuo to give 2,3-dihydro-benzo[1,4]dioxin-6-ol (26.92 g, 94percent).
94%
Stage #1: With 3-chloro-benzenecarboperoxoic acid In dichloromethane at 50℃; for 16 h; Stage #2: With sodium hydroxide In methanol; water for 2 h;
To a solution of 2,3-dihydro-benzo[1,4]dioxin-6-carboxaldehyde (30.0 g, 183 mmol) in 500 ml CH2Cl2 was added mCPBA (37.85 g, 219 mmol). The suspension was heated to 50° C. After 16 h saturated NaHCO3 was added and the mixture was extracted with CH2Cl2. The combined organics were concentrated in vacuo and taken up in MeOH and 200 ml 4M NaOH was added. After 2 h the mixture was acidified with 4M HCl and extracted with ethyl acetate. The combined organics were washed with saturated NaHCO3, washed with brine, concentrated in vacuo, and taken up in CH2Cl2. The solution was filtered to remove the precipitate. The resulting solution was stirred with saturated NaHCO3 for 1 h, separated, dried over MgSO4, filtered and concentrated in vacuo to give 2,3-dihydro-benzo[1,4]dioxin-6-ol (26.92 g, 94percent).
92%
for 0.0833333 h;
Procedure: 2,3-dihydrobenzo[b][1 ,4]dioxine-6-carbaldehyde (2 g, 12.2 mmol, 1 eq.) was placed in a mortar, mCPBA (4.5 g, 18.3 mmol, 1.5 eq.) was added and the solids were mixed with a pestle. The resulting paste left at room temperature for 5 min and then diluted with NaOH (10percent in H20). The solution was washed with Et20, adjusted to pH 7 with HCI (2 m) and extracted with DCM. After the combined organic layers were dried over Na2S04, the solvent was evaporated and the product was purified via flash chromatography (Si02, nHex/EtOAc/AcoH 79/20/1 ).Yield: 1.7 g, 1 1.2 mmol, 92percent (off white solid).TLC: PE/EtOAc/AcOH 74/25/11H NMR (CDCI3,200 MHz, ppm): δ 6.72 (dd, J = 8.6, 0.4 Hz, 1 H), 6.40 (dd, J = 2.9, 0.4 Hz, 1 H), 6.33 (dd, J = 8.6, 2.9 Hz, 1 H), 4.32 - 4.14 (m, 4H), 4.00 (s, 1 H).13C NMR (CDCI3, 50 Hz, ppm): δ 150.1 , 144.0, 137.7, 1 17.7, 108.5, 104.4, 64.7, 64.2.
78%
With 3-chloro-benzenecarboperoxoic acid In dichloromethane at 40℃; for 12 h; Inert atmosphere
To a solution of 21 (5 g, 30.48 mmol) in DCM (80 mL) was added mCPBA (9 g, 45.72 mmol) under N2 atmosphere, and the reaction mixture was stirred for 12 h at 40. The resulting reaction mixture was quenched by saturated NaHCO3 aqueous solution (50 ml) and extracted with CH2Cl2 (50 mL × 3). The combined organic layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was dissolved in MeOH (20 ml) and added NaOH (1.46 g, 36.58 mmol). After the mixture was stirred for 15 min, the reaction mixture was adjusted to PH 6-7 with HCl (4 N aqueous solution) and extracted with methyl tert-butyl ether (50 mL × 3). The combined organic layer was washed with saturated aqueous NaHCO3 solution (100 ml) and brine (100 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography eluting with ethyl acetate/petroleum ether (1:3-1:2) to afford the intermediate 22 (3.6 g, 78percent yield) as a yellow solid.1H NMR (400 MHz, DMSO-d6) δ 8.92 (s, 1H), 6.62 (d, J = 8.4 Hz, 1H), 6.25-6.21 (m, 2H), 4.19 – 4.14 (m, 2H), 4.14 – 4.08 (m, 2H). 13C NMR (101 MHz, DMSO-d6) δ 151.55 (s), 143.50 (s), 136.09 (s), 117.08 (s), 107.93 (s), 103.59 (s), 64.23 (s), 63.67 (s).
