Patent Application
20080064884
Potassium tert-butoxide (31,43 mmol; 3.64 g) was slurried with toluene (30.00 ml). (R.S)-(2,2,4-trimethyl-1,3-dioxolane-4-yl)-methanol (1.10 equiv; 34.57 mmol; 5.05 g) was diluted with toluene (10.00 ml) and added to the reaction mixture. 2,4-difluoronitrobenzene (1.00 equiv; 31.43 mmol; 5.00 g) was dissolved in a separate flask in toluene (10.00 ml) then added steadily at 0-10° C. The reaction was stirred at 0° C. for 1 h. Water (25.00 ml) was added and the two layers separated. Concentration of the organic phase in vacuo gave the title compound in 80-95% yield. Alternatively, the toluene solution can be used directly in the next stage. 1H NMR (399.826 MHz, DMSO) δ8.03 (dd, J=9.1, 6.0 Hz, 1H), 7.39 (dd, J=11.0, 2.6 Hz, 1H), 6.99 (ddd, j=9.0, 7.9, 2.5 Hz, 1H), 4.12 (d, J=9.7 Hz, 1H), 4.04 (d, J=9.7 Hz, 1H), 4.00 (d, J=8.7 Hz, 1H), 3.74 (d, J=8.7 Hz, 1H), 1.34 (s, 3H), 1.33 (s, 3H), 1.31 (s, 3H). m/z GCMS (Cl) 314 (M+C2H5+), 286 (MH+), 270 (MH+—O), 228 (MH+—CH3COCH3).
Potassium tert-butoxide (26.04 mmol; 3.01 g) was slurried with toluene (40.00 ml). (R.S)-(2,2,4-trimethyl-1,3-dioxolane-4-yl)-methanol (1.10 equiv; 28.65 mmol; 4.19 g) was diluted with toluene (20.00 ml) and added to the reaction 2,4-dichloronitrobenzene (1.00 equiv; 26.04 mmol; 5.00 g) was dissolved in a separate flask in toluene (10.00 ml) then added steadily at 0-10° C. The reaction was stirred overnight at room temperature. Water (25.00 ml) was added and the two layers separated. The organic phase was concentrated in vacuo to give the title compound in 80-95% yield. 1H NMR (299.947 MHz, DMSO) δ 7.94 (d, J=8.8 Hz, 1H), 7.57 (d, J=1.9 Hz, 1H), 7.20 (dd, J=8.6, 2.1 Hz, 1H), 4.16 (d, J=9.8 Hz, 1H), 4.07 (d, J=9.6 Hz, 1H), 3.99 (d, J=8.8 Hz, 1H), 3.74 (d, J=8.8 Hz, 1H), 1.35 (3×s, 9H), m/z GCMS (CI) 330 (M+C2H5+), 302 (MH+), 286 (MH+—O), 244 (MH+—CH3COCH3).
Method 1: Potassium tert-butoxide (2.74 mol; 316.64 g), N-methylpyrrolidone (300.00 ml) and toluene (700.00 ml) were added to a suitable reaction vessel at room temperature. (R,S)-(2,2,4-trimethyl-1,3-dioxolane-4-yl)-methanol (1.15 equiv; 1.46 mol; 214.02 g) in toluene (700.00 ml) was added to the reaction vessel. 3-Fluoro-4-nitrophenol (1.00 equiv; 1.27 mol; 200.00 g) was dissolved in N-methylpyrrolidone (200.00 ml) and toluene (300.00 ml) and added in a controlled manner to the reaction vessel. The reaction was heated for 1.5 h at 60-65° C. The reaction was cooled to ambient and quenched with water (1.00 l). The aqueous layer was acidified by addition of acetic acid (1.45 mol; 83.20 ml). Isopropyl acetate (2.00 l ) was added and the organic phase was separated. The product can be isolated by concentrating in vacuo to give the title compound in 95-100% yield. Alternatively, the isopropyl acetate solution can be used directly in the next stage.
Method 2: (R,s)-4-(5-fluoro-2-nitro-phenoxymethyl)-2,2,4-trimethyl-[1,3]dioxolane (1.00 equiv; 17.53 mmol; 5.00 g), as a toluene solution (30 ml) was charged to a flask containing benzyltrimethylammonium hydroxide (1.75 mmol; 771.43 μl; 732.86 mg) and 50% w/w potassium hydroxide (52.58 mmol; 4.90 ml; 5.90 g). The reaction was heated at reflux for 20 h. Water was added (35 ml) and the two phases separated. The aqueous phase was acidified with acetic acid to pH 6, then extracted with isopropyl acetate/NMP (12.5 ml/1.25 ml respectively). The organic phase was washed with water then concentrated in vacuo to give the title compound 70-90% yield. 1H NMR (399.826 MHz, DMSO) δ7.89 (d, J=9.0 Hz, 1H), 6.61 (d, J=2.3 Hz, 1H), 6.47 (dd, J=9.2, 2.3 Hz, 1H), 4.03 (d, J=8.7 Hz, 1H), 4.00 (d, J=9.5 Hz, 1H), 3.92 (d, J=9.2 Hz, 1H), 3.74 (d, J=8.7 Hz, 1H), 1.33 (2×s, 6H), 1.32 (s, 3H). m/z LCMS (ESI+ve) 306 MNa+, 226 (M+—CH3COCH3).
