2-chloro-N,N-dimethylethanamine;hydrochloride

Conditions: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 2-(2,4-dimethoxy-benzyl)-4-hydroxy-isoindole-1,3-dione (317 mg, 1.01 mmol), 2-dimethylaminoethyl chloride hydrochloride (160 mg, 1.11 mmol) and potassium carbonate (350 mg, 2.5 mmol) in DMF (4 mL) was heated at 60° C. for 18 hours. The mixture was concentrated in vacuo, taken up in ethyl acetate and extracted twice with 1N hydrochloric acid. The aqueous extracts were made basic with solid potassium carbonate and extracted with ethyl acetate (×2). The combined organic extracts were washed with brine, dried (MgSO4) and concentrated to give the title compound (236 mg, 61%) as an off-white solid. 1H NMR (methanol-d4) 7.73 (1H, t), 7.44-7.40 (2H, m), 7.02 (1H, d), 6.51 (1H, d), 6.42 (1H, dd), 4.72 (2H, s), 4.33 (2H, t), 3.80 (3H, s), 3.76 (3H, s), 2.87 (2H, t), 2.40 (6H, s). MS: [M+H]+ 385. The mixture was concentrated in vacuo extracted twice with 1N hydrochloric acid extracted with ethyl acetate (×2) The combined organic extracts were washed with brine dried (MgSO4) concentrated

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a stirred suspension of 6-nitro-3,4-dihydro-2H-benzo[b][1,4]thiazine (500 mg, 2.55 mmol), 2-chloro-N,N-dimethylethanamine hydrochloride (734 mg, 5.10 mmol), and tetrabutylammonium bromide (41.1 mg, 0.127 mmol) in dichloromethane (5 mL) was added 50% aqueous NaOH (5 mL). The reaction vessel was then sealed, and the mixture was stirred vigorously overnight at room temperature. The mixture was then diluted with water and extracted with dichloromethane (3×). The combined organics were dried, filtered, concentrated, and then chromatographed in 1:4:5 (2M NH3 in methanol):ethyl acetate:dichloromethane, giving the desired product (80 mg, 11.74%) and significant amounts of starting material. 1H NMR (DMSO-d6) δ 7.44 (d, J=2.4 Hz, 1H), 7.36 (dd, J=8.4, 2.4 Hz, 1H), 7.19 (d, J=8.4 Hz, 1H), 3.69-3.64 (m, 2H), 3.48 (t, J=6.9 Hz, 2H), 3.14-3.09 (m, 2H), 2.45 (t, J=6.9 Hz, 2H), 2.22 (s, 6H); ESI-MS (m/z, %): 268 (MH+, 100). The reaction vessel was then sealed extracted with dichloromethane (3×) The combined organics were dried filtered concentrated chromatographed in 1:4:5 (2M NH3 in methanol)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 6-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazine (1.0 g, 5.55 mmol) in anhydrous DMF (25 mL) under argon was cooled and treated portionwise with sodium hydride (0.677 g, 16.93 mmol) at 5-10° C. 2-chloro-N,N-dimethylethanamine hydrochloride (1.599 g, 11.10 mmol) was added portionwise at 5-10° C., and the resulting heterogeneous red-brown mixture was allowed to warm to room temperature. After 3 hours at room temperature, the mixture was heated to 90° C. and stirred for 30 minutes. The mixture was cooled to room temperature, quenched by the addition of water (25 mL), and diluted with EtOAc. A small amount of 1 N NaOH was added to basify the mixture to pH ˜9-10. The organic layer was separated, and the aqueous layer was further extracted with EtOAc. The combined organic layers were washed with brine (×2), dried (Na2SO4), filtered, and concentrated to afford a dark red oil. The material was purified on silica gel, eluting with 5% MeOH/CH2Cl2, to yield the title compound as a dark orange-red oil (458 mg, 32.8%). 1H NMR (DMSO-d6) δ 7.49-7.39 (m, 2H), 6.87-6.84 (m, 1H), 4.27-4.25 (m, 2H), 3.50-3.37 (m, 4H), 2.43 (t, 2H, J=6.7 Hz), 2.19 (s, 6H); ESI-MS (m/z, %): 252 (MH+, 100). the mixture was heated to 90° C. The mixture was cooled to room temperature quenched by the addition of water (25 mL) diluted with EtOAc A small amount of 1 N NaOH was added The organic layer was separated the aqueous layer was further extracted with EtOAc The combined organic layers were washed with brine (×2) dried (Na2SO4) filtered concentrated to afford a dark red oil The material was purified on silica gel eluting with 5% MeOH/CH2Cl2

