N-(2-氯乙基)吡咯烷盐酸盐

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

实验步骤: A mixture of 7-nitro-3,4-dihydro-2H-benzo[b][1,4]thiazine (1 g, 5.10 mmol), 1-(2-chloroethyl)pyrrolidine hydrochloride (1.734 g, 10.19 mmol), and nBu4NBr (0.082 g, 0.255 mmol) in CH2Cl2 (10 mL) and 50% NaOH solution (10 mL) was stirred at room temperature for 16 hours. The mixture was diluted with CH2Cl2 (25 mL) and water (50 mL). The mixture was transferred to a separatory funnel, and the layers were separated. The aqueous layer was extracted in CH2Cl2 (2×25 mL). The combined organic layers were dried (Na2SO4), filtered, and concentrated. The red crude material was subjected to flash chromatography on silica gel (CH2Cl2, then 1.75-5% (2M NH3 in MeOH)/CH2Cl2) to give 7-nitro-4-(2-(pyrrolidin-1-yl)ethyl)-3,4-dihydro-2H-benzo[b][1,4]thiazine as a brown viscous oil (0.63 g, 42%). 1H NMR (DMSO-d6) δ 7.86-7.82 (m, 2H), 6.82 (d, J=9.0 Hz, 1H), 3.81 (t, J=4.8 Hz, 2H), 3.58 (t, J=6.9 Hz, 2H), 3.33 (s, 4H), 3.05 (t, J=5.1 Hz, 2H), 2.63 (t, J=6.9 Hz, 2H), 2.50 (s, 4H), 1.67 (s, 4H); ESI-MS (m/z, %): 296, 294 (MH+, 100), 98 (13). The mixture was transferred to a separatory funnel the layers were separated The aqueous layer was extracted in CH2Cl2 (2×25 mL) The combined organic layers were dried (Na2SO4) filtered concentrated

反应条件: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A solution of 7-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazine (300 mg, 1.665 mmol) in DMF (10 mL) was treated with NaH (213 mg, 5.33 mmol, 60% wt in mineral oil) at 0° C., resulting in a bright orange suspension. The mixture was stirred for 10 minutes. 2-chloroethyl-pyrrolidine hydrochloride (566 mg, 3.33 mmol) was then added, and the reaction turned into a bright red suspension. The reaction was heated to 90° C. for 1 hour and then cooled to room temperature. The mixture was then diluted with water (20 mL), transferred to a separatory funnel, and extracted into EtOAc (2×15 mL). The combined organic layers were washed with brine (3×5 mL), dried (Na2SO4), filtered, and concentrated. The residue was subjected to flash chromatography on silica gel using CH2Cl2 followed by 5:95 (2M NH3 in MeOH):CH2Cl2 to give a solid (330 mg, 72%). 1H-NMR (DMSO-d6) δ 7.75 (dd, J=2.7, 9.3 Hz, 1H), 7.47 (d, J=2.7 Hz, 1H), 6.80 (d, J=9.0 Hz, 1H), 4.18 (t, J=4.2 Hz, 2H), 3.58-3.55 (m, 4H), 2.63 (t, J=6.9 Hz, 2H), 2.58-2.48 (m, 4H), 1.70-1.63 (m, 4H); ESI-MS (m/z, %): 278 (MH+, 100), 98 (20). resulting in a bright orange suspension cooled to room temperature transferred to a separatory funnel extracted into EtOAc (2×15 mL) The combined organic layers were washed with brine (3×5 mL) dried (Na2SO4) filtered concentrated

