氢氯噻嗪杂质19

反应条件: temp:0.00; pressure:0.00; stir:

反应条件: temp:0.00; pressure:0.00; stir:

反应条件: temp:0.00; pressure:0.00; stir:

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A solution of tert-butyl (3S,6R,7S,8S,10E,12Z,15S,16E)-5-oxo-3,15-bis(triethylsilyloxy)-17-(2-(2,2,2-trichloroethoxycarbonyloxymethyl)thiazol-4-yl)-4,4,6,8,12,16-hexamethyl-7-(2,2,2-trichloroethoxycarbonyloxy)-heptadeca-10,12,16-trienoate (2.8 g) in 12 mL of CH2Cl2 is treated with 2,6-lutidine (0.86 mL) and triethylsilyl trifluoromethanesulfonate (0.98 g) at 0° C. for 30 minutes, then at ambient temperature for 10 hours. The mixture is diluted with 50 mL of ethyl acetate and poured into 20 mL of 1 N HCl. The organic phase is separated, washed with pH 7 phosphate buffer, dried with Na2SO4, filtered, and concentrated. The residue is dissolved in 5 mL of THF and treated with 0.5 mL of 0.1 N HCl in methanol. The reaction is monitored by thin-layer chromatography, with additional aliquots of methanolic HCl being added to achieve complete reaction. When complete, the reaction is poured into 15 mL of pH 7 phosphate buffer and extracted with ethyl acetate. The extract is washed with brine, dried with Na2SO4, filtered, and evaporated. The product is purified by flash chromatography on SiO2 (1:1 hexanes/ethyl acetate). The organic phase is separated washed with pH 7 phosphate buffer dried with Na2SO4 filtered concentrated The residue is dissolved in 5 mL of THF treated with 0.5 mL of 0.1 N HCl in methanol added reaction extracted with ethyl acetate The extract is washed with brine dried with Na2SO4 filtered evaporated The product is purified by flash chromatography on SiO2 (1:1 hexanes/ethyl acetate)

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A solution of tert-butyl (3S,6R,7S,8S,10E,12Z,15S,16E)-5-oxo-3,15-bis(triethylsilyloxy)-17-(2-methylthiazol-4-yl)-4,4,6,8,12,16-hexamethyl-7-(2,2,2-trichloroethoxycarbonyloxy)-heptadeca-10,12,16-trienoate (2.38 g) in 12 mL of CH2Cl2 is treated with 2,6-lutidine (0.86 mL) and triethylsilyl trifluoromethanesulfonate (0.98 g) at 0° C. for 30 minutes, then at ambient temperature for 10 hours. The mixture is diluted with 50 mL of ethyl acetate and poured into 20 mL of 1 N HCl. The organic phase is separated, washed with pH 7 phosphate buffer, dried with Na2SO4, filtered, and concentrated. The residue is dissolved in 5 mL of THF and treated with 0.5 mL of 0.1 N HCl in methanol. The reaction is monitored by thin-layer chromatography, with additional aliquots of methanolic HCl being added to achieve complete reaction. When complete, the reaction is poured into 15 mL of pH 7 phosphate buffer and extracted with ethyl acetate. The extract is washed with brinei dried with Na2SO4, filtered, and evaporated. The product is purified by flash chromatography on SiO2 (1:1 hexanes/ethyl acetate). The organic phase is separated washed with pH 7 phosphate buffer dried with Na2SO4 filtered concentrated The residue is dissolved in 5 mL of THF treated with 0.5 mL of 0.1 N HCl in methanol added reaction extracted with ethyl acetate The extract is washed with brinei dried with Na2SO4 filtered evaporated The product is purified by flash chromatography on SiO2 (1:1 hexanes/ethyl acetate)

反应条件: temp:0.00; pressure:0.00; stir:

