* 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.
Stage #1: With methanesulfonic acid; Celite In hexane for 1 h; Heating / reflux Stage #3: at 20℃;
Method B: A solution of the crude 1- (2, 2-diethoxyethylsulfanyl)-3-methoxybenzene (8.27 g, 32.3 mmole) in hexane (100 ml) was added, dropwise, to a solution of [METHANESULFONIC] acid (1.05 [ML,] 1.55 g, 16.1 mmole) in hexane (1000 [ML)] containing 16.5 [G] of celite (2 wt. eq. ). The resultant solution was heated at reflux for one hour. After cooling to room temperature, the reaction was quenched by addition of Et3N (4.5 ml, 3.26 g, 32.3 [MMOLE).] The crude reaction mixture was filtered and the filtrate was concentrated, in vacuo, to give a red oil which was purified by silica gel chromatography. Elution with hexane: [ET20] (98: 2) and evaporation of the appropriate fractions gave 3.35 g (63percent) of a [COLORLESS OIL.APOS;H] NMR [(DMSO-D6)] 8 7.74 [(1 H,] d, [J=8. 7HZ),] 7.56 [(1 H,] d, [J = 2. 3 HZ),] 7.52 [(1 H,] d, [J=5. 3HZ),] 7.33 (1 H, d, J = 5.3Hz), 6.99 (1 H, dd, J = 2.3, 8.7 Hz), 3.81 (3H, s). Anal. Calcd. for [C9HBOS :] C, 65.82 ; H, 4.91 ; S, 19.53. Found: C, 66.01 ; H, 5.00 ; S, 19.40.
52%
Stage #1: With boron trifluoride diethyl etherate In dichloromethane at 20℃; for 0.5 h; Stage #2: With water; sodium hydrogencarbonate In dichloromethane
Step B: The product from Step A (15.0 g, 58.5 mmol) was dissolved in methylene chloride (125 mL) and the solution was added to a solution of boron trifluoride diethyl etherate (7.86 mL, 62 mmol) in methylene chloride (900 mL) at room temperature under nitrogen. The reaction mixture was stirred for 30 minutes. Saturated sodium bicarbonate solution was added to the mixture until both phases were clear. The organic layer was extracted with methylene chloride twice. The combined organic extracts were dried over sodium sulfate and concentrated to an oil. The oil was purified by column chromatography (100percent hexanes) to give the desired 6-methoxy benzothiophene (5.0 g, 52percent) as a colorless oil: 1H NMR (500 MHz, CDCl3) δ 7.50 (d, J=5.6 Hz, 1H), 7.46 (d, J=8.1 Hz, 1H), 7.3 (d, J=5.6 Hz, 1H), 7.29-7.25 (m, 1H), 6.75 (d, J=7.8 Hz, 1H), 3.96 (s, 3H).
39%
Stage #1: With boron trifluoride diethyl etherate In dichloromethane at 20℃; for 0.5 h; Stage #2: With sodium hydrogencarbonate In water for 1 h;
A solution of this crude [1- (2, 2-DIETHOXYETHYLSULFANYL)-3-METHOXYBENZENE] (6.41 g, 25 mmole) in [CH2CI2] (50 ml) was added, dropwise, to a solution of boron [TRIFLUORIDE] etherate (3.4 [MI,] 3.81 g, 27 mmole) in CH2CI2 (500 [ML).] The resultant solution was stirred at ambient temperature for an additional 30 minutes. Aqueous saturated NaHCO3 (200 [ML)] was added and the two-phase mixture was stirred for another hour. The layers were separated and the aqueous phase was extracted with CH2CI2 (150 ml). The combined organic extracts were dried over [NA2SO4] and concentrated, in vacuo, to give 4.3 [G] of a red oil which was purified by silica gel chromatography. Elution with hexane: [ET2O] (98: 2) and evaporation of the appropriate fractions gave 1.62 g (39percent) of a colourless oil.
Reference：
[1] Patent: WO2003/106462, 2003, A1, . Location in patent: Page 34
[2] Patent: US2006/52378, 2006, A1, . Location in patent: Page/Page column 149
[3] Patent: WO2003/106462, 2003, A1, . Location in patent: Page 34
[4] Patent: WO2005/73206, 2005, A1, . Location in patent: Page/Page column 23-27
[5] Patent: US2009/286863, 2009, A1, . Location in patent: Page/Page column 7-8
[6] Patent: US6756388, 2004, B1, . Location in patent: Page/Page column 51
[7] International Journal of Chemical Kinetics, 2012, vol. 44, # 11, p. 736 - 744,9
[8] Journal of Physical Organic Chemistry, 2012, vol. 25, # 11, p. 925 - 932
2
[ 105126-91-8 ]
[ 90560-10-4 ]
Yield
Reaction Conditions
Operation in experiment
61%
Stage #1: With boron trifluoride diethyl etherate In dichloromethane at 0℃; for 0.45 h; Stage #2: With sodium hydrogencarbonate In dichloromethane; water at 8℃; for 0.0833333 h;
Boron trifluoride etherate (8.15 ml.) dissolved in dry dichloromethane (407 ml.) was stirred rapidly at 0 °C under nitrogen and a solution of (3-methoxyphenylsulphanyl)acetaldehyde (1 1.5 g, 63.10 mmol) in dry dichloromethane (29 ml.) was added dropwise over 25 min. The resultant green solution was stirred for 2 min and then saturated aqueous sodium bicarbonate solution (150 ml.) was added at a rate so as to maintain the temperature <8°C. The reaction mixture was stirred for 5 min and then the layers were separated and the organic layer was washed with saturated aqueous sodium bicarbonate solution (100 ml.) and water (100 mL). The organic phase was dried (MgSO4), and concentrated in vacuo. The product was purified by distillation to afford the title compound as a colourless oil (6.29 g, 61 percent, b.p. 83-88 °C at 16 mBar).
61%
Stage #1: at 8℃; for 0.45 h; Stage #2: With sodium hydrogencarbonate In dichloromethane; water at 8℃; for 0.0833333 h;
Boron trifluoride etherate (8.15 mL) dissolved in dry dichloromethane (407 mL) was stirred rapidly at 0 C. under nitrogen and a solution of (3-methoxyphenylsulphanyl)acetaldehyde (11.5 g, 63.10 mmol) in dry dichloromethane (29 mL) was added dropwise over 25 min. The resultant green solution was stirred for 2 min and then saturated aqueous sodium bicarbonate solution (150 mL) was added at a rate so as to maintain the temperature <8 C. The reaction mixture was stirred for 5 min and then the layers were separated and the organic layer was washed with saturated aqueous sodium bicarbonate solution (100 mL) and water (100 mL). The organic phase was dried (MgSO4), and concentrated in vacuo. The product was purified by distillation to afford the title compound as a colourless oil (6.29 g, 61percent, b.p. 83-88 C. at 16 mBar).
