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Structure of 1526-17-6 * Storage: {[proInfo.prStorage]}
* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Reference：
[1] Chemical Communications, 2006, # 18, p. 1941 - 1943
2
[ 367-12-4 ]
[ 1526-17-6 ]
Reference：
[1] Chinese Chemical Letters, 2010, vol. 21, # 11, p. 1283 - 1286
[2] Patent: WO2013/28474, 2013, A1, . Location in patent: Page/Page column 83
[3] Patent: WO2014/126944, 2014, A2, . Location in patent: Page/Page column 54
[4] Patent: EP2744499, 2016, B1, . Location in patent: Paragraph 0192
3
[ 367-12-4 ]
[ 7440-44-0 ]
[ 1526-17-6 ]
[ 403-19-0 ]
Yield
Reaction Conditions
Operation in experiment
30 %
With nitric acid In hexane; dichloromethane
A. 2-Fluoro-4-nitrophenol To a stirred solution of 2-fluorophenol (32.3 g, 0.288 mole) in methylene chloride which was cooled to -10° C. (ice-salt bath), was slowly added 90 percent nitric acid (22 g, 0.31 mole HNO3) over a one-hour period. During the addition, the temperature was maintained at about -5° C. After the addition was complete, stirring was continued at 0° C. for an additional hour. At the end of this period, the precipitate which had formed was filtered and washed with several portions of cold methylene chloride. G.C. and thin-layer chromatography (silica gel, 7:3 hexane-acetone) showed that this material was essentially a single compound and was the more polar and less volatile of the two products which formed in the reaction. This solid was taken up in ether, washed with water, dried (MgSO4) and the solvent evaporated. The resulting solid was recrystallized from methylcyclohexane to give 13 g of a light yellow solid: m.p.=119°-121° C. NMR (CDCl3) showed this to be the desired 2-fluoro-4-nitrophenol. The methylene chloride mother liquor was washed with water, dried (MgSO4) and the solvent evaporated. The solid which resulted was triturated with boiling hexane (3*150 ml). This effectively removed all of the least polar-more volatile reaction product. This hexane solution was treated with charcoal, filtered, concentrated to about 300 ml and cooled to give 13.5 g (30 percent) of by-product 2-fluoro-6-nitrophenol as a yellow solid: m.p.=70°-86° C.
30 %
With nitric acid In hexane; dichloromethane
A. 2-Fluoro-4-nitrophenol To a stirred solution of 2-fluorophenol (32.3 g, 0.288 mole) in methylenechloride which was cooled to -10°C (ice-salt bath), was slowly added 90 percent nitric acid (22 g, 0.31 mole HNO3) over a one-hour period. During the addition, the temperature was maintained at about -5°C. After the addition was complete, stirring was continued at 0°C for an additional hour. At the end of this period, the precipitate which had formed was filtered and washed with several portions of cold methylene chloride. G.C. and thin-layer chromatography (silica gel, 7:3 hexane-acetone) showed that this material was essentially a single compound and was the more polar and less volatile of the two products which formed in the reaction. This solid was taken up in ether, washed with water, dried (MgSO4) and the solvent evaporated. The resulting solid was recrystallized from methylcyclohexane to give 13 g of a light yellow solid: m.p. = 119-121°C. NMR (CDCl3) showed this to be the desired 2-fluoro-4-nitrophenol. The methylene chloride mother liquor was washed with water, dried (MgSO4) and the solvent evaporated. The solid which resulted was triturated with boiling hexane (3 x 150 ml). This effectively removed all of the least polar - more volatile reaction product. This hexane solution was treated with charcoal, filtered, concentrated to about 300 ml and cooled to give 13.5 g (30 percent) of 2-fluoro-6-nitrophenol as a yellow solid: m.p. = 70-86°C.
