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Structure of 452-80-2 * 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] Journal of the American Chemical Society, 1959, vol. 81, p. 94,95, 97
3
[ 446-34-4 ]
[ 452-80-2 ]
Reference：
[1] Journal of the American Chemical Society, 1959, vol. 81, p. 94,95, 97
[2] Acta Chemica Scandinavica (1947-1973), 1955, vol. 9, p. 1079,1083
[3] Bl.Soc.Sci.Lett.Lodz, 1952, vol. <3>3, # 15, p. 6
[4] Journal of Organic Chemistry, 1961, vol. 26, p. 3351 - 3356
[5] Journal of Medicinal Chemistry, 2000, vol. 43, # 26, p. 5017 - 5029
4
[ 51632-16-7 ]
[ 446-34-4 ]
[ 452-80-2 ]
Reference：
[1] Patent: US4243819, 1981, A,
5
[ 452-74-4 ]
[ 452-80-2 ]
Reference：
[1] Journal of Organic Chemistry, 2012, vol. 77, # 17, p. 7471 - 7478
6
[ 352-70-5 ]
[ 452-80-2 ]
Reference：
[1] Journal of Organic Chemistry, 1961, vol. 26, p. 3351 - 3356
7
[ 106-49-0 ]
[ 452-80-2 ]
[ 452-77-7 ]
Reference：
[1] Journal of Fluorine Chemistry, 2005, vol. 126, # 4, p. 661 - 667
8
[ 452-80-2 ]
[ 75-36-5 ]
[ 326-67-0 ]
Yield
Reaction Conditions
Operation in experiment
87%
With triethylamine In dichloromethane at 0℃; for 2 h;
To a solution of 2-fluoro-4-methyl-aniline (250 g, 2 mol) and triethylamine (202 g, 2 mol) in 2 L of dichloromethane was added dropwise acetylchloride (156 g, 2 mol). The reaction mixture was stirred for 2 hours at a temperature of 00C and subsequently washed with dilute hydrochloric acid. The organic phase was dried with sodium sulfate and concentrated under reduced pressure to yield 2-fluoro-4-methyl-acetanilide as a crude intermediate (334 g, 87percent).
87%
With triethylamine In dichloromethane at 0℃; for 2 h;
To a solution of 2-fluoro-4-methyl-aniline (250 g, 2 mol) and triethylamine (202 g, 2 mol) in 2 L of dichloromethane was added dropwise acetyl chloride (156 g, 2 mol). The reaction mixture was stirred for 2 hours at a temperature of 0°C and subsequently washed with dilute hydrochloric acid. The organic phase was dried with sodium sulfate and concentrated under reduced pressure to yield 2-fluoro-4- methyl-acetanilide as a crude intermediate (334 g, 87percent).
87%
With triethylamine In dichloromethane at 0℃; for 2 h;
To a solution of 2-fluoro-4-methyl-aniline (250 g, 2 mol) and triethylamine (202 g, 2 mol) in 2 L of dichloromethane was added dropwise acetyl chloride (156 g, 2 mol). The reaction mixture was stirred for 2 hours at a temperature of 0°C and subsequently washed with dilute hydrochloric acid. The organic phase was dried with sodium sulfate and concentrated under reduced pressure to yield 2-fluoro-4- methyl-acetanilide as a crude intermediate (334 g, 87percent).
Reference：
[1] The Journal of organic chemistry, 2002, vol. 67, # 17, p. 5869 - 5875
[2] Patent: US2006/111416, 2006, A1, . Location in patent: Page/Page column 13
[3] Organic and Biomolecular Chemistry, 2017, vol. 16, # 1, p. 101 - 107
[4] Patent: WO2018/15797, 2018, A1, . Location in patent: Page/Page column 50
[5] Patent: WO2018/15852, 2018, A1, . Location in patent: Page/Page column 60; 61
[6] Patent: WO2018/51252, 2018, A2, . Location in patent: Page/Page column 79
10
[ 106-49-0 ]
[ 452-80-2 ]
[ 452-77-7 ]
Reference：
[1] Journal of Fluorine Chemistry, 2005, vol. 126, # 4, p. 661 - 667
11
[ 452-80-2 ]
[ 452-79-9 ]
Yield
Reaction Conditions
Operation in experiment
66%
With potassium iodide; sodium nitrite In sulfuric acid
Preparation 8 3-Fluoro-4-iodotoluene (10a) To a suspension of 2-fluoro-4-methylaniline (2.0 g, 16 mmol) in aqueous sulfuric acid (~7 N) was added an aqueous solution of sodium nitrite (1.10 g, 16 mmol, 10 mL water) dropwise at 0° C. and the resulting light orange solution was stirred for 30 minutes. This solution was carefully poured into an aqueous solution of potassium iodide (3.98 g, 24 mmol, 16 mL water) at 80° C. and the resulting red mixture was stirred 1.5 hours at 80° C., and overnight at 50° C. The reaction was cooled to room temperature, poured into water (300 mL), and sodium bisulfite added until the light yellow color remained constant. The aqueous was extracted with diethyl ether (2*125 mL) and the organics were combined, washed with brine, dried (sodium sulfate), filtered, and the ether evaporated to give 2.5 g (66percent) of crude product as a yellow green oil. Used without further purification. 1H NMR (CDCl3) δ2.32 (s, 3H,), 6.72 (dd, 1H, J=1.28 Hz, J=8.05 Hz), 6.88 (dd, 1H, J=1.28 Hz, JH=8.97 Hz), 7.58 (dd, 1H, J=1.08 Hz, J=6.78 Hz).
Stage #1: With hydrogenchloride; sodium nitrite In water at -5℃; Stage #2: With sodium hydrogencarbonate In water Stage #3: at 60℃; for 2 h;
a) 2-Fluoro-4-methylbenzonitrile A solution of sodium nitrite (4.22 g, 61.16 mmol) in water (40 mL) was added slowly to a stirred suspension of (2-fluoro-4-methylphenyl)amine (4.60 mL, 40.73 mmol) in hydrogen chloride (1M, 340 mL) at -5 °C, and the mixture was stirred at this temperature. After 10 minutes, sodium bicarbonate was added until the pH was 7-8. The reaction mixture was added slowly to a stirred solution of cyanocopper (12.22 g, 136.44 mmol) and potassium cyanide (8.10 g, 124.39 mmol) in water (150 mL). The reaction was warmed to 60 °C. After heating for 2 hours, ethyl acetate was added to the mixture and the aqueous layer was extracted with more ethyl acetate. The organic layer was washed with brine, dried (Na2S04) and evaporated. Purification of the crude by flash chromatography (85:15 hexanes/ethyl acetate) gave the title compound (2.56 g, 46percent). LRMS (m/z): 136 (M+1)+.1H NMR (300 MHz, CHLOROFORM-d) δ ppm 2.45 (s, 3 H) 6.98 - 7.12 (m, 2 H) 7.51 (t, J=6.87 Hz, 1 H)
46%
Stage #1: With hydrogenchloride; sodium nitrite In water at -5℃; for 0.166667 h; Stage #2: With sodium hydrogencarbonate In water Stage #3: at 60℃; for 2 h;
INTERMEDIATE 10; rV-Cyclopropyl-7-iodo-6-methyl-1 ,2-benzisoxazol-3-aminea) 2-Fluoro-4-methylbenzonitrile; A solution of sodium nitrite (4.22 g, 61.16 mmol) in water (40 mL) was added slowly to a stirred suspension of (2-fluoro-4-methylphenyl)amine (4.60 mL, 40.73 mmol) in hydrogen chloride (1M, 340 mL) at -5 °C, and the mixture was stirred at this temperature. After 10 minutes, sodium bicarbonate was added until the pH was 7-8. The reaction mixture was added slowly to a stirred solution of cyanocopper (12.22 g, 136.44 mmol) and potassium cyanide (8.10 g, 124.39 mmol) in water (150 mL). The reaction was warmed to 60 °C. After heating for 2 hours, ethyl acetate was added to the mixture and the aqueous layer was extracted with more ethyl acetate. The organic layer was washed with brine, dried (Na2S04) and evaporated. Purification of the crude by flash chromatography (85:15 hexanes/ethyl acetate) gave the title compound (2.56 g, 46percent).LRMS (m/z): 136 (M+1)+. 1 H NMR (300 MHz, CHLOROFORM-d) δ ppm 2.45 (s, 3 H) 6.98 - 7.12 (m, 2 H) 7.51 (t, J=6.87 Hz, 1 H)
To a solution of <strong>[452-80-2]2-fluoro-4-methylaniline</strong> (250 mg, 2.0 mmol) in THF (7 mL) was added di-fer/-butyl dicarbonate (117 mg, 0.54 mmol). The resulting solution was stirred overnight at 60°C. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (15:85). This resulted in 300 mg (67percent) of the title compound as a colorless oil. LCMS (ESI, m/z): [M+H]+ = 226.1.