With boron trifluoride diethyl etherate In dichloromethane at 20℃; Inert atmosphere
To the obtained (2,2-diethoxyethyl)(3-methoxyphenyl)sulfane (91, 3.6 g, 14.0 mmol) dissolved in a dichloromethane solution (70 mL) was slowly added trifluoroborane etherate (BF3-Et2O; 1.75 mL, 13.72 mmol) at room temperature under nitrogen, and the reaction mixture was stirred for one hour and neutralized with a sodium bicarbonate solution at room temperature. Organic layer was isolated, organic compounds in water were extracted with dichloromethane, the recovered organic solution was evaporated after a treatment with sodium sulfate, and concentrated under reduced pressure. After concentration, residues were purified by column chromatography to give the target compounds 4-methoxybenzothiophene (92a, 368 mg, 16percent) and 6-methoxybenzothiophene compounds (92b, 1.38 g, 60percent) as transparent liquids.Preparation Example 14-methoxybenzothiophene (92a); 1H NMR (400 MHz, CDCl3) δ 3.95 (s, 3H), 6.74 (d, J=7.6 Hz, 1H), 7.27 (d, J=8.0 Hz, 1H), 7.32 (d, J=5.6 Hz, 1H), 7.46 (dd, J=0.8, 7.2 Hz, 1H), 7.50 (d, J=5.6 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 55.42, 103.72, 114.76, 120.44, 124.48, 125.15, 130.35, 141.21, 154.93.Preparation Example 26-methoxybenzothiophene (92b); 1H NMR (400 MHz, CDCl3) δ 3.82 (s, 3H), 7.01 (dd, J=8.8, 2.0 Hz, 1H), 7.56 (d, J=2.0 Hz, 2H), 7.82 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 56.0, 105.3, 114.9, 125.1, 131.4, 135.3, 138.9, 144.9, 158.0.
Reference：
[1] Helvetica Chimica Acta, 2016, vol. 99, # 5, p. 384 - 392
[2] Patent: US2010/261727, 2010, A1, . Location in patent: Page/Page column 17
[3] Journal of Medicinal Chemistry, 1989, vol. 32, # 12, p. 2548 - 2554
[4] Journal of Organic Chemistry, 1995, vol. 60, # 7, p. 1936 - 1938
[5] Phosphorus, Sulfur and Silicon and the Related Elements, 1994, vol. 96, # 1-4, p. 441 - 444
[6] Bioorganic and Medicinal Chemistry Letters, 1999, vol. 9, # 5, p. 759 - 764
[7] Patent: WO2009/5998, 2009, A1, . Location in patent: Page/Page column 177-178
[8] Patent: WO2008/157270, 2008, A1, . Location in patent: Page/Page column 93-94
4
[ 98733-08-5 ]
[ 90560-10-4 ]
Yield
Reaction Conditions
Operation in experiment
407 mg
With polyphosphoric acid In toluene at 80℃; for 1 h;
To a stirred solution of 1 -[(2,2-dimethoxyethyt)sutfanyt]-3-methoxybenzene (1.0 g) in chlorobenzene (40 mL) was added polyphosphoric acid (1.0 g; CASRN: [8017-16-1]; >83percent phosphate (as P205) from Sigma-Aldrich; Order No. 04101) and the mixture was heated to 80CC for 1 h. The mixture was cooled to0°C with an ice-bath and an aqueous solution of sodium hydroxide was addedwith ice bath cooling until pH7 was reached. The mixture was extracted with dichloromethane, the organic phase was dried (sodium sulfate) and the solvent was removed in vacuum. Silicagel chromatography gave 407 mg of the title compound, containing approx. 20percent of a second isomer. This mixture was used for the next step without further purification. 1H-NMR (400 MHz, DMSO-d6), 6 [ppm] = 3.81 (3H), 6.99 (1H), 7.31-7.35 (1H),7.51 (1H), 7.56 (IH), 7.74 (1H). The product contains approx. 20percent of a second isomer.
Reference：
[1] Proceedings - Indian Academy of Sciences, Section A, 1951, # 33, p. 35,40
[2] Patent: WO2014/195276, 2014, A1, . Location in patent: Page/Page column 117
[3] Patent: WO2014/198594, 2014, A1, . Location in patent: Page/Page column 113; 114
5
[ 15570-12-4 ]
[ 2032-35-1 ]
[ 90560-10-4 ]
Reference：
[1] Journal of Medicinal Chemistry, 2002, vol. 45, # 7, p. 1399 - 1401
[2] Patent: EP2103620, 2009, A1, . Location in patent: Page/Page column 72-73
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 1999, vol. 9, # 5, p. 759 - 764
[2] Journal of Medicinal Chemistry, 1989, vol. 32, # 12, p. 2548 - 2554
[3] European Journal of Medicinal Chemistry, 1986, vol. 21, # 3, p. 223 - 229
[4] International Journal of Chemical Kinetics, 2012, vol. 44, # 11, p. 736 - 744,9
[5] Patent: WO2014/195276, 2014, A1,
[6] Patent: WO2014/198594, 2014, A1,
9
[ 15570-12-4 ]
[ 96803-85-9 ]
[ 2032-35-1 ]
[ 90560-10-4 ]
Yield
Reaction Conditions
Operation in experiment
63%
With methanesulfonic acid; trifluoroborane diethyl ether; sodium hydrogencarbonate; potassium carbonate; triethylamine In hexane; dichloromethane; acetone
Example (1a) 6-methoxybenzo[b]thiophene A mixture of 3-methoxybenzenethiol (10 ml, 11.30 g, 80 mmole), K2CO3 (11.15 g, 80 mmole) and bromoacetaldehyde diethyl acetal (12 ml, 15.72 g, 80 mmole) in acetone (100 ml) was stirred at ambient temperature for 16 hours, then filtered. The filtrate was subsequently concentrated, in vacuo. The residue obtained was partitioned between H2O (150 ml) and Et2O (150 ml). The layers were separated and the aqueous phase was extracted with Et2O (150 ml). The combined organic extracts were washed with 0.5 M KOH (aq), H2O and brine, then dried over Na2SO4 and concentrated, in vacuo, to give 20.4 g of an amber oil which was used directly in the subsequent cyclization without any further purification. Method A: A solution of this crude 1-(2,2-diethoxyethylsulfanyl)-3-methoxybenzene (6.41 g, 25 mmole) in CH2Cl2 (50 ml) was added, dropwise, to a solution of boron trifluoride etherate (3.4 ml, 3.81 g, 27 mmole) in CH2Cl2 (500 ml). The resultant solution was stirred at ambient temperature for an additional 30 minutes. Aqueous saturated NaHCO3 (200 ml) was added and the two-phase mixture was stirred for another hour. The layers were separated and the aqueous phase was extracted with CH2Cl2 (150 ml). The combined organic extracts were dried over Na2SO4 and concentrated, in vacuo, to give 4.3 g of a red oil which was purified by silica gel chromatography. Elution with hexane: Et2O (98:2) and evaporation of the appropriate fractions gave 1.62 g (39percent) of a colourless oil. Method B: A solution of the crude 1-(2,2-diethoxyethylsulfanyl)-3-methoxybenzene (8.27 g, 32.3 mmole) in hexane (100 ml) was added, dropwise, to a solution of methanesulfonic acid (1.05 ml, 1.55 g, 16.1 mmole) in hexane (1000 ml) containing 16.5 g of celite (2 wt. eq.). The resultant solution was heated at reflux for one hour. After cooling to room temperature, the reaction was quenched by addition of Et3N (4.5 ml, 3.26 g, 32.3 mmole). The crude reaction mixture was filtered and the filtrate was concentrated, in vacuo, to give a red oil which was purified by silica gel chromatography. Elution with hexane: Et2O (98:2) and evaporation of the appropriate fractions gave 3.35 g (63percent) of a colorless oil. 1H NMR (DMSO-d6) δ7.74 (1H, d, J=8.7 Hz), 7.56 (1H, d, J=2.3 Hz), 7.52 (1H, d, J=5.3 Hz) 7.33 (1H, d, J=5.3 Hz), 6.99 (1H, dd, J=2.3, 8.7 Hz), 3.81 (3H, s). Anal. Calcd. for C9H8OS: C, 65.82; H, 4.91; S, 19.53. Found: C, 66.01; H, 5.00; S, 19.40.