Reference：
[1] Bulletin de la Societe Chimique de France, 1980, vol. 2, # 3-4, p. 175 - 178
7
[ 367-12-4 ]
[ 1526-17-6 ]
[ 681227-38-3 ]
Reference：
[1] Journal of the Chemical Society, 1940, p. 810
8
[ 367-12-4 ]
[ 1526-17-6 ]
[ 351-49-5 ]
Reference：
[1] Journal of the Chemical Society, 1940, p. 810
9
[ 1526-17-6 ]
[ 394-50-3 ]
Reference：
[1] Bulletin de la Societe Chimique de France, 1980, vol. 2, # 3-4, p. 175 - 178
10
[ 367-12-4 ]
[ 7440-44-0 ]
[ 1526-17-6 ]
[ 403-19-0 ]
Yield
Reaction Conditions
Operation in experiment
30 %
With nitric acid In hexane; dichloromethane
A. 2-Fluoro-4-nitrophenol To a stirred solution of 2-fluorophenol (32.3 g, 0.288 mole) in methylene chloride which was cooled to -10° C. (ice-salt bath), was slowly added 90 percent nitric acid (22 g, 0.31 mole HNO3) over a one-hour period. During the addition, the temperature was maintained at about -5° C. After the addition was complete, stirring was continued at 0° C. for an additional hour. At the end of this period, the precipitate which had formed was filtered and washed with several portions of cold methylene chloride. G.C. and thin-layer chromatography (silica gel, 7:3 hexane-acetone) showed that this material was essentially a single compound and was the more polar and less volatile of the two products which formed in the reaction. This solid was taken up in ether, washed with water, dried (MgSO4) and the solvent evaporated. The resulting solid was recrystallized from methylcyclohexane to give 13 g of a light yellow solid: m.p.=119°-121° C. NMR (CDCl3) showed this to be the desired 2-fluoro-4-nitrophenol. The methylene chloride mother liquor was washed with water, dried (MgSO4) and the solvent evaporated. The solid which resulted was triturated with boiling hexane (3*150 ml). This effectively removed all of the least polar-more volatile reaction product. This hexane solution was treated with charcoal, filtered, concentrated to about 300 ml and cooled to give 13.5 g (30 percent) of by-product 2-fluoro-6-nitrophenol as a yellow solid: m.p.=70°-86° C.
30 %
With nitric acid In hexane; dichloromethane
A. 2-Fluoro-4-nitrophenol To a stirred solution of 2-fluorophenol (32.3 g, 0.288 mole) in methylenechloride which was cooled to -10°C (ice-salt bath), was slowly added 90 percent nitric acid (22 g, 0.31 mole HNO3) over a one-hour period. During the addition, the temperature was maintained at about -5°C. After the addition was complete, stirring was continued at 0°C for an additional hour. At the end of this period, the precipitate which had formed was filtered and washed with several portions of cold methylene chloride. G.C. and thin-layer chromatography (silica gel, 7:3 hexane-acetone) showed that this material was essentially a single compound and was the more polar and less volatile of the two products which formed in the reaction. This solid was taken up in ether, washed with water, dried (MgSO4) and the solvent evaporated. The resulting solid was recrystallized from methylcyclohexane to give 13 g of a light yellow solid: m.p. = 119-121°C. NMR (CDCl3) showed this to be the desired 2-fluoro-4-nitrophenol. The methylene chloride mother liquor was washed with water, dried (MgSO4) and the solvent evaporated. The solid which resulted was triturated with boiling hexane (3 x 150 ml). This effectively removed all of the least polar - more volatile reaction product. This hexane solution was treated with charcoal, filtered, concentrated to about 300 ml and cooled to give 13.5 g (30 percent) of 2-fluoro-6-nitrophenol as a yellow solid: m.p. = 70-86°C.
Reference：
[1] Bulletin de la Societe Chimique de France, 1980, vol. 2, # 3-4, p. 175 - 178
14
[ 1526-17-6 ]
[ 437-83-2 ]
Reference：
[1] Journal of Medicinal Chemistry, 2007, vol. 50, # 2, p. 199 - 210
[2] Bulletin de la Societe Chimique de France, 1980, vol. 2, # 3-4, p. 175 - 178
[3] Patent: WO2013/28474, 2013, A1,
[4] Patent: WO2014/126944, 2014, A2,
[5] Patent: EP2744499, 2016, B1,
15
[ 1526-17-6 ]
[ 77-78-1 ]
[ 484-94-6 ]
Reference：
[1] Journal of the American Chemical Society, 1959, vol. 81, p. 94,95, 97
[2] Bulletin de la Societe Chimique de France, 1980, vol. 2, # 3-4, p. 175 - 178
[3] Journal of Medicinal Chemistry, 2007, vol. 50, # 2, p. 199 - 210
[4] Patent: WO2006/89054, 2006, A1, . Location in patent: Page/Page column 51-53
[5] Patent: WO2005/19228, 2005, A1, . Location in patent: Page/Page column 54-55
With palladium 10% on activated carbon; hydrogen In methanol for 1 h;
To a of solution of 2-fluoro-6-nitrophenol (6.37 mmol, 1.00 g) in methanol (100 mL), 10percent palladium on activated carbon (10 wtpercent of 2-fluoro-6-nitrophenol,0.10 g) was added. The reaction was flushed with argon followed by hydrogen for fifteen minutes each with constant magnetic stirring. The reaction was then maintained under hydrogen atmosphere at ordinary pressure (balloon) for one hour. Argon was again flushed through the reaction vessel for 15 minutes. Then the reaction contents were filtered over a thin pad of celite which was then washed with methanol (50 mL). The filtrate was concentrated in vacuo yielding a red solid. Silica gel column chromatography (1:1 hexanes/chloroform) provided a crystalline white solid in an 87percent yield.