4-(2-fluoro-4-methylanilino)-6-methoxy-7-(1-methylpiperidin-4-ylmethoxy)quinazoline[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
61%
Example 6 A suspension of 4-chloro-6-methoxy-7-(1-methylpiperidin-4-ylmethoxy)quinazoline (200mg, 0.622mmol), (prepared as described for the starting material in Example 2c) and <strong>[452-80-2]2-fluoro-4-methylaniline</strong> (94mg, 0.764mmol) in isopropanol (5ml) containing 6.2M hydrogen chloride in isopropanol (110mul) was stirred at 80°C for 1.5 hours. After cooling, the precipitate was collected by filtration, washed with isopropanol, followed by ether and dried under vacuum. The solid was purified by column chromatography, eluding with methylene chloride/methanol (90/10) followed by 5 percent ammonia in methanol/methylene chloride (10/90). Evaporation of the fractions containing the expected product gave 4-(2-fluoro-4-methylanilino)-6-methoxy-7-(1-methylpiperidin-4-ylmethoxy)quinazoline (170mg, 61percent). MS - ESI: 411 [MH]+ 1H NMR Spectrum: (DMSOd6) 1.3-1.45 (m, 2H), 1.8 (d, 2H), 1.7-1.9 (m, 1H), 1.9 (t, 2H), 2.2 (s, 3H), 2.35 (s, 3H), 2.8 (d, 2H), 3.95 (s, 3H), 4.01 (d, 2H), 7.1 (d, 1H), 7.13 (d, 1H), 7.16 (s, 1H), 7.4 (t, 1H), 7.81 (s, 1H), 8.32 (s, 1H), 9.4 (s, 1H)
To a mixture of <strong>[452-80-2]2-fluoro-4-methylaniline</strong> (5.50 g, 43.95 mmol, 1 equiv.) in chloroform (30 ml), a solution of acetic anhydride (4.49 g, 43.95 mmol, 1 equiv.) in chloroform (20 ml) was slowly added at 0 °C. The reaction mixture was then stirred at room temperature for 3 hours. The reaction mixture was then quenched into sodium bicarbonate solution and the product was extracted with dichloromethane. The combined organic layer was washed by sodium bicarbonate solution followed by distilled water, dried over sodium sulfate, filtered and concentrated under reduced pressure to get 5.92 g of the crude product as white solid. The crude product thus obtained was further used as such without any purification. 1H NMR (CDC13) : 6 8.14-8.10 (m, 1H), 7.25 (bs, 1H), 6.93-6.88 (m,2H) , 2.31 (s, 3H) , 2.20 (s, 3H)
In chloroform; at 0 - 20℃; for 3h;
To a mixture of 2?fluoro?4?methylaniline (5.50 g, 43.95 mmol, 1 equiv.) in chloroform (30 ml), a solution of acetic anhydride (4.49 g, 43.95 mmol, 1 equiv.) in chloroform (20 ml)was slowly added at 0 °C. The reaction mixture was then stirred at room temperature for 3 hours. The reaction mixture was then quenched into sodium bicarbonate solution and the product was extracted with dichloromethane. The combined organic layer was washed by sodium bicarbonate solution followed by distilled water,dried over sodium sulfate, filtered and concentrated under reduced pressure to get 5.92 g of the crude product as white solid. The crude product thus obtained was further used as such without any purification.?H R (CDC13) : 6 8.14-8.10 (m, 1H), 7.25 (bs, 1H), 6.93-6.88 (m,2H) , 2.31 (s, 3H) , 2.20 (s, 3H)
In chloroform; at 0 - 20℃; for 3h;
To a mixture of <strong>[452-80-2]2-fluoro-4-methylaniline</strong>(5.50 g,43.95 mmol,1 equiv.)in chloroform(30 ml),a solution of acetic anhydride(4.49 g,43.95 mmol,1 equiv.)in chloroform(20 ml)was slowly added at 0 °C. The reaction mixture was then stirred at room temperature for 3 hours. The reaction mixture was then quenched into sodium bicarbonate solution and the product was extracted with dichloromethane. The combined organic layer was washed by sodium bicarbonate solution followed by distilled water,dried over sodium sulfate,filtered and concentrated under reduced pressure to get 5.92 g of the crude product as white solid. The crude product thus obtained was further used as such without any purification . NMR(CDCI3): delta 8.14-8.10(m,1H),7.25(bs,1H),6.93-6.88(m, 2H),2.31(s,3H),2.20(s,3H).
With sulfuric acid; nitric acid; at -10℃; for 3h;Cooling with ice;
To H2SO4 (250 mL) was slowly added <strong>[452-80-2]2-fluoro-4-methylaniline</strong> (25.03 g, 200 mmol) while cooling the mixture on ice to prevent excessive warming, and the resulting mixture was stirred until all precipitated solids dissolved to give a transparent brown solution. This aniline solution was then cooled to -10 °C. A second solution was prepared by careful addition of 68-70percent m/m HNO3 (20.0 g, 14.1 mL, -220 mmol) to H2S0 (28 mL) while cooling the mixture on ice to maintain the temperature at room temperature or below. The HNO3/H2SO4 solution was then added to the cooled aniline solution dropwise over 3 h, taking care not to allow the internal temperature to rise above -5 °C. At the end of the addition, the reaction mixture was carefully poured into ice water (1.5 L) and the resulting mixture was carefully basified by slow addition of an NaOH solution (-450 g dissolved in 600 mL water) , cooling the mixture in an ice bath to maintain the internal temperature below 60 °C at all times. The resulting precipitate was collected by filtration, washed thoroughly with water (4x), and dried to provide the pure product 10 as a yellow solid (32.65 g, 96percent). *H NMR (500 MHz, CDCla) delta 7.49 (d, J= 8.2 Hz, 1H) , 6.92 (d, J= 11.2 Hz, 1H) , 3.89 (br s, 2H) , 2.48 (s, 3H); 13C NMR (126 MHz, CDCI3) delta 154.5 and 152.5, 145.0, 133.5 and 133.3, 125.1 and 125.0, 119.0 and 118.8, 113.2 and 113.1, 20.21.
85%
To a concentrated sulfuric acid (15.0 mL) <strong>[452-80-2]2-fluoro-4-methylaniline</strong> (1.80 mL, 16.0 mmol) was added dropwise at 0 0C. The mixture was stirred until a clear solution formed. To the obtained solution concentrated nitric acid <n="76"/>(68-70percent) (5.14 ml_) was added dropwise while maintaining the bath temperature at - 10 0C. The mixture was stirred at - 10 0C for 30 min and poured into ice water. The resulting mixture was extracted with EtOAc. The combined EtOAc extracts were washed with NaHCO3, brine, dried over MgSO4, filtered and concentrated. The residue was purified by column chromatography (ethyl acetate:hexane; 1 :9) to afford 2-fluoro-4-methyl-5-nitro-aniline as a yellow solid (2.30 g, 85percent). 1H NMR (CDCI3, 400 MHz,): 2.50 (s, 3H), 3.92 (br. s, 2H), 6.93 (d, J = 11.2 Hz, 1 H), 7.51 (d, J = 8.2 Hz, 1 H). 13C NMR (CDCI3, 100 MHz): 20.0, 113.0, 118.7, 124.9, 133.3, 153.3.
With potassium iodide; sodium nitrite; In sulfuric acid;
Preparation 8 3-Fluoro-4-iodotoluene (10a) To a suspension of 2-fluoro-4-methylaniline (2.0 g, 16 mmol) in aqueous sulfuric acid (~7 N) was added an aqueous solution of sodium nitrite (1.10 g, 16 mmol, 10 mL water) dropwise at 0 C. and the resulting light orange solution was stirred for 30 minutes. This solution was carefully poured into an aqueous solution of potassium iodide (3.98 g, 24 mmol, 16 mL water) at 80 C. and the resulting red mixture was stirred 1.5 hours at 80 C., and overnight at 50 C. The reaction was cooled to room temperature, poured into water (300 mL), and sodium bisulfite added until the light yellow color remained constant. The aqueous was extracted with diethyl ether (2*125 mL) and the organics were combined, washed with brine, dried (sodium sulfate), filtered, and the ether evaporated to give 2.5 g (66%) of crude product as a yellow green oil. Used without further purification. 1H NMR (CDCl3) delta2.32 (s, 3H,), 6.72 (dd, 1H, J=1.28 Hz, J=8.05 Hz), 6.88 (dd, 1H, J=1.28 Hz, JH=8.97 Hz), 7.58 (dd, 1H, J=1.08 Hz, J=6.78 Hz).
Step 7: The product from the previous step was dissolved in dry toluene (8mL) under argon. A portion of this stock solution (ImL) was added to a reaction-vial in a Mettler-Toledo Bohdan block using an atmosphere of argon to exclude air. 2-Fluoro-l-iodo-4-methyl-benzene (0.33mmol; prepared from 2-fluoro-4-methyl-phenylamine according to a general literature procedure [S. E. Tunney and J. K. Stille, J. Org. Chem., 52, 748-53 (1987)]) was added as a toluene solution (ImL) followed by 0.5mL of a freshly prepared toluene stock of solution of <n="18"/>tris(dibenzylideneacetone)dipalladium(0) (Pd2dba3) and bis[(2-diphenyl- phosphanyl)phenyl] ether DPEphos (corresponding to 0.3 equivalents palladium and 0.6 equivalents DPEphos). Potassium t°t-butoxide (0.66mmol) was added followed by tetra-n- butyl ammonium fluoride (TBAF; 1.0M in THF; 80 microliter). The mixture was stirred at 1000C overnight under argon. Next morning, the volatiles were removed using a Genevac instrument. The residue was dissolved in methanol (4mL) and loaded onto a VacMaster SCX- column (activated with 10% acetic acid in methanol). The product was eluted with acetonitrile. The volatiles were removed in vacuo. The residue was dissolved in methanol (1.5mL) and 4M HCl in diethyl ether (1.5mL) was added. The mixture was shaken at room temperature over the weekend before the volatiles were removed in vacuo. The residue was dissolved in dimethyl sulfoxide (0.18mL) and filtered. A few drops of 20% acetonitrile in water were added, and the mixture was filtered again. The product was isolated by preparative LC/MS as described, concentrated in vacuo, and the product was dissolved in dimethyl sulfoxide (0.78mL) to give a 1OmM solution. LC/MS-data: Method 14, retention time (UV) 2.152 min; UV-purity 79.5%; ELS-purity 100%; mass observed 337.407.