With n-butyllithium; In tetrahydrofuran; hexane; at -75 - 20℃; for 1h;
A 2.5 M solution of n-butyllithium in hexanes (20 [ML,] 50 [MMOLE)] was added under argon to a solution of 6-methoxybenzo [b] thiophene 1a (3.68 g, 22.4 mmole) in THF (150 ml) [AT-75°.] After [STIRRING AT-75°] for a further 30 minutes, the cooling bath was exchanged and the reaction warmed [TO-10°C] prior to addition of CH31 (4.2 ml, 9.58 g, 67 mmole). The resultant mixture was stirred at [0°C] for an additional 30 minutes, then allowed to gradually warm to room temperature before diluting with saturated [NAHC03] (150 ml). The layers were separated and the aqueous phase was extracted with EtOAc (2 x 100 ml). The combined organic extracts were dried over [NA2SO4] and concentrated, in vacuo, to give 4.2 [G] of an amber oil which was purified by silica gel chromatography. Elution with hexane: [ETZO] (98: 2) and evaporation of the appropriate fractions gave 3.63 [G] (91percent) of a colourless oil.'H NMR (DMSO-d6) 8 7.57 (1 H, d, J = 8.7 Hz), 7.43 (1 H, d, J = 2.4 Hz), 6.99 (1 H, s), 6.92 (1 H, dd, [J =] 2.4, 8.7 Hz), 3.78 (3H, s), 2.50 (3H, s). Anal. Calcd. for [C, OHIOOS] : C, 67.38 ; H, 5.66 ; S, 17.99. Found: C, 67.42 ; H, 5.74 ; S, 17.87.
With 3-chloro-benzenecarboperoxoic acid; In dichloromethane; for 5.33333 - 5.5h;Heating / reflux;
To a mixture of 3-methoxythiophenol and potassium carbonate in 850 mL of acetone is added dropwise bromoacetaldehyde diethyl acetal at room temperature. The heterogeneous mixture is stirred for 18 hrs and then filtered through a glass frit to remove salts. The filtered cake is washed (2 x 250 mL) with acetone and the filtrate is concentrated using a rotor evaporator. The filtrate is dissolved in diethyl ether (840 mL) and washed with water (850 mL), IN NaOH (850 mL), and then brine (850 mL). The organic layer is dried over magnesium sulfate and concentrated using a rotor evaporator to give 212g of a crude intermediate. A 12 L flask is charged with 51 mL of boron trifluoride etherate and dissolved in 7.6 L of dichloromethane. 100 g of the crude intermediate prepared above is dissolved in 771 mL of dichloromethane and placed in a 1 L addition funnel. This mixture is added dropwise over the course of 30-45 min. After the addition is complete, the mixture is stirred for an additional hour and then 1 L of sat. sodium bicarbonate is added. The mixture is stirred until both layers are clear. The aqueous layer is extracted with an additional 500 mL of dichloromethane. The combined organic solutions are dried over magnesium sulfate and concentrated under a rotor evaporator (63.1 g crude). The residue is purified by the following protocol: 250 mL of heptane is added to the mixture and stirred for 15 min. This mixture is filtered through a silica gel plug which is washed with heptane (5 x 250 mL) and concentrated (40.83 g). The residue is distilled under vacuum (148 °C/3 mm Hg) to provide <strong>[90560-10-4]6-methoxybenzothiophene</strong>. A 5 L flask is charged with <strong>[90560-10-4]6-methoxybenzothiophene</strong> (25.26g) and dissolved in 1.4 L of dichloromethane. m-CBPA (85g) is added in portions over a 20-30 minute period. The mixture is heated to reflux for about 5 hours and the reaction monitored by HPLC. The mixture is cooled to room temperature and 950 mL of sodium hydrogen sulfite is added. The solution is stirred for 15 minutes. The aqueous layer is removed and the organic phase is washed with aqueous sodium bicarbonate (-2x950 mL). The organic phase is separated, dried over magnesium sulfate and concentrated to give the sulfone compound as a greenish solid (26.56g crude). Purification of the sulfone is conducted as follows: the crude material is first recrystallized from EtOH/hexanes to give 15.64g of product (59percent recovery). A second crop is recrystallized from EtOH to give 2.26g of product, improving the recovery to 68percent. A flask is charged with <strong>[90560-10-4]6-methoxybenzothiophene</strong> sulfone (6. 31g) and dissolved in 115 mL of chloroform. Bromine (dissolved in 10 mL of chloroform) is added dropwise over the course of 10 minutes. After about 4.5 hours TLC reveals consumption of starting material. The reaction is quenched by addition of triethylamine (5 mL). After stirring at room temperature for about 30 minutes, 450 mL of H20 is added. The organic layer is separated and washed with 450 mL of brine, dried over magnesium sulfate and concentrated (11.50 g crude). After charcoal treatment, 7.73g of 6-methoxy-2- bromobenzothiophene sulfone is isolated. The brominated sulfone is purified according to the following protocol: 50 mL of EtOH is added to the crude material and the mixture is heated to reflux for 45 minutes and brought to room temperature. After cooling in an ice bath for 30 minutes the solid is filtered through a glass frit and washed with cold EtOH (-3x20 mL). 6-Methoxy-2-bromobenzothiophene sulfone (6.29 g) is recovered as a first crop (81percent). A flask is charged with 6-methoxy-2-bromobenzothiophene sulfone (8.05g) and 100 mL of chloroform is added. Bromine (7.0 g, 1.5 eq. ) in 50 mL of chloroform is added via addition funnel over the course of 20-30 minutes. After stirring for about 13 hours HPLC shows 3.5percent starting material. 10 mL of triethylamine is added. After stirring at room temperature for 4 hours, 450 mL of H20 is added and the organic layer is extracted. The organic layer is washed with 450 mL of brine and subsequently dried over magnesium sulfate and concentrated to give 6-methoxy-2,3-dibromobenzothiophene sulfone as a brownish solid. The dibrominated sulfone compound is purified according to the following protocol: 70 mL of EtOH is added to the compound and the mixture is heated to reflux for 45 minutes. The hot solution is cooled to room temperature and placed in an ice bath for 30 minutes. The crystals are filtered through a glass frit and washed with several portions of cold EtOH (-3x20 mL) to give the dibrominated product (8.18 g) in 79percent overall yield. A flask is charged with 6-methoxy-2,3-dibromobenzothiophene sulfone (11.42 g) and 311 mL of THF is added. The temperature is reduced to 5 °C and the mixture is stirred at this temperature for about 15 minutes. Solid 4- (2-piperidin-1-yl-ethoxy)-phenol (7. 84 g, 1.1 eq. ) is added, followed by cesium carbonate (31.5 g, 3.0 eq. ). The mixture is stirred for 15 minutes and the...
