达卡巴嗪杂质3

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

实验步骤: 2-[4-(2-Furanyl)butyl]-1H-isoindole-1,3(2H)-dione (5.38 g), paraformaldehyde (1.2 g) and dimethylamine hydrochloride (3.26 g) were refluxed in absolute ethanol (100 ml). After 6 hr further paraformaldehyde (0.6 g) and dimethylamine hydrochloride (1.6 g) were added and heating continued for a further 20 hr. The solvent was removed, the residue made strongly basic with 5 N sodium hydroxide, extracted with ethyl acetate and the organic layer evaporated. The crude product was purified by column chromatography to give an amber oil (3.25 g) Rf 0.4 silica/methanol. NMR (CDCl3) 8-8.6 m (4H); 7.75 s (6H); 7.3 m (2H); 6.55 s (2H); 6.3 m (2H); 4.0 m (2H); 1.9-2.4 m (4H). heating The solvent was removed extracted with ethyl acetate the organic layer evaporated The crude product was purified by column chromatography

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

实验步骤: 2-[[2-(2-Furanyl)ethyl]thio]ethyl-1H-isoindole-1,3(2H)-dione (0.5 g), dimethylamine hydrochloride (0.27 g) and paraformaldehyde (0.102 g) were heated together under reflux in ethanol. After 5 hr further dimethylamine hydrochloride (0.27 g) and paraformaldehyde (0.102 g) were added and the heating continued for a further 16 hr. Solvent was removed, the residue basified and extracted with ethyl acetate to give an oil which after column chromatography (silica/methanol) gave 2-[2-[[2-[5-(dimethylamino)methyl-2-furanyl]ethyl]thio]ethyl]-1H-isoindole-1,3(2H)-dione as a pale oil (0.43 g). Solvent was removed extracted with ethyl acetate to give an oil which after column chromatography (silica/methanol)

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

实验步骤: A solution of 2-chloro-N-{4-[(2S)-4-((1R)-1-phenylethyl)morpholin-2-yl]phenyl}acetamide (0.9 g, 2.5 mmol), potassium carbonate (1.72 g, 12.5 mmol), and dimethylamine hydrochloride (1.00 g, 12.5 mmol) in tetrahydrofuran (40 ml) and acetonitrile (80 ml) was stirred at 95° C. for 10 hours. After filtration, the solvent was removed in vacuo and the residue was partitioned between water and dichloromethane. The organic layer was dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure to give N2,N2-dimethyl-N1-{4-[(2S)-4-((1R)-1-phenylethyl)morpholin-2-yl]phenyl}glycinamide (1.15 g, quant.) as a yellow oil. After filtration the solvent was removed in vacuo the residue was partitioned between water and dichloromethane The organic layer was dried over anhydrous sodium sulfate the solvent was evaporated under reduced pressure

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

实验步骤: To a solution of 5-nitro-2-chlorobenzoic acid (1 g), 1-hydroxybenzotriazolemonohydrate (1.14 g) and 1-ethyl-3-(3-dimethylaminopyridyl)carbodiimide hydrochloride (1.42 g) in N,N′-dimethylformamide (10 mL) were added dimethylamine hydrochloride (0.61 g) and triethylamine (1 mL). The mixture was stirred for all day and night, and then water was added. The reaction solution was extracted with ethyl acetate, and the extract was washed with saturated aqueous sodium bicarbonate and saturated brine, dried over magnesium sulfate, and concentrated to give the title compound (1.13 g). The reaction solution was extracted with ethyl acetate the extract was washed with saturated aqueous sodium bicarbonate and saturated brine dried over magnesium sulfate concentrated

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

实验步骤: HATU (152 mg, 0.40 mmol) was added in one portion to lithium 3-(4-(tert-butoxycarbonylamino)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxamido)-3-(4-chlorophenyl)propanoate (Intermediate 97) (200 mg, 0.36 mmol), dimethylamine hydrochloride (48.0 mg, 0.59 mmol) and N,N-diisopropylethylamine (0.190 mL, 1.09 mmol) in N-methyl-2-pyrrolidinone (3.0 mL) at room temperature under argon. The resulting solution was stirred overnight. Diethyl ether added to precipitate the crude product which formed as a gum. This was rinsed with Et2O and dried to give the crude gum (770 mg) which was used in subsequent reactions without further purification. to precipitate the crude product which formed as a gum This was rinsed with Et2O dried