反应条件: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A suspension of 7-nitro-2H-benzo[b][1,4]oxazin-3(4H)-one (0.5 g, 2.575 mmol), 1-(2-chloroethyl)pyrrolidine hydrochloride (0.43 g, 2.575 mmol) and K2CO3 (1.06 g, 7.726 mmol) in dry DMF (5 mL) was stirred at 100° C. overnight (18 hours). The reaction was brought to room temperature, diluted with water (100 mL), and the product was extracted into ethyl acetate (2×25 mL). The combined ethyl acetate layers were washed with brine (20 mL) and dried (Na2SO4). The solvent was evaporated, and the crude material was purified by column chromatography (3:97 (2M NH3 in MeOH):CH2Cl2) to obtain the title compound (0.49 g, 65%) as a solid. 1H NMR (DMSO-d6) δ 1.62-1.70 (m, 4H), 2.46-2.54 (m, 4H, merged with DMSO-d6 resonance), 2.60 (t, 2H, J=6.9 Hz), 4.08 (t, 2H, J=6.9 Hz), 4.80 (s, 2H), 7.44 (d, 1H, J=9.3 Hz), 7.80 (d, 1H, J=2.4 Hz), 7.96 (dd, 1H, J=2.7, 9.0 Hz); ESI-MS (m/z, %): 292 (MH+, 100). was brought to room temperature the product was extracted into ethyl acetate (2×25 mL) The combined ethyl acetate layers were washed with brine (20 mL) dried (Na2SO4) The solvent was evaporated the crude material was purified by column chromatography (3:97 (2M NH3 in MeOH):CH2Cl2)

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

实验步骤: 1-(2-Chloroethyl)pyrrolidine hydrochloride (213 mg, 1.25 mmol) was added to a suspension of 2-bromo-5-(1H-indazol-5-yl)furo[3,2-c]pyridin-4(5H)-one (187 mg, 0.570 mmol) and Cs2CO3 (1.11 g, 3.42 mmol) in anhydrous DMSO (3 mL) and the resulting suspension was stirred at 25° C. for 14 h. H2O (10 mL) was added and the aqueous suspension was filtered. The solid was dried under reduced pressure. Flash chromatography on silica gel [4.75:4.75:0.5 MTBE/CH2Cl2/(9:1 EtOH/NH4OH)] afforded the title compound (113 mg, 47%) as a light yellow powder with data matching those reported in Example 9. the aqueous suspension was filtered The solid was dried 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 2-(3-chlorophenyl)-5-(1H-indazol-5-yl)furo[3,2-c]pyridin-4(5H)-one (0.365 g, 0.732 mmol) in DMSO (1.5 mL) and NMP (0.94 mL) was added (2-chloroethyl)pyrrolidine hydrochloride (0.273 g, 1.61 mmol) and Cs2CO3 (1.43 g, 4.39 mmol). The reaction mixture was stirred at ambient temperature for 18 h; then the reaction mixture was diluted with H2O (10 mL) and EtOAc (20 mL). The desired solids were collected by filtration. Purification by flash chromatography (silica gel, CH2Cl2/(80:18:2 CH2Cl2/MeOH/NH4OH), 100:0 to 0:100) yielded the title compound (83.8 mg, 25%) as a light yellow solid: 1H NMR (500 MHz, CDCl3) δ 8.05 (s, 1H), 7.79 (t, J=2.0 Hz, 1H), 7.72 (d, J=1.5 Hz, 1H), 7.66 (d, J=7.5 Hz, 1H), 7.56 (d, J=9.0 Hz, 1H), 7.42 (dd, J=8.5, 2.0 Hz, 1H), 7.39-7.35 (m, 2H), 7.33-7.31 (m, 1H), 7.29 (s, 1H), 6.68 (d, J=7.5 Hz, 1H), 4.58 (t, J=7.5 Hz, 2H), 3.03 (t, J=7.0 Hz, 2H), 2.60 (m, 4H), 1.80 (m, 4H); ESI MS m/z 459 [M+H]+; HPLC (Method A) >99% (AUC), tR=16.7 min. The desired solids were collected by filtration Purification by flash chromatography (silica gel, CH2Cl2/(80:18:2 CH2Cl2/MeOH/NH4OH), 100:0 to 0:100)