A solution of <strong>[452-80-2]2-fluoro-4-methylaniline</strong> compound 50 (400 mg, 3.2 mmol) in pyridine (4 [MQ)] was reacted by dropwise addition [OF BENZYLCHLOROFORMATE] (0. 68 [MG,] 4.8 mmol) at [0 C.] After being stirred for 20 min at [0 C,] the reaction was stopped by addtion of 0.2 mg ethanol. The reaction mixture was diluted with distilled water, filtered. The residue was purified by column chromatography on Silica gel with EtOAc/hexanes (1: 10) solvent mixture as an eluant to give 730 mg of pale pink solid of benzyl [N- (2-] fluoro-4-methylphenyl) carbamate compound 51 (yield: [88percent).] - melting point: [66 C] [H-NMR] [(CDCL3)] 8 : 7.93 (bt, [1] H), 7.3-7. 45 (m, 5 H, Ph), 6. [86-6.] 93 (m, 2 H), 6.80 (bs, 1 H, NH), 5.21 (s, 2 H, [OCH2PH),] 2.30 (s, 3 H, CH3)
With Iodine monochloride; In methanol; dichloromethane; at 20℃;
Preparation of 2-fluoro-6-iodo-4-methylaniline Iodine monochloride (8.9 mL, 1 M in DCM, 8.9 mmol) was added drop wise over 20 min to a solution of <strong>[452-80-2]2-fluoro-4-methylaniline</strong> (0.5 mL, 4.45 mmol) in MeOH (5 mL) and CH2CI2 (10 mL) at room temperature then the mixture was stirred at room temperature overnight. NaOH (1 N) was added slowly at 5°C, the organic layer was separated, washed with aq. Na2S03, then water, dried over MgS04, the solids were removed by filtration and the solvent of the filtrate was removed under reduced pressure. Purification was carried out by flash chromatography over silica gel (silica, 15-35 muiotatauiota, Heptane/EtOAc 95/5). Pure fractions were collected and evaporated to give 2-fluoro-6-iodo-4-methylaniline as colorless oil (0.662 g, 95percent).
44%
With dihydrogen peroxide; iodine; In methanol; at 20℃; for 0.25h;
A solution of <strong>[452-80-2]2-fluoro-4-methylphenylamine</strong> (1.25 g, 10 mmol) in 5 mL of methanol was treated with a solution of iodine (1.27 g, 5 mmol) in a mixture of 25 mL of methanol and 3 mL of hydrogen peroxide over a period of 15 minutes at room temperature. After 18 hours, the reaction mixture was quenched with 30 mL of saturated aqueous sodium thiosulfate and extracted with three 50 mL portions of dichloromethane. The combined organic layers were washed with two 30 ML portions of saturated sodium bisulfite solution, three 50 mL portions of water, dried over sodium sulfate, and concentrated in vacuo. Chromatography on SIO2 (10percent ethyl acetate in hexanes) gave 1.1 g of the title product as a light brownish oil (44percent yield).
With sodium acetate; Iodine monochloride; In acetic acid; at 20℃; for 0.5h;
A solution of <strong>[452-80-2]2-fluoro-4-methylaniline</strong> (1.0 g, 8 mmol) (bought from Avocado, Lancaster or Aldrich) in glacial acetic acid (10 ml) was treated with sodium acetate trihydrate (2.2 g, 16 mmol) then iodine monochloride (1.3 g). After 30min at room temperature aqueous sodium bicarbonate / sodium sulfite and diethyl ether were added, and the organic phase was dried (MgSO4), evaporated and chromatographed on silica eluting with 0 to 30percent ethyl acetate in hexane to give the title compound, 370 mg.
With sodium acetate; Iodine monochloride; In acetic acid; at 20℃; for 0.5h;
A solution of <strong>[452-80-2]2-fluoro-4-methylaniline</strong> (1.0 g, 8 mmol) in glacial acetic acid (10 ml) was treated with sodium acetate trihydrate (2.2 g, 16 mmol) then iodine monochloride (1.3 g). After 30min at room temperature aqueous sodium bicarbonate / sodium sulfite and diethyl ether were added, and the organic phase was dried (MgSO4), evaporated and chromatographed on silica eluting with 0 to 30percent ethyl acetate in hexane to give the title compound (370 mg).
With potassium cyanide; sodium nitrite;CuCN; In hydrogenchloride;
Step 1 2-fluoro-4-methylbenzonitrile 2-Fluoro-4-methylaniline (15 g, 120 mmol, 1 eq) was dissolved in 600 ml 1M HCl at 0 C. and a 120 ml aqueous solution of sodium nitrite (12.4 g, 180 mmol, 1.5 eq) was added dropwise, maintaining the temperature under 5 C. The solution was neutralized with solid NaHCO3 and poured into a 600 ml aqueous solution of 36 g KCN and 23.8 g CuCN at 60 C. The solution was stirred for 30 min and cooled to RT. The product was extracted 3 times with EtOAc and the combined organic layers were washed with brine and dried with sodium sulfate. The solvent was removed and 16 g (98%) of product was obtained.
With sodium hydroxide; sodium methylate; potassium carbonate In methanol; N,N,N,N,N,N-hexamethylphosphoric triamide
38 EXAMPLE 38
EXAMPLE 38 A solution of α-bromoisovaleric acid (8.17 mmole) in methanol is titrated to the phenophthalein end point using sodium methoxide. The solvent is removed by rotoevaporation and then there is added potassium carbonate (1.69 g), 2-fluoro-4-methylaniline (16.38 mmole) and 3 ml HMPT. The reaction is heated at 60° for about 5 hours and then worked up with 5% sodium hydroxide/ether and washed with water (3*). The basic layer is acidified and extracted with ether, washed with water and brine, dried over sodium sulfate and rotoevaporated to yield α-(2-fluoro-4-methylphenylamino)isovaleric acid.
α-(2-fluoro-4-methylphenylamino)isovaleric acid, potassium carbonate[ No CAS ]
[ 51632-16-7 ]
[ 446-34-4 ]
[ 452-80-2 ]
Yield
Reaction Conditions
Operation in experiment
With hydrogen; In tetrahydrofuran; N,N,N,N,N,N-hexamethylphosphoric triamide; ethanol;
(2-Fluoro-4-methylaniline is prepared from 3-fluoro-4-nitrotoluene in a Parr bottle using platinum oxide and hydrogen in ethanol.) To a mixture of 5.15 mmole of alpha-(2-fluoro-4-methylphenylamino)isovaleric acid, potassium carbonate (6.44 mmole), 4 ml of HMPT and 3 ml of THF, stirred, is added 5.13 mmole of <strong>[51632-16-7]m-phenoxybenzyl bromide</strong>. The reaction is stirred overnight at RT. The reaction is poured into 5% sodium hydroxide/ether, extracted with water (2*) and then washed with water (2*), dried over sodium sulfate and rotoevaporated under vacuum. The crude product is subjected to preparatory TLC eluding with 10% ether/hexane to give m-phenoxybenzyl ester of N-(2-fluoro-4-methylphenyl)valine. nmr (CDCl3) delta 0.98 [d, 3, J-7 Hz, CH(CH3)2 ], 1.02 [d, 3, J=7 Hz, CH(CH3)2 ], 2.22 STR20 and 5.13 ppm (s, 2, ArCH2 O). IR (neat)) 1734 cm-1 (C=O).
With N-Bromosuccinimide; In acetic acid; at 15 - 20℃; for 1.66667h;
A stirred solution of 4-methyl-2-fluoroaniline (15g, 0.12 mol) in acetic acid (120ml) at 150C under argon was treated portionwise over 20 minutes with solid N-bromosuccinimide (24g, 0.135 mol), then allowed to warm to room temperature and stirred for 1 hr. The reaction mixture was treated with water (500ml) and extracted with ethyl acetate (2 x 300ml). The combined extract was washed with water (2 x 500ml), then excess 10% Na2CO3 solution (400ml). The ethyl acetate solution was dried (Na2SO4) and concentrated under vacuum to leave the title compound as a dark red oil (24.Og, 98%). 1H NMR delta (CDCI3, 400MHz): 2.22 (3H, s), 3.95 (2H, br s), 6.78 (1H, d), 7.02 (1H, s).
87%
With N-Bromosuccinimide; In N,N-dimethyl-formamide; for 3h;Cooling;
In a well-dried 200 mL three-necked eggplant flask (with a condenser, three-way cock, and magnetic stir bar)4-amino-3-fluorotoluene5.00 g (40.0 mmol),After adding 150 mL of N, N-dimethylformamide,While cooling with water, 7.11 g (40.0 mmol) of N-bromosuccinimide was dissolved in 50 mL of N, N-dimethylformamide and added dropwise, and reacted for 3 hours. Add 300 mL of water to this reaction solution,After extraction with hexane, the organic layer is washed with pure water,The crude product was obtained by drying over MgSO4 and distilling off the solvent under reduced pressure. Crude product is silica gel column chromatograph(Eluent: hexane / ethyl acetate = 97/3)Compound 20 by purifying with7.09 g (87%, white solid) was obtained.
86%
With bromine; acetic acid; In methanol; at 0 - 20℃; for 4.5h;
Step 1) Synthesis of 2-bromo-6-fluoro-4-methyl anilinesodium sulfite (300 mL), and the resulting mixture was concentrated in vacuo to remove organic solvent. The residue was extracted with ethyl acetate (100 mL x 2), and the organic layers were combined. The combined organic layers were washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated in vacuo. The residue was purified by silica-gel column chromatography (ethyl acetate/petroleum ether (v/v) = 1/100) to give the title compound as an orange solid (17.5 g, 86%).MS (ES-API, pos. ion) m/z: 204.9 [M + 2].
With bromine; calcium carbonate; In tert-butyl methyl ether; water; at 10 - 18℃;
6-fluoro-4-methylanilme 6 (15 kg) was added to a mixture of MTBE (92 L, 66.6 kg) calcium carbonate (12 kg) and water (135kg), inerted and cooled to < 5 0C. Bromine (18.22 kg) was charged, keeping T< 10 0C. Age for 30 minutes at T <10 0C. The batch was warmed to ~ 18 0C and allowed to settle.The lower aqueous layer was cut away and the organics washed with 5% aq sodium metabisulfite (75 L) then water (75 L). The organic phase was solvent-switched to toluene (at < 40 0C using vacuum), final volume 45 - 6OL, then passed through a silica pad (15kg) in an oyster filter, washing with toluene (60 L, 52 kg). The filtrates were combined and reduced by vacuum distillation (T <40 0C).
