6-Methoxybenzo(b)thiophene

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.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: 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.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 (MgSOBoron 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).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 (BFTo 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. Example (1a) To a solution of Preparation of (+/-)N-t-Butoxycarbonyl-4-hydroxy-4-(6-methoxybenzo[b]thiophen-2-yl)-2-methylpiperidine. [CHEMMOL-00033] [0138] Scheme IA, Step A: To a solution of Scheme IA, Step A: To a solution of To a mixture of 3-methoxybenzenethiol (14.9 mL), potassium carbonate (16.6 g) and acetone (150 mL) was added a solution of 2-bromo-1, 1-diethoxyethane (16.5 mL) in acetone (20 mL), and the mixture was stirred at room temperature overnight. The reaction mixture was filtered to remove solid, and the filtrate was concentrated. Water was added to the residue, and the mixture was extracted with diethyl ether. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the obtained residue (29.3 g) was dissolved in chlorobenzene (150 mL). The solution was added to a mixture (heated to 150°C) of diphosphoric pentaoxide (45 g) and polyphosphoric acid (150 g). The mixture was stirred at 150°C for 30 min and allowed to cool. The supernatant was separated and washed with ethyl acetate. The organic layer was washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was subjected to silica gel column chromatography (eluent, ethyl acetate:hexane=1:99-->5:95). The object fraction was concentrated under reduced pressure to give a crude product (10.98 g) of To a solution of A solution of 6-(methyloxy)- 1 -benzothiophene (3.5 g, 21.3 mmol) in tetrahydrofuran (30 mL) was cooled between -60 0C and -70 0C in a dry ice/acetone bath and a solution of n-butyl lithium (1.6 M in hexanes) ( 14.8 mL, 23.7 mmol) was added slowly, dropwise, with stirring under a nitrogen atmosphere. The reaction mixture became a viscous suspension upon addition of the n-butyl lithium. The reaction mixture was manually swirled to facilitate mixing. Once the addition of n-butyl lithium was complete, the reaction mixture was stirred and occasionally swirled between -65 0C and -75 0C for 30 min. To the cold suspension was slowly added triisopropyl borate (5.6 mL, 24.3 mmol). The reaction mixture was manually swirled during addition of the triisopropyl borate, however, toward the end of the addition, the reaction mixture became a very thick mass. The reaction mixture was allowed to warm to 0 0C. The reaction mixture was partitioned between ethyl acetate and 1 N hydrochloric acid. The organic phase was separated, dried over magnesium sulfate, filtered, and the filtrate was concentrated to give the crude product as a pale yellow solid. The solid was triturated with hexanes: diethyl ether (1 : 1) to give 1.92 g (43percent) of [6-(methyloxy)-l-benzothien-2-yl]boronic acid as a pale yellow powder. 1H NMR (400 MHz, DMSO-J6): delta 7.79 (d, J = 9 Hz, IH), 7.75 (s, IH), 7.52 (d, J = 2 Hz, IH), 6.97 (dd, J = 9, 2 Hz, IH), 3.81 (s, 3H). ESI-LCMS m/z 207 (M-H).Dissolve 6-methoxy-benzo [b] thiophene (J. Med. Chem. 32: 2548, 1989; 26.1 g, 146 mmol) in DMF (500 mL). Add ethanethiol sodium salt (37 g, 440 mmol) and heat to 150°C with stirring overnight. Add additional ethanethiol sodium salt (12.8 g, 152 mmol) and continue to heat at 150°C overnight. Concentrate in vacuo to /4 volume. Partition reaction mixture between ethyl acetate (500 mL) and water (500 mL), separate layers, wash organic layer with water (2 X 500 mL), brine (500 mL), and dry with magnesium sulfate. Filter and concentrate in vacuo to give 8 g of benzo [b] thiophen-6-ol. Back extract aqueous layers with ethyl acetate (3 X 1000 mL) wash organics with brine, and dry with magnesium sulfate. Concentrate in vacuo to obtain an additional 15 grams of benzo [b] thiophen-6-ol. Distill off remaining DMF to yield 