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

实验步骤: A mixture of 35% aqueous formaldehyde solution (3.2 ml, 40.7 mmol) and dimethylamine hydrochloride (3.44 g, 42.4 mmol) was added to pyrrole (2.72 g, 40.47 mmol) at room temperature with stirring over a 20-minute interval, and the resulting mixture was stirred at room temperature for 2 hours. After stirring, 10% aqueous sodium hydroxide solution (18 ml) was added to the reaction mixture, and the reaction mixture was extracted with dichloromethane. The extract was washed with saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. After filtration, the solvent was removed in vacuo, and the residue was purified by chromatography on a silica gel column using a mixed solvent of dichloromethane and methanol (10:1) as the eluent to afford 2-(N,N-dimethylaminomethyl)pyrrole (4.55 g, quantitative yield). the resulting mixture was stirred at room temperature for 2 hours After stirring the reaction mixture was extracted with dichloromethane The extract was washed with saturated aqueous sodium chloride solution dried over anhydrous sodium sulfate After filtration the solvent was removed in vacuo the residue was purified by chromatography on a silica gel column

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

实验步骤: A mixture of 35% aqueous formaldehyde solution (9 ml, 105 mmol) and dimethylamine hydrochloride (9.0 g, 110 mmol) was added to 1-ethylpyrrole (10.0 g, 105 mmol) with stirring under ice-cooling over a 90-minute interval, and then the resulting mixture was stirred at room temperature for 6 hours. After stirring, 10% aqueous sodium hydroxide solution (150 ml) was added to the reaction mixture, and the resulting mixture was extracted with ether. The extract was washed with saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. After filtration, the solvent was removed in vacuo, and the residue was purified by chromatography on a silica gel column using a mixed solvent of dichloromethane and methanol (9:1) as the eluent to afford 2-(N,N-dimethylaminomethyl)-1-ethylpyrrole (15.6 g, yield: 97%). cooling over a 90-minute interval the resulting mixture was stirred at room temperature for 6 hours After stirring the resulting mixture was extracted with ether The extract was washed with saturated aqueous sodium chloride solution dried over anhydrous sodium sulfate After filtration the solvent was removed in vacuo the residue was purified by chromatography on a silica gel column

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

实验步骤: A mixture of 35% aqueous formaldehyde solution (20.8 ml, 264.3 mmol) and dimethylamine hydrochloride (22.70 g, 278.4 mmol) was added to 1-methylpyrrole (21.42 g, 264.1 mmol) with stirring under ice-cooling over a 90-minute interval, and then the resulting mixture was stirred at room temperature for 6 hours. After stirring, 10% aqueous sodium hydroxide solution (150 ml) was added to the reaction mixture, and the reaction mixture was extracted with ether. The extract was washed with saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. After filtration, the solvent was removed in vacuo, and the residue was purified by chromatography on a silica gel column using a mixed solvent of dichloromethane and methanol (10:1) as the eluent to afford 2-(N,N-dimethylaminomethyl)-1-methylpyrrole (31.47 g, yield: 86%). cooling over a 90-minute interval the resulting mixture was stirred at room temperature for 6 hours After stirring the reaction mixture was extracted with ether The extract was washed with saturated aqueous sodium chloride solution dried over anhydrous sodium sulfate After filtration the solvent was removed in vacuo the residue was purified by chromatography on a silica gel column

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

实验步骤: Dissolve 2-methyl-2-phenyl-propionic acid (15.0 g, 91.2 mmol) in toluene (80 mL) and add, by dropwise addition over 5 minutes, thionyl chloride (15 mL, 206 mmol). Stir at room temperature overnight, add additional thionyl chloride (3 mL, 41.1 mmol) and heat to reflux for 1 hour. Remove excess thionyl chloride by azeotropic distillation with toluene (40 mL). Add toluene (20 mL) to the reaction mixture along with a solution of potassium carbonate (28.0 g, 203 mmol) in water (40 mL). Add, by dropwise addition, a 40% aqueous solution of dimethylamine hydrochloride (20 mL, 0.18 mol) without cooling and stir for 2 hours. Add tert-butylmethyl ether (75 mL) following by slow addition of aqueous HCl (2N, 75 mL) with vigorous stirring. Separate the organic layer and wash with aqueous HCl (2N, 75 mL), saturated sodium hydrogen carbonate (25 mL) and brine (50 mL). Dry the organic layer over (Na2SO4), filter, evaporate the filtrate in vacuo and purify by crystallization to give 2-methyl-2-phenyl-propionic acid, dimethylamide (15.35 g, 88%) as a white solid; mp 57-59° C. add, by dropwise addition over 5 minutes heat to reflux for 1 hour Remove excess thionyl chloride by azeotropic distillation with toluene (40 mL) Add, by dropwise addition stir for 2 hours Separate the organic layer wash with aqueous HCl (2N, 75 mL), saturated sodium hydrogen carbonate (25 mL) and brine (50 mL) Dry the organic layer over (Na2SO4) filter evaporate the filtrate in vacuo purify by crystallization