Method 1: (R,S)-4-Nitro-3-(2,2,4-trimethyl-[1,3]dioxolan-4-ylmethoxy)-phenol (4.5 g, 15.89 mmol), 5% Pd/C (0.135 g, 0.63 mmol) and ethyl acetate (67.5 ml) were charged to a hydrogenator. Hydrogenation started at ambient temperature/3-5 barg H2. Upon completion, the reaction mixture was filtered and the solids washed with ethyl acetate (45 ml). The combined filtrates were evaporated to dryness to give the title compound in 95-100% yield.
Method 2: (R,S)-4-Nitro-3-(2,2,4-trimethyl-[1,3]dioxolan-4-ylmethoxy)-phenol (1.00 equiv; 2.39 mmol; 500.00 mg;) was added to a solution of sodium dithionite (16 mmol; 2.8 g) in water (44.07 mmol; 8.00 ml; 8.00 g;) at room temperature. The pH was adjusted to 14 using NaOH (10 M). At the end of addition the reaction was quenched by addition of 2 M HCl to pH5. The resulting precipitate was collected by filtration. The solid was dried overnight in a vacuum oven at 40° C. to give the title compound in 78% yield. 1H NMR (299.947 MHz, DMSO) δ8.44 (s, 1H), 6.45 (d, J=8.4 Hz, 1H), 6.29 (d, J=2.3 Hz, 1H), 6.14 (dd, J=8.3, 2.4 Hz, 1H), 4.03 (m, 3H), 3.76 (m, 2H), 3.69 (d, J=9.0 Hz, 1H), 1.34 (overlapping s, 9H). m/z LCMS (ESI+ve) 276 (MNa+), 254 (MH+), 196 (MH+—CH3COCH3)
5% Pd/C (897.50 μmol; 4.51 g), (R,S)-4-nitro-3-(3,2,4-trimethyl-[1,3]dioxolan-4-ylmethoxy)-phenol (1.00 equiv; 89.75 mmol; 25.42 g) in isopropyl acetate (190 ml) and acetic acid anhydride (98.72 mmol; 9.2 ml) were charged to a suitable vessel. The mixture was hydrogenated at 20-25° C. and 4 barg H2 overnight. The reaction was filtered and washed with water (50 ml). The isopropyl acetate was removed by distillation at atmospheric pressure (volume distilled=250 ml). The resulting solution was cooled to 20° C. and isohexane (100 ml) was added. The resulting slurry was heated to 50° C. then cooled to 20° C. over 1 h. The solid was collected by filtration and dried in a vacuum oven overnight. The title compound was isolated in 68% yield. 1H NMR (399.819 MHz, DMSO) δ9.29 (s, 1H), 8.69 (s, 1H), 7.33 (d, J=8.5 Hz, 1H), 6.42 (d, J=2.6 Hz, 1H), 6.30 (dd, J=8.6, 2.4 Hz, 1H), 4.10 (d, J=8.7 Ha, 1H), 3.81 (d, J=9.5 Hz, 1H), 3.73 (m, 2H), 1.97 (s, 3H), 1.33 (3×s, 9H). m/z GCMS (EI) 295 (M+), 280 (M+—CH3), 220 (M+—C3H7O2), 125 (C6H7NO2+).
(R,S)-4-Nitro-3-(2,2,4-trimethyl-[1,3]dioxolan-4-ylmethoxy)-phenol (2.0 mmol, 0.5 g) was dissolved in ethyl acetate (5 ml) and added to a solution of 2 M HCl (0.5 ml) at room temperature. Upon completion of reaction, the two phases were separated. The organic phase was concentrated in vacuo to give the title compound in 90-95% yield. 1H NMR (399.819 MHz, DMSO) δ10.83 (s, 1H), 7.88 (d, J=9.2 Hz, 1H), 6.56 (d, J=2.6 Hz, 1H), 6.45 (dd, J=9.0, 2.3 Hz, 1H), 3.93 (d, J=9.0 Ha, 1H), 3.78 (d, J=9.0 Hz, 1H), 3.36 (m, 2H), 1.14 (s, 3H). m/z LCMS (ESI+ve)266 (MNa+), 226 MH+—H2O
(R,S)-N-[4-hydroxy-2-(2,2,4-trimethyl-[1,3]dioxolan-4-ylmethoxy)-phenyl]-acetamide (3.8 mmol, 0.98 g) was dissolved in 2-methyl tetrahydrofuran (10 ml) at ambient temperature. Aqueous hydrochloric acid (2 M, 5 ml) was added and stirring continued at ambient temperature. At the end of reaction, ethyl acetate (10 ml) and water (10 ml) were added and the layers separated. The organic layer was washed with water (10 ml) then 20% brine (5 ml). The organic layer was evaporated to dryness in vacuo to leave the title compound in 44% yield. 1H NMR (399.826 MHz, DMSO) δ9.22 (s, 1H), 8.87 (s, 1H), 7.55 (d, J=8.5 Hz, 1H), 6.39 (d, J=2.6 Hz, 1H), 6.28 (dd, J=8.6, 2.4 hz, 1H), 4.76 (s, 1H), 4.71 (t, J=5.6 Hz, 1H), 3.76 (d, J=9.0 Hz, 1H), 3.69 (d, J=8.6 Hz, 1H), 3.45 (dd, J=10.6, 5.5 Hz, 1H), 3.27 (m, 1H), 2.02 (s, 3H), 1.13 (s, 3H). m/z LCMS (ESI+ve) 256 (MH+).
