4-propan-2-yloxyphenol

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: NaH (60%, 480 mg, 12.0 mmol) was added in several portions to a stirred solution of Example 17A (1.52 g, 10.0 mmol) in DMSO (15 mL) at room temperature. After 20 min, 4-nitrothiophene-2-carbaldehyde (1.57 g, 10.0 mmol) was added in one portion. The mixture was stirred at room temperature for 30 minutes. The reaction mixture was poured into water, extracted with ether (2×). The ether layer was washed with 10% NaOH (1×), brine (1×), dried over MgSO4 and concentrated. The residue was purified on silica gel eluting with ethyl acetate: hexane gradient to give the desired product as a brown oil (206 mg, 7.8%). extracted with ether (2×) The ether layer was washed with 10% NaOH (1×), brine (1×) dried over MgSO4 concentrated The residue was purified on silica gel eluting with ethyl acetate

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of Example 1A (1.18 g, 7.75 mmol) in N,N-dimethylformamide (50 mL) was added potassium carbonate (1.1 g, 7.96 mmol), 2-chlorothiazole-5-carbonitrile (CAS 51640-36-9, 1.12 g, 7.75 mmol) and then the reaction was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate (100 mL) and washed with water (3×50 mL) and brine (50 mL). The organics were dried over magnesium sulfate, filtered, and evaporated. The product was purified via silica-gel column chromatography using dichloromethane as the eluent. The title compound was obtained as white solid (2.0 g), 1H NMR (300 MHz, CDCl3) δ ppm 7.76 (s, 1H) 7.12-7.23 (m, 2H) 6.87-7.00 (m, 2H) 4.44-4.65 (heptet, J=6.25 Hz, 1H) 1.36 (d, J=6.25 Hz, 6H), MS (DCI): m/z 261 (M+H)+. washed with water (3×50 mL) and brine (50 mL) The organics were dried over magnesium sulfate filtered evaporated The product was purified via silica-gel column chromatography

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a mixture of Example 17A (1.50 g, 9.86 mmol), 4-bromobenzaldehyde (2.20 g, 11.9 mmol.), (K2CO3 (2.85 g, 20.6 mmol) and pyridine (50 mL) at 80° C. was added Cu(II) oxide (1.95 g, 24.5 mmol). After the addition, the mixture was refluxed vigorously for 20 hours. After cooling, dichloromethane was added and the mixture was filtered through Celite. The filtrate was concentrated to dryness. The residue was dissolved in ether, which was washed with 10% HCl (2×), 1N NaOH (2×), brine (1×), dried over MgSO4, and concentrated to dryness. The residue was purified on silica gel eluting with a hexane and ethyl acetate gradient to give the desired product as a white solid (1.42 g, 56%). After the addition the mixture was refluxed vigorously for 20 hours After cooling the mixture was filtered through Celite The filtrate was concentrated to dryness The residue was dissolved in ether which was washed with 10% HCl (2×), 1N NaOH (2×), brine (1×) dried over MgSO4 concentrated to dryness The residue was purified on silica gel eluting with a hexane and ethyl acetate gradient

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a mixture of hydroquinone (20.0 g, 0.182 mmol) and 2-iodopropane (30.9 g, 0.182 mmol) in ethanol (25 mL) at refluxing was added KOH (88%, 12.2 mg, 0.191 mmol) in water (30 mL) over a period of 60 minutes. The resulting mixture was refluxed for 3 hours. The mixture was poured into 1N NaOH and extracted with ether (1×). The aqueous layer was acidified with 10% HCl to pH ˜5 and extracted with ether (2×). The combined extracts were washed with brine, dried over MgSO4 and concentrated. The residue was purified on silica gel eluting with ethyl acetate:hexane (1:8) to provide the title compound (13.01 g, 47.0%). at refluxing The resulting mixture was refluxed for 3 hours extracted with ether (1×) extracted with ether (2×) The combined extracts were washed with brine dried over MgSO4 concentrated The residue was purified on silica gel eluting with ethyl acetate:hexane (1:8)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of Example 1A (15.5 g, 0.1 mol), 2-bromothiazole (18.2 g, 0.11 mol) and potassium carbonate (15.2 g, 0.11 mol) in dimethylsulfoxide was heated at 160° C. under nitrogen for six hours. After cooling and treating with water, the aqueous phase was extracted with dichloromethane. The organic layer was washed with brine, dried, and concentrated to give 27.5 g of the crude as a dark brown oil, which was purified on a silica gel (ethyl acetate/hexane 5-35%) to afford 21.5 g of the product as a brown oil (91% yield) 1H NMR (500 MHz, CDCl3) δ ppm 1.32-1.36 (m, 6H) 1.34 (none, 6H) 1.34 (none, 5 H) 4.45-4.57 (m, 1H) 6.76 (d, J=3.91 Hz, 1H) 6.87-6.93 (m, 2H) 7.15-7.20 (m, 2H) 7.21 (d, J=3.91 Hz, 1H). MS (ESI): m/z 236 (M+H). After cooling the aqueous phase was extracted with dichloromethane The organic layer was washed with brine dried concentrated to give 27.5 g of the crude as a dark brown oil, which was purified on a silica gel (ethyl acetate/hexane 5-35%)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of potassium hydroxide (78.5 g, 0.5 mol) in water (100 mL) was added to a solution of hydroquinone (55.7 g, 0.5 mol) and 2-iodopropane (57.5 g, 0.33 mol) in ethanol. The dark brown solution was then refluxed for 16 hours Ethanol was removed and the aqueous phase was acidified with 2N HCl and extracted with ethyl acetate (3×200 mL). The combined organic layers were washed with brine, dried over magnesium sulfate and filtered. The filtrate was concentrated to give over 70 g of crude material, which was triturated with dichloromethane and filtered. The filtrate was concentrated and purified on silica gel (ethyl acetate/hexane, 5˜35%) to give 23.0 g of product as a brown oil (46% yield). 1H NMR (300 MHz, CDCl3) δ ppm 1.30 (d, J=5.88 Hz, 6H) 4.30-4.50 (m, 1H) 4.78 (s, 1H) 6.66-6.86 (m, 4H), MS (ESI): m/z 151 (M−H), was removed extracted with ethyl acetate (3×200 mL) The combined organic layers were washed with brine dried over magnesium sulfate filtered The filtrate was concentrated to give over 70 g of crude material, which was triturated with dichloromethane filtered The filtrate was concentrated purified on silica gel (ethyl acetate/hexane, 5˜35%)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of Example 1A (15.5 g, 0.1 mol), 2-bromothiazole (18.2 g, 0.11 mol) and potassium carbonate (15.2 g, 0.11 mol) in dimethylsulfoxide was heated at 160° C. under nitrogen for 6 hours. It was then cooled and treated with water, and the aqueous phase was extracted with methylene chloride. The organic layer washed with brine, dried (MgSO4) and concentrated to give 27.5 g of the crude material which was purified on silica gel (5˜35% ethyl acetate in hexane) to afford 21.5 g of the title compound (91% yield) 1H NMR (500 MHz, CDCl3) δ ppm 1.32-1.36 (m, 6 H) 1.34 (none, 6 H) 1.34 (none, 5 H) 4.45-4.57 (m, 1 H) 6.76 (d, J=3.91 Hz, 1 H) 6.87-6.93 (m, 2 H) 7.15-7.20 (m, 2 H) 7.21 (d, J=3.91 Hz, 1 H). MS (ESI): m/z 236 (M−H). It was then cooled the aqueous phase was extracted with methylene chloride The organic layer washed with brine dried (MgSO4) concentrated to give 27.5 g of the crude material which was purified on silica gel (5˜35% ethyl acetate in hexane)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of Example 1A (15.5 g, 0.1 mol), 2-bromothiazole (18.2 g, 0.11 mol) and potassium carbonate (15.2 g, 0.11 mol) in dimethylsulfoxide was heated at 160° C. under nitrogen for 6 hours. It was then cooled and treated with water, and the aqueous phase was extracted with methylene chloride. The organic layer washed with brine, dried (MgSO4) and concentrated to give 27.5 g of the crude material which was purified on silica gel (5˜35% ethyl acetate in hexane) to afford 21.5 g of the title compound (91% yield) 1H NMR (500 MHz, CDCl3) δ ppm 1.32-1.36 (m, 6 H) 1.34 (none, 6 H) 1.34 (none, 5 H) 4.45-4.57 (m, 1 H) 6.76 (d, J=3.91 Hz, 1 H) 6.87-6.93 (m, 2 H) 7.15-7.20 (m, 2 H) 7.21 (d, J=3.91 Hz, 1 H). MS (ESI): m/z 236 (M−H). It was then cooled the aqueous phase was extracted with methylene chloride The organic layer washed with brine dried (MgSO4) concentrated to give 27.5 g of the crude material which was purified on silica gel (5˜35% ethyl acetate in hexane)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of hydroquinone (55.7 g, 0.5 mol) and 2-iodopropane (57.5 g, 0.33 mol) in ethanol was added a solution of potassium hydroxide (78.5 g, 0.5 mol) in water (100 mL). The dark brown solution was then refluxed for 16 hours. The solution was concentrated and the remaining aqueous phase was acidified with 2N HCl and extracted with ethyl acetate (3×200 mL). The combined organic layers were washed with brine, dried over magnesium sulfate and filtered. The filtrate was concentrated to give over 70 g of crude material, which was triturated with methylene chloride and filtered. The filtrate was concentrated and purified on silica gel (5˜35% ethyl acetate in hexane) to give 23.0 g of the title compound (46% yield). 1H NMR (300 MHz, CDCl3) δ ppm 1.30 (d, J=5.88 Hz, 6 H) 4.30-4.50 (m, 1 H) 4.78 (s, 1 H) 6.66-6.86 (m, 4 H). MS (ESI): m/z 151 (M−H). The dark brown solution was then refluxed for 16 hours The solution was concentrated extracted with ethyl acetate (3×200 mL) The combined organic layers were washed with brine dried over magnesium sulfate filtered The filtrate was concentrated to give over 70 g of crude material, which was triturated with methylene chloride filtered The filtrate was concentrated purified on silica gel (5˜35% ethyl acetate in hexane)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of tert-butyl 4-[4-(chloromethyl)benzyl]piperazine-1-carboxylate (4.00 g) in DMF (25 mL) were added 4-isopropoxyphenol (2.81 g) and K2CO3 (3.40 g) at room temperature, then the reaction mixture was stirred for 2 days. The reaction mixture was diluted with H2O, and extracted with AcOEt. The organic layer was washed with water and saturated aqueous NaCl, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane/AcOEt=3/1 to 1/1) to afford tert-butyl 4-(4-{[4-(propan-2-yloxy)phenoxy]methyl}benzyl)piperazine-1-carboxylate as a colorless solid (5.42 g). extracted with AcOEt The organic layer was washed with water and saturated aqueous NaCl dried over anhydrous Na2SO4 concentrated under reduced pressure The residue was purified by silica gel column chromatography (n-hexane/AcOEt=3/1 to 1/1)