With N-Bromosuccinimide; In acetic acid; at 20℃; for 1h;Inert atmosphere;
A stirred solution of 5.00 g Compound BDlO-1 (i.e. <strong>[452-80-2]2-fluoro-4-methylaniline</strong>) in (0335) AcOH (20.00 mL) at 20C under argon was treated portion wise over 20 minutes with solid NBS (7.96 g, 44.75 mmol), then allowed to warm to 20C and stirred for 1 hour. LCMS showed the production of Compound BD10-2. The reaction mixture was treated with water (300 mL) and extracted with ethyl acetate (300 mL * 3). The combined extracts were washed with water (300 mL *2) and then a 10 % wt Na2C03 solution (400 mL * 2). The ethyl acetate extract was then dried over Na2S04 and concentrated under vacuum to leave the Compound BD10-2 (8.00g, crude) as a dark red oil which was used into the next step without further purification.
Example 54 6-Bromo-4-[(2-fluoro-4-methylphenyl)amino]-7-methoxycinnoline-3-carboxamide hydrochloride To a suspension of 6-bromo-4-chloro-7-methoxycinnoline-3-carboxamide (Method21, 8.89 g, 28.09 mmol) in ethanol (70 ml) was added <strong>[452-80-2]2-fluoro-4-methylaniline</strong> (3.49 ml, 30.89 mmol) and acetic acid (0.016 ml, 0.28 mmol). The reaction mixture was stirred at 80 0C for 1 hour, cooled, and filtered. The solid material was washed with ethanol and dried to give 9.16 g (74 percent) of a brown solid, assumed to be the HCl salt. 1H NMR: 12.15 (s, 1 H), 8.79 (s, 1 H), 8.13 (s, 1 H), 7.73 (s, 1 H), 7.66 (s, 1 H), 7.33 (m, 2 H), 7.12 (m, 1 H), 4.07 (s, 3 H), 2.38 (s, 3 H); m/z 406.
A vessel was cooled via ice bath, was charged with AICI3 pellets, 10OmL DCE, and BCI3/DCM solution HOmL under N2 with an outlet into an aqueous NaOH solution bath. A solution of SM-aniline was then added dropwise with caution to keep t<20C. Upon completion, the grey slurry was added SM-nitrile in one portion, and extra DCE was used to rinse the RBF. The ice bath was removed, and the reaction was heated to reflux.After 6h of reflux, the mixture was cooled, quenched with 2N HCl 8OmL, and heated to reflux for 20 min. The mixture was extracted with DCM, washed with 2N HCl, water, and brine. After concentration, the solid was stirred with 25 mL hexanes, cooled via an ice bath, filtered, and washed with extra 5OmL hexanes, A dark yellow solid was obtained.The combined HCl wash was treated with NaOH (pellets, 14.7g) to pH = 5-6, extracted with MTBE/Heptane (1:1) and concentrated.
Stage #1: maleic anhydride; 2-fluoro-4-methylaniline In N,N-dimethyl-formamide at 30℃; for 1h;
Stage #2: With acetic anhydride In N,N-dimethyl-formamide at 80℃; for 16h;
To a mixture of of <strong>[452-80-2]2-fluoro-4-methyl-phenylamine</strong> (300.0 mg; 2.397 mmol) in glacial acetic acid (2.1 mL) and conc. H2S04 (1 mL) was added sodium nitrite(172 mg, 2.487 mmol) in water (1.5 mL) dropwise under vigorous stirring at 0 -5 °C. After 10 mm aqueous urea was added to the reaction mixture to remove excess sodium nitrite. Then sodium azide (171 mg, 2.637 mmol) in water (1.5 mL) was added to the reaction mixture at 0-5 °C for 3 h. The reaction mixture was stirred at room temperature for 14 h, poured into ice water and theresulting mixture was rendered basic with sodium hydroxide and extracted with ethyl acetate. The combined organic phases were washed with water, dried over sodium sulfate and concentrated to give corresponding the azide, which was used in the next step without purification; yield: 150 mg (39percent)brown oil; Rt: 2.50.
Reference Example 186 (2-fluoro-4-methylphenyl)hydrazine To a solution of sodium nitrite (28.7 g) in water (100 mL) was added dropwise a solution of <strong>[452-80-2]2-fluoro-4-methylaniline</strong> (40 g) in concentrated hydrochloric acid (640 mL) at -20° C., and the mixture was stirred at the same temperature for 1 hr. A solution of tin(II) chloride (121 g) in concentrated hydrochloric acid (200 mL) was added dropwise at -20° C., and the mixture was stirred at 0° C. for 2 hr. The resulting solid was collected by filtration, and washed with water and hexane. The obtained solid was dissolved in water (500 mL), the solution was adjusted to pH 12 with 2 mol/L aqueous sodium hydroxide solution, and extracted twice with dichloromethane. The extract was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the title compound as a white solid (28.4 g, yield 63percent). 1H-NMR (CDCl3) delta: 2.26 (3H, s), 3.53 (2H, brs), 5.35 (1H, brs), 6.80 (1H, dd, J=12.4, 1.2 Hz), 6.87 (1H, d, J=8.0 Hz), 6.96 (1H, t, J=8.4 Hz).
59%
Stepi:(2-fluoro-4-methylphenyl)hydrazine 1.0 g (7.99 mmo[) 2-f[uoro-4-methy[ani[ine was suspended in 7 mL 37percent aqueous hydroch[oric acid. At 0 to -4CC 717 mg (10.39 mmo[) sodium nitrite in 2.5 mL water were added. It was stirred 0.5 h at this temperature. At 0C 3.03 g (15.98 mmo[)tin(II) ch[oride in 2.5 mL 37percent aqueous hydroch[oric acid were added. It was stirred 2 h at 0CC. The reaction mixture was poured into ice water and extracted with dich[oromethane. The aqueous [ayer was made a[ka[ine with 32percent aqueous sodium hydroxide and extracted three times with dich[oromethane. These combined organic phases were washed with water, dried over magnesium su[fate and concentrated. 700mg (59percent) product was obtained.1H-NMR (400MHz, DMSO-d6): 6 [ppm]= 2.14 (5, 3H), 3.90 (5, 2H), 6.29 (5, 1H), 6.73 -6.81 (m, 2H), 6.96 - 7.03 (m, 1H).
A mixture of 2-fluoro-5-methyl aniline (997 mg, 7.97 mmol) and cone HC1 (10 mL) was cooled to 0 "C, whereupon a solution of NaN<3/4 (660 mg, 9.56 mmol) and water (2 mL) was added dropwise over 2 min. The resulting mixture was stirred at 0 °C for 1 h. A solution of tin (II) chloride dehydrate (7.19 g, 31.9 mmol) and cone HC1 (10 mLO was added dropwise over 3 min. The resulting mixture was stirred at rt for 3 h. Water (40 mL) was added and the mixture was washed with Et20 (3 x 30 mL). The aqueous layer was brought to pH = 13 using 20percent NaOH. The mixture was extracted with Et20 (3 x 50 mL). The combined organic extracts were dried (MgS04) and concentrated in vacuo to give the title compound as a pale yellow solid. .H NMR (400 MHz, DMSO- d6) delta 9.95 (br s, 2H), 7.65 (br s, 1H), 7.05-7.01 (m, 2H), 6.87 (m, 1H), 2.17 (s, 3H).
Stage #1: 2-fluoro-4-methylaniline With hydrogenchloride; sodium nitrite In water; acetic acid at -5℃; Cooling;
Stage #2: With sulfur dioxide; copper dichloride In water; acetic acid at -5℃; for 0.25h; Cooling;
Stage #3: With ammonium hydroxide In 1,4-dioxane; water for 0.5h; Cooling;
To a suspension of 7-bromo-4-chlorocinnoline-3 -carboxamide (Method 94, 1.3 g, 4.54 mmol) in ethanol (11.3 mL) was added <strong>[452-80-2]2-fluoro-4-methylaniline</strong> (0.77 ml, 6.81 mmol) and acetic acid (0.026 mL, 0.45 mmol), and the reaction mixture stirred at 80 0C for 2 hours. After cooling, the reaction mixture was filtered, and the residue washed with ethanol and then dried to give 1.39 g (82 percent) of a brown solid. 1H NMR: 11.71 (s, 1 H), 8.90 (s, 1 H), 8.54 (s, 1 H), 8.11 (s, 1 H), 7.67 (d, 1 H), 7.41 (d, 1 H), 7.23 (m, 2 H), 7.04 (m, 1 H), 2.34 (s, 3 H); m/z 374
6-bromo-4-[(2-fluoro-4-methylphenyl)amino]-7-methoxycinnoline-3-carboxamide hydrochloride[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
74%
With acetic acid; In ethanol; at 80℃; for 1h;
To a suspension of 6-bromo-4-chloro-7-methoxycinnoline-3-carboxamide (Method 21, 8.89 g, 28.09 mmol) in ethanol (70 ml) was added <strong>[452-80-2]2-fluoro-4-methylaniline</strong> (3.49 ml, 30.89 mmol) and acetic acid (0.016 ml, 0.28 mmol). The reaction mixture was stirred at 80 0C for 1 hour, cooled, and filtered. The solid material was washed with ethanol and dried to give 9.16 g (74 percent) of a brown solid, assumed to be the HCl salt. 1H NMR: 12.15 (s, 1 H), 8.79 (s, 1 H), 8.13 (s, 1 H), 7.73 (s, 1 H), 7.66 (s, 1 H), 7.33 (m, 2 H), 7.12 (m, 1 H), 4.07 (s, 3 H), 2.38 (s, 3 H); m/z 406
With triethylamine; In dichloromethane; at 0℃; for 2h;
To a solution of <strong>[452-80-2]2-fluoro-4-methyl-aniline</strong> (250 g, 2 mol) and triethylamine (202 g, 2 mol) in 2 L of dichloromethane was added dropwise acetylchloride (156 g, 2 mol). The reaction mixture was stirred for 2 hours at a temperature of 00C and subsequently washed with dilute hydrochloric acid. The organic phase was dried with sodium sulfate and concentrated under reduced pressure to yield 2-fluoro-4-methyl-acetanilide as a crude intermediate (334 g, 87percent).