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

实验步骤: 1-(2-Chloroethyl)pyrrolidine hydrochloride (9.88 g, 58.1 mmol) was added to a suspension of 5-iodo-1H-indazole (8.86 g, 36.3 mmol) and Cs2CO3 (50.8 g, 456 mmol) in anhydrous DMSO (100 mL) and the resulting suspension was stirred at 25° C. for 14 h. H2O (100 mL) was added and the aqueous solution was extracted with EtOAc (3×200 mL). The combined organic extracts were washed with brine (2×200 mL), dried over MgSO4 and concentrated under reduced pressure. Flash chromatography on silica gel (9:1 Et2O/Et3N) afforded 6.473 g (52%) of the title compound as a yellow solid: 1H NMR (300 MHz, CDCl3) δ 8.08 (br d, J=13 Hz, 1H), 7.91 (d, J=0.9 Hz, 1H), 7.60 (dd, J=87, 1.3 Hz, 1H), 7.25 (d, J=8.7 Hz, 1H), 4.50 (t, J=7.4 Hz, 2H), 2.98 (t, J=7.4 Hz, 2H), 2.59-2.50 (m, 4H), 1.82-1.70 (m, 4H). the aqueous solution was extracted with EtOAc (3×200 mL) The combined organic extracts were washed with brine (2×200 mL) dried over MgSO4 concentrated under reduced pressure

反应条件: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: 1-(2-Chloro-ethyl)-pyrrolidine hydrochloride (1.2 g, 7.0 mmol, 1.1 equiv) is added to a suspension of 2-fluoro-4-nitrophenol (1 g, 6.4 mmol) and cesium carbonate (5.2 g, 15.9 mmol, 2.5 equiv) in DMF (20 mL). The resulting mixture is heated to 80° C. and stirred for 18 h. Additional 1-(2-chloro-ethyl)-pyrrolidine hydrochloride (1 g) is added and the mixture is stirred for 3 h at 80° C. The reaction mixture is cooled to RT, diluted with EtOAc and H2O. The layers are separated and the aqueous layer is extracted with EtOAc. The organic phase is washed with H2O, dried (Na2SO4), filtered and concentrated. The residue is purified by silica gel column chromatography (DCM/MeOH+1% NH3aq, 95:5) to provide the title compound as a yellow solid. ESI-MS: 255.1 [MH]+; tR=2.57 min (system 1); TLC: Rf=0.55 (DCM/MeOH+1% NH3aq, 95:5). the mixture is stirred for 3 h at 80° C The reaction mixture is cooled to RT The layers are separated the aqueous layer is extracted with EtOAc The organic phase is washed with H2O dried (Na2SO4) filtered concentrated The residue is purified by silica gel column chromatography (DCM/MeOH+1% NH3aq, 95:5)

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

实验步骤: A mixture of (4-methoxyphenyl)-(4-hydroxyphenyl)-1,2,3,4-tetrahydronaphth-1-yl-methane (400 mg, 0.001 mol), anhydrous K2CO3 (2.0 gm, 0.14 mol), 1-(2-chloroethyl)pyrrolidine hydrochloride (400 mg, 0.002) and dry acetone (25.0 ml) was refluxed for 10 hrs. K2CO3 was filtered off, acetone was distilled off and the residue was diluted with water. The reaction mixture was extracted with ethyl acetate, washed with water, dried over sodium sulphate and concentrated to give an oil which was filtered through basic alumina column using benzene as the eluent, and concentrated to give an oil. The oil thus obtained was treated with ethanolic HCl. The solvent was evaporated and the compound was crystallized with absolute alcohol and dry ether, filtered under anhydrous conditions, and dried to give the title compound of formula I. Yield 350 mg. (68.35%). was refluxed for 10 hrs K2CO3 was filtered off acetone was distilled off the residue was diluted with water The reaction mixture was extracted with ethyl acetate washed with water dried over sodium sulphate concentrated to give an oil which was filtered through basic alumina column concentrated to give an oil The oil thus obtained The solvent was evaporated the compound was crystallized with absolute alcohol and dry ether filtered under anhydrous conditions dried

