oxane

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

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

Conditions: temp:100.01; pressure:0.00; stir:

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

Procedure: A solution composed of 0.457 g of (E)-2-[3-[3-[2-[4-(cyclobutyl)-2-thiazolyl]ethenyl]phenylamino]-3-oxopropyl]benzoic acid ethyl ester, 25 ml of tetrahydropyran, 8 ml of methanol, 8 ml of water and 0.282 g of lithium hydroxide monohydrate was allowed to stand at room temperature for 20 hr. The solvents were removed by rotary evaporation and the residual materials were taken up in 30 ml of water. Addition of excess acetic acid caused the precipitation of 0.42 g of (E)-2-[3-[3-[2-[4-(cyclobutyl)-2-thiazolyl]ethenyl]phenylamino]-3-oxopropyl]benzoic acid; m.p. 238°-239° C. The solvents were removed by rotary evaporation Addition of excess acetic acid the precipitation of 0.42 g of (E)-2-[3-[3-[2-[4-(cyclobutyl)-2-thiazolyl]ethenyl]phenylamino]-3-oxopropyl]benzoic acid

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

Procedure: A solution of 0.5 g of (E)-2-[2-(3-aminophenyl)ethenyl]-4-thiazolecarboxylic acid ethyl ester, 0.3 g of homophthalic anhydride, 15 ml of toluene and 5 ml of tetrahydropyran was heated to reflux for 0.5 hr. Upon cooling, a solid formed which was filtered to yield 0.8 g of (E)-2-[2-[3-[2-[4-(ethoxycarbonyl)-2-thiazolyl]ethenyl]phenylamino]-2-oxoethyl]benzoic acid; m.p. 221°-223° C. from ethanol. to reflux for 0.5 hr Upon cooling a solid formed which was filtered

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

Procedure: A solution composed of 0.5 g of (E)-4-[2-[3-[2-[4-(cyclobutyl)-2-thiazolyl]ethenyl]phenylamino]-2-oxoethyl]benzoic acid methyl ester, 20 ml of tetrahydropyran, 3 ml of methanol, 3 ml of water and 0.35 g of lithium hydroxide monohydrate was allowed to stand at room temperature for 20 hr. The solvents were removed by rotary evaporation and the residual materials were taken up in 30 ml of water. Addition of an excess of acetic acid caused the precipitation of 0.5 g of (E)-4-[2-[3-[2-[4-(cyclobutyl)-2-thiazolyl]ethenyl]phenylamino]-2-oxoethyl]benzoic acid; m.p. 262°-263° C. after recrystallization from 2-propanol. The solvents were removed by rotary evaporation Addition of an excess of acetic acid the precipitation of 0.5 g of (E)-4-[2-[3-[2-[4-(cyclobutyl)-2-thiazolyl]ethenyl]phenylamino]-2-oxoethyl]benzoic acid m.p. 262°-263° C. after recrystallization from 2-propanol

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

Procedure: At room temperature, potassium hydride (2.5 g, 35 wt % oil dispersion, 0.88 g KH, 22 mmol) was washed twice with hexane and suspended in DMF (30 mL), followed by addition of t-butyl alcohol (2.1 mL, 1.63 g, 22 mmol). 4'-Hydroxy-4-cyanobiphenyl (3.9 g, 20 mmol) was added as a solid all at once to give a deep yellow solution. The mixture was stirred 5 min at room temperature and the tetrahydropyran of 6-bromohexanol (5.8 g, 22 mmol) was added all at once with a mild exotherm. After 2 h, more bromide (1.0 g) was added and the reaction mixture was stirred for 1 h. The mixture was diluted with water, acidified with 5 N hydrochloric acid and extracted with ether-dichloromethane (4:1). An insoluble white solid had to be removed by filtration through glass fiber to obtain good separation of phases. The extracts were washed with water, dried (MgSO4) and concentrated to a solid (7.7 g). The solid was stirred with tetrahydrofuran-2.5 N hydrochloric acid (4:1, 50 mL) overnight at room temperature and then heated to reflux for 2.0 h. The ethanol was removed and the aqueous phase was extracted with ether-dichloromethane (4:1). The extracts were washed with water, dried (MgSO4) and concentrated to a solid that was recrystallized from ethanol-ether to give 4'-(6-hydroxyhexyloxy)-4-cyanobiphenyl: (3.25 g, 55%): mp 87-89° C., nematic phase 89-106° C.; 1H NMR (CDCl3) 7.63(s, 4H), 7.46 and 6.90(2d, 4H), 3.97(t, 2H), 3.62(t, 2H), 1.9-1.3(m, 8H); IR (KBr) 3300, 2225, 1601, 1580, 1525 cm-1. to give a deep yellow solution After 2 h the reaction mixture was stirred for 1 h extracted with ether-dichloromethane (4:1) to be removed by filtration through glass fiber to obtain good separation of phases The extracts were washed with water dried (MgSO4) concentrated to a solid (7.7 g) The solid was stirred with tetrahydrofuran-2.5 N hydrochloric acid (4:1, 50 mL) overnight at room temperature heated to reflux for 2.0 h The ethanol was removed the aqueous phase was extracted with ether-dichloromethane (4:1) The extracts were washed with water dried (MgSO4) concentrated to a solid that was recrystallized from ethanol-ether

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

Procedure: At room temperature, potassium hydride (2.5 g, 35 wt % oil dispersion, 0.88 g KH, 22 mmol) was washed twice with hexane and suspended in DMF (30 mL), followed by addition of t-butyl alcohol (2.1 mL, 1.63 g, 22 mmol). 4'-Hydroxy-4-cyanobiphenyl (3.9 g, 20 mmol) was added as a solid all at once to give a deep yellow solution. The mixture was stirred 5 min at room temperature and the tetrahydropyran of 6-bromohexanol (5.8 g, 22 mmol) was added all at once with a mild exotherm. After 2 h, more bromide (1.0 g) was added and the reaction mixture was stirred for 1 h. The mixture was diluted with water, acidified with 5 N hydrochloric acid and extracted with ether-dichloromethane (4:1). An insoluble white solid had to be removed by filtration through glass fiber to obtain good separation of phases. The extracts were washed with water, dried (MgSO4) and concentrated to a solid (7.7 g). The solid was stirred with tetrahydrofuran-2.5 N hydrochloric acid (4:1, 50 mL) overnight at room temperature and then heated to reflux for 2.0 h. The ethanol was removed and the aqueous phase was extracted with ether-dichloromethane (4:1). The extracts were washed with water, dried (MgSO4) and concentrated to a solid that was recrystallized from ethanol-ether to give 4'-(6-hydroxyhexyloxy)-4-cyanobiphenyl: (3.25 g, 55%): mp 87-89° C., nematic phase 89-106° C.; 1H NMR (CDCl3) 7.63(s, 4H), 7.46 and 6.90(2d, 4H), 3.97(t, 2H), 3.62(t, 2H), 1.9-1.3(m, 8H); IR (KBr) 3300, 2225, 1601, 1580, 1525 cm-1. to give a deep yellow solution After 2 h the reaction mixture was stirred for 1 h extracted with ether-dichloromethane (4:1) to be removed by filtration through glass fiber to obtain good separation of phases The extracts were washed with water dried (MgSO4) concentrated to a solid (7.7 g) The solid was stirred with tetrahydrofuran-2.5 N hydrochloric acid (4:1, 50 mL) overnight at room temperature heated to reflux for 2.0 h The ethanol was removed the aqueous phase was extracted with ether-dichloromethane (4:1) The extracts were washed with water dried (MgSO4) concentrated to a solid that was recrystallized from ethanol-ether

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

Procedure: 2-hydroxy-5-phenylbenzoic acid was synthesized as follows. A solution of tetrahydropyran (THP)-protected 4-phenylphenol (474 mg. 2 mmol., prepared from 4-phenylphenol by standard methods described in Green and Wuts at pp. 31-34) in anhydrous THF (5 mL) was cooled to -78° C. and treated with n-Butyllithium (2 mL of 1.6M in hexanes). The reaction mixture was stirred and warmed to ambient temperature during which a tan suspension formed. After 2 hours, the reaction mixture was cooled to -78° C. and treated with excess anhydrous CO2 for several minutes. The reaction mixture was stirred and warmed to ambient temperature. After 2 hours, the reaction mixture was partitioned between ethyl ether and aqueous 1N NaOH. The aqueous layer was cooled to 0° C. with ice and acidified to pH 2 with aqueous 1N HCl. The aqueous solution was partitioned with methylene chloride. The organic layer was dried over magnesium sulfate. Concentration in vacuo yielded crude product as an off-white solid (258 mg, 2-hydroxy-5-phenylbenzoic acid). NMR spectroscopy of the crude material was consistent with the expected structure. 1H NMR (DMSO-d6) δ8.04 (d, J=3 Hz, 1H), 7.76 (dd, J=9, 3 Hz, 1H), 7.62 (d, J=7 Hz, 2H), 7.44 (t, J=7 Hz, 2H), 7.32 (t, J=7 Hz, 1H), 7.00 (d, J=9 Hz, 1H). Mass calculated: 466.5. Mass found 467.2. LC Gradient 25-45% acetonitrile over 13 minutes. LC retention time 3.5 minutes. The material was used without further purification. formed the reaction mixture was cooled to -78° C. The reaction mixture was stirred warmed to ambient temperature After 2 hours the reaction mixture was partitioned between ethyl ether and aqueous 1N NaOH The aqueous layer was cooled to 0° C. with ice The aqueous solution was partitioned with methylene chloride The organic layer was dried over magnesium sulfate Concentration in vacuo

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

Procedure: 2-hydroxy-5-phenylbenzoic acid was synthesized as follows. A solution of tetrahydropyran (THP)-protected 4-phenylphenol (474 mg. 2 mmol., prepared from 4-phenylphenol by standard methods described in Green and Wuts at pp. 31-34) in anhydrous THF (5 mL) was cooled to -78° C. and treated with n-Butyllithium (2 mL of 1.6M in hexanes). The reaction mixture was stirred and warmed to ambient temperature during which a tan suspension formed. After 2 hours, the reaction mixture was cooled to -78° C. and treated with excess anhydrous CO2 for several minutes. The reaction mixture was stirred and warmed to ambient temperature. After 2 hours, the reaction mixture was partitioned between ethyl ether and aqueous 1N NaOH. The aqueous layer was cooled to 0° C. with ice and acidified to pH 2 with aqueous 1N HCl. The aqueous solution was partitioned with methylene chloride. The organic layer was dried over magnesium sulfate. Concentration in vacuo yielded crude product as an off-white solid (258 mg, 2-hydroxy-5-phenylbenzoic acid). NMR spectroscopy of the crude material was consistent with the expected structure. 1H NMR (DMSO-d6) δ8.04 (d, J=3 Hz, 1H), 7.76 (dd, J=9, 3 Hz, 1H), 7.62 (d, J=7 Hz, 2H), 7.44 (t, J=7 Hz, 2H), 7.32 (t, J=7 Hz, 1H), 7.00 (d, J=9 Hz, 1H). Mass calculated: 466.5. Mass found 467.2. LC Gradient 25-45% acetonitrile over 13 minutes. LC retention time 3.5 minutes. The material was used without further purification. formed the reaction mixture was cooled to -78° C. The reaction mixture was stirred warmed to ambient temperature After 2 hours the reaction mixture was partitioned between ethyl ether and aqueous 1N NaOH The aqueous layer was cooled to 0° C. with ice The aqueous solution was partitioned with methylene chloride The organic layer was dried over magnesium sulfate Concentration in vacuo

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

Procedure: To a solution of about 4.50 g of N-acetyl-L-serine, methyl ester in about 100 ml of dry methylene chloride was added about 2.93 ml of distilled tetrahydro-2H-pyran and about 0.34 ml of borontrifluoroetherate. The mixture was stirred under argon for about 7 hours, then washed with saturated sodium bicarbonate and brine, dried and the solvent removed under reduced pressure, giving about 6 g of the desired title compound. washed with saturated sodium bicarbonate and brine dried the solvent removed under reduced pressure

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

Procedure: According to the procedure described for the synthesis of 217, 215 (6.98 g, 17.1 mmol) was reacted with NaH (0.82 g, 20.5 mmol, 60% in mineral oil), 207g (5.8 g, 18.9 mmol), and tetrabutylammonium iodide (0.63 g, 1.7 mmol) in anhydrous DMSO (100 mL) for 24 h at room temperature. The crude intermediate (10.9 g) obtained after aqueous workup was heated to reflux in concentrated HCl (18 mL) and methanol (100 mL) overnight. After extraction and column chromatography (silica gel; hexanes/ethyl acetate=80/20), 219 (2.3 g, 48%) was obtained as a colorless oil. 1H NMR (CDCl3): δ 3.30 (s, 4H), 2.48-2.34 (m, 4H), 1.85 (br., 2H), 1.66-1.46 (m, 4H), 1.24-1.14 (m, 10H), 0.85 (s, 12H). 13C NMR (CDCl3): δ 211.8, 71.8, 71.6, 42.7, 42.6, 38.4, 38.2, 34.9, 30.1, 24.6, 23.8, 23.8, 23.7, 23.6, 23.4. HRMS (LSIMS, gly): Calcd for C18H37O3 (MH+): 301.2743, found: 301.2745. HPLC: 97.4% pure. The crude intermediate (10.9 g) obtained after aqueous workup was heated After extraction and column chromatography (silica gel; hexanes/ethyl acetate=80/20)