(R,S)-Acetic acid 4-acetylamino-3-(2,2,4-trimethyl-[1,3]dioxolan-4-ylmethoxy)-phenyl ester (3.2 mmol, 0.96 g) was dissolved in 2-methyl tetrahydrofuran (10 ml) at ambient temperature and aqueous hydrochloric acid (2 M, 5 ml) was added at ambient temperature. After 5 h, water (10 ml), 20% sodium chloride solution (20 ml) and toluene (10 ml) were added. The organic layer was separated and washed with water (10 ml), 20% brine (5 ml) and then evaporated to dryness in vacuo to leave the title compound in 37% yield. 1H NMR (399.817 MHz, CDCl3) δ8.35 (d, J=8.7 Hz, 1H), 7.88 (s, 1H), 6.72 (m, 2H), 4.12 (d, J=10.8 Hz, 1H), 3.97 (d, J=11.0 Hz, 1H), 2.92 (d, J=4.6 Hz, 1H), 2.78 (d, J=4.6 Hz, 1H), 2.27 (s, 3H), 2.20 (s, 3H), 1.48 (s, 3H). m/z LCMS (ESI+ve) 320 (M+Na+), 298 (MH+).
(R,S)-4-Amino-3-(2,2,4-trimethyl-[1,3]dioxolan-4-ylmethoxy)-phenol (3.5 mmol, 0.88 g) was dissolved in 2-methyl tetrahydrofuran (9 ml) and charged to the reaction flask. Triethylamine (1.45 ml) was added and the mixture cooled in ice-water. Acetyl chloride was added at a controlled rate so that the internal temperature was maintained below 15° C. The cooling bath was removed and the reaction mixture was allowed to warm to ambient temperature and stirred overnight. Water (9 ml) was added to the reaction mixture and stirring continued briefly. The layers were separated and the organic layer washed with 20% sodium chloride solution (5 ml). The organic layer was concentrated to dryness in vacuo to leave the title compound in 85% yield. 1H NMR (399.819 MHz, DMSO) δ8.88 (s, 1H), 7.70 (d, J=8.7 Hz, 1H), 6.89 (d, J=2.6 Hz, 1H), 6.66 (dd, J=8.6, 2.4 Hz, 1H), 4.13 (d, J=8.7 Hz, 1H), 3.89 (d, J=9.5 Hz, 1H), 3.79 (d, J=9.5 Hz, 1H), 3.74 (d, J=8.7 Hz, 1H), 2.24 (s, 3H), 2.04 (s, 3H), 1.34 (m, 9H). m/z LCMS (ESI+ve) 360 (MNa+), 338 (MH+), 280 (MH+—CH3COCH3).
To a 50 ml 3-neck flask was added (R,S)-N-{4-hydroxy-2-[(2,2,4-trimethyl-1,3-dioxolan-4-yl)methoxy]phenyl}acetamide#(1.00 equiv; 6.77 mmol; 2.00 g) and acetic acid (20.00 ml). After stirring for 10 min, 33% w/w hydrogen bromide in acetic acid (20.85 mmol; 3.60 ml; 5.11 g) was added over a period of 2 min. After 4.5 h, the reaction was quenched with sodium hydroxide (100.00 ml), and extracted with tetrahydrofuran (20.00 ml). The organic phase was separated. The aqueous phase was extracted with a further portion of tetrahydrofuran (20.00 ml). The combined organic phases were concentrated in vacuo to give the title compound in 85% yield. 1H NMR (299.947 MHz, DMSO) δ8.80 (s, 1H), 7.27 (d, J=8.4 Hz, 1H), 6.42 (d, J=2.5 Hz, 1H), 6.33 (dd, J=8.4, 2.3 Hz, 1H), 4.19 (d, J=9.6 Hz, 1H), 4.07 (m, 3H), 2.00 (s, 3H), 1.91 (s, 3H). m/z LCMS (ESI+ve) 382 (MNa+), 360 (MH+).
#(R,S)-N-{4-hydroxy-2-[(2,2,4-trimethyl-1,3-dioxolan-4-yl)methoxy]phenyl}acetamide can be substituted with (R,S)-Acetic acid 4-acetylamino-3-(2,3-dihydroxy-2-methyl-propoxy)-phenyl ester, (R,S)-N-[2-(2,3-Dihydroxy-2-methyl-propoxy)-4-hydroxy-phenyl]-acetamide or (R,S)-Acetic acid 4-acetylamino-3-(2,2,4-trimethyl-[1,3]-dioxolan-4-ylmethoxy)-phenyl ester or mixtures thereof.