63%
Stage #1: With 3-chloro-benzenecarboperoxoic acid In dichloromethane at 50℃; for 48 h; Stage #2: at 20℃; for 2 h; Stage #3: With hydrogenchloride; water In methanol
EXAMPLE 37 Scheme 37a[00319] Synthesis of N-(6-(6-(2,3-dihydrobenzo[λ] [1,4]dioxin-6-yloxy)pyrimidin-4- ylamino)pyridin-2-yl)acrylamide (1-95)Step lTo a stirred solution of 2,3-dmydrobenzo[6][1,4]dioxine-6-carbaldehyde (1 g, 6.09 mmol) in CH2Cl2 (16 mL) was added /w-CPBA (4.204 g, 24.36 mmol). The suspension was heated at 50 °C for 2 days, was cooled to it, was quenched with saturated NaHCO3 soln. and was extracted with CH2Cl2 (3x10 mL). The combined extract was concentrated under reduced pressure, and then was dissolved in MeOH containing NaOH. The solution was stirred at rt for 2 h, was acidified with HCl and was extracted with ethyl acetate (3x10 mL). The combined extract was washed with saturated NaHCO3 solution and brine, was dried over anhydrous Na2SO4, was filtered and was concentrated under reduced pressure. The residue was dissolved in CH2Cl2 and was filtered. The DCM solution was dried over anhydrous Na2SO4, was filtered and was concentrated under reduced pressure to give 2,3-dihydrobenzo[Z>][1,4]dioxin-6-ol (0.591 g, 63percent) as a reddish brown oily liquid.
Reference：
[1] Patent: US2005/209260, 2005, A1, . Location in patent: Page/Page column 114
[2] Patent: US2007/49609, 2007, A1, . Location in patent: Page/Page column 102
[3] Patent: WO2018/134254, 2018, A1, . Location in patent: Page/Page column 68
[4] Chemistry and Biodiversity, 2010, vol. 7, # 4, p. 887 - 897
[5] Bioorganic and Medicinal Chemistry, 2002, vol. 10, # 6, p. 2051 - 2066
[6] European Journal of Medicinal Chemistry, 2018, vol. 157, p. 380 - 396
[7] Patent: WO2009/51822, 2009, A1, . Location in patent: Page/Page column 150
[8] Bioscience, Biotechnology, and Biochemistry, 1992, vol. 56, # 2.3.4., p. 630 - 635
[9] Tetrahedron, 2004, vol. 60, # 40, p. 8899 - 8912
[10] Patent: US2011/87027, 2011, A1, . Location in patent: Page/Page column 11-12
[11] Patent: WO2012/49555, 2012, A1, . Location in patent: Page/Page column 56-57
2
[ 22013-33-8 ]
[ 10288-72-9 ]
Reference：
[1] European Journal of Medicinal Chemistry, 1989, vol. 24, p. 619 - 622
[2] Journal of the American Oil Chemists' Society, 1956, vol. 33, p. 414
[3] Journal of the Chemical Society, 1957, p. 3445
[4] European Journal of Medicinal Chemistry, 1990, vol. 25, # 1, p. 45 - 51
[5] Tetrahedron Letters, 1988, vol. 29, # 22, p. 2665 - 2666
[6] Patent: US5736543, 1998, A,
With potassium carbonate; In N,N-dimethyl-formamide; at 20℃;
(2) (2.0 g, 13 mmol) was dissolved in 6 mL of DMF, MeI (2.8 g, 20 mmol) and K2CO3 (2.7 g, 20 mmol) were added, and the mixture was stirred at room temperature overnight.The reaction solution was extracted with EtOAc, and the organic layer was washed with 1N NaOHaq. And a saturated saline solution, dried over Na2SO4, and concentrated under reduced pressure.The residue was purified by silica gel column chromatography (n-hexane: EtOAc = 3: 1) to obtain compound (3) (2.1 g, 94%).
85%
With tetra-(n-butyl)ammonium iodide; potassium carbonate; In DMF (N,N-dimethyl-formamide); for 16h;
To a mixture of K2CO3 (47.54 g, 344 mmol) and Bu4NI (1.256 g, 3.4 mmol) in DMF was added 2,3-dihydro-benzo[1,4]dioxin-6-ol (26.2 g, 172 mmol) followed by iodomethane (16.1 ml, 258 mmol). After 16 hours the mixture was filtered. The solution was mixed with H2O and extracted with ethyl acetate. The combined organics were washed with brine, dried over MgSO4, filtered and concentrated in vacuo. Purification via flash chromatography (95:5 hexane/ethyl acetate) afforded methyl 6-methoxy-2,3-dihydro-benzo[1,4]dioxine (24.23 g, 85%) as a clear oil.
