舒尼替尼杂质1

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

实验步骤: Ethyl 4-bromocrotonate (7.0 mL) was added to triethylphosphite (9.9 mL) at 120 to 130° C. during 60 minutes periods. After the generation of ethyl bromide ceased, the reaction solution was stirred at the same temperature for 3 hours. After cooling, the resulting reaction solution was concentrated under reduced pressure. Then the residue was purified by distillation at 150 to 210° C. under reduced pressure (17 to 21 hPa) to give triethyl 4-phosphonocrotonate as colorless oil. After cooling the resulting reaction solution was concentrated under reduced pressure Then the residue was purified by distillation at 150 to 210° C. under reduced pressure (17 to 21 hPa)

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

实验步骤: Analogously to the procedure described in Example 5, the use of 11.4 g of 4-(1-adamantyl)-phenol and 14.5 g of 4-bromocrotonic acid ethyl ester as starting materials gives 4-[4-(1-adamantyl)-phenoxy]-crotonic acid ethyl ester of melting point 91°-93° C (from methanol).

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

实验步骤: Analogously to the procedure described in Example 5, the use of 11.4 g of 4-(1-adamantyl)-phenol and 14.5 g of 4-bromocrotonic acid ethyl ester as starting materials gives 4-[4-(1-adamantyl)-phenoxy]-crotonic acid ethyl ester of melting point 91°-93° C (from methanol).

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

实验步骤: A mixture of ethyl-4-bromocrotonate (193 mg), piperidine (94 mg) and potassium carbonate (276 mg) in acetonitrile (10 ml) was stirred and heated at reflux for 3 hours. The reaction mixture was cooled and the solvent was removed in vacuo. The residue was partitioned between water (2×15 ml) and ethyl acetate (20 ml). The organic extracts were dried (Na2SO4), filtered and concentrated in vacuo to give the title compound as an orange oil (157 mg). heated at reflux for 3 hours The reaction mixture was cooled the solvent was removed in vacuo The residue was partitioned between water (2×15 ml) and ethyl acetate (20 ml) The organic extracts were dried (Na2SO4) filtered concentrated in vacuo

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

实验步骤: 2.0 ml of THF and 0.071 ml of chlorotrimethylsilane were added to 73 mg of zinc, followed by stirring at room temperature for 15 minutes. Then, 200 mg of ethyl (2E)-4-bromobut-2-enoate was added thereto, followed by stirring at room temperature for 30 minutes. To the reaction mixture was added 7-(cyclohexylamino)-1-(1-ethylpropyl)-6-fluoro-4-oxo-1,4-dihydro quinoline-3-carbaldehyde, followed by overnight stirring at room temperature. Water was added to the reaction mixture, followed by extraction with chloroform. The organic layer was washed with aqueous saturated sodium chloride, dried over anhydrous sodium sulfate and then evaporated under a reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 30 mg of ethyl (2E)-5-[7-(cyclohexylamino)-1-(1-ethylpropyl)-6-fluoro-4-oxo-1,4-dihydroquinolin-3-yl]-5-hydroxypent-2-enoate. by stirring at room temperature for 30 minutes followed by overnight stirring at room temperature followed by extraction with chloroform The organic layer was washed with aqueous saturated sodium chloride dried over anhydrous sodium sulfate evaporated under a reduced pressure The resulting residue was purified by silica gel column chromatography

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

实验步骤: To a solution of 2,6-di-tert-butyl-4-mercaptophenol (II) (590 mg; 2.48 mmol) in dry ether (10 ml), triethylamine (303 mg; 3 mmol) was added, and a solution of ethyl 4-bromocrotonate (580 mg; 3 mmol) in dry ether (5 ml) was added while cooling with ice, followed by stirring at room temperature for 2 hours. The reaction mixture was combined with water (50 ml) and extracted with ether (50 ml). The extract was washed with water (50 ml) two times and concentrated under reduced pressure. The crude intermediate product as pale yellow oil was dissolved in ethanol (30 ml), 10 % sodium hydroxide solution (3 ml) was added thereto, and the resultant mixture was stirred at room temperature for 2 hours. To the reaction mixture, acetic acid (2 ml) was added, and the resulting mixture was concentrated under reduced pressure to make a volume of about 10 ml, which was extracted with ethyl acetate (50 ml). The extract was washed with water (50 ml) two times, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residual oil was chromatographed on silica gel and eluted with ethyl acetate. The collected fractions were concentrated under reduced pressure, and the crystalline residue was recrystallized from n-pentane to give the objective compound (Ih) (270 mg). m.p., 104°-106° C. Yield, 34 %. while cooling with ice extracted with ether (50 ml) The extract was washed with water (50 ml) two times concentrated under reduced pressure The crude intermediate product as pale yellow oil was dissolved in ethanol (30 ml) 10 % sodium hydroxide solution (3 ml) was added the resultant mixture was stirred at room temperature for 2 hours To the reaction mixture, acetic acid (2 ml) was added the resulting mixture was concentrated under reduced pressure was extracted with ethyl acetate (50 ml) The extract was washed with water (50 ml) two times dried over anhydrous sodium sulfate concentrated under reduced pressure The residual oil was chromatographed on silica gel eluted with ethyl acetate The collected fractions were concentrated under reduced pressure the crystalline residue was recrystallized from n-pentane to give the objective compound (Ih) (270 mg) m.p., 104°-106° C Yield

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

实验步骤: Substantially the same procedure as in Step A of Reference Example 1 was repeated using 6-iodo-2-methoxyphenol [Heterocyclic Communications, 289 (1995)] (0.4 g) and ethyl 4-bromocrotonate (0.29 ml) to give Compound IIbc-a (0.52 g, 90%) as a pale-yellow oily substance. to give Compound IIbc-a (0.52 g, 90%) as a pale-yellow oily substance