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A solution of Compound 60 (1.657 g, 5.69 mmol) in dichloromethane (10 mL) was treated with 2,6-lutidine (2.00 mL, 17.1 mmol) and triethylsilyl trifluoromethanesulfonate (2.58 mL, 11.4 mmol) at zero degrees C. The solution was stirred 30 minutes, anhydrous methanol (2 mL) was added, the mixture was poured into brine (50 mL) and extracted with dichloromethane (3×50 mL). The organic extracts were dried (Na2SO4), concentrated and purified by flash chromatography (20% Et2O in petroleum ether) to give Compound 61 (2.204 g, 96 percent) as a white solid, m.p. =108 °-109° C. (from CH2Cl2); Rf =0.43 (30 percent Et2O in petroleum ether); [a]D25 =-15.4° (c 2.8, CH2Cl2); IR (thin film) νmax 3307, 2116, 1721, 1646 cm-1 ; 1H NMR (500 MHz, CDCl3) δ 9.50 (s, 1 H, C=CH--O), 6.57 (s, 1 H, C=CH--CO2), 4.38-4.31 (m, 2 H, ethylene ketal), 4.18-4.10 (m, 2 H, ethylene ketal), 3.74 (s, 3 H, CO2Me), 2.66 (s, 1 H, C}C--H), 2.61 (ABq, J =14.0 Hz, Δν =34 Hz, 2 H, CH2), 0.92 (t, J =7.9 Hz, 9 H, Si(CH2CH3)3), 0.70 (q, J =7.9 Hz, 6 H, Si(CH2CH3)3); 13C NMR (125 MHz, CDCl3) δ 166.5, 161.3, 160.7, 143.8, 114.5, 111.9, 100.6, 83.2, 76.9, 70.9, 65.0, 64.8, 51.6, 49.8, 6.8, 5.9; FAB HRMS (NBA/CsI) m/e 538.0652, M+Cs+ calcd for C20H27NO6Si 538.0662. extracted with dichloromethane (3×50 mL) The organic extracts were dried (Na2SO4) concentrated purified by flash chromatography (20% Et2O in petroleum ether)

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A solution of Compound 60 (1.657 g, 5.69 mmol) in dichloromethane (10 mL) was treated with 2,6-lutidine (2.00 mL, 17.1 mmol) and triethylsilyl trifluoromethanesulfonate (2.58 mL, 11.4 mmol) at zero degrees C. The solution was stirred 30 minutes, anhydrous methanol (2 mL) was added, the mixture was poured into brine (50 mL) and extracted with dichloromethane (3×50 mL). The organic extracts were dried (Na2SO4), concentrated and purified by flash chromatography (20% Et2O in petroleum ether) to give Compound 61 (2.204 g, 96 percent) as a white solid, m.p. =108 °-109° C. (from CH2Cl2); Rf =0.43 (30 percent Et2O in petroleum ether); [a]D25 =-15.4° (c 2.8, CH2Cl2); IR (thin film) νmax 3307, 2116, 1721, 1646 cm-1 ; 1H NMR (500 MHz, CDCl3) δ 9.50 (s, 1 H, C=CH--O), 6.57 (s, 1 H, C=CH--CO2), 4.38-4.31 (m, 2 H, ethylene ketal), 4.18-4.10 (m, 2 H, ethylene ketal), 3.74 (s, 3 H, CO2Me), 2.66 (s, 1 H, C}C--H), 2.61 (ABq, J =14.0 Hz, Δν =34 Hz, 2 H, CH2), 0.92 (t, J =7.9 Hz, 9 H, Si(CH2CH3)3), 0.70 (q, J =7.9 Hz, 6 H, Si(CH2CH3)3); 13C NMR (125 MHz, CDCl3) δ 166.5, 161.3, 160.7, 143.8, 114.5, 111.9, 100.6, 83.2, 76.9, 70.9, 65.0, 64.8, 51.6, 49.8, 6.8, 5.9; FAB HRMS (NBA/CsI) m/e 538.0652, M+Cs+ calcd for C20H27NO6Si 538.0662. extracted with dichloromethane (3×50 mL) The organic extracts were dried (Na2SO4) concentrated purified by flash chromatography (20% Et2O in petroleum ether)

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a solution of 17-ethyl-1-hydroxy-12-[2'-(4"-hydroxy-4"-[but-3-en-1-yl]-3"-methoxycyclohexyl)-1'-methylvinyl]-14-t-butyl-dimethylsilyloxy-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone (0.9 gm, 0.94 mmol) in CH2Cl2 (25 ml) at room temperature was added 2,6-lutidine (0.33 mL) followed by triethylsilyltriflate (0.52 mL, 2.3 mmole) and the reaction mixture was stirred at room temperature. The reaction progress was monitored by TLC (silica, 20% acetone:hexanes). After 1 hr, the reaction was diluted with CH3OH and partitioned between diethyl ether and H2O. The organic layer was washed successively with 1N H2SO4, H2O, NaHSO3 and brine solutions. The organic fraction was then dried over MgSO4, filtered and concentrated in vacuo to give the title compound (1.47 gm). MASS: (FAB) 1080 (M+ + Li). partitioned between diethyl ether and H2O The organic layer was washed successively with 1N H2SO4, H2O, NaHSO3 and brine solutions The organic fraction was then dried over MgSO4 filtered concentrated in vacuo