87%
With triethylamine; In dichloromethane; at 0℃; for 2h;
To a solution of <strong>[452-80-2]2-fluoro-4-methyl-aniline</strong> (250 g, 2 mol) and triethylamine (202 g, 2 mol) in 2 L of dichloromethane was added dropwise acetyl chloride (156 g, 2 mol). The reaction mixture was stirred for 2 hours at a temperature of 0°C and subsequently washed with dilute hydrochloric acid. The organic phase was dried with sodium sulfate and concentrated under reduced pressure to yield 2-fluoro-4- methyl-acetanilide as a crude intermediate (334 g, 87percent).
87%
With triethylamine; In dichloromethane; at 0℃; for 2h;
To a solution of <strong>[452-80-2]2-fluoro-4-methyl-aniline</strong> (250 g, 2 mol) and triethylamine (202 g, 2 mol) in 2 L of dichloromethane was added dropwise acetyl chloride (156 g, 2 mol). The reaction mixture was stirred for 2 hours at a temperature of 0°C and subsequently washed with dilute hydrochloric acid. The organic phase was dried with sodium sulfate and concentrated under reduced pressure to yield 2-fluoro-4- methyl-acetanilide as a crude intermediate (334 g, 87percent).
With triethylamine; In dichloromethane; at 0℃; for 2h;
To a solution of <strong>[452-80-2]2-fluoro-4-methyl-aniline</strong> (250 g, 2 mol) and triethylamine (202 g, 2 mol) in 2 L of dichloromethane was added dropwise acetyl chloride (156 g, 2 mol). The reaction mixture was stirred for 2 hours at a temperature of 0°C and subsequently washed with dilute hydrochloric acid. The organic phase was dried with sodium sulfate and concentrated under reduced pressure to yield 2-fluoro-4- methyl-acetanilide as a crude intermediate (334 g, 87percent).
First, commercially available tri-substituted aromatic compounds (1a to 1d) including different halogens were used as a starting material and converted to aldehyde compounds (2a to 2d) by subjecting their amino group ends to a formylation reaction.Such conversion can be performed, for example, in accordance with the following steps: In step i, a diazotization reaction is performed by using hydrochloric acid/sodium nitrate/copper sulfate/sodium sulfite/sodium acetate. Then, in step ii, the resulting product is treated with hydroximic amine hydrochloride in the presence of paraformaldehyde. Then, in step iii, the resulting product is degraded by using hydrochloric acid to obtain the aldehyde compound of interest.
a) 2-Fluoro-4-methylbenzonitrile A solution of sodium nitrite (4.22 g, 61.16 mmol) in water (40 mL) was added slowly to a stirred suspension of (2-fluoro-4-methylphenyl)amine (4.60 mL, 40.73 mmol) in hydrogen chloride (1M, 340 mL) at -5 C, and the mixture was stirred at this temperature. After 10 minutes, sodium bicarbonate was added until the pH was 7-8. The reaction mixture was added slowly to a stirred solution of cyanocopper (12.22 g, 136.44 mmol) and potassium cyanide (8.10 g, 124.39 mmol) in water (150 mL). The reaction was warmed to 60 C. After heating for 2 hours, ethyl acetate was added to the mixture and the aqueous layer was extracted with more ethyl acetate. The organic layer was washed with brine, dried (Na2S04) and evaporated. Purification of the crude by flash chromatography (85:15 hexanes/ethyl acetate) gave the title compound (2.56 g, 46%). LRMS (m/z): 136 (M+1)+.1H NMR (300 MHz, CHLOROFORM-d) delta ppm 2.45 (s, 3 H) 6.98 - 7.12 (m, 2 H) 7.51 (t, J=6.87 Hz, 1 H)
46%
INTERMEDIATE 10; rV-Cyclopropyl-7-iodo-6-methyl-1 ,2-benzisoxazol-3-aminea) 2-Fluoro-4-methylbenzonitrile; A solution of sodium nitrite (4.22 g, 61.16 mmol) in water (40 mL) was added slowly to a stirred suspension of (2-fluoro-4-methylphenyl)amine (4.60 mL, 40.73 mmol) in hydrogen chloride (1M, 340 mL) at -5 C, and the mixture was stirred at this temperature. After 10 minutes, sodium bicarbonate was added until the pH was 7-8. The reaction mixture was added slowly to a stirred solution of cyanocopper (12.22 g, 136.44 mmol) and potassium cyanide (8.10 g, 124.39 mmol) in water (150 mL). The reaction was warmed to 60 C. After heating for 2 hours, ethyl acetate was added to the mixture and the aqueous layer was extracted with more ethyl acetate. The organic layer was washed with brine, dried (Na2S04) and evaporated. Purification of the crude by flash chromatography (85:15 hexanes/ethyl acetate) gave the title compound (2.56 g, 46%).LRMS (m/z): 136 (M+1)+. 1 H NMR (300 MHz, CHLOROFORM-d) delta ppm 2.45 (s, 3 H) 6.98 - 7.12 (m, 2 H) 7.51 (t, J=6.87 Hz, 1 H)
With palladium diacetate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; sodium t-butanolate; In N,N-dimethyl-formamide; toluene; at 140℃; for 0.333333h;Microwave irradiation;
A mixture of 2-bromo-N-ieri-butyl-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3- b]pyrazine-7-carboxamide (150 mg, 351 muiotaetaomicron), <strong>[452-80-2]2-fluoro-4-methylaniline</strong> (65.9 mg, 526 muiotaetaomicron), BINAP (10.9 mg, 17.5 muiotaetaomicron), palladium (II) acetate (19.7 mg, 87.7 muiotaetaomicron) and sodium tert- butoxide (84.3 mg, 877 muiotaetaomicron) in DMF (1 mL) and toluene (500 was heated in a microwave at 140°C for 20 min. The reaction mixture was diluted with water then extracted into ethyl acetate (3x). The combined organic extracts were washed with brine then dried over magnesium sulfate. Purification by chromatography (silica, 20-50percent ethyl acetate/hexanes) gave 2-(2-fluoro-4-methylphenylamino)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3- b]pyrazine-7-carboxamide (87 mg, 184 muiotaetaomicron, 53 percent) as an off-white solid. MS (EI CI) m/z 470.1 [M - H].
With triethylamine; In dichloromethane; at 0℃; for 2h;
Step 1: 2,2,2-Trifluoro-N-(2-fluoro-4-methylphenyl)acetamide (VI-1) At 0° C., 27.5 g of <strong>[452-80-2]2-fluoro-4-methylaniline</strong> are initially charged in 300 ml of dichloromethane, 26.7 g of triethylamine are added and 50.8 g of trifluoroacetic anhydride are then added dropwise. The mixture is stirred at 0° C. for another 2 h and then concentrated by rotary evaporation. The residue is taken up in water and extracted twice with ethyl acetate. The combined organic phases are dried over sodium sulfate and filtered and the solvent is removed under reduced pressure. This gives 49.0 g (100percent of theory) of the trifluoroacetamide (VI-1). log P(HCOOH): 2.40
100%
With triethylamine; In dichloromethane; water; at 0℃; for 2h;
At 0° C., 27.5 g of <strong>[452-80-2]2-fluoro-4-methylaniline</strong> are initially charged in 300 ml of dichloromethane, 26.7 g of triethylamine are added and 50.8 g of trifluoroacetic anhydride are then added dropwise. The mixture is stirred at 0° C. for 2 h and then concentrated by rotary evaporation. The residue is taken up in water and extracted twice with ethyl acetate. The combined organic phases are dried over sodium sulphate and filtered and the solvent is removed under reduced pressure. This gives 49.0 g (100percent of theory) of the title compound. log P[a]: 2.40
100%
With triethylamine; In dichloromethane; at 0℃; for 2h;
In 0 °C lower, first of all the 27.5g of <strong>[452-80-2]2-fluoro-4-methylaniline</strong> is added to 300 ml of methylene chloride, by adding 26.7g triethylamine, then adding dropwise 50.8g of trifluoroacetic anhydride. The mixture is in the 0 °C lower stirring 2 hours, then concentrated by rotary evaporation. The residue is placed in water, then extracted twice with ethyl acetate. The combined organic phase is dried with sodium sulfate and filtered, then reduced pressure to remove the solvent. Therefore, the obtained 49.0g (of the theoretical 100percent) of the subject compound.
100%
With triethylamine; In dichloromethane; at 0℃; for 2h;
j1637] At 0° C., 27.5 g of <strong>[452-80-2]2-fluoro-4-methylaniline</strong> are initially charged in 300 ml of dichioromethane, 26.7 g of triethylamine are added and 50.8 g of trifluoroacetic anhydride are then added dropwise. The mixture is stirred at 0° C. for 2 h and then concentrated by rotary evaporation. The residue is taken up in water and extracted twice with ethyl acetate. The combined organic phases are dried over sodium sulphate and filtered, and the solvent is removed under reduced pressure. This gives 49.0 g (100percent of theory) of the title compound.11638 a:
With lithium hexamethyldisilazane; In tetrahydrofuran; at -70 - 20℃;
To a solution of <strong>[452-80-2]2-fluoro-4-methylaniline</strong> (1.3 mg, 10.4 iimol) and 4-chloro- 1,3,8- trimethylpyrido[2,3-d]pyridazine-2,5(1H,6H)-dione (57g) (2.3 mg, 9.6 iimol) in THF (0.5 ml)was added lithium bis(trimethylsilyl)amide (1 M, 0.7 ml, 0.7 mmol) dropwise at -70 °C, and the mixture was warmed to RT naturally, quenched with saturated aqueous ammonium chloride solution and extracted with EA. The EA layer was dried over Na2SO4 and purified by preparative thin layer chromatography to give the title compound 57 (1.5 mg). MS-ESI (m/z): 329 [M + 1]+.