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

实验步骤: A mixture of (4-methoxyphenyl)-(3-methyl-4-hydroxyphenyl)-naphth-1-yl-methane (0.3 gm, 0.008 mol), anhydrous K2CO3 (2.0 gm), 1-(2-chloroethyl)pyrrolidine hydrochloride (0.3 gm, 0.0017 mol) and anhydrous acetone (25 ml) was refluxed for 10 hrs, K2CO3 was filtered off, acetone was distilled off, and the residue was diluted with water. The reaction mixture was extracted with ethyl acetate washed with water, dried over Na2SO4 and concentrated to give an oil. This oil was passed through basic alumina using benzene as eluent. Solvent was distilled off. The oil thus obtained was treated with ethanolic HCl. The solvent was evaporated and compound was crystallized with absolute alcohol and anhydrous ether to give the title compound as a salt of general formula I. Yield 170 mg(46%). was refluxed for 10 hrs K2CO3 was filtered off acetone was distilled off the residue was diluted with water The reaction mixture was extracted with ethyl acetate washed with water dried over Na2SO4 concentrated to give an oil Solvent was distilled off The oil thus obtained The solvent was evaporated compound was crystallized with absolute alcohol and anhydrous ether

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

实验步骤: A solution of 2,2,2-trifluoro-1-[1-(4-hydroxyphenyl)-6-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]ethanone (18.98 g, 54.0 mmol) in anhydrous DMF (200 ml) was added to a suspension of NaH (2.592 g, 108.0 mmol) in anhydrous DMF (400 ml) at rt under N2. After stirring at rt for 1 hr, a solution of 1-(2-chloroethyl)pyrrolidine hydrochloride (9.184 g, 54.0 mmol) in anhydrous DMF (200 ml) was added and the reaction mixture was heated to 100° C. for 4 hr. The reaction mixture was cooled to rt, diluted with H2O (2000 ml), and extracted with EtOAc (4×250 ml). The combined extracts were washed with H2O (3×250 ml), dried over MgSO4, and concentrated in vacuo to give 21.15 g of yellow oil. Purification by flash chromatography, eluting with EtOAc:MeOH (8:2) gave 10.503 g (43% yield) of yellow oil. the reaction mixture was heated to 100° C. for 4 hr The reaction mixture was cooled to rt extracted with EtOAc (4×250 ml) The combined extracts were washed with H2O (3×250 ml) dried over MgSO4 concentrated in vacuo

反应条件: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a solution of N-(2-hydroxy-5-nitrophenyl)acetamide (870 mg, 4.44 mmol) in DMF (5 mL) was added NaH (196 mg, 5.32 mmol) and K2CO3 (2.11 g, 13.32 mmol), followed by 1-(2-chloroethyl)pyrrolidine hydrochloride (905 mg, 5.32 mmol). After heating at 100° C. for 20 h, the solution was poured to ice, and was extracted with EtOAc, organic layer was washed with Sat. NaHCO3, brine, dried and concentrated to give N-(5-nitro-2-(2-(pyrrolidin-1-yl)ethoxy)phenyl)acetamide (430 mg). the solution was poured to ice was extracted with EtOAc, organic layer was washed with Sat. NaHCO3, brine dried concentrated

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

实验步骤: 1-[2-(2,6-dimethyl-4-nitrophenoxy)ethyl]pyrrolidine was prepared in a manner analogous to the alkylation described in Example 1, from 2,6-dimethyl-4-nitrophenol (1.0 g, 5.98 mmol), 1-(2-chloroethyl)pyrrolidine hydrochloride (1.52 g, 8.97 mmol) and caesium carbonate (5.83 g, 17.94 mmol) to give the desired product as a brown oil. 6H (CDCl3) 7.89 (2H, s), 3.96 (2H, t, J 6.1 Hz), 2.93 (2H, t, J 6.1 Hz), 2.65 (4H, m), 2.35 (6H, s) and 1.83 (4H, m). MS (ES+) 265 (MH+).