55.3%
With tin(ll) chloride In tetrahydrofuran; waterReflux
2-fluoro-6-nitrophenol (322 mg, 2.05 mmol) and THF (6.4 ml),It was dissolved in water (6.4 ml),Thereto tin chloride (1.943 g, 10.25 mmol) was heated at reflux overnight added. After the reaction, the addition of a saturated aqueous sodium bicarbonate solution and ethyl acetate. The precipitate was filtered. The filtrate was extracted with ethyl acetate. It was washed with saturated brine. Dried over magnesium sulfate, the solvent was distilled off to obtain the title compound (144 mg, 55.3percent) as a white solid.
12%
Stage #1: With water; tin(ll) chloride In tetrahydrofuran at 80℃; for 2 h; Stage #2: With sodium hydrogencarbonate In water
Step 1. 2-amino-6-fluorophenol To 2-fluoro-6-nitrophenol (SynQuest) (2.4 g, 15 mmol) in THF (70 mL), and water (70 mL) was added tin dichloride (14.6 g, 76.4 mmol). The mixture was then heated at 80° C. for 2 h. The THF was removed in vacuo. A solution of sat'd NaHCO3 was added, followed by EtOAc. Insoluble material was removed by filtration. The layers of the filtrate were separated and the aqueous portion was extracted with ethyl acetate three times. The combined extracts were washed with brine, dried over sodium sulfate, filtered through a plug of silica gel and concentrated. The product was purified by silica gel chromatography, eluting with 0-60percent ethyl acetate in hexanes (230 mg, 12percent).1H NMR (300 MHz, CD3OD): δ 6.56 (ddd, 1H), 6.51 (ddd, 1H), 6.41 (ddd, 1H); 19F NMR (300 MHz, CD3OD): δ -141.27 (dd, 1F); LCMS (M+H)+: 128.1.
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2014, vol. 24, # 15, p. 3521 - 3525
[2] Patent: JP2016/124812, 2016, A, . Location in patent: Paragraph 0115
[3] Patent: US2010/298334, 2010, A1, . Location in patent: Page/Page column 46
[4] Patent: WO2005/118561, 2005, A1, . Location in patent: Page/Page column 25
[5] Patent: US2005/124667, 2005, A1, . Location in patent: Page/Page column 17
With potassium carbonate; In acetonitrile; at 90℃; for 2h;
<strong>[1526-17-6]2-Fluoro-6-nitrophenol</strong> (10 g, 63.65 mmol) was dissolved in acetonitrile (120 mL). Ethyl bromoacetate (7.76 mL, 70.02 mmol) and potassium carbonate (17.59 g,127.31 mmol) were added. The reaction mixture was stirred for 2 h at 90C, then allowed to cool to room temperature. The solvent was removed in vacuo and the residue was dissolved in dichloromethane (70 mL). The organic layer was washed sequentially with saturated aqueous sodium hydrogencarbonate solution (50 mL), then the aqueous layer was further extracted with dichloromethane (50 mL). The organic layers were combined,dried over sodium sulfate and concentrated in vacuo, to afford the title compound (11.57 g, 74.7%) as a dark yellow oil. H (250 MHz, CDC13) 7.62 (dt, J 8.2, 1.6 Hz, 1H), 7.35 (ddd, J 10.9, 8.4, 1.7 Hz, 1H), 7.17 (td, J 8.3, 4.9 Hz, 1H), 4.81 (d, J 0.7 Hz, 2H), 4.24 (q, J7.1 Hz,2H), 1.27 (t,J7.1 Hz,3H).