68%
To a mixture of 3-methoxythiophenol and potassium carbonate in 850 mL of acetone is added dropwise bromoacetaldehyde diethyl acetal at room temperature. The heterogeneous mixture is stirred for 18 hrs and then filtered through a glass frit to remove salts. The filtered cake is washed (2 x 250 mL) with acetone and the filtrate is concentrated using a rotor evaporator. The filtrate is dissolved in diethyl ether (840 mL) and washed with water (850 mL), 1N NaOH (850 mL), and then brine (850 mL). The organic layer is dried over magnesium sulfate and concentrated using a rotor evaporator to give 212g of a crude intermediate. A 12 L flask is charged with 51 mL of boron trifluoride etherate and dissolved in 7.6 L of dichloromethane. 100 g of the crude intermediate prepared above is dissolved in 771 mL of dichloromethane and placed in a 1 L addition funnel. This mixture is added dropwise over the course of 30-45 min. After the addition is complete, the mixture is stirred for an additional hour and then 1 L of sat. sodium bicarbonate is added. The mixture is stirred until both layers are clear. The aqueous layer is extracted with an additional 500 mL of dichloromethane. The combined organic solutions are dried over magnesium sulfate and concentrated under a rotor evaporator (63.1 g crude). The residue is purified by the following protocol: 250 mL of heptane is added to the mixture and stirred for 15 min. This mixture is filtered through a silica gel plug which is washed with heptane (5 x 250 mL) and concentrated (40.83 g). The residue is distilled under vacuum (148 °C/3 mm Hg) to provide <strong>[90560-10-4]6-methoxybenzothiophene</strong>. A 5 L flask is charged with <strong>[90560-10-4]6-methoxybenzothiophene</strong> (25.26g) and dissolved in 1.4 L of dichloromethane. m-CBPA (85g) is added in portions over a 20-30 minute period. The mixture is heated to reflux for about 5 hours and the reaction monitored by HPLC. The mixture is cooled to room temperature and 950 mL of sodium hydrogen sulfite is added. The solution is stirred for 15 minutes. The aqueous layer is removed and the organic phase is washed with aqueous sodium bicarbonate (-2x950 mL). The organic phase is separated, dried over magnesium sulfate and concentrated to give the sulfone compound as a greenish solid (26.56g crude). Purification of the sulfone is conducted as follows: the crude material is first recrystallized from EtOH/hexanes to give 15.64g of product (59percent recovery). A second crop is recrystallized from EtOH to give 2.26g of product, improving the recovery to 68percent. A flask is charged with <strong>[90560-10-4]6-methoxybenzothiophene</strong> sulfone (6.31g) and dissolved in 115 mL of chloroform. Bromine (dissolved in 10 mL of chloroform) is added dropwise over the course of 10 minutes. After about 4.5 hours TLC reveals consumption of starting material. The reaction is quenched by addition of triethylamine (5 mL). After stirring at room temperature for about 30 minutes, 450 mL of H20 is added. The organic layer is separated and washed with 450 mL of brine, dried over magnesium sulfate and concentrated (11.50 g crude). After charcoal treatment, 7.73g of 6-methoxy-2- bromobenzothiophene sulfone is isolated. The brominated sulfone is purified according to the following protocol: 50 mL of EtOH is added to the crude material and the mixture is heated to reflux for 45 minutes and brought to room temperature. After cooling in an ice bath for 30 minutes the solid is filtered through a glass frit and washed with cold EtOH (-3x20 mL). 6-Methoxy-2-bromobenzothiophene sulfone (6.29 g) is recovered as a first crop (81percent). A flask is charged with 6-methoxy-2-bromobenzothiophene sulfone (8. 05g) and 100 mL of chloroform is added. Bromine (7.0 g, 1.5 eq. ) in 50 mL of chloroform is added via addition funnel over the course of 20-30 minutes. After stirring for about 13 hours HPLC shows 3.5percent starting material. 10 mL of triethylamine is added. After stirring at room temperature for 4 hours, 450 mL of H20 is added and the organic layer is extracted. The organic layer is washed with 450 mL of brine and subsequently dried over magnesium sulfate and concentrated to give 6-methoxy-2, 3-dibromobenzothiophene sulfone as a brownish solid. The dibrominated sulfone compound is purified according to the following protocol: 70 mL of EtOH is added to the compound and the mixture is heated to reflux for 45 minutes. The hot solution is cooled to room temperature and placed in an ice bath for 30 minutes. The crystals are filtered through a glass frit and washed with several portions of cold EtOH (~ 3x20 mL) to give the dibrominated product (8. 18 g) in 79percent overall yield. A flask is charged with 6-methoxy-2,3-dibromobenzothiophene sulfone (11.42 g) and 311 mL of THF is added. The temperature is reduced to 5 °C and the mixture is stirred at this temperature for about 15 minutes. Solid 4- (2-piperidin-1-yl-ethoxy)-phenol (7.84 g, 1. 1 eq. ) is added, followed by cesium carbonate (31.5 g, 3.0 eq. ). The mixture is stirred for 15 minutes and ...