Conditions: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a stirred suspension of 7-nitro-2H-benzo[b][1,4]thiazin-3(4H)-one (1.02 g, 4.85 mmol) and potassium carbonate (4.69 g, 34.0 mmol) in a pressure flask in DMF (30 mL) under argon was added 2-chloro-N,N-dimethylethanamine hydrochloride (3.49 g, 24.26 mmol). The flask was immediately sealed and heated with stirring to 90° C. overnight. The mixture was then cooled to room temperature, diluted with water and extracted (2× ethyl acetate). The combined organics were then washed with a 1:1 mixture of brine and water (3×) then brine (1×). The organic phase was dried, filtered, concentrated, and then chromatographed in 5% (2M NH3 in MeOH) in dichloromethane, giving the desired product (755 mg, 55.3%). 1H NMR (DMSO-d6) δ 8.30 (d, J=2.7 Hz, 1H), 8.13 (dd, J=9.3, 2.7 Hz, 1H), 7.59 (d, J=9.3 Hz, 1H), 4.11 (t, J=6.9 Hz, 2H), 3.62 (s, 2H), 2.41 (t, J=6.9 Hz, 2H), 2.17 (s, 6H); MS-EI: (m/z, %) 281 (M+, 55), 251 (65), 58 (100). The flask was immediately sealed heated The mixture was then cooled to room temperature extracted (2× ethyl acetate) The combined organics were then washed with a 1:1 mixture of brine and water (3×) The organic phase was dried filtered concentrated chromatographed in 5% (2M NH3 in MeOH) in dichloromethane

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 7-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazine (240 mg, 1.33 mmol) in DMF (10 mL) was treated with NaH (170 mg, 4.26 mmol, 60% wt in mineral oil) at 0° C., resulting in an orange mixture. The mixture was then treated with 2-chloro-N,N-dimethylethanamine hydrochloride (384 mg, 2.66 mmol), resulting in a dark red mixture. The reaction was stirred at room temperature for 1 hour. At this time, the reaction was then heated to 90° C. and stirred for another 45 minutes. The reaction was cooled to room temperature, water (15 mL) was added, and the reaction was extracted into EtOAc (2×12 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: CH2Cl2 followed by 5:95 (2M NH3 in MeOH):CH2Cl2 to give a yellow/orange solid (210 mg, 63%). 1H-NMR (DMSO-d6) δ 7.75 (dd, J=2.7, 9.0 Hz, 1H), 7.48 (d, J=2.7 Hz, 1H), 6.82 (d, J=9.0 Hz, 1H), 4.18 (t, J=4.5 Hz, 2H), 3.57-3.53 (m, 4H), 2.54-2.45 (m, 2H), 2.23 (s, 6H). resulting in an orange mixture resulting in a dark red mixture At this time, the reaction was then heated to 90° C. stirred for another 45 minutes The reaction was cooled to room temperature the reaction was extracted into EtOAc (2×12 mL) The combined organic layers were washed with brine (3×5 mL) dried (Na2SO4) filtered concentrated

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A suspension of 7-nitro-2H-benzo[b][1,4]oxazin-3(4H)-one (0.5 g, 2.575 mmol), 2-chloro-N,N-dimethylethanamine hydrochloride (0.37 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 then 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 (0.52 g, 76%) as a yellow solid. 1H NMR (DMSO-d6) δ 2.17 (s, 6H), 2.42 (t, 2H, J=6.6 Hz), 4.07 (t, 2H, J=6.6 Hz), 4.79 (s, 2H), 7.45 (d, 1H, J=9.0 Hz), 7.80 (d, 1H, J=2.7 Hz), 7.96 (dd, 1H, J=2.4, 9.0 Hz); ESI-MS (m/z, %): 266 (MH+, 100), 221 (66). 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)