[(5-benzyloxy-2-{2-[2-(bis-methoxycarbonylmethyl-amino)-6-fluoro-phenoxy]-ethoxy}-4-formyl-phenyl)-methoxycarbonylmethyl-amino]-acetic acid methyl ester[ No CAS ]
2-(6-(bis-methoxycarbonylmethyl-amino)-5-{2-[2-(bis-methoxycarbonylmethyl-amino)-6-fluoro-phenoxy]-ethoxy}-benzofuran-2-yl)-oxazole-5-carboxylic acid ethyl ester[ No CAS ]
2-(6-(bis-acetoxymethoxycarbonylmethyl-amino)-5-{2-[2-(bis-acetoxymethyl-amino)-6-fluoro-phenoxy]-ethoxy}-benzofuran-2-yl)-oxazole-5-carboxylic acid acetoxymethyl ester[ No CAS ]
With potassium carbonate; In acetone; for 5h;Heating / reflux;
A mixture of <strong>[1526-17-6]2-fluoro-6-nitrophenol</strong> (5.31 g, 33.8 MMOL), METHYLBROMOACETATE (3.90 MI, 41.2 MMOL) and potassium carbonate (6.59 g, 44.7 mmol) in acetone (130 ML) was stirred at reflux (70C) for 5 h. The resulting reaction mixture was concentrated in vacuo, taken-up in ethyl acetate (100 ML), washed with water (2 x 100 ML) and dried (NA2SO4). The solvent was removed in vacuo affording the title compound (D57) as a yellow oil (7.24 g, 93%). MS; (ES) m/z: 230.20 [MH]'. C9H8 F05N requires 229.16. 'H-NMR (300 MHz, CDCI3) 8 : 7.65 (d, 1 H), 7.30 (t, 1 H), 7.25-7. 15 (m, 1 H), 4.85 (s, 2 H), 3.80 (s, 3 H).
With palladium 10% on activated carbon; hydrogen; In methanol; for 1h;
To a of solution of 2-fluoro-6-nitrophenol (6.37 mmol, 1.00 g) in methanol (100 mL), 10% palladium on activated carbon (10 wt% of 2-fluoro-6-nitrophenol,0.10 g) was added. The reaction was flushed with argon followed by hydrogen for fifteen minutes each with constant magnetic stirring. The reaction was then maintained under hydrogen atmosphere at ordinary pressure (balloon) for one hour. Argon was again flushed through the reaction vessel for 15 minutes. Then the reaction contents were filtered over a thin pad of celite which was then washed with methanol (50 mL). The filtrate was concentrated in vacuo yielding a red solid. Silica gel column chromatography (1:1 hexanes/chloroform) provided a crystalline white solid in an 87% yield.
55.3%
With tin(ll) chloride; In tetrahydrofuran; water;Reflux;
2-fluoro-6-nitrophenol (322 mg, 2.05 mmol) and THF (6.4 ml),It was dissolved in water (6.4 ml),Thereto tin chloride (1.943 g, 10.25 mmol) was heated at reflux overnight added. After the reaction, the addition of a saturated aqueous sodium bicarbonate solution and ethyl acetate. The precipitate was filtered. The filtrate was extracted with ethyl acetate. It was washed with saturated brine. Dried over magnesium sulfate, the solvent was distilled off to obtain the title compound (144 mg, 55.3%) as a white solid.
12%
Step 1. 2-amino-6-fluorophenol To 2-fluoro-6-nitrophenol (SynQuest) (2.4 g, 15 mmol) in THF (70 mL), and water (70 mL) was added tin dichloride (14.6 g, 76.4 mmol). The mixture was then heated at 80 C. for 2 h. The THF was removed in vacuo. A solution of sat'd NaHCO3 was added, followed by EtOAc. Insoluble material was removed by filtration. The layers of the filtrate were separated and the aqueous portion was extracted with ethyl acetate three times. The combined extracts were washed with brine, dried over sodium sulfate, filtered through a plug of silica gel and concentrated. The product was purified by silica gel chromatography, eluting with 0-60% ethyl acetate in hexanes (230 mg, 12%).1H NMR (300 MHz, CD3OD): delta 6.56 (ddd, 1H), 6.51 (ddd, 1H), 6.41 (ddd, 1H); 19F NMR (300 MHz, CD3OD): delta -141.27 (dd, 1F); LCMS (M+H)+: 128.1.