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

实验步骤: Substantially the same procedure as in Step A of Reference Example 1 was repeated using 6-iodo-2-methoxyphenol [Heterocyclic Communications, 289 (1995)] (0.4 g) and ethyl 4-bromocrotonate (0.29 ml) to give Compound IIbc-a (0.52 g, 90%) as a pale-yellow oily substance. to give Compound IIbc-a (0.52 g, 90%) as a pale-yellow oily substance

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

实验步骤: Prepared according to WO 2010/031816. In a 250 mL RBF, sodium diformylamide (Fluka; 2.66 g, 28.0 mmol) and NaI (3.49 g, 23.31 mmol) were treated with ACN (60 mL) and (E)-ethyl 4-bromobut-2-enoate (Aldrich; 4.28 mL, 23.31 mmol) and the flask was fitted with a reflux condenser and heated at reflux overnight (16 h). The mixture was concentrated in vacuo and the crude residue was treated with water and extracted with EtOAc (100 mL). The organic extract was washed with brine, then dried over MgSO4, filtered, and concentrated. The resulting light-brown solid was suspended in Et2O (ca. 10 mL), filtered, and washed with Et2O (5 mL), then dried by drawing air through the filtercake for 2 min to afford (E)-ethyl 4-(N-formylformamido)but-2-enoate (3.66 g, 19.76 mmol, 85% yield) as a brown amorphous solid: 1H NMR (400 MHz, CDCl3) δ ppm 8.91 (2H, br. s.), 6.74-6.84 (1H, m), 5.90 (1H, dt, J=15.8, 1.6 Hz), 4.40 (2H, d, J=4.5 Hz), 4.13-4.24 (2H, m), 1.20-1.33 (3H, m). m/z (ESI, +ve ion) 186.1 (M+H)+. The crude material was used in the subsequent step without further purification. Prepared the flask was fitted with a reflux condenser heated at reflux overnight (16 h) The mixture was concentrated in vacuo the crude residue was treated with water extracted with EtOAc (100 mL) The organic extract was washed with brine dried over MgSO4 filtered concentrated filtered washed with Et2O (5 mL) dried for 2 min

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

实验步骤: 5-Bromo-2-nitrophenol (10 g, 45.9 mmol) and K2CO3 (8.24 g, 59.6 mmol) were suspended in NMP (81 mL) (a bright red suspension) and ethyl 4-bromocrotonate (10.26 mL, 59.63 mmol) was added dropwise at room temperature. The reaction was stirred at room temperature over night (20 h). The mixture was poured into ice/water (500 mL) and stirred for 30 min. The precipitate was collected by filtration and washed with water (2×200 mL), air dried for 10 min and then washed with heptane (200 mL). Heptane (200 mL) was added to the solid and stirred for 1 h. The solid was filtered off, washed with heptane (2×50 mL) and dried in vacuo to afford a beige solid. The title compound (15.0 g, 99%) was obtained and was used without further purification. was added dropwise at room temperature stirred for 30 min The precipitate was collected by filtration washed with water (2×200 mL), air dried for 10 min washed with heptane (200 mL) Heptane (200 mL) was added to the solid stirred for 1 h The solid was filtered off washed with heptane (2×50 mL) dried in vacuo to afford a beige solid

反应条件: temp:25.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A mixture of 3-fluoro-6-nitrophenol (200 g, 1.27 mol), anhydrous K2CO3 (202 g, 1.46 mol) and NMP (1.2 L) under nitrogen atmosphere was stirred at 25° C. for 30 min. Ethyl 4-bromocrotonate (80% tech., 252 mL, 1464 mmol) was added during 2-3 min to the obtained red suspension and the resulting mixture was stirred over night at ambient temperature. The yellowish suspension was then poured into ice-water (8.0 L) under stirring. After stirring for 1 h the solids were filtered off, washed with water (5×1.0 L), heptane (4×0.50 L) and then dried over night at 50° C. in vacuo affording the title compound (332 g, 1.20 mmol, 98% w/w, 95% yield). the resulting mixture was stirred over night at ambient temperature under stirring After stirring for 1 h the solids were filtered off washed with water (5×1.0 L), heptane (4×0.50 L) dried over night at 50° C. in vacuo

反应条件: temp:25.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: 2-(Benzylamino)ethanol (19.05 ml, 132 mmol) and triethylamine (18.44 ml, 132 mmol) was added to water (150 ml) and the resulting mixture was heated to reflux temperature. (E)-Ethyl 4-bromobut-2-enoate (18.24 ml, 132 mmol) was added dropwise for 10 min The resulting mixture was further maintained at reflux temperature for 5 h. The reaction mixture was cooled to 25° C. and added NaOH (5.29 g, 132 mmol) after that the solvent was removed by distillation under reduced pressure to give orange oil. Ethyl acetate (150 mL) was added and the resulting solution was washed with water (2×50 mL). Ethyl acetate was distilled off under reduced pressure to give crude compound (15 g). This crude compound was purified by flash chromatography (Biotage) using eluent 20% ethyl acetate in hexane to yield 13 g of pure title compound as colorless viscous oil. m/z 264.08. the resulting mixture was heated to reflux temperature was further maintained at reflux temperature for 5 h was removed by distillation under reduced pressure to give orange oil the resulting solution was washed with water (2×50 mL) Ethyl acetate was distilled off under reduced pressure to give crude compound (15 g) This crude compound was purified by flash chromatography (Biotage)