1.5 mg
With lithium hexamethyldisilazane; In tetrahydrofuran; at -70℃;
4-((2-fluoro-4-methylphenyl)amino)-1,3,8-trimethylpyrido[2,3-d]pyridazine-2,5(1H,6H)-dione (57) To a solution of <strong>[452-80-2]2-fluoro-4-methylaniline</strong> (1.3 mg, 10.4 mumol) and 4-chloro-1,3,8-trimethylpyrido[2,3-d]pyridazine-2,5(1H,6H)-dione (57g) (2.3 mg, 9.6 mumol) in THF (0.5 ml) was added lithium bis(trimethylsilyl)amide (1 M, 0.7 ml, 0.7 mmol) dropwise at -70° C., and the mixture was warmed to RT naturally, quenched with saturated aqueous ammonium chloride solution and extracted with EA. The EA layer was dried over Na2SO4 and purified by preparative thin layer chromatography to give the title compound 57 (1.5 mg). MS-ESI (m/z): 329 [M+1]+.
methyl 3-(2-fluoro-4-methylphenyl)-2-methyl-4-oxo-3,4-dihydroquinazoline-6-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
85%
With phosphorus trichloride; In acetonitrile; at 50℃;
General procedure: To a solution of the 2-acetamido-5-(methoxycarbonyl)benzoic acid (6 mmol) in CH3CN was added a solution of the substituted aniline (8 mmol) in CH3CN (10 mL) at room temperature to give a white suspension. PCl3 (12 mmol) was added via syringe, andthe resulting mixture was warmed to 50 °C and stirred for an additional 6?10 h. The mixture was cooled to room temperature and diluted with EtOAc. The mixture was quenched by the additionof 1 N aqueous HCl. The organic layer was separated, washed with 15percent aqueous NaHCO3 solution, and evaporated under vacuum to give a solid, which crystallized on standing. The crude products were recrystallized from ethyl acetate/petroleum ether to give the desired products of 8a?x.
methyl 4-(((2-fluoro-4-methylphenyl)amino)methyl)benzoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
68.5%
A solution of <strong>[452-80-2]2-fluoro-4-methylaniline</strong> (0.500 g, 3.995 mmol), methyl 4-formylbenzoate (0.689 g, 4.195 mmol) and sodium triacetoxyborohydride (0.931 g, 4.395 mmol) in dichloromethane (20 mL) was stirred at the room temperature for 6 hr. Then, saturated aqueous sodium bicarbonate solution was added to the reaction mixture, followed by extraction with dichloromethane. The organic layer was washed with brine, dried (anhydrous MgS04), filtered, and concentrated in vacuo. The concentrate was purified and concentrated by column chromatography (Si02, 12 g cartridge; ethyl acetate / hexane = 5 percent to 20 percent) to give the title compound methyl 4-(((2-fluoro-4-methylphenyl)amino)methyl)benzoaie as- light yellow solid (0.748 g, 68.5 percent).
64%
With sodium cyanoborohydride; acetic acid; In methanol; for 24h;
(Formula 1-2: methyl 4-((2-fluoro-4-methylphenylamino)methyl)benzoate)[965][966]Compound ofFormula 1-1(<strong>[452-80-2]2-fluoro-4-methylbenzenamine</strong>; 3.0 g, 23.9 mmol) and methyl 4-formylbenzoate (3.94 g, 23.9 mmol) were dissolved in methanol (500 mL) and stirred at room temperature for 2 hours. Then, acetic acid (1.44 mL, 23.9 mmol) and sodium cyanoborohydride (1.51 g, 23.9 mmol) were added and stirred for 1 day. The methanol was partially removed by air-drying to precipitate a solid, and the resulting solid was filtered and dried to give the desired compound ofFormula 1-2(4.2 g, 64percent) in the form of a white solid.
tert-butyl ((6-bromo-1-(pyridin-3-ylsulfonyl)-1H-indol-3-yl)methyl)(methyl)carbamate[ No CAS ]
tert-butyl ((6-((2-fluoro-4-methylphenyl)amino)-1-(pyridin-3-ylsulfonyl)-1H-indol-3-yl)methyl)(methy1)carbamate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
55%
With tris-(dibenzylideneacetone)dipalladium(0); tri-tert-butyl phosphine; caesium carbonate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In toluene; at 110℃; for 12h;
Step 5: Preparation of tert-butyl((6-((2-fluoro-4-methylphenyl)amino)-1-(pyridin-3-ylsulfonyl)-1H-indol-3-yl)methyl)(methy1)carbamate Tert-butyl((6-bromo-1-(pyridin-3-ylsulfonyl)-1H-indol-3-yl)methyl)(methyl)carbamate (100 mg,0.2 mmole) prepared in Step 4; tris(dibenzylideneacetone)dipalladium(O) (12 mg, 0.02 mmole); tri-tert-butylphosphine, 50percent solution in toluene (7.5 f-tl, 0.03 mmole);4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene (18 mg, 0.03 mmole); cesium carbonate (110 mg, 0.3 mmole); and <strong>[452-80-2]2-fluoro-4-methylaniline</strong> (9.3 mg, 0.07 mmole) were suspended in 1 ml of toluene, and stirred at 110°C for 12 hours. The reaction mixture was filtrated with celite, and the filtrate was added with water and then extracted with ethyl acetate. The resulting extract was washed with saturated brine, dried on anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate : nhexane = 1 : 2 (v/v)) to obtain 60 mg of a title compound (yield: 55percent).[579] 1H NMR (300 MHz, CDCb): 9.06 (d, 1H), 8.77 (dd, 1H), 8.08 (td, 1H), 7.62 (s, 1H),7.38-7.48 (m, 2H), 7.31 (s, 1H), 7.16 (t, 1H), 6.89-6.97 (m, 3H), 4.46 (s, 2H), 2.73 (s,3H), 2.32 (s, 3H), 1.48 (s, 9H)
tert-butyl ((6-bromo-1-((3-fluorophenyl)sulfonyl)-1H-indol-3-yl)methyl)(methyl)carbamate[ No CAS ]
tert-butyl ((6-((2-fluoro-4-methylphenyl)amino)-1-((3-fluorophenyl)sulfonyl)-1H-indol-3-yl)methyl)(methyl)carbamate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
36.8%
With tris-(dibenzylideneacetone)dipalladium(0); tri-tert-butyl phosphine; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In toluene; at 110℃; for 24h;
Step 3: Preparation of tert-butyl((6-((2-fluoro-4-methylphenyl)amino)-1-((3-fluorophenyl)sulfonyl)-1H-indol-3-yl)methyl)(methyl)carbamate Tert-butyl((6-bromo-1-((3-fluorophenyl)sulfonyl)-lH-indol-3-yl)methyl)(methyl)carbamate (30 mg, 0.06 mmole); tris(dibenzylideneacetone)dipalladium(O) (3.5 mg, 0.006 mmole); tri-tert-butylphosphine, 50percent solution in toluene (2.3 f-tl, 0.009 mmole);4,5-Bis(diphenylphosphino)-9,9-dime; and <strong>[452-80-2]2-fluoro-4-methylaniline</strong> (11 mg, 0.09 mmole) were suspended in 1 ml of toluene solution, and stirred at 11ooc for 24 hours.The reaction mixture was filtered with celite, and the resulting filtrate was added with water and extracted with ethyl acetate. The resulting extract was washed with saturated brine, dried on anhydrous magnesium sulfate, and concentrated under reducedpressure. The resulting residue was purified by silica gel column chromatography(ethyl acetate: n-hexane = 1 : 2 (v/v)) to obtain 12 mg of a title compound (yield:36.8percent).[1138] 1H NMR (300 MHz, CDCb): 7.61 (d, 2H), 7.55 (dd, lH), 7.43-7.48 (m, 2H),7.26-7.31 (m, 2H), 7.16 (t, lH), 6.88-6.97 (m, 3H), 4.47 (s, 2H), 2.73-2.75 (m, 3H),2.33 (s, 3H), 1.47 (s, 9H)
tert-butyl (6-bromo-1-(pyridin-3-ylsulfonyl)-1H-indol-3-yl)(methyl)carbamate[ No CAS ]
tert-butyl (6-((2-fluoro-4-methylphenyl)amino)-1-(pyridin-3-ylsulfonyl)-lH-indol-3-yl)(methyl)carbamate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
74.3%
With tri-tert-butyl phosphine; caesium carbonate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; bis(dibenzylideneacetone)-palladium(0); In toluene; at 110℃; for 15h;
Step 2: Preparation of tert-butyl(6-((2-fluoro-4-methylphenyl)amino)-1-(pyridin-3-ylsulfonyl)-lH-indol-3-yl)(meth yl)carbamate Tert-butyl (6-bromo-1-(pyridin-3-ylsulfonyl)-1H-indol-3-yl)(methyl)carbamate (100mg, 0.2 mmol) prepared in Step 1; Bis(dibenzylideneacetone)palladium(O) (12 mg,0.02 mmole); tri-tert-butylphosphine, 50percent solution in toluene (7.7 f-tl, 0.03 mmole);4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene (18 mg, 0.03 mmole); cesium carbonate(l13 mg, 0.3 mmole); and <strong>[452-80-2]2-fluoro-4-methylaniline</strong> (36 f-tl, 0.3 mmole) were suspended in 1 ml of toluene, and stirred at 110°C for 15 hours. The reaction mixture was filtered with celite, and the resulting filtrate was added with water and extracted with ethyl acetate. The resulting extract was washed with saturated brine, dried on anhydrous magnesium sulfate, and concentrated under reduced pressure. The resultingresidue was purified by silica gel column chromatography (ethyl acetate : n-hexane = 1: 1 (v/v)) to obtain 81 mg of a title compound (yield:74.3percent).[2133] 1H NMR (300 MHz, CDCb): 9.11 (d, 1H), 8.82 (dd, 1H), 8.16-8.20 (m, 2H), 7.65 (d,1H), 7.44 (d, 2H), 7.41-7.48 (m, 3H), 6.88 (s, 1H), 4.38 (s, 3H), 2.31 (s, 3H), 1.46 (s,9H)
tert-butyl ((6-bromo-1-((3-fluorophenyl)sulfonyl)-1H-pyrrolo[3,2-b]pyridin-3-yl)methyl)(methyl)carbamate[ No CAS ]
tert-butyl ((6-((2-fluoro-4-methylphenyl)amino)-1-((3-fluorophenyl)sulfonyl)-1H-pyrrolo[3,2-b]pyridin-3-yl)methyl)(methyl)carbamate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
60%
With tri-tert-butyl phosphine; caesium carbonate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; bis(dibenzylideneacetone)-palladium(0); In toluene; at 110℃; for 15h;
Step 4: Preparation of tert-butyl((6-((2-fluoro-4-methylphenyl)amino)-1-((3-fluorophenyl)sulfonyl)-1H-pyrrolo[3,2-b]pyridin-3-yl)methyl)(methyl)carbamate Tert-butyl((6-bromo-1-((3-fluorophenyl)sulfonyl)-1H-pyrrolo[3,2-b]pyridin-3-yl)methyl)(methyl)carbamate (20 mg, 0.04 mmol) prepared in Step 3; Bis(dibenzylideneacetone)palladium(O) (2.3 mg, 0.004 mmole); tri tert-butylphosphine, 50percent solution in toluene (2.9 f-tl, 0.006 mmole);4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene (3.5 mg, 0.006 mmole); cesium carbonate(21 mg, 0.06 mmole), and <strong>[452-80-2]2-fluoro-4-methylaniline</strong> (7.5 mg, 0.06 mmole) were suspended in 1 ml of toluene, and stirred at 110°C for 15 hours. The reaction mixture was filtered with celite, and the resulting filtrate was added with water and extracted with ethyl acetate. The resulting extract was washed with saturated brine, dried on anhydrous magnesium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate : nhexane = 1 : 2 (v/v))to obtain 13 mg of a title compound (yield: 60percent).[2190] 1H NMR (300 MHz, CDCb): 8.61 (d, 2H), 8.55 (dd, 1H), 8.43-8.48 (m, 2H),8.26-8.31 (m, 2H), 8.16 (t, 1H), 7.88-7.97 (m, 2H), 4.45 (s, 2H), 2.75 (m, 3H), 2.32 (s,3H), 1.45 (s, 9H)
With Oxone; In 1,4-dioxane; at 90℃;Schlenk technique; Inert atmosphere;
General procedure: A Schlenk tube was charged with Oxone (0.398 g, 0.648mmol) and trifloroacetic acid (0.099 mL, 1.296 mmol) in anhydrous dioxane (2 mL) under argon. To this mixture was added 2-fluoroaniline (0.06 g, 0.54 mmol), and the reaction mixture was heated to 90 °C under argon until starting material was consumed. As the reaction progressed, the color turned from lightred to dark red. The mixture was then cooled to room temperature and washed with a saturated aqueous sodium bicarbonate.The mixture was extracted with EtOAc (2 × 20 mL) and the combined organic layers were dried over Na2SO4. After filtering andremoval of the solvent under reduced pressure in vacuo, theresidue was purified by silica gel (100?200 mesh) column chromatography(hexane?EtOAc, 9:1), to afford a pale-brown solid(65percent) of 2-hydroxy-N-trifluoroacetanilides from 2-fluoroaniline(2a).
With scandium tris(trifluoromethanesulfonate); In ethanol; at 20℃; for 7h;
General procedure: Methyl 2-formylbenzoate (0.5 mmol), amine (0.5 mmol), TMSCN (1.0 mmol) and 2.5 molpercent Sc(OTf)3 were dissolved in EtOH (1 mL), and the homogeneous solution was stirred at room temperature for 7 h. After completing the reaction (judged by running TLC), the mixture was concentrated in vacuo and the crude product was purified over silica gel by column chromatography (20?30percent EtOAc in hexane).
N-(4-methyl-2-fluorophenyl)imidazole-2-carboxamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
40%
To <strong>[452-80-2]2-fluoro-4-methylaniline</strong> (6.3 ml, 27 mmol) in THF (37 ml), cooled in a -10 °C bath, (128 ml, 128 mmol, 1.0 M) sodium bis-(trimethylsilyl) amide in THF was added. The mixture was stirred for 1 h, and a suspension of 1 (5 g, 26.55 mmol) in THF (57 mL) was added and allowed to warm to room temperature. The mixture was stirred for 2 h, and acetic acid was added to pH 7. The reaction mixture was concentrated in vacuum followed by the addition of water and saturated NaHCO3. The solid was collected by filtration, washed with water and cyclohexane, and dried under high vacuum to give 2a as a beige solid (yield, 40percent). 1H NMR (300 MHz, DMSO-d6) delta: 10.50 (s, 2H), 8.15 (dd, 1H), 7.07 (s, 2H), 7.04 (dd, 1H), 6.92 (m, 1H), 2.20 (s, 3H). 19F NMR: 126. 13C NMR (300 MHz, DMSO-d6) delta: 152.65, 150.92, 150.52, 136.94, 126.78, 126.34, 123.08, 121.03, 119.53, 116.88, 22.49.
<strong>[452-80-2]2-fluoro-4-methyl aniline</strong> (25.3g, 202mmol) the (Tokyo Kasei Kogyo Co., Ltd.) and triethylamine (30.7g, 304mmol) acetyl in dichloromethane solution (200ml) of chloride (17.4g, 222mmol) 0 It was added at ° C., and stirred at room temperature for 4 hours. To the reaction mixture was poured the water, and extracted with chloroform. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The concentrate was washed with n- hexane to obtain white crystals (yield 28.0 g, 83percent yield).The resulting crystals chloro sulfonic acid (58.0g, 498mmol) was added at 0 , and the mixture was stirred for 2 hours at 80 . The reaction mixture was poured into ice water and extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The concentrate was washed with diisopropyl ether to give white crystals (yield 19.3 g, 43percent yield).The resulting crystals of acetic acid solution (80 ml) to red phosphorus (7.87 g, 254 mmol) and iodine (921 mg, 3.63 mmol) was added at room temperature, the mixture was heated under reflux for 2 hours. To the reaction mixture was poured into ice water and extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The concentrate was washed with n- hexane to obtain white crystals (yield 16.3 g, 93percent yield).The resulting added crystals in a 10percent sodium hydroxide solution (400ml), was heated under reflux for 3 hours. The reaction mixture was adjusted to pH7 was added dilute hydrochloric acid, and extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography to give (eluting solvent ethyl acetate / n-hexane = 1/3) to give the title compound as white crystals (yield 8.50 g, 80percent yield)
(+/-)-methyl 3-(5-amino-4-(cyclohexyl(isobutyl)amino)-2-fluorophenyl)pentanoate[ No CAS ]
[ 7693-46-1 ]
(+/-)-3-(4-(cyclohexyl(isobutyl)amino)-2-fluoro-5-(3-(2-fluoro-4-methylphenyl)ureido)phenyl)pentanoic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
52%
To a homogeneous mixture of (+/-)-methyl 3-(5-amino-4-(cyclohexyl(isobutyl)amino)-2-fluoro-phenyl)pentanoate (compound 951D, 45 mg, 0.12 mmol) in THF (1 mL), at room temperature in a sealable vial, was added 4-nitrophenyl carbonochloridate (34 mg, 0.17 mmol). The resulting mixture was stirred at ambient temperature for 40 minutes before 3-methylisoxazol-5-amine (35 mg, 0.35 mmol) and TEA (0.10 mL, 0.72 mmol) were added. The mixture was then stirred at 50° C. for 13 hours, then at room temperature for two hours, before MeOH (0.5 mL) was added to the reaction vial followed by LiOH (aq) (1M solution, 0.5 mL, 0.50 mmol). After 6.5 hours, the reaction was treated with NaOH (aq) (2M solution, 0.2 mL, 0.4 mmol) and stirred for 20 hours before being treated with acetic acid (0.06 mL, 1.05 mmol). The mixture was diluted with DMSO then purified by preparative RP HPLC (MeCN/H2O gradient+10-mM NH4OAc) to afford Example 1113 (23.9 mg, 41percent yield); 12333] Example 1116 (20.5 mg, 31percent yield) was prepared following a procedure analogous to that for the synthesis of Example 1113, except that 4-ethoxy-2-fluoroaniline, HC1 (68 mg, 0.35 mmol) was used instead of 3-methylisoxazol- 5-amine and the amount of TEA (0.15 mE, 1.08 mmol) used was increased; 12339] Example 1119 (31.8 mg, 52percent yield) was prepared following a procedure analogous to that for the synthesis of Example 1116, except that <strong>[452-80-2]2-fluoro-4-methylaniline</strong> (44 mg, 0.35 mmol) was used instead of 3-methylisoxazol-5-amine. ?H NMR (500 MHz, DMSO-d5) oe 9.19 (s, 1H), 7.93 (s, 1H), 7.81-7.69 (m, 2H), 7.05 (d, J=11.9 Hz, 1H), 6.99-6.88 (m, 2H), 3.20-3.09 (m, 1H), 2.82-2.66 (m, 2H), 2.58-2.51 (m, 3H (integration distorted by solvent peak)), 2.26 (s, 3H),1.86-1.75 (m, 2H), 1.71-1.57 (m, 3H), 1.54-1.41 (m, 2H),1.39-1.28 (m, 1H), 1.26-1.15 (m, 2H), 1.12-0.95 (m, 3H),0.81 (d, J=6.6 Hz, 6H), 0.73 (t, J=7.3 Hz, 3H). MS(ES):m1z516 [M+H]. Tr=2.37 mm (Method C).