Conditions: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of (2,4-bis-benzyloxy-5-isopropenyl-phenyl)-(5-hydroxy-7-methyl-1,3-dihydro-isoindol-2-yl)-methanone (164 mg, 0.32 mmol), potassium carbonate (112 mg, 0.81 mmol) and 2-(dimethylamino)ethyl chloride hydrochloride (93 mg, 0.64 mmol) in DMF (5 mL) was heated at 60° C. for 17 hours then 90° C. for 6 hours. Further portions of potassium carbonate (112 mg, 0.81 mmol) and 2-(dimethylamino)ethyl chloride hydrochloride (93 mg, 0.64 mmol) were added and the mixture maintained at 60° C. for 72 hours and finally, a further 24 hours at 90° C. The mixture was concentrated in vacuo then the residue was partitioned between ethyl acetate and 0.5N aqueous sodium hydroxide. The organic phase was washed with brine (×2), dried (MgSO4) and concentrated to give a residue which was purified by preparative HPLC (acidic method) to afford the title compound as a formate salt (37 mg, 20%). 1H NMR (MeOH-d4) 8.51 (1H, br.s), 7.43-7.27 (7H, m), 7.24-7.20 (3H, m), 7.17 (0.5H, s), 7.16 (0.5H, s), 6.85 (0.5H, s), 6.84 (0.5H, s), 6.81 (0.5H, s), 6.77 (0.5H, s), 6.74 (0.5H, s), 6.62 (0.5H, s), 5.16 (1H, s), 5.14 (3H, s), 5.09 (1H, m), 5.06 (1H, m), 4.83 (1H, s), 4.74 (1H, s), 4.60 (1H, s), 4.48 (1H, s), 4.28 (1H, t), 4.23 (1H, t), 3.41 (1H, t), 3.37 (1H, t), 2.84 (3H, s), 2.81 (3H, s), 2.27 (1.5H, s), 2.09 (3H, s), 2.07 (1.5H, s). MS: [M+H]+ 577. the mixture maintained at 60° C. for 72 hours a further 24 hours at 90° C The mixture was concentrated in vacuo the residue was partitioned between ethyl acetate and 0.5N aqueous sodium hydroxide The organic phase was washed with brine (×2) dried (MgSO4) concentrated to give a residue which was purified by preparative HPLC (acidic method)

Conditions: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 2-(2,4-dimethoxy-benzyl)-4-hydroxy-isoindole-1,3-dione (317 mg, 1.01 mmol), 2-dimethylaminoethyl chloride hydrochloride (160 mg, 1.11 mmol) and potassium carbonate (350 mg, 2.5 mmol) in DMF (4 mL) was heated at 60° C. for 18 hours. The mixture was concentrated in vacuo, taken up in ethyl acetate and extracted twice with 1N hydrochloric acid. The aqueous extracts were made basic with solid potassium carbonate and extracted with ethyl acetate (×2). The combined organic extracts were washed with brine, dried (MgSO4) and concentrated to give the title compound (236 mg, 61%) as an off-white solid. 1H NMR (methanol-d4) 7.73 (1H, t), 7.44-7.40 (2H, m), 7.02 (1H, d), 6.51 (1H, d), 6.42 (1H, dd), 4.72 (2H, s), 4.33 (2H, t), 3.80 (3H, s), 3.76 (3H, s), 2.87 (2H, t), 2.40 (6H, s). MS: [M+H]+ 385. The mixture was concentrated in vacuo extracted twice with 1N hydrochloric acid extracted with ethyl acetate (×2) The combined organic extracts were washed with brine dried (MgSO4) concentrated

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Following the procedure as described in EXAMPLE 13 and making non-critical variations using 1′-(4-hydroxybenzyl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1H)-one to replace 1′-(3-hydroxybenzyl)-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one, and 2-(dimethylamino)ethyl chloride hydrochloride to replace 2-iodoacetamide, 1′-{4-[2-(dimethylamino)ethoxy]benzyl}-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1H)-one was obtained (26%) as a colorless solid: mp 77-79° C.; 1H NMR (300 MHz, CDCl3) δ 7.30-7.11 (m, 4H), 7.05-6.97 (m, 1H), 6.92-6.86 (m, 2H), 6.82-6.78 (m, 1H), 6.51 (s, 1H), 6.21 (s, 1H), 4.88 (ABq, J=77.2, 15.3 Hz, 2H), 4.79 (ABq, J=83.8, 8.9 Hz, 2H), 4.23-4.05 (m, 6H), 2.84-2.75 (m, 2H), 2.40 (s, 6H); 13C NMR (300 MHz, CDCl3) δ 177.5, 158.3, 155.2, 144.6, 142.1, 138.3, 132.3, 128.7, 127.9, 123.8, 123.3, 121.1, 114.9, 111.5, 109.3, 99.4, 80.2, 65.8, 64.5, 63.9, 58.2, 58.0, 45.8, 43.6; MS (ES+) m/z 472.8 (M+1).