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

实验步骤: A mixture of 1-undecyl-2-(4-fluorobenzyl)thio-5-(1-(carboxymethyl)-2-oxopyrimid-5-ylmethyl)pyrimidin-4-one, dimethylamine hydrochloride (0.02 g), diisopropylethylamine (0.045 ml), hydroxybenzotriazole (0.005 g) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.045 g) in dry methylene chloride were stirred together for 24 h and diluted with 3% methanol in methylene chloride and 5% aqueous potassium carbonate. The organic layer was added directly to a SepPak cartridge (SiO2, 10 g) and eluted with 0-20% methanol in ethyl acetate to give the desired product (0.085 g). 1H-NMR (CDCl3) δ0.8-0.95 (3H,m), 1.15-1.4 (16H,m), 1.6-1.85 (2H,m), 2.98 (3H,s), 3.13 (3H,s), 3.49 (2H,s), 3.77 (2H,t), 4.46 (2H,s), 4.74 (2H,s), 6.9-7.1 (2H,m), 7.14 (1H,s), 7.3-7.45 (2H,m), 7.78 (1H,bd), 8.49 (1H,bd); MS (APCI+) found (M+1)=584; C31H42FN5O3S requires 583. The organic layer was added directly to a SepPak cartridge (SiO2, 10 g) eluted with 0-20% methanol in ethyl acetate

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

实验步骤: N-Boc-4-(4-chlorophenyl)-4-piperidine carboxylic acid Compound 2-1 (5.96 g, 18 mmol, Arch Chemical) was dissolved in DMF (175 mL) and chilled in an ice bath temp. To the solution was added N-methylmorpholine (5.76 mL, 53 mmol), HOBt (1.18 g, 8.8 mmol), dimethylamine hydrochloride (1.41 g, 18 mmol), and HBTU (10.0 g, 26 mmol). The solution was allowed to warm overnight to rt, poured into 1N sodium hydroxide solution (100 mL), and extracted with EtOAc (3×75 mL). The combined organic layers were washed with 1N NaOH (2×), 1N hydrochloric acid solution (2×), and brine (3×); and dried over Na2SO4 and concentrated to give Compound 2-2 (6.1 g, 17 mmol, 94%) as a white solid. 1H NMR (300 MHz, CDCl3,) δ 7.32 (d, J=9 Hz, 2H), 7.17 (d, J=9 Hz, 2H), 4.2-3.8 (br m, 2H), 3.0-2.6 (br m, 2H), 2.96 (s, 3H), 2.80 (s, 3H), 2.25 (m, 2H), 2.1-1.7 (br m, 2H), 1.45 (s, 9H). chilled in an ice bath temp to warm overnight to rt extracted with EtOAc (3×75 mL) The combined organic layers were washed with 1N NaOH (2×), 1N hydrochloric acid solution (2×), and brine (3×) and dried over Na2SO4 concentrated

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

实验步骤: Trithylamine (37.5 ml, 0.27 mol, 2.8 equiv) was dissolved in THF (100 ml), and dimethylamine hydrochloride (9.3 g, 0.114 mol, 1.2 equiv) was added. Methyl 4-bromocrotonate (20 g, 85% purity, 0.095 mol, 1.00 equiv) in 100 ml of THF was added drop-wise to the resulting solution at room temperature while stirring. The reaction mixture was allowed to react overnight at room temperature. The reaction mixture was filtered, and the filtrate was evaporated under reduced pressure to give yellow oil. The oil was dissolved in 50 ml of isopropanol, and hydrogen chloride was added until pH 2.0 was reached. The white solid was formed and filtered and dried to give 7.1 g product. MS (ESI) m/z: 563 (M+1). to react overnight at room temperature The reaction mixture was filtered the filtrate was evaporated under reduced pressure to give yellow oil The white solid was formed filtered dried