With ammonium formate;palladium 10% on activated carbon; In methanol; at 20℃; for 0.5h;
Example 1: Synthesis of 2-(7-fluoro-2-oxo-1,3-benzoxazol-3(2H)-yl)acetamide; 12. 1.1 Synthesis of 2-amino-6-fluorophenol 1.; In a three neck flask, fitted with a magnetic stirrer, under inert atmosphere, a suspension of 2-fluoro-6-nitrophenol (5 g, 31.83 mmol), ammonium formate (6 g, 95.50 mmol) and Pd-C (10 % w/w, 0.34 g, 3.2 mmol) in MeOH (100 ml) is stirred 0.5 h at room temperature. The reaction mixture is filtered through celite and concentrated in vacuo to give 2-amino-6-fluorophenol 1 (4 g) which is used in the next step without any further purification. ¹H NMR ((CD3)2S0, 250 MHz) : 4.66-4.98 (s (broad), 2H) ; 6.315 (ddd, J: 1.51; 8.10 and 10.57 Hz, 1H); 6.41 (ddd, J: 1.30, 1.30 and 8.10 Hz, 1H); 6.52 (ddd, J: 5.80, 8.10 and 8.10 Hz, 1H); 8 .60-9.40 (s(broad) , 1H).
With hydrogen;nickel; In methanol; under 760.051 Torr;
6 nitro-2-fluorophenol (4.6 g) were dissolved in methanol, Raney nickel was added and the mixture was submitted to hydrogenation at atmospheric pressure until the absorption was complete. The mixture was filtrated, the filtrate was filtrated on activated coal and evaporated to give a residue which was crystallized in ether to yield 2 g of 26A which melted at 115 C. and used without further purification in the next step.
A. 2-Fluoro-4-nitrophenol To a stirred solution of 2-fluorophenol (32.3 g, 0.288 mole) in methylene chloride which was cooled to -10 C. (ice-salt bath), was slowly added 90 percent nitric acid (22 g, 0.31 mole HNO3) over a one-hour period. During the addition, the temperature was maintained at about -5 C. After the addition was complete, stirring was continued at 0 C. for an additional hour. At the end of this period, the precipitate which had formed was filtered and washed with several portions of cold methylene chloride. G.C. and thin-layer chromatography (silica gel, 7:3 hexane-acetone) showed that this material was essentially a single compound and was the more polar and less volatile of the two products which formed in the reaction. This solid was taken up in ether, washed with water, dried (MgSO4) and the solvent evaporated. The resulting solid was recrystallized from methylcyclohexane to give 13 g of a light yellow solid: m.p.=119-121 C. NMR (CDCl3) showed this to be the desired 2-fluoro-4-nitrophenol. The methylene chloride mother liquor was washed with water, dried (MgSO4) and the solvent evaporated. The solid which resulted was triturated with boiling hexane (3*150 ml). This effectively removed all of the least polar-more volatile reaction product. This hexane solution was treated with charcoal, filtered, concentrated to about 300 ml and cooled to give 13.5 g (30 percent) of by-product 2-fluoro-6-nitrophenol as a yellow solid: m.p.=70-86 C.
13.5 g (30%)
With nitric acid; In hexane; dichloromethane;
A. 2-Fluoro-4-nitrophenol To a stirred solution of 2-fluorophenol (32.3 g, 0.288 mole) in methylenechloride which was cooled to -10C (ice-salt bath), was slowly added 90 percent nitric acid (22 g, 0.31 mole HNO3) over a one-hour period. During the addition, the temperature was maintained at about -5C. After the addition was complete, stirring was continued at 0C for an additional hour. At the end of this period, the precipitate which had formed was filtered and washed with several portions of cold methylene chloride. G.C. and thin-layer chromatography (silica gel, 7:3 hexane-acetone) showed that this material was essentially a single compound and was the more polar and less volatile of the two products which formed in the reaction. This solid was taken up in ether, washed with water, dried (MgSO4) and the solvent evaporated. The resulting solid was recrystallized from methylcyclohexane to give 13 g of a light yellow solid: m.p. = 119-121C. NMR (CDCl3) showed this to be the desired 2-fluoro-4-nitrophenol. The methylene chloride mother liquor was washed with water, dried (MgSO4) and the solvent evaporated. The solid which resulted was triturated with boiling hexane (3 x 150 ml). This effectively removed all of the least polar - more volatile reaction product. This hexane solution was treated with charcoal, filtered, concentrated to about 300 ml and cooled to give 13.5 g (30 percent) of 2-fluoro-6-nitrophenol as a yellow solid: m.p. = 70-86C.