Methanol (3.00 ml) was added to (R,S)-acetic acid 1-(2-acetylamino-5-hydroxy-phenoxymethyl)-2-bromo-1-methyl-ethyl ester (0.84 mmol, 0.2 g) to give a dark brown solution. 25% w/w sodium methoxide in methanol (1.49 mmol; 340.00 μl; 321.30 mg) was added dropwise. The reaction was allowed to progress at ambient temperature. After 30 min the reaction was quenched with 10 ml of saturated ammonium chloride and 8 ml of brine. The phases were separated. The aqueous phase was washed with a further portion of ethyl acetate (10.00 ml). The organic phases were combined and washed with brine (10 ml), dried over magnesium sulfate, filtered, and concentrated under vacuum to give the title compound in 50% yield. 1H NMR (299.947 MHz, DMSO) δ9.30 (s, 1H), 8.81 (s, 1H), 7.32 (d, J=8.6 Hz, 1H), 6.42 (d, J=2.3 Hz, 1H), 6.31 (dd, J632 8.4, 2.5 Hz, 1H), 4.06 (d, J=10.9 Hz, 1H), 3.83 (d, J=10.9 Hz, 1H), 2.83 (d, J=5.0 Hz, 1H, 2.68 (d, J=5.0 Hz, 1H), 1.99 (s, 3H), 1.37 (s, 3H). m/z LCMS (ESI+ve) 260 (MNa+), 238 (MH+), 220 (MH+—H2O).
To a 25 ml 3-neck flask was added N-[4-hydroxy-2-(2-methyl-oxiranylmethoxy)-phenyl]-acetamide (1.00 equiv; 842.97 μmol; 200.00 mg). After purging with nitrogen, methanol (600.00 μl) then 1-(4-chloro-benzyl)-piperidin-4-ylamine (1.00 equiv; 845.45 μmol; 190.00 mg) in with isopropyl acetate (600.00 μl) was added. The orange solution was heated to 55° C. After stirring overnight, methanol (1.00 ml) was added. Assay of the reaction mixture against an authentic sample showed the product in 72% yield.
A solution of (R,S)-(2,2,4-trimethyl-[1,3]-dioxolan-4-yl)methanol (8.31 g; 56.8 mmol) in toluene (40 ml) was added slowly to a stirred slurry of potassium tert-butoxide (7.69 g, 67% w/w, 45.9 mmol) in toluene (100 ml) under an atmosphere of nitrogen. The mixture was stirred for 30 min. then cooled to −5° C. A solution of 1-chloro-2,4-difluoro-5-nitrobenzene (10.0 g; 51.7 mmol) in toluene (20 ml) was then slowly added, maintaining the temperature in the reaction vessel between −5 and 0° C. The resulting mixture was stirred for 1 h at −5 to 0° C. then analysed by HPLC. The reaction was found to be incomplete and a further portion of potassium tert-butoxide (1.77 g, 67% w/w, 10.6 mmol) was added. The mixture was stirred for a further 1 h at −5 to 0° C. after which time the reaction had reached completion. Water (70 ml) was then added slowly to the cooled (−5° C.) mixture. The mixture was allowed to warm to 20-25° C. and allowed to separate. The organic phase was washed with water (70 ml) then evaporated at low pressure at 45-50° C. to give an oil. The oil was treated with n-heptane (20 ml) then re-evaporated to again give an oil. The oil was stirred with fresh n-heptane (70 ml) for 30 min., which resulted in the precipitation of a solid. The suspension was cooled to 15° C., and then filtered. The collected solid was washed with n-heptane (20 ml) then dried in vacuo to give 4-(4-chloro-5-fluoro-2-nitro-phenoxymethyl)-2,2,4-trimethyl-[1,3]dioxolane (12.5 g; 76%). 99.5 area % purity by HPLC analysis. 1H-NMR (200.13 MHz, CDCl3) δ8.05 (d, J=7.4 Hz, 1H), 6,92 (d, J=10.2 Hz, 1H), 4.17 (d, J=9.0 Hz, 1H), 4.02-3.78 (m, 3H), 1.47 (s, 3H), 1.42 (s, 6H). m/z LCMS (ES+): 320 MH+), 342 (M+Na+)
A 40% w/w aqueous solution of potassium hydroxide (7.83 g, 55.8 mmol) was added as one portion to a solution of 4-(4-chloro-5-fluoro-2nitro-phenoxymethyl)-2,2,4-trimethyl-[1,3]dioxolane (3.0 g; 9.4 mmol) in N-methyl pyrrolidine (10.5 ml) at 20-25° C. The resulting brown mixture was stirred for approximately 7 h at 20-25° C., by which time the reaction had reached completion by HPLC analysis. The pH of the reaction mixture was then adjusted to pH range 5-5.5 by the addition of glacial acetic acid (ca. 2 ml). The resulting hazy mixture was extracted with chloroform (25 ml). The organic layer was separated and evaporated under reduced pressure to give a yellow oil. n-Hexane (10 ml) was added to the oily liquid and stirred well at 20-25° C. A yellow solid precipitated and was collected by filtration and dried in vacuo at 30-40° C. to give 2-chloro-4-nitro-5-(2,2,4-trimethyl-[1,3]dioxolan-4-ylmethoxy)phenol (2.75 g; 92%), 99.5 area % purity by HPLC analysis. 1H-NMR (300.13 MHz, CDCl3) δ8.10 (s, 1H), 6.73 (s, 1H), 6.26 (br.s, 1H), 4.22 (d, J=9.1 Hz, 1H), 4.01-3.81 (m, 3H), 1.50 (s, 3H), 1.45 (s, 6H). m/z LCMS (ES−): 316 (M-H)−