With 3-chloro-benzenecarboperoxoic acid; In chloroform; at 0 - 20℃; for 2h;
To a stirred solution of 6-methoxy-1 -benzothiophene (700 mg) in chloroform (1 1 mL) at 0°C was added 3-chlorobenzenecarboperoxoic acid (1 .99 g) and the mixture was stirred for 2 h at r.t.. An aqueous solution of disodium sulfurothioate was added, the mixture was stirred for 30 minutes and was consecutively extracted with ethyl acetate and with dichloromethane. Both organic phases were washed with a half saturated sodium bicarbonate solution and with saturated sodium chloride solution. The organic phases were combined, dried (sodium sulfate) and the solvent was removed in vacuum. Silicagel chromatography gave 612 mg of the title compound, containing approx. 20percent of a second isomer. This mixture was used for the next step without further purification.1H-NMR (400 MHz, DMSO-d6), delta [ppm] = 3.86 (3H), 7.15-7.22 (2H), 7.45 (1 H), 7.49 (1 H), 7.54 (1 H).
612 mg
With 3-chloro-benzenecarboperoxoic acid; In chloroform; at 0 - 20℃; for 2h;
To a stirred soLution of <strong>[90560-10-4]6-methoxy-1-benzothiophene</strong> (700 mg) in chloroform (11 mL) at 0°C was added 3-chlorobenzenecarboperoxoic acid (1 .99 g) and themixture was stirred for 2 h at r.t.. An aqueous solution of disodium sulfurothioate was added, the mixture was stirred for 30 minutes and was consecutively extracted with ethyl acetate and with dichloromethane. Both organic phases were washed with a half saturated sodium bicarbonate solution and with saturated sodium chloride solution. The organic phases werecombined, dried (sodium sulfate) and the solvent was removed in vacuum. Siticagel chromatography gave 612 mg of the title compound, containing approx. 20percent of a second isomer. This mixture was used for the next step without further purification.1H-NMR (400 MHz, DMSO-d6), 6 [ppm] = 3.86 (3H), 7.15-7.22 (2H), 7.45 (1H),7.49 (1H), 7.54 (1H).
Method B: A solution of the crude 1- (2, 2-diethoxyethylsulfanyl)-3-methoxybenzene (8.27 g, 32.3 mmole) in hexane (100 ml) was added, dropwise, to a solution of [METHANESULFONIC] acid (1.05 [ML,] 1.55 g, 16.1 mmole) in hexane (1000 [ML)] containing 16.5 [G] of celite (2 wt. eq. ). The resultant solution was heated at reflux for one hour. After cooling to room temperature, the reaction was quenched by addition of Et3N (4.5 ml, 3.26 g, 32.3 [MMOLE).] The crude reaction mixture was filtered and the filtrate was concentrated, in vacuo, to give a red oil which was purified by silica gel chromatography. Elution with hexane: [ET20] (98: 2) and evaporation of the appropriate fractions gave 3.35 g (63%) of a [COLORLESS OIL.'H] NMR [(DMSO-D6)] 8 7.74 [(1 H,] d, [J=8. 7HZ),] 7.56 [(1 H,] d, [J = 2. 3 HZ),] 7.52 [(1 H,] d, [J=5. 3HZ),] 7.33 (1 H, d, J = 5.3Hz), 6.99 (1 H, dd, J = 2.3, 8.7 Hz), 3.81 (3H, s). Anal. Calcd. for [C9HBOS :] C, 65.82 ; H, 4.91 ; S, 19.53. Found: C, 66.01 ; H, 5.00 ; S, 19.40.
52%
Step B: The product from Step A (15.0 g, 58.5 mmol) was dissolved in methylene chloride (125 mL) and the solution was added to a solution of boron trifluoride diethyl etherate (7.86 mL, 62 mmol) in methylene chloride (900 mL) at room temperature under nitrogen. The reaction mixture was stirred for 30 minutes. Saturated sodium bicarbonate solution was added to the mixture until both phases were clear. The organic layer was extracted with methylene chloride twice. The combined organic extracts were dried over sodium sulfate and concentrated to an oil. The oil was purified by column chromatography (100% hexanes) to give the desired 6-methoxy benzothiophene (5.0 g, 52%) as a colorless oil: 1H NMR (500 MHz, CDCl3) delta 7.50 (d, J=5.6 Hz, 1H), 7.46 (d, J=8.1 Hz, 1H), 7.3 (d, J=5.6 Hz, 1H), 7.29-7.25 (m, 1H), 6.75 (d, J=7.8 Hz, 1H), 3.96 (s, 3H).
39%
A solution of this crude [1- (2, 2-DIETHOXYETHYLSULFANYL)-3-METHOXYBENZENE] (6.41 g, 25 mmole) in [CH2CI2] (50 ml) was added, dropwise, to a solution of boron [TRIFLUORIDE] etherate (3.4 [MI,] 3.81 g, 27 mmole) in CH2CI2 (500 [ML).] The resultant solution was stirred at ambient temperature for an additional 30 minutes. Aqueous saturated NaHCO3 (200 [ML)] was added and the two-phase mixture was stirred for another hour. The layers were separated and the aqueous phase was extracted with CH2CI2 (150 ml). The combined organic extracts were dried over [NA2SO4] and concentrated, in vacuo, to give 4.3 [G] of a red oil which was purified by silica gel chromatography. Elution with hexane: [ET2O] (98: 2) and evaporation of the appropriate fractions gave 1.62 g (39%) of a colourless oil.
boron trifluoride diethyl etherate; In dichloromethane; for 0.5 - 0.75h;
To a mixture of 3-methoxythiophenol and potassium carbonate in 850 mL of acetone is added dropwise bromoacetaldehyde diethyl acetal at room temperature. The heterogeneous mixture is stirred for 18 hrs and then filtered through a glass frit to remove salts. The filtered cake is washed (2 x 250 mL) with acetone and the filtrate is concentrated using a rotor evaporator. The filtrate is dissolved in diethyl ether (840 mL) and washed with water (850 mL), IN NaOH (850 mL), and then brine (850 mL). The organic layer is dried over magnesium sulfate and concentrated using a rotor evaporator to give 212g of a crude intermediate. A 12 L flask is charged with 51 mL of boron trifluoride etherate and dissolved in 7.6 L of dichloromethane. 100 g of the crude intermediate prepared above is dissolved in 771 mL of dichloromethane and placed in a 1 L addition funnel. This mixture is added dropwise over the course of 30-45 min. After the addition is complete, the mixture is stirred for an additional hour and then 1 L of sat. sodium bicarbonate is added. The mixture is stirred until both layers are clear. The aqueous layer is extracted with an additional 500 mL of dichloromethane. The combined organic solutions are dried over magnesium sulfate and concentrated under a rotor evaporator (63.1 g crude). The residue is purified by the following protocol: 250 mL of heptane is added to the mixture and stirred for 15 min. This mixture is filtered through a silica gel plug which is washed with heptane (5 x 250 mL) and concentrated (40.83 g). The residue is distilled under vacuum (148 C/3 mm Hg) to provide 6-methoxybenzothiophene. A 5 L flask is charged with 6-methoxybenzothiophene (25.26g) and dissolved in 1.4 L of dichloromethane. m-CBPA (85g) is added in portions over a 20-30 minute period. The mixture is heated to reflux for about 5 hours and the reaction monitored by HPLC. The mixture is cooled to room temperature and 950 mL of sodium hydrogen sulfite is added. The solution is stirred for 15 minutes. The aqueous layer is removed and the organic phase is washed with aqueous sodium bicarbonate (-2x950 mL). The organic phase is separated, dried over magnesium sulfate and concentrated to give the sulfone compound as a greenish solid (26.56g crude). Purification of the sulfone is conducted as follows: the crude material is first recrystallized from EtOH/hexanes to give 15.64g of product (59% recovery). A second crop is recrystallized from EtOH to give 2.26g of product, improving the recovery to 68%. A flask is charged with 6-methoxybenzothiophene sulfone (6. 31g) and dissolved in 115 mL of chloroform. Bromine (dissolved in 10 mL of chloroform) is added dropwise over the course of 10 minutes. After about 4.5 hours TLC reveals consumption of starting material. The reaction is quenched by addition of triethylamine (5 mL). After stirring at room temperature for about 30 minutes, 450 mL of H20 is added. The organic layer is separated and washed with 450 mL of brine, dried over magnesium sulfate and concentrated (11.50 g crude). After charcoal treatment, 7.73g of 6-methoxy-2- bromobenzothiophene sulfone is isolated. The brominated sulfone is purified according to the following protocol: 50 mL of EtOH is added to the crude material and the mixture is heated to reflux for 45 minutes and brought to room temperature. After cooling in an ice bath for 30 minutes the solid is filtered through a glass frit and washed with cold EtOH (-3x20 mL). 6-Methoxy-2-bromobenzothiophene sulfone (6.29 g) is recovered as a first crop (81%). A flask is charged with 6-methoxy-2-bromobenzothiophene sulfone (8.05g) and 100 mL of chloroform is added. Bromine (7.0 g, 1.5 eq. ) in 50 mL of chloroform is added via addition funnel over the course of 20-30 minutes. After stirring for about 13 hours HPLC shows 3.5% starting material. 10 mL of triethylamine is added. After stirring at room temperature for 4 hours, 450 mL of H20 is added and the organic layer is extracted. The organic layer is washed with 450 mL of brine and subsequently dried over magnesium sulfate and concentrated to give 6-methoxy-2,3-dibromobenzothiophene sulfone as a brownish solid. The dibrominated sulfone compound is purified according to the following protocol: 70 mL of EtOH is added to the compound and the mixture is heated to reflux for 45 minutes. The hot solution is cooled to room temperature and placed in an ice bath for 30 minutes. The crystals are filtered through a glass frit and washed with several portions of cold EtOH (-3x20 mL) to give the dibrominated product (8.18 g) in 79% overall yield. A flask is charged with 6-methoxy-2,3-dibromobenzothiophene sulfone (11.42 g) and 311 mL of THF is added. The temperature is reduced to 5 C and the mixture is stirred at this temperature for about 15 minutes. Solid 4- (2-piperidin-1-yl-ethoxy)-phenol (7. 84 g, 1.1 eq. ) is added, followed by cesium carbonate (31.5 g, 3.0 eq. ). The mixture is stirred for 15 minutes and then slowly brought to room tempera...
With boron trifluoride diethyl etherate; In dichloromethane; for 4h;
244 ml of boron trifluoride/ethyl ether complex (1.94 mol) are dissolved in 20 l of dichloromethane at 15 C. Unit 1 is subsequently dissolved in 5 l of dichloromethane at 20 C. and added dropwise over the course of 1 h. The reaction mixture is stirred for 3 h, 5 l of water are added, and the mixture is stirred for a further 1 h. The organic phase is separated off, washed with 3 l of water and 4 l of a saturated sodium hydrogencarbonate solution, dried over sodium sulfate, filtered and evaporated, giving a red oil (341 g, 75% yield), which is identified as unit 2.