With potassium carbonate; In diethyl ether; acetone;
Step (1) Preparation of 2-Fluoro-6-nitrophenyl Trifluoromethanesulfonate A mixture consisting of <strong>[1526-17-6]2-fluoro-6-nitrophenol</strong> (20 g, 0.14 mol) and potassium carbonate (20 g, 0.14 mol) in acetone (350 mL) was stirred at room temperature for 20 minutes. A solution of trifluoromethanesulfonyl chloride (23.7 g, 0.14 mol) in acetone (100 mL) was added dropwise at room temperature. Stirring was continued for 3 hours. The reaction was filtered, and the filtrate was concentrated. The residue was dissolved in diethyl ether (300 mL), washed with 0.1N NaOH, water, dried (MgSO4), filtered and evaporated to give 21.5 g of the title compound. 1 H NMR (CDCl3): delta 8.0 (m, 1H), 7.6 (m, 2H).
With triphenylphosphine; diethylazodicarboxylate; In dichloromethane; at 20℃; for 20h;
Compound 108: 3-(2-Fluoro-6-nitro-phenoxy)-tetrahydro-furan2-Fluoro-6-nitro-phenol (1.0 g, 6.37 mmol, 1.0 eq) was dissolved in DCM (10 ml) and 3-hydroxy-tetrahydrofuran (0.56 g, 6.37 mmol, 1.0 eq), triphenylphosphine (2.0 g, 7.64 mmol, 1.2 eq), and diazodiethyldicarboxylate (1.22 g, 7.01 mmol, 1.2 eq) were added sequentially. The reaction was stirred at room temperature for 20 hours. The reaction mixture was filtered and the solvent removed in vacuo from the filtrate. The resultant residue was purified by column chromatography using 1 %DCM/MeOH as eluent to give the title compound (0.99 g, 4.35 mmol, 68%). 1H NMR indicates desired compound in ca. 95% purity.
EXAMPLE 78 4-Amino-8-(2,4-dimethoxyphenyl)-7-fluoro-N-propylcinnoline-3-carboxamide Synthetic Scheme for Making Compound 78: A 2 L, 3-necked flask equipped with a mechanical stirrer was charged with 4-amino7-fluoro-8-iodo-N-propylcinnoline-3-carboxamide (40.5 g, 108.2 mmol), DME (700 mL, anhydrous), and ethanol (200 mL, absolute). A nitrogen dispersion tube was fitted into the suspension and the mixture was stirred until a solution was obtained. Water (300 mL) and PdCl2(PPh3)2 (7.6 g, 10 mol %) were added. After 5 minutes, 2,4-dimethoxyphenyl boronic acid (39.4 g, 216.5 mmol) was added followed by cesium carbonate (70.3 g, 216.5 mmol). Nitrogen was bubbled through the suspension for 5 minutes. The mixture was heated to approximately 80 C. Additional 7:3:2 DME:H2O:EtOH (340 mL) was added as the reflux started. The reaction was refluxed 18 hours and then cooled to room temperature, diluted with ethyl acetate (1.5 L), and washed with water (3×500 mL). The aqueous layers were extracted with ethyl acetate (3×150 mL). The combined organic layers were stirred for 1 hour with 40 g of DARCO, dried over sodium sulfate, and filtered through Celite. The solids were washed with 5% methanol in chloroform (3×200 mL) and the filtrates concentrated to a dark semisolid. This was taken up in 200 mL 1% methanol in chloroform and warmed to solubilize the material. The solution was divided into two portions. Each portion was filtered through Whatman fluted filter paper onto a 330 g silica gel column and eluted with 5% ethyl acetate in dichloromethane. (Note: Some solid catalyst appeared to be removed via the filter paper.) The purest fractions from each column were combined in 5-10% ethyl acetate in dichloromethane. The solution was concentrated to approximately 200 mL, diluted with hexane (200 mL), and let stand at room temperature overnight. The resulting solids were isolated by filtration, washed with ether (3 times), and dried under vacuum at room temperature to afford the desired product (26.4 g, 63%). 1H NMR (500.333 MHz, CDCl3) delta 8.51 (bs, 1H), 7.86 (dd, J=9.4, 5.2 Hz, 1H), 7.50 (t, J=8.8 Hz, 1H), 7.27 (d, J=9.2, 1H), 6.66 (dd, J=8.2, 2.3 Hz, 1H), 6.63 (d, J=2.3 Hz, 1H), 3.87 (s, 3H), 3.71 (s, 3H), 3.44 (q, J=6.7 Hz, 2H), 1.64 (sextet, J=7.3 Hz, 2H), 0.99 (t, J=7.4 Hz, 3H). MS APCI, m/z=385 (M+H). HPLC: 2.61 min.
