吉西他滨杂质19

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

实验步骤: The title compound was prepared by a similar procedure to 8-(1-isopropyl-azetidin-3-yl)-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene using (R)-(+)-2,2-dimethyl-1,3-dioxolane-4-carboxaldehyde instead of acetone and adding 1.0 eq. diisopropylethylamine to the reaction mixture. The product was isolated as a colourless oil (127 mg, 32%). LCMS: RT=3.37 min, [M+H]+=482

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

实验步骤: 1.50 g (11.53 mmol) (R)-2,2-Dimethyl-1.3-dioxolane-4-carboxaldehyde (Fluorochem, Hadfield, UK) was dissolved in 60 ml of DCM and treated with 1.64 g (11.53 mmol) sodium sulfate. The reaction mixture was flushed with argon and treated with a solution of 1.42 g (11.53 mmol) N-benzyl-hydroxylamine (prepared from the commercially available hydrochloride salt) in 20 ml of CH2Cl2. The reaction mixture was stirred under argon at RT for 16.5 h and then filtered. Silicagel was added to the filtrate is and preabsorbed, before being purified by chromatography on silicagel (gradient: Heptane/EtOAc 0%-100% in 30 min). Fr. 20-80 were collected and evaporated to dryness and dried under vacuum overnight to give 1.48 g of a white solid (˜100% pure by HPLC, Rt=1.43); ESI-MS: 236.2 [M+H]+(LC-MS 1)) The reaction mixture was flushed with argon filtered Silicagel was added to the filtrate preabsorbed before being purified by chromatography on silicagel (gradient: Heptane/EtOAc 0%-100% in 30 min) 20-80 were collected evaporated to dryness dried under vacuum overnight

反应条件: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a stirring -78° C. solution, under argon, of 556 ml of 1M allylmagnesium bromide is added, dropwise over 20 minutes, a solution of 36.4 g of product from Example 330 in 17 ml of tetrahydrofuran. The reaction mixture is stirred at -78° C. for 2 hours. Thin layer chromatography indicates the presence of starting material. An additional 280 ml of 1M allylmagnesium bromide is added and the reaction is stirred overnight at -78° C. The reaction is quenched with dropwise addition of saturated ammonium chloride, filtered through diatomaceous earth and washed with diethyl ether, ethyl acetate and 20% isopropyl alcohol/chloroform. The combined extracts are washed with saturated sodiumchloride, dried and concentrated in vacuo to give, after Kugelrohr distillation at 85° C., 38.25 g of the desired product. the reaction is stirred overnight at -78° C The reaction is quenched with dropwise addition of saturated ammonium chloride filtered through diatomaceous earth washed with diethyl ether, ethyl acetate and 20% isopropyl alcohol/chloroform The combined extracts are washed with saturated sodiumchloride dried concentrated in vacuo to give after Kugelrohr distillation at 85° C.

反应条件: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a stirring -78° C. solution, under argon, of 556 ml of 1M allylmagnesium bromide is added, dropwise over 20 minutes, a solution of 36.4 g of product from Example 330 in 17 ml of tetrahydrofuran. The reaction mixture is stirred at -78° C. for 2 hours. Thin layer chromatography indicates the presence of starting material. An additional 280 ml of 1M allylmagnesium bromide is added and the reaction is stirred overnight at -78° C. The reaction is quenched with dropwise addition of saturated ammonium chloride, filtered through diatomaceous earth and washed with diethyl ether, ethyl acetate and 20% isopropyl alcohol/chloroform. The combined extracts are washed with saturated sodium chloride, dried and concentrated in vacuo to give after Kugelrohr distillation at 85° C., 38.25 g of the desired product. the reaction is stirred overnight at -78° C The reaction is quenched with dropwise addition of saturated ammonium chloride filtered through diatomaceous earth washed with diethyl ether, ethyl acetate and 20% isopropyl alcohol/chloroform The combined extracts are washed with saturated sodium chloride dried concentrated in vacuo to give after Kugelrohr distillation at 85° C.

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

实验步骤: The preparation was carried out as already described above starting from 100 mg (0.27 mmol) of 1-[4-(5,5-dimethyl-5,6,7,8-tetrahydronaphthalen-2-yl)thiazol-2-yl]piperidin-4-ylamine hydrochloride and 34 mg (0.27 mmol) of (R)-2,2-dimethyl-1,3-dioxolane-4-carbaldehyde. The protecting group was cleaved off as described by means of a 1.25 N HCl/methanol solution. The product was converted into the hydrochloride.