85%
With tetra-(n-butyl)ammonium iodide; potassium carbonate; In N,N-dimethyl-formamide; for 16h;
To a mixture of K2CO3 (47.54 g, 344 mmol) and Bu4NI (1.256 g, 3.4 mmol) in DMF was added 2,3-dihydro-benzo[1,4]dioxin-6-ol (26.2 g, 172 mmol) followed by iodomethane (16.1 ml, 258 mmol). After 16 hours the mixture was filtered. The solution was mixed with H2O and extracted with ethyl acetate. The combined organics were washed with brine, dried over MgSO4, filtered and concentrated in vacuo. Purification via flash chromatography (95:5 hexane/ethyl acetate) afforded methyl 6-methoxy-2,3-dihydro-benzo[1,4]dioxine (24.23 g, 85%) as a clear oil.
With potassium fluoride; 3-chloro-benzenecarboperoxoic acid; In dichloromethane; at 20℃;Cooling with ice;
The above (1) (2.7 g, 16 mmol) was dissolved in 230 mL of CH2Cl2 and cooled with ice water.To this solution, mCPBA (4.2 g, 24 mmol) and KF (1.4 g, 24 mmol) were added, and the mixture was stirred at room temperature overnight.The reaction solution was filtered with n-hexane, and the filtrate was concentrated under reduced pressure.The obtained residue was dissolved in MeOH (10 mL), 1N NaOHaq. (5 mL) was added, and the mixture was stirred at room temperature overnight.1N HCl was added to the reaction solution, extracted with EtOAc, and the organic layer was washed with water and saturated saline, dried over Na2SO4, concentrated under reduced pressure, and then concentrated.The residue was purified by silica gel column chromatography (n-hexane: EtOAc = 3: 1) to obtain compound (2) (2.4 g, 98%).
94%
With 3-chloro-benzenecarboperoxoic acid; In dichloromethane; at 50℃; for 16h;
To a solution of 2,3-dihydro-benzo[1,4]dioxin-6-carboxaldehyde (30.0 g, 183 mmol) in 500 ml CH2Cl2 was added mCPBA (37.85 g, 219 mmol). The suspension was heated to 50 C. After 16 h saturated NaHCO3 was added and the mixture was extracted with CH2Cl2 The combined organics were concentrated in vacuo and taken up in MeOH and 200 ml 4M NaOH was added. After 2 h the mixture was acidified with 4M HCl and extracted with ethyl acetate. The combined organics were washed with saturated NaHCO3, washed with brine, concentrated in vacuo, and taken up in CH2Cl2. The solution was filtered to remove the precipitate. The resulting solution was stirred with saturated NaHCO3 for 1 h, separated, dried over MgSO4, filtered and concentrated in vacuo to give 2,3-dihydro-benzo[1,4]dioxin-6-ol (26.92 g, 94%).
94%
To a solution of 2,3-dihydro-benzo[1,4]dioxin-6-carboxaldehyde (30.0 g, 183 mmol) in 500 ml CH2Cl2 was added mCPBA (37.85 g, 219 mmol). The suspension was heated to 50 C. After 16 h saturated NaHCO3 was added and the mixture was extracted with CH2Cl2. The combined organics were concentrated in vacuo and taken up in MeOH and 200 ml 4M NaOH was added. After 2 h the mixture was acidified with 4M HCl and extracted with ethyl acetate. The combined organics were washed with saturated NaHCO3, washed with brine, concentrated in vacuo, and taken up in CH2Cl2. The solution was filtered to remove the precipitate. The resulting solution was stirred with saturated NaHCO3 for 1 h, separated, dried over MgSO4, filtered and concentrated in vacuo to give 2,3-dihydro-benzo[1,4]dioxin-6-ol (26.92 g, 94%).