40%
With potassium carbonate; In acetone; at 20℃; for 4h;
(2-Fluoro-6-nitro-phenyl)-propyl-amine A solution of <strong>[1526-17-6]2-fluoro-6-nitro-phenol</strong> (1.00 g, 6.37 mmol) in acetone (18 ml) was treated with K2CO3 (880 mg, 6.37 mmol), stirred for 20 min at RT, and trifluoromethanesulfonic anhydride (1.07 ml, 6.36 mmol) was then added dropwise. The mixture was stirred for 4 h at RT, diluted with Et2O, washed with an aq. 0.1N NaOH solution, dried over Na2SO4, filtered, and concentrated in vacuo to give trifluoro-methanesulfonic acid 2-fluoro-6-nitro-phenyl ester (0.75 g, ca. 40%) as brownish liquid which was used as it is for the next step. A solution of trifluoro-methanesulfonic acid 2-fluoro-6-nitro-phenyl ester (12.04 g, 38.7 mmol) in NMP (20 ml) was treated with propylamine (3.55 ml, 42.6 mmol) and heated to 130 C. for 18 h. The mixture was allowed to cool to RT, diluted with Et2O, and washed twice with water. The org. layer was then concentrated in vacuo to give a dark brown liquid, which was purified by flash chromatography (Hex/EtOAc 90:10) providing (2-fluoro-6-nitro-phenyl)-propyl-amine (1.94 g, 25%). HPLC (System 3, 30-100% CH3CN): tR=3.417 min, MS (LC-MS): 199 [M+1].
~ 40%
2-Fluoro-6-nitro-phenyl)-propyl-amineA solution of <strong>[1526-17-6]2-fluoro-6-nitro-phenol</strong> (1.00 g, 6.37 mmol) in acetone (18 ml) was treated withK2CO3 (880 mg, 6.37 mmol), stirred for 20 min at RT, and trifluoromethanesulfonic anhydride (1.07 ml, 6.36 mmol) was then added dropwise. The mixture was stirred for 4 h at RT, diluted with Et2O, washed with an aq. 0.1 N NaOH solution, dried over Na2SO4, filtered, and concentratred in vacuo to give trifluoro-methanesulfonic acid 2-fluoro-6-nitro-phenyl ester (0.75 g, ca. 40 %) as brownish liquid which was used as it is for the next step.
With potassium carbonate; In acetone; at 65℃; for 3h;
Intermediate 6: (2-Fluoro-6-nitrophenoxy)acetic acid, methyl esterA stirred mixture of <strong>[1526-17-6]2-fluoro-6-nitrophenol</strong> (2.2g, 0.0140mol), methyl bromoacetate (3.2mL, 0.0177 mol), K2C03 (4 g, 0.0184mol) in acetone (lOOmL) was heated at 65C for 3h. The reaction mixture was concentrated under vacuum and the resultant solid was dissolved in dichloromethane. Water was then added and the mixture was extracted with dichloromethane. The organic phase was dried (MgS04) and the solvent removed under reduced pressure. The residue was triturated with diethyl ether to afford (2-fluoro-6-nitrophenoxy)acetic acid, methyl ester as brown oil (1.44g, 98%) which was used directly in the next stage.Mass: (ES+) 198 (M+H)+
(S)-2-(tert-butoxycarbonylamino)-3-(2-fluoro-6-nitrophenoxy)propanoic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
30%
a) (S)-2-tert-Butoxycarbonylamino-3-(2-fluoro-6-nitro-phenoxy)-propionic acid benzyl ester; A solution of 3.00 g (19 mmol) <strong>[1526-17-6]2-fluoro-6-nitrophenol</strong>e and 7.26 g (28 mmol) triphenylphosphine in 20 ml tetrahydrofurane was treated at -3 C. with 4.34 ml (28 mmol) diethyl azodicarboxylate for 10 minutes. Then 5.44 g (18 mmol) N-tert-butoxycarbonyl-L-serine benzyl ester was added and after stirring at room temperature for 16 hrs the solvent was removed by distillation and the residue was purified by chromatography on silicagel with heptane/ethylacetate (gradient 0-100 to 50:50) to yield 2.40 g (30%) (S)-2-tert-butoxycarbonylamino-3-(2-fluoro-6-nitro-phenoxy)-propionic acid benzyl ester as yellow oil, MS m/e (%): 452.1 (M+NH4+, 100).