(Method A, using sodium dithionite to reduce the nitro group)
Dimethylformamide (15 ml) was charged to a reaction vessel, and cooled to 10° C. Potassium hydroxide (2.52 g; 84% w/w assay; 37.7 mmol) was then added, maintaining the temperature between 5 and 10° C. 4(4-chloro-5-fluoro-2-nitro-phenoxymethyl)-2,2,4-trimethyl-[1,3]dioxolane (1.50 g; 4.72 mmol), sodium dithionite (3.38 g; 85% w/w assay; 16.5 mmol) and water 98 ml) were added to the stirred mixture, maintaining the temperature between 5 and 10° C. The mixture was then heated to 50° c. and stirred at this temperature for 1 h. The reaction mixture was analyzed by HPLC which indicated formation of the intermediate product 4-amino-2-chloro-5-(2,2,4-trimethyl-[1,3]dioxolan-4-ylmethoxy)phenol. The mixture was cooled to 20-25° C. then filtered through a bed of hyflo supercel. The filter agent was washed with dimethylformamide (3 ml). The combined filtrates were acidified to ca. pH 6-6.5 with 20% v/v aqueous acetic acid (3 ml), then diluted with water (15 ml). The mixture was extracted with ethyl acetate 93×15 ml) and the combined ethyl acetate extracts were washed with water 92×15 ml). To the ethyl acetate solution of 4-amino-2-chloro-5-(2,2,4-trimethyl-[1,3]dioxolan-4-ylmethoxy)phenol was slowly added acetic anhydride (0.75 g; 98% w/w; 7.20 mmol) maintaining the temperature of the solution between 20 and 25° C. After the reaction had reached completion (HPLC analysis), the mixture was evaporated under reduced pressure at 45-50° C. down to a volume of approximately 10 ml. The concentrated solution was cooled to 20-25° C. and a solid precipitated. This was collected by filtration, and dried in vacuo at 40° C. to afford N-[5-chloro-4-hydroxy-2-(2,2,4-trimethyl-[1,3]dioxolan-4-ylmethoxy)phenyl] acetamide as a white solid (0.7 g; 45%), 100 area % purity by HPLC analysis. 1H-NMR (300.13 HMz, CDCl3) δ8.41 (s, 1H), 8.14 (br.s, 1H), 6.56 (s, 1H), 4.16 (d, J=8.8 Hz, 1H), 4.01 (d, J=9.6 Hz, 1H), 3.86 (d, J=8.8 Hz, 1H), 3.76 (d, J=9.6 Hz, 1H), 2.17 (s, 3H), 1.51 (s, 3H), 1.45 (s, 3H), 1.42 (s, 3H). m/z LCMS (ES+): 328 (M-H)−
(method B, using catalytic hydrogenation to reduce the nitro group)
4(4-Chloro-5fluoro-2nitro-phenoxymethyl)-2,2,4-trimethyl-[1,3]dioxolane (1.0 g; 3.15 mmol) was charged to a Buchi glass hydrogenation vessel followed by ethyl acetate (15 ml) and acetic acid (0.4 g). The resulting solution was inerted with nitrogen and 5% palladium on carbon (50% water wet, 140 mg) was charged to the vessel followed by additional ethyl acetate (10 ml). The mixture was then hydrogenated at 3.0 barg pressure and heated to 45-50° C. The reaction was monitored by HPLC and determined to be complete after 4 h. The mixture was cooled to 20-25° C., inerted with nitrogen, and the catalyst filtered off through a bed of hyflo supercel. The filtrate (a solution of 4-amino-2-chloro-5-(2,2,4-trimethyl-[1,3]dioxolan-4-ylmethoxy)phenol) was transferred to a clean vessel and acetic anhydride (0.48 g; 4.7 mmol) was slowly added with stirring, maintaining the temperature between 20 and 25° C. the mixture was stirred for 90 min after which time the reaction had reached completion (HPLC analysis). The solvent was evaporated under reduced pressure at 45-50° C., and n-heptane (10 ml) added to the residue. The resulting slurry was stirred for 30 min then filtered. The collected solid was washed with n-heptane (2 ml) then dried in vacuo at 40° C. to constant weight. This afforded N-[5chloro-4-hydroxy-2(2,2,4-trimethyl-[1,3]dioxolan-4-ylmethoxy)phenyl]acetamide 90.6 g; 58%), 97.99 area % purity by HPLC analysis, containing the des-chloro impurity N-[4-hydroxy-2-(2,2,4-trimethyl-[1,3]dioxolan-4-ylmethoxy)phenyl]acetamide: 1.71 area % by HPLC.