22.7 g (100percent) of benzo [b] thiophen-6-ol. Dissolve benzo [b] thiophen-6-ol (10 g, 67 mmol) in pyridine (300 mL). Add 2, 2- dimethyl-propionyl chloride (38 mL, 308 mmol) dropwise, and stir at room temperature for 8 hours. Concentrate in vacuo to 1/4 volume, partition between ethyl acetate (250 mL) and water (250 mL). Separate layers, wash organic layer with water (250 mL) and brine (200 mL). Dry with magnesium sulfate, filter, and concentrate in vacuo to give 15 g of 2, 2-dimethyl-propionic acid benzo [b] thiophen-6-yl ester (98percent). Dissolve 2, 2-dimethyl-propionic acid benzo [b] thiophen-6-yl ester (22.0 g, 94. 0 mmol) in dichloromethane (500 mL). Add bromine (12.6 mL, 244 mmol), dropwise, and stir at room temperature for 2 hours. Add the reaction mixture into saturated aqueous sodium thiosulfate (500 mL). Separate the layers and extract the aqueous layer with dichloromethane (500 mL). Combine the organic layers and wash with brine (100 mL). Dry with magnesium sulfate, filter, and concentrate in vacuo to give the crude solid material. Wash the solid with hexane (20 mL), diethyl ether (20 mL) and dichloromethane (20 mL). Dry in vacuo to give 30 g (81percent) of 2, 2-dimethyl-propionic acid 2, 3-dibromo-benzo [b] thiophen-6-yl ester. Dissolve 2, 2-dimethyl-propionic acid 2, 3-dibromo-benzo [b] thiophen-6-yl ester (32 g, 82 mmol) in ethanol (725 mL), add 50percent aqueous solution of potassium hydroxide (39 mL, 328 mmol) and heat to reflux for 4 hours. Concentrate in vacuo to 1/2 volume, partition between ethyl acetate (500 mL) and saturated aqueous ammonium chloride (500 mL), separate layers, wash organic with saturated aqueous ammonium chloride (2x 500 mL), and brine (300 mL). Dry with sodium sulfate, filter, and concentrate in vacuo to give 25.5 g of 2, 3-dibromo-benzo [b] thiophen-6-ol (100percent). Add a solution of 2, 3-dibromo-benzo [b] thiophen-6-ol (43. 9 g, 143 mmol) in DMF (1000 mL), dropwise, to a suspension of sodium hydride in DMF (1.5 L) at 0°C. Stir for 20 minutes, add benzyl bromide (17mL, 143 mmol). Remove ice bath, and stir at room temperature for 2 hours. Pour reaction mixture into water (8 L) and ethyl acetate (4 L) and stir overnight. Separate layers and wash organic layer with water (3 X 800 mL) and brine (800 mL). Dry with sodium sulfate, filter, and concentrate in vacuo to give 52.-4 g of 6-benzyloxy-2, 3-dibromo-benzo [b] thiophene (92percent). Dissolve 6-benzyloxy-2, 3-dibromo-benzo [b] thiophene (20 g, 50 mmol) in dichloromethane (88 mL) and add trifluoroacetic acid (88 mL). Stir for 10 minutes, then add 30percent aqueous solution of hydrogen peroxide (5. 1 mL, 50 mmol) and stir for 4 hours. Add solid sodium bisulfite (2.2 g, 21 mmol), dilute with water (30 mL), stir for 15 minutes, and then concentrate in vacuo. Partition residue between dichloromethane (150 mL) and saturated aqueous sodium bicarbonate (150 mL), separate layers, wash organic layer with additional saturated aqueous sodium bicarbonate (150 mL) and brine (100 mL). Dry with sodium sulfate, filter, and concentrate in vacuo. Chromatograph on a Si02 column eluting with 100percent dichloromethane to give 12.8 g of 6-benzyloxy-2, 3-dibromo- benzo [b] thiophene 1-oxide (62percent). Dissolve 6-benzyloxy-2, 3-dibromo-benzo [b] thiophene 1-oxide (5.9 g, 14.2 mmol) in THF (120 mL). Add a suspension of 4- (2-piperidin-1-yl-ethoxy)-phenol (3. 14 g, 14. 2 mmol) and potassium tert-butoxide (1.75 g, 15.6 mmol) in THF (120 mL) and stir at 45°C for 1 hour. Partition reaction mixture between dichloromethane (400 mL) and saturated aqueous NH4C1 (400 mL) and separate. Wash the organic layer with saturated aqueous NH4C1 (400 mL) and brine. Dry with sodium sulfate, filter, and concentrate in vacuo. Chromatograph the residue on a Si02 column eluting with methanol in dichloromethane (0 to 5percent) to give 6.9 g of l- {2- [4- (6-benzyloxy-2-bromo-l-oxo-lH-l- benzo [b] thiophen-3-yloxy)-phenoxy]-ethyl}-piperidine (88percent). Dissolve 1- {2- [4- (6-benzyloxy-2-bromo-1-oxo-1 