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 4-Methyl-3-nitrophenol (2.0 g, 13 mmol), 1-chloro-2-dimethylaminoethane hydrochloride (3.8 g, 26 mmol), and K2CO3 (5.4 g, 39 mmol) were added to 2-butanone (30 mL). The mixture was refluxed for 12 h after which TLC analysis revealed consumption of the starting phenol. The reaction was cooled, diluted with saturated NH4Cl, and extracted with EtOAc. The organic layers were dried (Mg2SO4), filtered, concentrated, and purified via flash silica gel chromatography to afford the title compound (2.6 g, 89% yield). 1H NMR (400 MHz, CDCl3) δ ppm 2.34 (s, 6H), 2.53 (s, 3H), 2.74 (t, J=5.6 Hz, 2H), 4.09 (t, J=5.5 Hz, 2H), 7.10 (dd, J=8.4, 2.7 Hz, 1H), 7.22 (d, J=8.6 Hz, 1H), 7.53 (d, J=2.6 Hz, 1H). The mixture was refluxed for 12 h after which TLC analysis consumption of the starting phenol The reaction was cooled diluted with saturated NH4Cl extracted with EtOAc The organic layers were dried (Mg2SO4) filtered concentrated purified via flash silica gel chromatography

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a slurry containing 5.0 g (33 mmol) of 2-methyl-3-nitrophenol, 9.4 g (65.2 mmol) of (2-chloroethyl)dimethylamine hydrochloride, 9.0 g (65.3 mmol) of K2CO3, and 100 mL of H2O was added 100 mL of butanol and the reaction mixture was heated at 80° C. for 13 h. The reaction mixture was extracted with EtOAc and the combined organic layers were dried over MgSO4 and filtered. The solvents were removed under reduced pressure and the residue was subjected to silica gel chromatography to give 7.4 g (100%) of dimethyl{2-[(2-methyl-3-nitrophenyl)oxy]ethyl}amine as a brown oil. 1HNMR (400 MHz, DMSO-d6) δ 7.29-7.42 (m, 3H), 4.11 (t, J=5.6 Hz, 2H), 2.66 (t, J=5.6 Hz, 2H), 2.22 (s, 3H), 2.20 (s, 6H). MS (ESI+) m/z 225 [M+H]. The reaction mixture was extracted with EtOAc the combined organic layers were dried over MgSO4 filtered The solvents were removed under reduced pressure

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To 3-aminophenol (10.9 g, 100 mmol) in DMF (100 mL) cooled with an ice/H2O bath was added NaH (8.90 g, 222 mmol) in 4 portions. 2-(Dimethylamino)ethylchloride hydrochloride (15.8 g, 110 mmol) was then added in 3 portions and the reaction was stirred at rt overnight. The reaction was poured into H2O (600 mL) and extracted with EtOAc. The combined organic layer was washed with brine, dried (MgSO4) and concentrated. Purification by flash column chromatography (flash chromatography), treatment with HCl (50.0 mL, 4M in dioxane, 200 mmol) and concentration provided the title compound (14.0 g, 56.0 mmol, 56%). 1H NMR (400 MHz, DMSO-d6) δ ppm 2.80 (s, 6H), 3.46 (t, J=4.8 Hz, 2H), 4.30 (t, J=4.9 Hz, 2H), 6.58-6.66 (m, 3H), 7.18 (t, J=8.2 Hz, 1H), 8.55 (br.s., 2H), 10.70 (br.s., 1H). extracted with EtOAc The combined organic layer was washed with brine dried (MgSO4) concentrated Purification by flash column chromatography (flash chromatography), treatment