92%
With 3-chloro-benzenecarboperoxoic acid; for 0.0833333h;
Procedure: 2,3-dihydrobenzo[b][1 ,4]dioxine-6-carbaldehyde (2 g, 12.2 mmol, 1 eq.) was placed in a mortar, mCPBA (4.5 g, 18.3 mmol, 1.5 eq.) was added and the solids were mixed with a pestle. The resulting paste left at room temperature for 5 min and then diluted with NaOH (10% in H20). The solution was washed with Et20, adjusted to pH 7 with HCI (2 m) and extracted with DCM. After the combined organic layers were dried over Na2S04, the solvent was evaporated and the product was purified via flash chromatography (Si02, nHex/EtOAc/AcoH 79/20/1 ).Yield: 1.7 g, 1 1.2 mmol, 92% (off white solid).TLC: PE/EtOAc/AcOH 74/25/11H NMR (CDCI3,200 MHz, ppm): delta 6.72 (dd, J = 8.6, 0.4 Hz, 1 H), 6.40 (dd, J = 2.9, 0.4 Hz, 1 H), 6.33 (dd, J = 8.6, 2.9 Hz, 1 H), 4.32 - 4.14 (m, 4H), 4.00 (s, 1 H).13C NMR (CDCI3, 50 Hz, ppm): delta 150.1 , 144.0, 137.7, 1 17.7, 108.5, 104.4, 64.7, 64.2.
78%
With 3-chloro-benzenecarboperoxoic acid; In dichloromethane; at 40℃; for 12h;Inert atmosphere;
To a solution of 21 (5 g, 30.48 mmol) in DCM (80 mL) was added mCPBA (9 g, 45.72 mmol) under N2 atmosphere, and the reaction mixture was stirred for 12 h at 40. The resulting reaction mixture was quenched by saturated NaHCO3 aqueous solution (50 ml) and extracted with CH2Cl2 (50 mL × 3). The combined organic layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was dissolved in MeOH (20 ml) and added NaOH (1.46 g, 36.58 mmol). After the mixture was stirred for 15 min, the reaction mixture was adjusted to PH 6-7 with HCl (4 N aqueous solution) and extracted with methyl tert-butyl ether (50 mL × 3). The combined organic layer was washed with saturated aqueous NaHCO3 solution (100 ml) and brine (100 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography eluting with ethyl acetate/petroleum ether (1:3-1:2) to afford the intermediate 22 (3.6 g, 78% yield) as a yellow solid.1H NMR (400 MHz, DMSO-d6) delta 8.92 (s, 1H), 6.62 (d, J = 8.4 Hz, 1H), 6.25-6.21 (m, 2H), 4.19 - 4.14 (m, 2H), 4.14 - 4.08 (m, 2H). 13C NMR (101 MHz, DMSO-d6) delta 151.55 (s), 143.50 (s), 136.09 (s), 117.08 (s), 107.93 (s), 103.59 (s), 64.23 (s), 63.67 (s).
63%
EXAMPLE 37 Scheme 37a[00319] Synthesis of N-(6-(6-(2,3-dihydrobenzo[lambda] [1,4]dioxin-6-yloxy)pyrimidin-4- ylamino)pyridin-2-yl)acrylamide (1-95)Step lTo a stirred solution of 2,3-dmydrobenzo[6][1,4]dioxine-6-carbaldehyde (1 g, 6.09 mmol) in CH2Cl2 (16 mL) was added /w-CPBA (4.204 g, 24.36 mmol). The suspension was heated at 50 C for 2 days, was cooled to it, was quenched with saturated NaHCO3 soln. and was extracted with CH2Cl2 (3x10 mL). The combined extract was concentrated under reduced pressure, and then was dissolved in MeOH containing NaOH. The solution was stirred at rt for 2 h, was acidified with HCl and was extracted with ethyl acetate (3x10 mL). The combined extract was washed with saturated NaHCO3 solution and brine, was dried over anhydrous Na2SO4, was filtered and was concentrated under reduced pressure. The residue was dissolved in CH2Cl2 and was filtered. The DCM solution was dried over anhydrous Na2SO4, was filtered and was concentrated under reduced pressure to give 2,3-dihydrobenzo[Z>][1,4]dioxin-6-ol (0.591 g, 63%) as a reddish brown oily liquid.
With 3-chloro-benzenecarboperoxoic acid; In dichloromethane;Reflux; Industry scale;
SYNTHETIC PREPARATION 6 Synthesis of 2,3-dihydro-1,4-benzodioxin-6-ol Compound of formula (12) A 2000 L reactor was charged with dichloromethane (1303.4 kg) followed by 2,3-dihydro-1,4-benzodioxine-6-carbaldehyde (98.0 kg, 597 mol) and stirred until a homogeneous solution was obtained. 3-Chloroperoxybenzoic acid (144.3 kg, 836 mol) was added. The mixture was heated to reflux at a rate of 8-10 C./h, heated at reflux for a further 6 h and allowed to cool to 20 C. The resultant suspension was filtered through a 500 L Nutsche filter and the filter cake was washed with dichloromethane (391 kg). The filtrate and wash solution were transferred to a 2000 L reactor. A 7% by weight aqueous solution of sodium bicarbonate (212.7 kg) was added and the mixture was stirred for 0.5 h. The stirring was stopped and the phases were allowed to separate over 0.5 h. The aqueous layer was removed. The aqueous sodium bicarbonate washing procedure was repeated three times in total. The organic phase was concentrated to dryness under reduced pressure at a temperature <30 C. Methanol (116.1 kg) was added and the resultant mixture was cooled to 0 C. A 15.5% by weight aqueous solution of sodium hydroxide (234.3 kg) was added at a rate of 30-40 kg/h such that the mixture's temperature was maintained between 0-10 C. The mixture was stirred at this temperature for a further 2.25 h and the pH of the mixture was adjusted to 6-7 by the addition of 4 N hydrochloric acid (266.5 kg) such that the mixture's temperature was maintained between 0-10 C. The mixture was allowed to warm to ambient temperature and was extracted three times in total with methyl tert-butyl ether (145 kg for each extraction) by stirring for 0.5 h, stopping the stirring and allowing the phases to separate for 0.5 h. The combined organic extracts were washed three times in total with a 7% aqueous solution of sodium bicarbonate (212.7 kg for each wash) by stirring for 0.5 h, stopping the stirring, allowing the phases to separate for 0.5 h and removing the aqueous phase. The organic phase was then washed with a 30% by weight aqueous solution of sodium chloride (212.7 kg) by stirring for 0.5 h, stopping the stirring, allowing the phases to separate for 0.5 h and removing the aqueous phase. The organic phase was concentrated to dryness under reduced pressure at a temperature <45 C. Tetrahydrofuran (170 kg) was added and the resultant solution concentrated to dryness under reduced pressure at a temperature <45 C. Further tetrahydrofuran (17.1 kg) was added and the resultant solution concentrated to dryness under reduced pressure at a temperature <45 C. Tetrahydrofuran (122.5 kg) was added to afford a brown - red solution of 2,3-dihydro-1,4-benzodioxin-6-ol (86.3 kg, 95%) in tetrahydrofuran which was carried forward without further purification: purity (HPLC-UV at 220 nm) 95.7%.
Intermediate- 19: 2,3-Dihydrobenzo[&][l,4]dioxin-6-ol: To a stirred solution of Intermediate- 18 (50.0 g, 30.4 mmol) in dichloromethane (250 ml) was added w-chloroperbenzoic acid (63.29 g, 36.58 mmol) at room temperature and the reaction mixture was stirred for 16 h at relux temperature. The course of reaction was monitored with TLC. The reaction mixture was quenched with addition of saturated NaHC03 and organic layer was washed with water (1 x 250 ml). The aqueous phase was again extracted with EtOAc (2 x 100 mL). The combined organic extracts were dried over anhydrous sodium sulphate, filtered and concentrated in vacuo. The crude liquid compound was dissolved in methanol (70 mL) and 4 N NaOH (250 mL) was added at 50 C. The reaction mixture was stirred at same temperature for 2 h. The reaction mixture was acidified with cone. HCl and methanol was evaporated under vacuo. The reaction mass was washed with water (2 x 100 mL) and liquid compound was extracted with EtOAc (2 x 250 mL). The combined organic extracts were dried over anhydrous sodium sulphate, filtered and concentrated in vacuo. The crude liquid compound was purified with silica using EtOAc : Hexane ( 30 : 70) (30 %) eluent, which result light yellow color liquid compound (24.5 g; 56.25 %). 1H NMR (400 MHz, DMSO-i/6): delta 9.85 (s, 1H), 7.44-7.41 (m, 2H), 6.95 (d, J= 8.4 Hz, 1H), 4.38 (m, 4H); MS (ES+) m/z 153.0 (M+l).