H-1 -benzo [b] thiophen-3- yloxy)-phenoxy]-ethyl}-piperidine (22.36 g, 40.3 mmol) in methanol (160 mL) and chloroform (80 mL). Add a 30percent solution of titaniu...6-Methoxybenzo[b]thiophene (6.15 g, 37.45 mmol) and pyridine hydrochloride (18.5 g) were heated together at 210 °C for 1 h. The mixture was cooled to 100 °C, diluted with water (125 ml.) and extracted with dichloromethane (3 x 70 ml_). The combined extracts were washed with water (125 ml_), dried (MgSO4) and evaporated in vacuo to give the title compound (5.54 g, 98 percent)6-Methoxybenzo[b]thiophene (6.15 g, 37.45 mmol) and pyridine hydrochloride (18.5 g) were heated together at 210 C. for 1 h. The mixture was cooled to 100 C., diluted with water (125 mL) and extracted with dichloromethane (3 70 mL). The combined extracts were washed with water (125 mL), dried (MgSO4) and evaporated in vacuo to give the title compound (5.54 g, 98percent)6-Methoxybenzothiophene (92b, 1.00 g, 6.09 mmol) obtained in Preparation and concentrated boric acid (48percent aqueous solution, 3.00 mL, 18.27 mmol) were added to [bmim][BF4] (10 mL) and heated at 130° C. for 3 hours. The reaction mixture was cooled to room temperature and water was added thereto. Then, organic compounds were extracted with ethyl acetate, and the solvents were removed under reduced pressure and purified by column chromatography to give the target compound 6-hydroxybenzothiophene (93, 732 mg, 80percent) as a pale pink solid.1H NMR (200 MHz, CDCl3) delta 5.67 (brs, 1H, OH), 6.90 (dd, J=1.8, 2.2 Hz, 1H), 7.22 (s, 2H), 7.29 (d, J=1.8 Hz, 1H), 7.64 (d, J=8.4 Hz, 1H); 13C NMR (50 MHz, CDCl3) delta 107.8, 114.2, 123.4, 123.8, 124.3, 133.9, 141.2, 152.9.Step C: The product from Step B (9.1 g, 55.0 mmol) was added neat to pyridine hydrochloride (25.6 g, 22 mmol) at 200° C. for over 2.5 hours. The mixture was allowed to cool then ice water was added and extracted with methylene chloride twice. The combined extract was dried over sodium sulfate, filtered and concentrated to an oil. The oil solidified on standing, which was then triturated with hexanes to give the desired product (4.42 g, 53.4percent): 1H NMR (500 MHz, CDCl3) delta 7.67 (d, J=8.6 Hz, 1H), 7.31 (d, J=2.2 Hz, 1H), 7.26-7.22 (m, 2H), 6.91 (dd, J=8.6, 2.3 Hz, 1H), 4.81 (s, 1H).General procedure: To a solution of Compound 164F (500 mg, 2.29 mmol) in dry THF (20 mL) was added dropwise n-BuLi (2.4Msolution in hexane, 1.3 mL, 3.44 mmol) at -30C under nitrogen and stirred for 30 minutes. To the reaction mixture was added sulfuryl dichloride (618 mg, 4.58 mmol) and stirred at -30 C for one hour. The reaction mixture was quenched with saturated NH4C1 solution (50 mL) and extracted with ethyl acetate (50 mL x 3). Thecombined organic extracts were washed with water (50 mL) and brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to yield a crude product, which was purified by silica gel column chromatography to furnish Compound 164G. 'H-NMR (CDC13, 400 IVIHz): (5(ppm) 1.65-1.68 (m, 2H), 1.88-1.92 (m, 6H), 4.84-4.87 (m, 1H), 7.08-7.09 (m, 1H), 7.25-7.26 (m, 1H), 7.80 (d, J= 9.2 Hz, 1H), 8.03 (s, 1H).General procedure: 17 g of polyphosphoric acid was dissolved in 150 ml of chlorobenzene and refluxed, and 6.6 g of (2, 2-diethoxyethyl)(2-methoxy-4-methylphenyl)thioether was added dropwise into the reaction mixture and refluxed overnight, and the solution was poured out at the next day. The residue was washed with ethyl acetate and then the organic phases were combined, concentrated and separated by column chromatography (100% petroleum ether) to afford 1.85 g of oily matter, yield 42%. 1H NMR (300 MHz, DMSO-d6) delta 7.68 (s, 1H), 7.34 (s, 1H), 7.28 (s, 1H), 6.78 (s, 1H), 3.93 (s, 3H), 2.43 (s, 3H).

Molecular Weight:164.23
XLogP3:2.9
Hydrogen Bond Acceptor Count:2
Rotatable Bond Count:1
Exact Mass:164.02958605
Monoisotopic Mass:164.02958605
Topological Polar Surface Area:37.5
Heavy Atom Count:11
Complexity:138
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes