异环磷酰胺EP杂质C

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

实验步骤: A solution of 2-chloroethylamine hydrochloride (6.25 g) in dry dimethylformamide was added dropwise to a stirred, cooled solution of potassium tert-butoxide (8.96 g) and 5-(dimethylamino)methyl-2-furanmethanol (12.4 g) in the same solvent. After 2 hr solvent was removed, the residue basified and extracted with ethyl acetate. The residue after removal of solvent was treated in ethanol with ethanolic oxalic acid. The crystalline salt was recrystallised from ethanol to give 2-[[5-(dimethylamino)methyl-2-furanyl]methoxy]ethanamine, bis oxalate, m.p. 130°-133° (3.05 g). After 2 hr solvent was removed the residue basified and extracted with ethyl acetate The residue after removal of solvent was treated in ethanol with ethanolic oxalic acid The crystalline salt was recrystallised from ethanol

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

实验步骤: Tetra-n-butylammonium hydrogensulfate (0.1 g, 0.33 mmol), powdered sodium hydroxide (1.3 g, 33 mmol) and 6-chloro-5-fluoroindole (1.4 g, 8.3 mmol) were stirred at room tempera in acetonitrile (40 mL) for 1 h. 2-Chloroethylamine hydrochloride (1.45 g, 12.5 mmol) was then added in 1 portion and the reaction was heated to reflux and stirred for 36 h. After allowing to cool to room temperature the mixture was poured into water (100 mL) and extracted with ethyl acetate (3×70 mL). The combined organic extracts were washed with brine (1×100 mL), dried (magnesium sulfate), filtered and the solvent removed under vacuo to leave a crude oil. The oil was purified by flash column chromatography [SiO2; ethyl acetate-methanol-ammonium hydroxide, (90:9:1)] to give the product as an orange oil (1.4 g, 80%). IR νmax (film)/cm−1 3377, 3104, 2937, 2868, 1675, 1568, 1505, 1479, 1449, 1400, 1357, 1327, 1291, 1236, 1143, 1090, 1030, 994, 862, 817, 753, 717, 698, 678, 646, 633, 596 and 579; NMR δH (400 MHz; DMSO-d6) 7.79 (1H, d, J 7 Hz), 7.51 (1H, d, J 10 Hz), 7.50 (1H, d, J 3.5 Hz), 6.46 (1H, m), 4.13 (2H, t, J 6.3 Hz), 2.86 (2H, t, J 6.3 Hz), 1.52 (1H, br. s). the reaction was heated to reflux extracted with ethyl acetate (3×70 mL) The combined organic extracts were washed with brine (1×100 mL) dried (magnesium sulfate) filtered the solvent removed under vacuo to leave a crude oil The oil was purified by flash column chromatography [SiO2; ethyl acetate-methanol-ammonium hydroxide, (90:9:1)]

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

实验步骤: 2-Chloroethylaminehydrochloride (5.8 g, 50 mmol) was used for reaction in the same manner as Production Example 310-1, purification was performed by silica gel column chromatography (hexane/ethyl acetate system), the obtained crystals were suspended in diethyl ether/hexane, and the crystals were filtered out, washed with hexane and dried by aspiration to obtain the title compound (6.088 g, 30.49 mmol, 60.99%) as colorless crystals. the crystals were filtered out washed with hexane dried by aspiration

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

实验步骤: Pivaloyl chloride (3.05 g, 25 mM) was added dropwise at -5° C. to compound 660 (7.45 g, 25 mM) and triethylamine (3.5 ml, 25 mM) dissolved in tetrahydrofuran (45 ml), then the mixture was stirred for 30 minutes. Chloroform (25 ml) in solution with 2-chloroethylamine hydrochloride (2.90 g) and triethylamine (3.5 ml) was added dropwise thereto, then the mixture was stirred for 1 hour with ice cooling and 4 hours at room temperature. Dilute aqueous potassium carbonate was added to the reaction mixture and the mixture was extracted twice with chloroform. The extract was dried with anhydrous sodium sulfate, and concentrated in vacuo. The residue was charged on a column of silica gel (C-200, 175 g) and eluted successively with benzene and benzene-ethyl acetate to obtain the product. (7.142 g, yield: 79.5%) the mixture was stirred for 1 hour with ice cooling and 4 hours at room temperature the mixture was extracted twice with chloroform The extract was dried with anhydrous sodium sulfate concentrated in vacuo The residue was charged on a column of silica gel (C-200, 175 g) eluted successively with benzene and benzene-ethyl acetate to obtain the product

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

实验步骤: Triethylamine (3.50 ml, 25 mM) was added to compound 037 (4.90 g, 25 mM) dissolved in tetrahydrofuran (50 ml) and pivaloyl chloride (3.05 g, 25 mM) was added dropwise at -5° C., then the mixture was stirred for 30 mintes. Chloroform (50 ml) in solution with 2-chloroethylamine hydrochloride (2.90 g, 25 mM) and triethylamine (3.9 ml, 28 mM) was added dropwise thereto, then the mixture was stirred for 4 hours while slowly reaching room temperature. The reaction mixture was concentrated in vacuo, the residue was dissolved in chloroform and washed with dilute aqueous potassium carbonate. The aqueous layer was extracted with chloroform. The organic layer was combined, dried with anhydrous magnesium sulfate, and concentrated in vacuo. The residue was charged on a column of silica gel (C-200, 40 g), and eluted successively with chloroform and chloroform-methanol (20:1) to obtain the product (5.66 g, yield: 7.5%) the mixture was stirred for 4 hours while slowly reaching room temperature The reaction mixture was concentrated in vacuo the residue was dissolved in chloroform washed with dilute aqueous potassium carbonate The aqueous layer was extracted with chloroform dried with anhydrous magnesium sulfate concentrated in vacuo The residue was charged on a column of silica gel (C-200, 40 g) eluted successively with chloroform and chloroform-methanol (20:1)

反应条件: temp:150.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A stirred mixture of the pyrazole (106 mg, 0.4 mmol) of Example 91 and 2-chloroethylamine hydrochloride (70 mg, 0.6 mmol) was heated at 150° C. under nitrogen for 18 hours. After cooling the mixture was partitioned between 10% aqueous potassium carbonate (40 ml) and dichloromethane (40 ml) and the organic layer was dried over magnesium sulphate, filtered and evaporated under reduced pressure. The crude product was purified by flash chromatography on silica gel eluting with a solvent gradient of dichloromethane:methanol (98:2, by volume) and then dichloromethane:methanol:0.880 ammonia (95:5:0.5, by volume) to give the title compound as a white solid (51 mg) m.p. 100-105°C. After cooling the mixture was partitioned between 10% aqueous potassium carbonate (40 ml) and dichloromethane (40 ml) the organic layer was dried over magnesium sulphate filtered evaporated under reduced pressure The crude product was purified by flash chromatography on silica gel eluting with a solvent gradient of dichloromethane:methanol (98:2, by volume)

反应条件: temp:150.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: The pyrazole of Example 11 (5.47 g, 19.3 mmol) was mixed with 2-chloroethylamine hydrochloride (2.46 g, 21.3 mmol) and heated neat at 150° C. for 20 hours. After cooling, the solid was partitioned between dichloromethane and 10% aqueous potassium carbonate solution. The organic extract was concentrated under reduced pressure. The crude material was purified by flash chromatography on silica gel eluting with a solvent gradient of dichloromethane:methanol:ammonia (95:5:0, by volume) gradually changing to dichloromethane:methanol:ammonia (90:10:1, by volume) to afford the title compound (3.37 g) as a colourless oil. After cooling the solid was partitioned between dichloromethane and 10% aqueous potassium carbonate solution The organic extract was concentrated under reduced pressure The crude material was purified by flash chromatography on silica gel eluting with a solvent gradient of dichloromethane:methanol:ammonia (95:5:0, by volume)

反应条件: temp:120.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A stirred suspension of the pyrazole (200 mg, 0.78 mmol) of Example 23 and 2-chloroethylamine hydrochloride (136 mg, 1.18 mmol) in toluene (1 ml) was heated at 120° C. in a sealed Reacti-vial (Trade Mark) for 18 hours. After cooling, the mixture was diluted with dichloromethane (30 ml), washed with 2 M aqueous sodium hydroxide solution (20 ml), dried over anhydrous magnesium sulphate, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography on silica gel eluting with methanol:dichloromethane:ammonia (5:95:0.5, by volume) to afford the title compound (45 mg) as white crystals, m.p. 70-72° C. After cooling washed with 2 M aqueous sodium hydroxide solution (20 ml) dried over anhydrous magnesium sulphate filtered concentrated under reduced pressure The crude product was purified by flash chromatography on silica gel eluting with methanol:dichloromethane:ammonia (5:95:0.5, by volume)

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

实验步骤: 74.8 g (0.4 mol) of N-benzylmaleimide are reacted with 58 g (0.5 mol) of 2-chloroethylamine hydrochloride and 50.5 g (0.5 mol) of triethylamine in accordance with the working instructions of Example Ia. After working up by chromatography, 81.6 g (77% of theory) of an oil with an RF value of 0.24 (on silica gel using ethyl acetate:petroleum ether=1:1) are obtained. are obtained

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

实验步骤: To a stirred (vigorously) mixture of 17.4 parts of 2-chloroethanamine hydrochloride, 20.7 parts of potassium carbonate and 225 parts of water was added dropwise a mixture of 31.3 parts of 2,6-dichlorobenzoyl chloride and 120 parts of dichloromethane at room temperature: slightly exothermic reaction. Upon completion, stirring at room temperature was continued for one hour. The organic phase was separated and the aqueous phase was extracted with dichloromethane. The combined organic phases were washed with water, dried, filtered and evaporated. The residue was crystallized from methylbenzene. The product was filtered off and dried, yielding 25.8 parts (68.8%) of 2,6-dichloro-N-(2-chloroethyl)benzamide; mp. 113.8° C. (intermediate 30). was added dropwise slightly exothermic reaction Upon completion, stirring at room temperature The organic phase was separated the aqueous phase was extracted with dichloromethane The combined organic phases were washed with water dried filtered evaporated The residue was crystallized from methylbenzene The product was filtered off dried

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

实验步骤: Pivaloyl chloride (3.05 g, 25 mM) was added dropwise at -5° C. to compound 660 (7.45 g, 25 mM) and triethylamine (3.5 ml, 25 mM) dissolved in tetrahydrofuran (45 ml), then the mixture was stirred for 30 minutes. Chloroform (25 ml) in solution with 2-chloroethylamine hydrochloride (2.90 g) and triethylamine (3.5 ml) was added dropwise thereto, then the mixture was stirred for 1 hour with ice cooling and 4 hours at room temperature. Dilute aqueous potassium carbonate was added to the reaction mixture and the mixture was extracted twice with chloroform. The extract was dried with anhydrous sodium sulfate, and concentrated in vacuo. The residue was charged on a column of silica gel (C-200, 175 g) and eluted successively with benzene and benzene-ethyl acetate to obtain the product. (7.142 g, yield: 79.5%). the mixture was stirred for 1 hour with ice cooling and 4 hours at room temperature the mixture was extracted twice with chloroform The extract was dried with anhydrous sodium sulfate concentrated in vacuo The residue was charged on a column of silica gel (C-200, 175 g) eluted successively with benzene and benzene-ethyl acetate to obtain the product

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

实验步骤: Triethylamine (3.50 ml, 25 mM) was added to compound 037 (4.90 g, 25 mM) dissolved in tetrahydrofuran (50 ml) and pivaloyl chloride (3.05 g, 25 mM) was added dropwise at -5° C., then the mixture was stirred for 30 minutes. Chloroform (50 ml) in solution with 2-chloroethylamine hydrochloride (2.90 g, 25 mM) and triethylamine (3.9 ml, 28 mM) was added dropwise thereto, then the mixture was stirred for 4 hours while slowly reaching room temperature. The reaction mixture was concentrated in vacuo, the residue was dissolved in chloroform and washed with dilute aqueous potassium carbonate. The aqueous layer was extracted with chloroform. The organic layer was combined, dried with anhydrous magnesium sulfate, and concentrated in vacuo. The residue was charged on a column of silica gel (C-200, 40 g), and eluted successively with chloroform and chloroformmethanol (20:1) to obtain the product (5.66 g, yield: 7.5%). the mixture was stirred for 4 hours while slowly reaching room temperature The reaction mixture was concentrated in vacuo the residue was dissolved in chloroform washed with dilute aqueous potassium carbonate The aqueous layer was extracted with chloroform dried with anhydrous magnesium sulfate concentrated in vacuo The residue was charged on a column of silica gel (C-200, 40 g) eluted successively with chloroform and chloroformmethanol (20:1)