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a solution of 17-ethyl-1-hydroxy-12-[2'-(4"-hydroxy-4"-[but-3-en-1-yl]-3"-methoxycyclohexyl)-1'-methylvinyl]-14-t-butyl-dimethylsilyloxy-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone (0.9 gm, 0.94 mmol) in CH2Cl2 (25 ml) at room temperature was added 2,6-lutidine (0.33 mL) followed by triethylsilyltriflate (0.52 mL, 2.3 mmole) and the reaction mixture was stirred at room temperature. The reaction progress was monitored by TLC (silica, 20% acetone:hexanes). After 1 hr, the reaction was diluted with CH3OH and partitioned between diethyl ether and H2O. The organic layer was washed successively with 1N H2SO4, H2O, NaHSO3 and brine solutions. The organic fraction was then dried over MgSO4, filtered and concentrated in vacuo to give the title compound (1.47 gm). MASS: (FAB) 1080 (M+ + Li). partitioned between diethyl ether and H2O The organic layer was washed successively with 1N H2SO4, H2O, NaHSO3 and brine solutions The organic fraction was then dried over MgSO4 filtered concentrated in vacuo

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a stirred solution of 660 mg (1.48 mmol) of the intermediate obtained in Step B in 3 mL of methylene chloride at room temperature was added 1.1 mL of N,N-diisopropylethylamine (0.81 g, 4.2 eq.) followed by 0.71 mL of triethylsilyl trifluoromethanesulfonate (0.83 g, 2.1 eq.). The resulting mixture was stirred at room temperature for 2 hours then partitioned between ethyl acetate and saturated aqueous sodium chloride (buffered to pH 9 with 2 drops of ammonium hydroxide). The organic layer was separated, washed with buffered brine, dried over magnesium sulfate, filtered and solvents evaporated under vacuum. The residue was purified by preparative high pressure liquid chromatography on silica, eluting with ethyl acetate/0.1% ammonium hydroxide in methanol (85:15), to afford 480 mg (1.07 mmol, 72%) of product. 1H NMR (200 MHz,CD3OD): 0.63 (q,8 Hz,6H), 0.97 (t,8 Hz,9H), 1.14 (s,6H), 1.18 (d,6 Hz,3H), 2.05 (m,1H), 2.28 (d,2Hz,2H), 2.35-3.00 (m,5H), 4.01 (m,1H), 4.44 (dd;8,12 Hz;1H), 7.05 (d,8 Hz,1H), 7.10-7.35 (m,3H). FAB-MS: calculated for C24H41N3O3Si 447; found 448 (M+H, 100%). then partitioned between ethyl acetate and saturated aqueous sodium chloride (buffered to pH 9 with 2 drops of ammonium hydroxide) The organic layer was separated washed with buffered brine dried over magnesium sulfate filtered solvents evaporated under vacuum The residue was purified by preparative high pressure liquid chromatography on silica eluting with ethyl acetate/0.1% ammonium hydroxide in methanol (85:15)

反应条件: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a 2.0 L RBF containing 1-(2,2-dimethoxyethyl)cyclopropanol (17.400 g, 119 mmol) was added DCM (550 ml) and the mixture was allowed to stir at 0° C. for 15 min. 2,4,6-Collidine (63.1 ml, 476 mmol) was added and the reaction was allowed to chill for 5 min before the addition of tert-butyldimethylsilyl triflate (27.3 ml, 119 mmol) over 10 min. The reaction was allowed to stir for 20 min and then analyzed by tlc which showed that all of the tertiary alcohol had been protected as its TBS ether. So, triethylsilyl trifluoromethanesulfonate (53.8 ml, 238 mmol) was added via syringe over 10 min. After 20 min, tlc showed all of the material was converted to a baseline Rf material (mixed acetal) and then water (300 mL) was added and the reaction was allowed to stir overnight. The layers were separated. The DCM was washed with dilute HCl to remove the 2,4,6-collidine. The aq. layer was back extracted with DCM. The combined organics were washed with sodium bicarbonate, brine, dried with sodium sulfate and filtered though a plug of silica gel. Desired fractions were collected to give the product. to stir for 20 min After 20 min to stir overnight The layers were separated The DCM was washed with dilute HCl to remove the 2,4,6-collidine The aq. layer was back extracted with DCM The combined organics were washed with sodium bicarbonate, brine dried with sodium sulfate filtered though a plug of silica gel Desired fractions were collected to give the product