1) 1,4-Benzodioxan-6-carboxaldehyde (5.20 g) was dissolved in MeOH (60 mL) containing conc. H2SO4 (0.6 mL). At 0 C. an aqueous solution of 30% H2O2 (4.7 mL) was added to the mixture over 5 minutes. The mixture was warmed to room temperature, stirred an additional 18 h and evaporated. The residue was taken up with H2O and extracted with CH2Cl2. The extract was dried (Na2SO4), filtered and evaporated. The residue was purified by column chromatography (silica gel; eluent: hexane to hexane/EtOAc 3:1) to give 6-hydroxy-1,4-benzodioxan (3.85 g). ESMS: m/z 153 MH+.
79
[ 1193-21-1 ]
[ 10288-72-9 ]
[ 862270-58-4 ]
Yield
Reaction Conditions
Operation in experiment
With MP-carbonate resin; In 1-methyl-pyrrolidin-2-one; at 20 - 110℃; for 2.1h;
A mixture of 2,3-dihydrobenzo[b][1,4]dioxin-6-ol from step (b) above (0.500 g, 3.29 mmol), 4,6-dichloropyrimidine (0.417 g, 2.80 mmol, Aldrich) and MP-carbonate resin (1.41 g, 4.09 mmol, 2.9 mmol/g, Argonaut) in NMP (3.0 mL) was stirred at room temperature for 2 h and then heated in a microwave synthesizer at 110 C. for 6 min. The reaction mixture was cooled to room temperature and the resin was removed by filtration. The filter cake was washed with methanol (10 mL) and the filtrate was evaporated under reduced pressure. The reddish-brown residue was purified by silica gel column chromatography (gradient: 0-5% MeOH/DCM) to afford the title compound as pale-yellow amorphous solid. MS (ESI, pos. ion.) m/z: 265 (M+1).
7-hydroxy-2,3-dihydro-benzo[1,4]dioxin-6-carboxylic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
52%
With carbon dioxide;
EXAMPLE 2 8,9-Dihydro-6aH, 11H-1,4-dioxan[2,3-g]oxazolo[2,3-b][1,3]benzoxazin-11-one (2) Synthesis was begun with the preparation of 4,5-ethylenedioxysalicylic acid from <strong>[10288-72-9]6-hydroxy-1,4-benzodioxan</strong> and carbon dioxide according to the procedure described above in Method 1, with the modification that 95% sodium hydride was used, the pressure of carbon dioxide was 900 psi, and the temperature was 245 C. The product acid was obtained as a beige solid in 52% yield. IR (thin film): 3072, 2975, 2876, 2656, 2546, 1680, 1573, 1415, 1299, 1258, 1186, 1061, 897, and 747 cm-1.
6a,7,8,9-tetrahydro-1,4-dioxin[2,3-g]pyrrolo[2,1-b][1,3]benzoxazine-9(11H)-one[ No CAS ]
2-ethoxymethoxy-4,5-ethylenedioxybenzylamine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
86%
With p-toluenesulfonic acid monohydrate; In tetrahydrofuran; diethyl ether; chloroform; water; mineral oil;
EXAMPLE 2 6a,7,8,9-Tetrahydro-1,4-dioxin[2,3-g]pyrrolo[2,1-b][1,3]benzoxazine-9(11H)-one <strong>[118-29-6]N-(hydroxymethyl)phthalimide</strong> (97.46 g, 42.1 mmol), 3,4-ethylenedioxyphenol (96.4 g, 42.1 mmol), and p-toluenesulfonic acid monohydrate (0.87 g, 4.6 mmol) were dissolved in 80 mL chloroform and the mixture was refluxed for three days under a Dean-Stark trap with occasional removal of water. The brown solution was filtered through a silica plug, the silica plug was washed with chloroform, and the combined organic solutions were evaporated to yield a yellow solid that was purified by flash chromatography with dichloromethane as eluent. The intermediate was obtained as a yellow solid (5.8 g) composed of a mixture of isomers, which was used without further purification. The solid from above (1.4 g, 4.5 mmol) was dissolved in 15 mL THF and treated with 0.7 g (7.4 mmol) chloromethyl ethyl ether and 0.3 g (7.5 mmol) sodium hydride (as a 60% dispersion in mineral oil) under argon for one hr. Water was added and the separated aqueous phase was extracted three times with dichloromethane. The combined organic phases were washed three times with 10% sodium hydroxide and once with brine prior to being dried over sodium sulfate. Evaporation of the solvent gave an oil that dissolved in ethyl ether and crystallized to yield 0.63 g (38%) white crystals. M.p.=97-98.5 C. IR: 1771 and 1709 cm-1. 1 H-NMR (200 MHz): delta 7.6-7.9 (4H, m); 6.70 (1H, s); 6.69 (1H, s); 5.17 (2H, s); 4.82 (2H, s); 4.18 (4H, m); 3.71 (2H, q, J=7.2 Hz); and 1.2 ppm (3H, t, J=7.1 Hz). N-(2-ethoxymethoxy-4,5-ethylenedioxybenzyl)phthalimide (625 mg, 1.69 mmol) was mixed with 0.2 mL (6.4 mmol) hydrazine in 30 mL ethanol and refluxed for three hr. The reaction mixture was cooled, 30 mL ethyl ether was added to the mixture, and a white precipitate was removed by filtration. The filter cake was washed three times with diethyl ether and the combined organic solutions were evaporated to yield a residue that was partitioned between ethyl ether and 10% sodium hydroxide. The organic phase was washed three times with 10% sodium hydroxide, and the aqueous washes were combined and back-extracted twice with dichloromethane. The organic solutions were combined and washed with brine and dried over sodium sulfate/potassium carbonate. Subsequent evaporation of solvent gave 2-ethoxymethoxy-4,5-ethylenedioxybenzylamine as a light yellow oil (346 g, 86% crude), which solidified upon standing. IR: 3375 cm-1.
(+/-)-1-(2,3-Dihydro-benzo[1,4]dioxin-6-yloxy)-4-pyridin-3-yl-butan-2-ol[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With sodium hydroxide; In ethanol; water;
b (+-)-1-(2,3-Dihydro-benzo[1,4]dioxin-6-yloxy)-4-pyridin-3-yl-butan-2-ol A solution of benzo-1,4-dioxan-6-ol (0.15 g; Tetrahedron, 1995, 3197) in ethanol (20 ml) at room temperature was treated with a solution of sodium hydroxide (0.044 g) in water (5 ml) and was then heated at reflux. A solution of (+-)-alpha-(chloromethyl)-3-pyridinepropanol (1.0 g) in ethanol (5 ml) was added dropwise to the latter and the resulting mixture heated at reflux for 1 hour. The reaction mixture was cooled and then water was added. The organic component was extracted with dichloromethane, the combined extracts dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography over silica eluding with ethyl acetate to give an oil (0.100 g). MS (EI) 301 (M)+ 1 H NMR (CDCl3) 8.55-8.45(2H, m); 7.6-7.55(1H, m); 7.3-7.2(1H, m); 6.8-6.75(1H, m); 7.5-7.35(2H, m); 4.3-4.2(4H, bs); 4.0-3.7(3H, m); 3.0-2.7(2H, m); 2.45(1H, bs); 1.95-1.8(2H, m).
With copper(l) iodide; caesium carbonate; In 1-methyl-pyrrolidin-2-one; at 100℃; for 16h;
Step 2A stirred mixture of 2,3-dihydrobenzo[E][1,4]dioxin-6-ol (0.137 g, 0.90 mmol), Cs2CO3 (0.734 g, 2.25 mmol), CuI (0.02 g, 10% w/w), and N2-(6-chloropyrimidin-4-yl)pyridine-2,6-diamine (0.29 g, 0.90 mmol) in nuMP (1 mL) was heated at 100 C for 16 h. The reaction mixture was cooled to rt and slowly added to demineralised water. The solid that precipitated was collected by filtration and was further purified by column chromatography (SiO2, 60-120, pet ether/ethyl acetate, 7/3) to give N2-(6-(2,3-dihydrobenzo[6][1,4]dioxin-6-yloxy)pyrimidin-4-yl)pyridine-2,6- diamine (0.088 g, 29%) as yellow solid.
D. Synthesis of 1-(diphenylmethyl)-3-hvdroxy-3-(7-hvdroxy-2,3-dihvdro-1 A- benzodioxin-6-yl)-1 ,3-dihydro-2/-/-pyrrolo[312-ib1pyridin-2-one; To a solution of 2,3-dihydrobenzo[b][1 ,4]dioxin-6-ol (0.45 g, 2.7 mmol) in tetrahydrofuran (18 ml_) was added isopropylmagnesium chloride (2.0 M solution in tetrahydrofuran, 1.6 ml_, 3.2 mmol) dropwise at 0 0C. The reaction mixture was stirred at 0 0C for 0.5 h and concentrated in vacuo. The residue was dissolved in dichloromethane (10 ml.) and a solution of 1-(diphenylmethyl)-1 /-/-pyrrolo[3,2- £>]pyridine-2,3-dione (0.77 g, 2.5 mmol) in dichloromethane (5 ml.) was added at 0 0C. The reaction mixture was stirred at ambient temperature for 3 h and saturated aqueous ammonium chloride (15 ml.) was added. The phases were separated and the aqueous phase was extracted with dichloromethane (2 x 150 mL). The combined organic extracts were washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography, and eluted with a 10% to 50% gradient of ethyl acetate in petroleum ether to afford 1-(diphenylmethyl)-3-hydroxy-3-(7-hydroxy-2,3-dihydro-1 ,4-benzodioxin- 6-yl)-1 ,3-dihydro-2/-/-pyrrolo[3,2-6]pyridin-2-one (0.95 g, 79%) as a yellow solid: 1H NMR (400 MHz, CD3OD) delta 7.84-7.82 (m, 1 H), 7.27-7.21 (m, 11 H), 6.90 (s, 1 H), 6.87- 6.84 (m, 1 H), 6.60-6.58 (m, 1 H), 6.11 (s, 1 H), 4.09-4.06 (m, 4H).
To a solution of 2,3-dihydrobenzo[b][1 ,4]dioxin-6-ol (17.3 g, 113 mmol) in tetrahydrofuran (173 mL) was added isopropylmagnesium chloride (57 mL, 2 M) dropwise at 0 0C. The resulting solution was stirred at 0 0C for 30 min. The mixture was concentrated in vacuo, the residue was dissolved in dichloromethane (360 mL) followed by the addition of a solution of 8-chloro-9/-/-imidazo[1 ,2-a]indol-9-one (17.9 g, 87.5 mmol) in dichloromethane (200 mL) dropwise at ambient temperature. The resulting mixture was stirred at ambient temperature for 16 h and diluted with ammonium chloride (100 mL) and filtered. The filter cake was washed with acetic acid/water (1/1 , 2 x 100 mL) and hexanes (2 x 100 mL) to give 8-chloro-9-(7-hydroxy-2,3-dihydro-1 ,4-benzodioxin-6-yl)-9H- imidazo[1 ,2-a]indol-9-ol (17.7 g, 51%) as a white solid: MS (ES+) mlz 357.0 (M + 1), 359.0 (M + 1).
methyl 2-chloro-6-((2,3-dihydrobenzo[b][1,4]-dioxin-6-yl)oxy)nicotinate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
84.11%
With 1,4-diaza-bicyclo[2.2.2]octane; triethylamine; In N,N-dimethyl-formamide; at 20℃;
A 250 mL eggplant flask was sequentially charged with <strong>[65515-28-8]methyl 2,6-dichloronicotinate</strong> (3.09g, 15 mmol), 2,3-dihydrobenzo[b][1,4]dioxo-6-phenol (2.28 g, 15 mmol), and 18 mL of N, N-dimethylformamide for dissolving them. 2.7mL (6.5 mmol) of triethylamine was added dropwise under stirring at room temperature, and after completion of thedropwise addition, 252 mg (0.75 mmol) of triethylene diamine was added. The mixture was stirred at room temperaturefor 4-5 hours and the solution changed from clear to turbid. Thin layer chromatography [V (petroleum ether) / V (ethylacetate) = 6/1] detected that most of the raw material disappeared. Then, 1.30 mL of HOAc, 25 mL of isopropanol and15 mL of ice water were sequentially added while the solution changed from turbid to clear, and stirred at room temperaturefor 0.5 hour. 40 mL of water was slowly dropwise added, and after completion of the dropwise addition, stirred at roomtemperature for 2 hours. A large number of white solid precipitated and was filtered. The filter cake was washed with amixed solution of isopropyl alcohol / water = 1: 1 and dried under vacuum at 50 C for 8 hours to obtain 4.05 g of methyl2-chloro-6-((2,3-dihydrobenzo[b][1,4]dioxo-6-yl) oxy) nicotinate as a solid, 84.11 %
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