Ferric nitrate nonahydrate (14.06 g; 98% w/w; 34 mmol) was added to a solution of 2-chloro-5-fluorophenol (5.0 g; 34mmol) in ethanol (125 ml). The resulting mixture (containing suspended solid) was stirred and heated to 50-55° C. and maintained in this temperature range for 4 to 5 h, by which time the suspended solid was almost completely dissolved. Analysis by HPLC revealed complete disappearance of the starting material. The mixture was cooled to 25-30° C. and water (50 ml) was added. The mixture was then extracted with chloroform (3×25 ml) and the combined chloroform extracts washed with water 92×25 ml). The chloroform layer was evaporated under reduced pressure at 35° C. Toluene (15 ml) was added to the residue and heated to 50-55° C. and maintained within that temperature range for 10 min to give a clear solution. n-Heptane was slowly added to the solution, maintaining the temperature at 50-55° C. Crystallisation of a solid was observed during the n-heptane addition. The resulting slurry was stirred at 50-55° C. for 30 min then slowly cooled to 30-35° C. The mixture was filtered at this temperature and the collected solid washed with n-heptane (15 ml). The product was dried in vacuo at 30-35° C. to give a fluffy solid, 2-chloro-5-fluoro-4-nitrophenol (2.95 g; 45%), >98 area % purity by HPLC analysis. 1H-NMR (200.13 MHz, CDCl3) δ8.21 (d, J=7.4 Hz, 1H), 6.95 (d, J=11.4 Hz, 1H), 6.27 (br.s, 1H). m/z LCMS (ES−): 190 (M-H)−
Potassium tert-butoxide (1.36 g; 95% w/w; 11.5 mmol) was added to a stirred solution of 2-chloro-5-fluoro-4-nitrophenol (1.0 g; 5.2 mmol) in acetonitrile (8 ml) under nitrogen. The resulting slurry was stirred for 10-15 min, and then a solution of racemic (2,2,4-trimethyl-[1,3]-dioxolan-4-yl)methanol (0.84 g; 5.7 mmol) in acetonitrile (2ml) was slowly added. The resulting mixture was heated to 42-50° C. and maintained at this temperature for 1-2 h after which time the reaction was complete by HPLC analysis. The mixture was cooled to 25-30° C. then filtered to remove some solid material. The solid was washed with acetonitrile (1 ml) and the combined filtrate was evaporated under reduced pressure and the residue diluted with water (20 ml) to give a 2-phase mixture. The aqueous phase was separated and extracted with chloroform (2×20 ml). The aqueous phase was then treated with dilute aqueous hydrochloric acid until pH 6 was reached. A yellow oily liquid separated out upon acidification. The 2-phase mixture was extracted with chloroform (2×20 ml). The chloroform extracts from the latter operation were combined and washed with water (10 ml). The chloroform layer was evaporated under reduced pressure at 35° C. to give 2-chloro-4-nitro-5-(2,2,4-trimethyl-[1,3]dioxolan-4-ylmethoxy)phenol (1.25 g; 76%), >98 area % purity by HPLC analysis.
Analytical data (1H-NMR and LCMS) was consistent with the product obtained from 4-(4-chloro-5fluoro-2nitro-phenoxymethyl)-2,2,4-trimethyl-[1,3]dioxolane as described previously (Example 13).
Toluene (126 ml) and N-methyl pyrrolidinone (54 ml) were added to potassium tert-butoxide (57.8 g, 2,25 equiv.). (R)-2,2,4-trimethyl-1,3-dioxolane-4-methanol 938.5 g, 1.15 equiv.) in toluene (90 ml) was added and the reaction was stirred for 30 min at room temperature. 3-Fluoro-4-nitrophenol (36 g, 1 equiv.), in N-methyl pyrrolidinone (54 ml) and toluene (36 ml) was added. The reaction was heated at 65° C. for 1.5 h. Water (180 ml) was added and the two layers were separated. Acetic acid (24.9 ml) was added to the aqueous layer and the title compound was extracted into isopropyl acetate (360 ml). The product can be isolated by concentration to dryness. Alternatively, the solution can be used directly in the next stage.
(S)-Nitro-3-(2,2,4-trimethyl-[1,3]dioxolan-4-ylmethoxy)-phenol in isopropyl acetate (32 g in 200 ml) and methanol (20 ml) were charged to Pd on C (3.1 g, 0.005 mol equiv.). The mixture was warmed to 25° C. Hydrogen was charged to the reaction at 4.25 barg. At the end of the reduction, acetic anhydride (11.2 ml) was added. The catalyst was removed by filtration. The product can be isolated by concentration to dryness. Alternatively, the solution can be used directly in the next stage.
para-Toluene sulphonic acid monohydrate (2.4 g, 0.045 equiv.) was charged to (S)-N-[4-hydroxy-2-(2,2,4-trimethyl-[1,3]dioxolan-4-ylmethoxy)-phenyl]-acetamide in isopropyl acetate and methanol (82 g in 750 ml). The reaction was heated to 72° C. for 30 min. The reaction mixture was cooled to 20° C. and the methanol was removed by distillation. The title compound was collected by filtration.
Hydrobromic acid in acetic acid (42.5 ml, 3 equiv.) was added to (s)-N-[2-(2,3-dihydroxy-2-methyl-propoxy)-4-hydroxy-phenyl]-acetamide (20 g) in acetic acid (40 ml) at 40° C. The reaction was heated at 40° C. for approximately 2 h. Isopropyl acetate (200 ml) was added followed by water. The aqueous phase was removed and the organic layer was washed sequentially with ammonium hydroxide solution and sodium sulfite solution. The product can be isolated by concentration to dryness. Alternatively, the solution can be used directly in the next stage.