With potassium carbonate; In N,N-dimethyl-formamide; at 80℃;
Preparation D: (2RS)-2-aminomethyl-9-fluoro-2,3-dihydro-1-oxa-3a-aza-phenalen-4-oneD.i. 1-fluoro-2-benzyloxy-3-nitro-benzeneTo a solution of <strong>[1526-17-6]2-fluoro-6-nitrophenol</strong> (25.1 g, 157 mmol) in DMF (430 mL) were added K2CO3 (43.7 g, 313 mmol) and benzyl bromide (21 mL, 172 mmol). The reaction mixture was stirred at 80 C. overnight. After cooling to rt, the reaction mixture was filtered. The filtrate was concentrated under reduced pressure. Water (100 mL) and EA (100 mL) were added and the phases were separated. The aq. layer was extracted once with EA (100 mL) and the combined org. layers were dried over Na2SO4, filtered and evaporated under reduced pressure. The residue was dried under HV to give the title compound as a yellow oil (39.9 g).1H NMR (d6-DMSO) delta: 7.65-7.75 (m, 2H); 7.28-7.40 (m, 6H); 5.21 (s, 2H).
With nitric acid; In dichloromethane; at 0℃; for 1h;
Step A: 2-fluoro-6-nitrophenol: Concentrated HN03 (95 %, 44 g, 0.62 mol) was added dropwise at 0-5 C to the solution of2-fluorophenol (64.6 g, 0.58 mol) in 1 L ofDCM. The mixture wasstirred at 0 C for 1 hour before filtration. The filtrate was washed with water and brine, driedover anhydrous Na2S04 and concentrated. The residue was purified by column chromatography(DCM: PE = 1 : 2) to afford 2-fluoro-6-nitrophenol.
With nitric acid; In dichloromethane; at 0 - 5℃; for 1h;
Concentrated HNO3 (95 %? 44 g, 0.62 mol) was added dropwiseat 0-5 Oc to the solution of 2-fluorophenol (64.6 g, 0.58 mol) in 1 L of DCM. The mixture wasstirred at o Oc for 1 hour before filtration. The filtrate was washed with water and brine, dried oyer anhydrous Na2504 and concentrated. The residue was purified by column chromatography (DCM : PE = 1 : 2) to afford 2-fluoro-6-nitrophenol.
With nitric acid; In dichloromethane; at 0℃; for 1h;
General procedure: Concentrated HNO3 (95 %, 44 g, 0.62 mol) was added dropwise at 0-5 C to thesolution of 2-fluorophenol (64.6 g, 0.58 mol) in 1 L of DCM. The mixture was stirred at 0 C for 1 hour before filtration.The filtrate was washed with water and brine, dried over anhydrous Na2SO4 and concentrated. The residue waspurified by column chromatography (DCM : PE = 1 : 2) to afford 2-fluoro-6-nitrophenol.
With potassium carbonate; In N,N-dimethyl-formamide; at 20 - 60℃; for 3.0h;
Step B: 1-fluoro-2-methoxy~3-nitrobenzene: Mel (27.1 g, 191 mmol) was added dropwise to the suspension of2-fluoro-6-nitrophenol (25.0 g, 159 mmol) and K2C03 (44.0 g, 318 mmol) in 200mL ofDMF. The mixture was stirred overnight at 25 C then warmed to 60 C and stirred for 3hours. The mixture was diluted with 1 L ofEtOAc and washed with water (3 X 100 mL) andbrine (1 00 mL), dried over anhydrous Na2S04 and concentrated to afford the title compound.
With potassium carbonate; In N,N-dimethyl-formamide; at 25 - 60℃; for 3.0h;
MeI (27.1 g, 191 mmol) was added dropwise to thesuspension of 2-fluoro-6-nitrophenol (25.0 g, 159 mmol) and K2c03 (44.0 g, 318 mmol) in 200m of DMF. The mixture was stirred oyernight at 25 Oc then warmed to 60 Oc and stirred for 3 hours. The mixture was diluted with 1 L of EtOAc and washed with water (3 X 100 mL) and brine (100 mL), dried oyer anhydrous Na2504 and concentrated to afford the title compound.
With potassium carbonate; In N,N-dimethyl-formamide; at 25 - 60℃; for 3.0h;
General procedure: MeI (27.1 g, 191 mmol) was added dropwise to the suspension of 2-fluoro-6-nitrophenol (25.0 g, 159 mmol) and K2CO3 (44.0 g, 318 mmol) in 200 mL of DMF. The mixture was stirredovernight at 25 C then warmed to 60 C and stirred for 3 hours. The mixture was diluted with 1 L of EtOAc andwashed with water (3 X 100 mL) and brine (100 mL), dried over anhydrous Na2SO4 and concentrated to afford thetitle compound.
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