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

实验步骤: The title compound was prepared by a similar procedure to 8-(1-isopropyl-azetidin-3-yl)-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene using (R)-(+)-2,2-dimethyl-1,3-dioxolane-4-carboxaldehyde instead of acetone and adding 1.0 eq. diisopropylethylamine to the reaction mixture. The product was isolated as a colourless oil (127 mg, 32%). LCMS: RT=3.37 min, [M+H]+=482

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

实验步骤: The title compound was prepared by a similar procedure to 8-(1-isopropyl-azetidin-3-yl)-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene using (R)-(+)-2,2-dimethyl-1,3-dioxolane-4-carboxaldehyde instead of acetone and adding 1.0 eq. diisopropylethylamine to the reaction mixture. The product was isolated as a colourless oil (127 mg, 32%). LCMS: RT=3.37 min, [M+H]+=482

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

实验步骤: The title compound was prepared by a similar procedure to 8-(1-isopropyl-azetidin-3-yl)-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene using (R)-(+)-2,2-dimethyl-1,3-dioxolane-4-carboxaldehyde instead of acetone and adding 1.0 eq. diisopropylethylamine to the reaction mixture. The product was isolated as a colourless oil (127 mg, 32%). LCMS: RT=3.37 min, [M+H]+=482

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

实验步骤: On a stirred solution of (R)-2,2-dimethyl-1,3-dioxolane-4-carbaldehyde (11.0 g, 0.063 mol, 75% assay, 94% ee) in THF (40 g) at 0° C. under nitrogen atmosphere, a vinyl magnesium bromide solution (1.0 M in THF, 88.7 ml, 0.0887 mol) was added over a period of 90 min. After 2 h stirring at 0° C., the temperature was raised to 10° C. and a saturated ammonium chloride solution (60 ml) was added dropwise in 30 min. The quenched reaction mixture at 20° C. was then diluted with ethyl acetate (100 ml) and demi water (50 ml) and the layers separated. The organic phase was further washed with demi water (50 ml). The organic phase was then dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to furnish 11.7 g of 1-((R)-2,2-dimethyl-1,3-dioxolan-4-yl)prop-2-en-1-ol as a light yellow oil. Spectroscopic data are conform to literature. the temperature was raised to 10° C. The quenched reaction mixture at 20° C. the layers separated The organic phase was further washed with demi water (50 ml) The organic phase was then dried over anhydrous magnesium sulfate filtered concentrated under reduced pressure

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

实验步骤: On a stirred solution of (R)-2,2-dimethyl-1,3-dioxolane-4-carbaldehyde (11.0 g, 0.063 mol, 75% assay, 94% ee) in THF (40 g) at 0° C. under nitrogen atmosphere, a vinyl magnesium bromide solution (1.0 M in THF, 88.7 ml, 0.0887 mol) was added over a period of 90 min. After 2 h stirring at 0° C., the temperature was raised to 10° C. and a saturated ammonium chloride solution (60 ml) was added dropwise in 30 min. The quenched reaction mixture at 20° C. was then diluted with ethyl acetate (100 ml) and demi water (50 ml) and the layers separated. The organic phase was further washed with demi water (50 ml). The organic phase was then dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to furnish 11.7 g of 1-((R)-2,2-dimethyl-1,3-dioxolan-4-yl)prop-2-en-1-ol as a light yellow oil. Spectroscopic data are conform to literature. the temperature was raised to 10° C. The quenched reaction mixture at 20° C. the layers separated The organic phase was further washed with demi water (50 ml) The organic phase was then dried over anhydrous magnesium sulfate filtered concentrated under reduced pressure

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

实验步骤: The title compound was prepared by a similar procedure to 8-(1-isopropyl-azetidin-3-yl)-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene using (R)-(+)-2,2-dimethyl-1,3-dioxolane-4-carboxaldehyde instead of acetone and adding 1.0 eq. diisopropylethylamine to the reaction mixture. The product was isolated as a colourless oil (127 mg, 32%). LCMS: RT=3.37 min, [M+H]+=482

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

实验步骤: On a stirred solution of (R)-2,2-dimethyl-1,3-dioxolane-4-carbaldehyde (11.0 g, 0.063 mol, 75% assay, 94% ee) in THF (40 g) at 0° C. under nitrogen atmosphere, a vinyl magnesium bromide solution (1.0 M in THF, 88.7 ml, 0.0887 mol) was added over a period of 90 min. After 2 h stirring at 0° C., the temperature was raised to 10° C. and a saturated ammonium chloride solution (60 ml) was added dropwise in 30 min. The quenched reaction mixture at 20° C. was then diluted with ethyl acetate (100 ml) and demi water (50 ml) and the layers separated. The organic phase was further washed with demi water (50 ml). The organic phase was then dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to furnish 11.7 g of 1-((R)-2,2-dimethyl-1,3-dioxolan-4-yl)prop-2-en-1-ol as a light yellow oil. Spectroscopic data are conform to literature. the temperature was raised to 10° C. The quenched reaction mixture at 20° C. the layers separated The organic phase was further washed with demi water (50 ml) The organic phase was then dried over anhydrous magnesium sulfate filtered concentrated under reduced pressure