Sodium methoxide (41.2 ml, 2.3 equiv.) was added to (S)-acetic acid 1-(2-acetylamino-5-hydroxy-phenoxymethyl)-2-bromo-1methyl-ethyl ester (approx 78 mmol, 160 ml), at −10°C. After 30 min at this temperature, acetic anhydride (10 ml, 1.35 mol equiv.) was added at −5° C. This reaction was stirred for 30 min then quenched by addition of water. The two phases were separated and the organic phase was washed with sodium bicarbonate solution. The organic phase was concentrated by distillation, then diluted with heptane 940 ml). The solution was cooled to induce crystallisation, and the title compound was isolated by filtration.
Methanol (6b 17 ml) and isopropyl acetate (8.5 ml) were charged to (S)-acetic acid 4-acetylamino-3(2-methyl-oxiranylmethoxy)-phenyl ester (10 g). The reaction mixture was heated at 40° C. and 1-(4-chloro-benzyl)-piperidin-4-ylamine in isopropyl acetate/methanol (23.9 g, 1 equiv.) was added. The reaction was heated to 55° C. for 16-24 h. Benzoic acid (3.9 g, 1 equiv.) was added and the mixture was seeded to include crystallisation. The mixture was cooled to −5° C. and the title compound was isolated by filtration. 1H-NMR (399.824 MHz, CD3OD) δ7.92 (m, 2H), 7.49-7.18 (m, 8H), 6.47 (d, J=2.6 Hz, 1H), 6.36 (dd, J=8.5, 2.6 Hz, 1H), 3.88 (s, 2H), 3.54 (s, 2H), 3.14 (d, J=12.3 Hz, 1H), 3.05-2.89 (m, 4H), 2.17 (t, J=11.7 Hz, 2H), 2.09 (s, 3H), 2.03 (d, J=11.7 Hz, 2H), 1.73-1.60 (m, 2H), 1.35 (s, 3H). m/z LCMS (ESI+ve) 462.20 (MH+).
Chiral HPLC showed that the product was enantiomerically enriched, with respect to the (S) enantiomer.
THF (400 ml) was added to ferric nitrate, nonahydrate (91 g, 223 mmol). The mixture was stirred vigorously for 10 min at room temperature. 3-Fluorophenol (50 g, 446 mmol) was dissolved in THF and heated to 42° C. The reaction was stirred overnight at this temperature, then filtered to remove the inorganic salts. The title compound can be isolated by crystallisation from toluene or by column chromatograhy. 1H-NMR (399.822 MHz, DMSO) δ11.48 (s, 1H), 8.07 (m, 1H), 6.84-6.76 (m, 2H). ·F-NMR (376.209 MHz, DMSO) δ−114.28. m/z LCMS (ESI−ve) 156.00 (M-H).
To a 100 ml 3-neck flask was added a 16.4% w/w solution of (R,S)-4-nitro-3-(2,2,4-trimethyl-[1,3]dioxolan-4-ylmethoxy)-phenol (12.2 g, 7.1 mmol) in isopropyl acetate. After stirring for 10 min at 45-50° C. 33% w/w hydrogen bromide in acetic acid (3.9 ml, 22.1 mmol) was added over a period of 2 min. After 1.5 h, the mixture was quenched with water (10 ml). After separation, the organic phase was sequentially washed with NH4OH 1 M (20 ml) and Na2SO3 12.5% w/v (20 ml). The organic solution was concentrated in vacuo to yield the title product in 95% yield. 1H-NMR (299.947 MHz, DMSO) δ10.95 (s, 1H), 7.92 (d, J=9.0 Hz, 1H), 6.62 (s, 1H), 6.52 (d, J=9.0 Hz, 1H), 4.36 (m, 2H), 3.99 (m, 2H), 2.00 (s, 3H), 1.63 (s, 3H). m/z LCMS (ESI−ve) 347 (M-H).
To a 50 ml 3-neck flask was added the isopropyl acetate solution of (R,S)-acetic acid 1-(2-nitro-5-hydroxy-phenoxymethyl)-2-bromo-1-methyl-ethyl ester (9.5 ml, 6.6 mmol). the mixture was cooled to −5° C. and 25% w/w sodium methoxide in methanol (3.7 ml, 16.24 mmol) was added dropwise. The reaction was allowed to progress at ambient temperature. After 30 min the reaction was quenched with water (10 ml). The biphasic mixture was separated and acetic acid (0.61 ml, 10.6 mmol) was added to the aqueous phase. The aqueous solution was extracted with isopropyl acetate (20 ml). The organic solution was concentrated in vacuo to yield the title product in 69% yield. 1H-NMR (299.947 MHz, DMSO) δ10.90 (s, 1H), 7.91 (d, J=9.0 Ha, 1H), 6.58 (s, 1H), 6.49 (d, J=9.0 Hz, 1H), 4.14 (dd, J=10.8, 85.1 Hz, 2H), 2.80 (dd, J=5.4, 43.8 Hz, 2H), 1.40 (s, 3H). m/z LCMS (ESI+ve) 226 (MH+).
To an hydrogenation reactor were charged 3-(2-methyl-oxiranylmethoxy)-4-nitro-phenol (5g, 22.2 mmol), isopropyl acetate (50 ml), triethylamine (9.3 ml, 66.6 mmol), acetic anhydride (7.4 ml, 77.5 mmol) and 1% platinum on charcoal (22.6 μmol Pt, 1 g, 55.9% water). The mixture was stirred at 25° C. under 4 barg of hydrogen. After complete hydrogenation, the reaction mixture was filtered on buchner to remove the catalyst. The organic solution was washed with sodium carbonate and brine. The washed organic solution was concentrated in vacuo to yield the title compound in 97% yield. 1H-NMR (299.947 MHz, DMSO) δ9.1 (s, 1H), 7.70 (d, J=8.7 Hz, 1H), 6.90 (d, J=2.4 Hz, 1H), 6.70 (dd, J632 2.4, 8.4 Hz, 1H), 4.05 (m, 2H), 2.80 (m, 2H), 2.3 (s, 3H), 2.1 (s, 3H), 1.40 (s, 3H). m/z LCMS (ESI+ve) 280.2 (MH+), 262.2 (MH+—H2O), 220.2 (MH+—H2O—CH3CO).
In addition to the racemic synthesis, the same set of reaction conditions can be used to prepare enantiomerically enriched products when (R,S)-2,2,4-trimethyl-1,3-dioxolane-4-methanol is replaced with (R)-2,2,4-trimethyl-1,3-dioxolane-4-methanol or (S)-2,2,4-trimethyl-1,3-dioxolane-4-methanol. An example with (R)-2,2,4-trimethyl-1,3-dioxolane-4-methanol is described below.
Potassium tert-butoxide (9.31 mmol; 1.04 g) and toluene (5.44 ml) were charge to a round bottomed flask under nitrogen with cooling from an ice-bath. A solution of (R)-2,2,4-trimethyl-1,3-dioxolane-4-methanol (1.08 equiv; 4.65 mmol; 680.21 mg) in toluene (1.36 ml) was added. 3-Fluoro-4-nitrophenol (1.00 equiv; 4.33 mmol; 680.00 mg) was dissolved in acetonitrile (1.70 ml) and added to the mustard slurry. The reaction was heated at 65-70° C. for 1 h. Water (6.80 ml) was added and the two layers separated. The aqueous phase was acidified with concentrated HCl (0.5 ml) to pH 5 (product oiled out during addition). Ethyl acetate (6.80 ml) was added and the two layers separated. The organic phase contained (R)-4-nitro-3-(2,2,4-trimethyl-[1,3]dioxolan-4-ylmethoxy)-phenol that was used directly in the next step.
5% Pd/C (43.42 μmol; 217.96 mg) and acetic anhydride (4.34 mmol; 410.44 μl; 443.27 mg) were charged to the organic phase and the mixture was hydrogenated at 25° C. and 5 barg overnight. The reaction was filtered and washed with water (7 ml). The organic phase was separated, washed with saturated sodium bicarbonate (3×7 ml) and concentrated in vacuo. The crude product was purified by flash chromatography using silica gel and isohexane/ethyl acetate to give 200 mg of (R)-N-[4-hydroxy-2-(2,2,4-trimethyl-[1,3]dioxolan-4-ylmethoxy)-phenyl]-acetamide.
This was dissolved in a mixture of acetic acid (50.61 mmol; 2.90 ml; 3.04 g) and 33% w/w hydrogen bromide in acetic anhydride (2.03 mmol; 350.00 μl; 497.00 mg) and heated to 35° C. After 45 min the reaction was quenched with sodium hydroxide (10.20 ml). The resulting slurry was washed into a separating funnel using ethyl acetate (10.00 ml). The two phases were separated. The aqueous was washed with a further portion of ethyl acetate (10.00 ml). The organics were combined and were washed with brine (7 ml) before being dried over magnesium sulfate, filtered, and concentrated in vacuo to give (R)-acetic acid 1-(2-acetylamino-5-hydroxy-phenoxymethyl)-2bromo-1-methyl-ethyl ester (0.2 g). this was dissolved in methanol (74.12 mmol; 3.00 ml; 2.38 g) and 25% w/w sodium methoxide in methanol (1.49 mmol; 340.00 μl; 321.30 mg) was added dropwise. After 30 min the reaction was quenched with 10 ml of saturated ammonium chloride. The two phases were separated. (To aid phase separation 8 ml of brine was added). The aqueous phase was washed with a further portion of ethyl acetate (10.00 ml). The combined organic extracts were combined, washed with brine (10 ml), dried over magnesium sulfate, filtered, and concentrated under vacuum to give the title compound in 62% yield from (R)-N-[4-hydroxy-2-(2,2,4-trimethyl-[1,3]dioxolan-4-ylmethoxy)-phenyl]-acetamide. Chiral HPLC showed that the product was enantiomerically enriched, with respect to the (S) enantiomer.
| Number | Date | Country | |
|---|---|---|---|
| 60799574 | May 2006 | US |