With boron trifluoride diethyl etherate; In dichloromethane; at 20℃; for 4.5h;
Example 16 [00381] Step 1 [00382] 1-(2,2-Diethoxy-ethylsulfanyl)-3-methoxy-benzene. To a solution of 3-methoxybenzenethiol (15.0 mL, 120 mmol) and potassium carbonate (16.6 gm, 120 mmol) in 150 mL of acetone at room temperature was added dropwise 2-bromo-1,1-diethoxy-ethane (16.5 mL, 110 mmol). The reaction mixture was stirred at room temperature for 16 hours. The solids in the reaction mixture were removed by filtration and were washed well with acetone. The filtrate was concentrated. The residue was diluted with water and extracted several times with ether. The ether layers were combined and washed with 0.5 M KOH, water, brine, and were then dried over anhydrous sodium sulfate, filtered, and concentrated to yield 28.2 gm of the title compound. [00383] Step 2 [00384] 6-Methoxy-benzo[b]thiophene. To a solution of boron trifluoride etherate (14.45 mL, 115 mmol) in 2000 mL of methylene chloride stirring in a cold water bath 20 C. was added dropwise 1-(2,2-Diethoxy-ethylsulfanyl)-3-methoxy-benzene (28.2 gm, 110 mmol) dissolved in 500 mL of methylene chloride. The addition was complete in 3 hrs. and then the reaction was warmed to room temperature for a further 1.5 hrs. The reaction mixture was then quenched with saturated sodium bicarbonate solution. The organic layer was separated and the aqueous layer was back extracted several times with methylene chloride. The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was chromatographed on silica gel (using a gravity column) using hexanes as the eluant to yield 10.9 gm of the title compound. [00385] General Procedure for the Synthesis of Compunds of Formula IV [00386] The general scheme is outlined in Scheme 8b. Three sets of conditions are used for the acylation step and they are described below. Table 2 lists the compounds with relevant data and which procedure was used in each case. [00387] Step 3 [00388] 6-Methoxy-2-phenyl-benzo[b]thiophene. To a solution of 6-Methoxy -benzo[b]thiophene (250 mg, 1.52 mmol) in 3.7 mL THF at -20 C. was added dropwise n-butyllithium (0.67 mL, 1.67 mmol). The mixture was stirred at 0 C. for 1.5 hrs. and at room temperature for 0.5 hrs. Anhydrous zinc chloride (269 mg, 1.97 mmol) in 1.9 mL of THF was added by cannula to the reaction. The reaction was then stirred at room temperature for 15 minutes and then Pd(Ph3P)4 (70 mg, 0.06 mmol) and iodobenzene (0.22 mL, 1.97 mmol) were added and the reaction stirred at room temperature for 3 hrs. Other aromatic or heteroaromatic bromides, iodides or triflates can replace iodobenzene in this procedure. If a triflate is used 3 equivalents of anhydrous lithium chloride must be added. The reaction can be refluxed overnight to push it towards completion. The solvent was evaporated and the residue was diluted water and extracted into ethyl acetate. The combined organic layers was dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was chromatographed on silica gel using 100% Hexanes to 1% ethyl acetate/hexanes as the gradient eluant to yield 250 mg of the title compound. [00389] Acylation Procedure A [00390] Step 4 [00391] (6-Hydroxy-2-phenyl-benzo[b]thiophen-3-yl)-[4-(2-piperidin-1-yl-ethoxy) -phenyl]-methanone. A solution of the product from Step 3, Example 16 (272 mg, 1.13 mmol), 4-(2-Piperidin-1-yl-ethoxy)-benzoyl chloride (7.9 mL, 1.53 mmol), and titanium tetrachloride (6.62 mL, 5.66 mmol) in 16.5 mL of methylene chloride was stirred at room temperature for 6 hrs. To demethylate, ethanethiol (0.335 mL, 4.53 mmol) and AlCl3 (600 mg, 4.53 mmol) in two portions were added to the reaction and it was stirred for an additional 2.5 hrs. The reaction was quenched with saturated sodium bicarbonate solution and the solution was extracted twice with methylene chloride. The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was chromatographed on silica gel using 1% MeOH: CH2Cl2 to 5% MeOH CH2Cl2 as the gradient eluant to obtain 231 mg of the title compound. [00392] 1H NMR (MeOH-d4) delta7.70(d, 2H), 7.40(m, 3H), 7.30(d, 1H), 7.25(m, 3H), 6.90(d, 1H), 6.85(d, 2H), 4.15(t, 2H), 2.75(t, 2H), 2.55(m, 4H), 1.60(m, 4H), 1.50(m, 2H)
2.4 g
With polyphosphoric acid; In chlorobenzene; at 110℃;
The intermediate (5 g) was dissolved in 50 mL of chlorobenzene, 5 g of polyphosphoric acid was added, and the mixture was heated to 110 C overnight, and TLC showed the reaction was completed. After cooling, 10% sodium hydroxide solution was added dropwise to adjust the pH to 7, and water and ethyl acetate were added for extraction.The organic phase was washed with water and saturated brine and dried over anhydrous sodium sulfate.Column chromatography gave 2.43 g of a white solid.
8 g
With boron trifluoride diethyl etherate; In dichloromethane; at 0 - 20℃; for 1h;
To BF3.Et20 (24 mL) in CH2CI2(2000 mL) at 0C was added a solution of (2,2- diethoxyethyl)(3-methoxyphenyl)sulfane T05-2 (25 g, 97.65 mmol) in CH2CI2(200 mL) drop wise. The reaction mixture was allowed to attain room temperature and stirred for 1 h. After completion of the reaction, the reaction mixture was quenched with saturated NaHC03solution and extracted with CH2CI2. The combined organic layer was dried over anhydrous Na2S04, filtered and concentrated under reduced pressure. The resulting crude compound was purified by silica gel column chromatography eluting with 0-5% CH2CI2in -hexane to afford 8 g (50% yield) of compound T05-4 as colourless oil.*H NMR (400 MHz, DMSO-afe) 5: 7.74 (d, J= 8.80 Hz, 1H), 7.55 (d, J= 2.45 Hz, 1H), 7.51 (d, J= 5.38 Hz, 1H), 7.32 (d, J= 5.38 Hz, 1H), 6.99 (dd, J= 2.45, 8.80 Hz, 1H), 3.80 (s, 3H).
With N-Bromosuccinimide; toluene-4-sulfonic acid; In 1,2-dichloro-ethane; at 70℃; for 0.583333h;
N-BROMOSUCCINIMIDE (14.70 g, 82.59 mmol) and p-toluenesulfonic acid (2.70 g, 15.68 mmol) were added to a solution of benzothiophene (3) (15. 10 g, 92.07 mmol) in 1,2-dichloroethane (300 ml). The mixture was maintained at 70°C for 35 min, cooled in an ice bath, and the succinimide was removed by filtration. The solution was extracted with saturated sodium bicarbonate solution, dried over Na2SO4, filtered, and concentrated under vacuum to give 22. 00 g as an oil. Crystallisation from pentane afforded a white solid (16.50 g, 74 percent), mp 62°C. 1H-NMR (CDC13) : 3. 85 (s, 3H), 6.9 (dd, 1H), 7.50 (m, 2H), 7.65 (d, 1H)
With boron trifluoride diethyl etherate; In dichloromethane; at 20℃;
A solution of (2) (13.00 g, 0.051 mol) in CH2C12 (100 ml) was added dropwise to a solution of BF3. Et2O (6.70 ML, 0.054 mol) in CH2CL2 (1000 ml) at room temperature under nitrogen atmosphere. After hydrolysis, the reaction mixture was stirred until both phases became clear. The CH2C12 layer was separated, and the aqueous layer was extracted with CH2C12. The combined organic phases were dried over NA2S04, filtered, and concentrated under vacuum to give 8. 68 g of a 1: 10 mixture of 4 and 6-methoxybenzothiophene (3) as a dark brown oil. The crude product was used without purification. Major isomer (3) 1H-NMR (CDC13): 3.85 (s, 3H), 6.98 (dd, 1H), 7.23 (s, 2H), 7.35 (d, 1H), 7.68 (d, 1 H).
With boron trifluoride diethyl etherate; sodium hydrogencarbonate; In dichloromethane; for 1.5 - 1.75h;
To a mixture of 3-methoxythiophenol and potassium carbonate in 850 mL of acetone is added dropwise bromoacetaldehyde diethyl acetal at room temperature. The heterogeneous mixture is stirred for 18 hrs and then filtered through a glass frit to remove salts. The filtered cake is washed (2 x 250 mL) with acetone and the filtrate is concentrated using a rotor evaporator. The filtrate is dissolved in diethyl ether (840 mL) and washed with water (850 mL), 1N NaOH (850 mL), and then brine (850 mL). The organic layer is dried over magnesium sulfate and concentrated using a rotor evaporator to give 212g of a crude intermediate. A 12 L flask is charged with 51 mL of boron trifluoride etherate and dissolved in 7.6 L of dichloromethane. 100 g of the crude intermediate prepared above is dissolved in 771 mL of dichloromethane and placed in a 1 L addition funnel. This mixture is added dropwise over the course of 30-45 min. After the addition is complete, the mixture is stirred for an additional hour and then 1 L of sat. sodium bicarbonate is added. The mixture is stirred until both layers are clear. The aqueous layer is extracted with an additional 500 mL of dichloromethane. The combined organic solutions are dried over magnesium sulfate and concentrated under a rotor evaporator (63.1 g crude). The residue is purified by the following protocol: 250 mL of heptane is added to the mixture and stirred for 15 min. This mixture is filtered through a silica gel plug which is washed with heptane (5 x 250 mL) and concentrated (40.83 g). The residue is distilled under vacuum (148 °C/3 mm Hg) to provide 6-methoxybenzothiophene. A 5 L flask is charged with 6-methoxybenzothiophene (25.26g) and dissolved in 1.4 L of dichloromethane. m-CBPA (85g) is added in portions over a 20-30 minute period. The mixture is heated to reflux for about 5 hours and the reaction monitored by HPLC. The mixture is cooled to room temperature and 950 mL of sodium hydrogen sulfite is added. The solution is stirred for 15 minutes. The aqueous layer is removed and the organic phase is washed with aqueous sodium bicarbonate (-2x950 mL). The organic phase is separated, dried over magnesium sulfate and concentrated to give the sulfone compound as a greenish solid (26.56g crude). Purification of the sulfone is conducted as follows: the crude material is first recrystallized from EtOH/hexanes to give 15.64g of product (59percent recovery). A second crop is recrystallized from EtOH to give 2.26g of product, improving the recovery to 68percent. A flask is charged with 6-methoxybenzothiophene sulfone (6.31g) and dissolved in 115 mL of chloroform. Bromine (dissolved in 10 mL of chloroform) is added dropwise over the course of 10 minutes. After about 4.5 hours TLC reveals consumption of starting material. The reaction is quenched by addition of triethylamine (5 mL). After stirring at room temperature for about 30 minutes, 450 mL of H20 is added. The organic layer is separated and washed with 450 mL of brine, dried over magnesium sulfate and concentrated (11.50 g crude). After charcoal treatment, 7.73g of 6-methoxy-2- bromobenzothiophene sulfone is isolated. The brominated sulfone is purified according to the following protocol: 50 mL of EtOH is added to the crude material and the mixture is heated to reflux for 45 minutes and brought to room temperature. After cooling in an ice bath for 30 minutes the solid is filtered through a glass frit and washed with cold EtOH (-3x20 mL). 6-Methoxy-2-bromobenzothiophene sulfone (6.29 g) is recovered as a first crop (81percent). A flask is charged with 6-methoxy-2-bromobenzothiophene sulfone (8. 05g) and 100 mL of chloroform is added. Bromine (7.0 g, 1.5 eq. ) in 50 mL of chloroform is added via addition funnel over the course of 20-30 minutes. After stirring for about 13 hours HPLC shows 3.5percent starting material. 10 mL of triethylamine is added. After stirring at room temperature for 4 hours, 450 mL of H20 is added and the organic layer is extracted. The organic layer is washed with 450 mL of brine and subsequently dried over magnesium sulfate and concentrated to give 6-methoxy-2, 3-dibromobenzothiophene sulfone as a brownish solid. The dibrominated sulfone compound is purified according to the following protocol: 70 mL of EtOH is added to the compound and the mixture is heated to reflux for 45 minutes. The hot solution is cooled to room temperature and placed in an ice bath for 30 minutes. The crystals are filtered through a glass frit and washed with several portions of cold EtOH (~ 3x20 mL) to give the dibrominated product (8. 18 g) in 79percent overall yield. A flask is charged with 6-methoxy-2,3-dibromobenzothiophene sulfone (11.42 g) and 311 mL of THF is added. The temperature is reduced to 5 °C and the mixture is stirred at this temperature for about 15 minutes. Solid 4- (2-piperidin-1-yl-ethoxy)-phenol (7.84 g, 1. 1 eq. ) is added, followed by cesium carbonate (31.5 g, 3.0 eq. ). The mixture is stirred for 15 minutes and ...
a) Butyllithium (2.5 M) (0.27 mol) was added dropwise to <strong>[90560-10-4]6-methoxybenzo[b]-thiophene</strong> (0.25 mol) in tetrahydrofuran (1000 ml), stirred at -30° C. The mixture was stirred for 10 min at -30° C. Ethylene oxide (0.38 mol in 100 ml tetrahydrofuran) was added dropwise at -30° C. The mixture was allowed to warm to room temperature and stirred for 3 hours. The mixture was acidified with dilute HCl solution. The solvent was evaporated. The residue was diluted with water and this mixture was extracted with CH2Cl2. The separated organic layer was dried, filtered and the solvent evaporated. The residue was stirred in hexane, filtered off and dried, yielding 41.3 g of <strong>[90560-10-4]6-methoxybenzo[b]thiophene</strong>-2-ethanol (interm. 3).
Butyl lithium (0.27 mol of a 2.5 M solution) was added dropwise to <strong>[90560-10-4]6-methoxybenzo[b]thiophene</strong> [prepared analogous to the procedure described in J. Med. Chem. 1989, 32(12), 2548-2554] (0.25 mol) in tetrahydrofuran (1000 ml), stirred at -30° C. The mixture was stirred for 10 minutes at -30° C. ethylene oxide (0.38 mol in 100 ml tetrahydrofuran) was added dropwise at -30° C. The mixture was allowed to warm to room temperature and stirred for 3 hours. The mixture was acidified with dilute HCl solution. The solvent was evaporated. The residue was diluted with water and this mixture was extracted with CH2Cl2. The separated organic layer was dried, filtered and the solvent evaporated. The residue was stirred in hexane, filtered off and dried, yielding 41.3 g of <strong>[90560-10-4]6-methoxybenzo[b]thiophene</strong>-2-ethanol (interm. 2).
Chemistry
Pharmaceutical Intermediates
Inhibitors/Agonists
Material Science
For Research Only
110K+ Compounds
Competitive Price
1-2 Day Shipping