With sulfuric acid; In nitrobenzene; at 150℃; for 3h;
To a solution of 2-fluoro-6-methylaniline (0.5 g, 4.0 mmol) in 75percent sulfuric acid (4 mL) was added nitrobenzene (409 EL, 4.0 mmol) and glycerol (588 EL, 8.0 mmol). The heterogeneous mixture was stirred at 150 °C for 3 h. This was allowed to cool, thenH20 was added to the mixture and extracted twice with EtOAc (2x5OmL). Thecombined organic layers were dried and concentrated under reduced pressure. Thecrude material was purified via silica gel column chromatography using a gradient of0 to 100percent EtOAc in hexanes. Yield = 0.17g(27percent). 1H NMR (500 MHz, CDCI3): S8.79 (dd, J = 4.2, 1.6 Hz, 1 H), 7.99 (d, J = 8.4 Hz, 1 H), 7.92 (s, 1 H), 7.34 (dd, J =8.4, 4.2 Hz, 1H), 7.15 (dd, J= 11.5, 1.8 Hz, 1H), 2.43 (d, J= 1.0 Hz, 3H). ESIMS(+): m/z 162.19 [M÷H}.
17β-(1-phenyl-4-(((2-fluoro-4-methylphenyl)amino)methyl)-3-pyrazolyl)androst-3β-ol[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
80%
With sodium tris(acetoxy)borohydride; In 1,2-dichloro-ethane; at 20℃;
NaBH(OAc)3 (212 mg, 1 mmol, 4 eq) was added to a solution of 4or 10 (0.25 mmol, 1 eq) and aniline derivatives in anhydrous DCE(15 mL) at RT. After stirring overnight, the solvent was removedunder vacuo, and the residue was diluted with saturated aqueousNaHCO3 (15 mL) and extracted with DCM (3 20 mL). The combinedorganic layers were washed with brine (10 mL), dried overNa2SO4, filtered and concentrated. The residue was purified bycolumn chromatography (CH2Cl2: MeOH: Et3N:: 50:1: 0.05, v/v/v or10:1: 0.1, v/v/v) to give products as colored glasslike solid.
3β-hydroxy-17-(4'-formyl-1'-phenyl-1'H-pyrazol-3'-yl)androsta-5,16-diene[ No CAS ]
17β-(1-phenyl-4-(((2-fluoro-4-methylphenyl)amino)methyl)-3-pyrazolyl)androst-5,16-diene-3β-ol[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
67%
With sodium tris(acetoxy)borohydride; In 1,2-dichloro-ethane; at 20℃;
NaBH(OAc)3 (212 mg, 1 mmol, 4 eq) was added to a solution of 4or 10 (0.25 mmol, 1 eq) and aniline derivatives in anhydrous DCE(15 mL) at RT. After stirring overnight, the solvent was removedunder vacuo, and the residue was diluted with saturated aqueousNaHCO3 (15 mL) and extracted with DCM (3 20 mL). The combinedorganic layers were washed with brine (10 mL), dried overNa2SO4, filtered and concentrated. The residue was purified bycolumn chromatography (CH2Cl2: MeOH: Et3N:: 50:1: 0.05, v/v/v or10:1: 0.1, v/v/v) to give products as colored glasslike solid.
N-(2-fluoro-4-methylphenyl)morpholine-4-carboxamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
36.7%
To a stirred solution of <strong>[452-80-2]2-fluoro-4-methylaniline</strong> (0.500 g, 3.995 mmol) and N,N-diisopropylethylamine (4.175 niL, 23.971 mmol) in dichloromethane (5 mL) was added at 0 °C triphosgene (0.593 g, 1.998 mmol). The reaction mixture was stirred at the same temperature for 0.1 min, treated at the room temperature with etaiotaomicronphietaomicronetaepsilon (0.346 mL, 3.995 mmol), and stirred for additional 2 hr. Then, water was added to the reaction mixture, followed by extraction with dichloromethane. The organic layer was washed with aqueous saturated sodium chloride solution, dried (anhydrous MgSO^), filtered, and concentrated in vacuo. The residue was diluted with diethylether (20 mL) and stirred at the ambient temperature. The resulting precipitates were collected by filtration, washed by diethylether, and dried to give N- (2-fluoro-4-methy]phenyl)morpholine-4-carboxamide as brown solid (0.349 g. 36.7 percent).
N-(2-fluoro-4-methylphenyl)-1H-pyrazole-5-carboxamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
87%
General procedure: To 2-fluoroaniline (4.1 mL, 42.4 mmol) in THF (45 mL) cooled ina -10 °C bath, sodium bis(trimethylsilyl)amide (106 mL, 106 mmol,1.0 M) in THF was added. After stirring for 1 h, a suspension of 15(4 g, 21.2 mmol) in THF (45 mL) was added. The mixture wasallowed to warm to room temperature and stirred for 2 h. Aceticacid was added to pH 7. The reaction mixture was concentrated invacuum followed by the addition of water and saturated aqueousNaHCO3 solution. The solid was collected by filtration, washed withwater and cyclohexane, and dried under high vacuum. The compoundis obtained as a beige solid (82percent yield).
N-(2-fluoro-4-methylphenyl)-2-(4-(trifluoromethoxy)phenyl)acetamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With pyridine; trichlorophosphate; at 0℃; for 0.25h;
To a solution of 2-fluoro-4-methylbenzenamine (2-14;1.1 g, 8.79 mmol, 1 equiv.) and 2- (4- (trifluoromethoxy) phenyl) acetic acid (3b-14; 2.12 g, 9.67 mmol, 1.1 equiv.) in pyridine (10 ml) slowly added P0C13 (1.6 ml, 17.58 mmol, 2 equiv.) at 0 C. The reaction was further maintained at the same temperature for 15 minutes. The reaction mixture was then quenched into ice and the product was then extracted with ethyl acetate. The combined organic layer was washed by IN HC1 solution followed by brine solution, dried over sodium sulfate, filtered and concentrated under reduced pressure to get 2.20 g of the crude product 4-14 as yellow solid. The crude product thus obtained was further used as such without any purification. 1H NMR (CDC13) : 8.10 (t, J = 8.6 Hz, 1H) , 7.39-7.37 (m, 2H) , 7.25- 7.23 (m, 3H) , 6.92-6.85 (m, 2H) , 3.75 (s, 2H) , 2.29 (s, 3H) .
With pyridine; trichlorophosphate; at 0℃; for 0.25h;
To a solution of 2-fluoro-4-methylaniline (2-14;1.1 g, 8.79 mmol, 1 equiv.) and 2-(4-(trifluoromethoxy) phenyl)acetic acid (3b-14; 2.12 g, 9.67 mmol, 1.1 equiv.) in pyridine(10 ml) slowly added POd3 (1.6 ml, 17.58 mmol, 2 equiv.) at 0 C.The reaction was further maintained at the same temperature for15 minutes. The reaction mixture was then quenched into ice andthe product was then extracted with ethyl acetate. The combined organic layer was washed by iN HC1 solution followed by brine solution, dried over sodium sulfate, filtered and concentrated under reduced pressure to get 2.20 g of the crude product 4-14 as yellow solid. The crude product thus obtained was further used assuch without any purification.?H R (CDC13) : 8.10 (t, J = 8.6 Hz, 1H), 7.39-7.37 (m, 2H), 7.25- 7.23 (m, 3H) , 6.92-6.85 (m, 2H) , 3.75 (s, 2H) , 2.29 (s, 3H)
N-(2-fluoro-4-methylphenyl)-2'-iodo-6,6'-dimethyl-[1,1'-biphenyl]-2-amine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
79%
With C50H46CuN6O4(1+)*F6P(1-); sodium carbonate; In dichloromethane; at 0℃; for 48h;Inert atmosphere; Schlenk technique;
General procedure: Under nitrogen atmosphere, a Schlenk tube was sequentially charged with cyclicdiaryliodonium salt (1.0 equiv), copper catalyst A1 or A2 (5.0 molpercent), Na2CO3 (3.0 equiv) anddichloromethane (0.05 M). After the mixture was chilled to proper temperature, the appropriateamine (1.2 equiv) was added and stirred for the time indicated in the experimental procedures.The reaction mixture was filtered through a plug of celite with ethyl acetate. The filtrate wasconcentrated under reduced pressure, and the residue was purified by column chromatographyon silica gel to deliver the corresponding product.
2-(4-chloro-3,5-dimethyl-1H-pyrazol-1-yl)-N-(2-fluoro-4-methylphenyl)acetamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
0.17 g
With pyridine; trichlorophosphate at 0℃; for 0.25h;
3 Production Example 3: Preparation of 2-(4-chloro-3,5-dimethyl-lH-pyrazol-1-yl)-N-(2-fluoro-4-methylphenyl)acetamide [4-(1A-1-234)]
To a solution of 2-fluoro-4-methylbenzenamine(2; 0.2 g,1.6 mmol,1 equiv.)and 2-(4-chloro-3,5-dimethyl-lH-pyrazol-1-yl)acetic acid(3B-(1A-1-234); 0.36 g,1.92 mmol,1.2 equiv.)in pyridine(3 ml)slowly added P0C13(0.37 g,2.40 mmol,1.5 equiv.)at 0 °C. The reaction was then stirred at the same temperature for 15 minutes. The reaction mixture was then quenched into ice and the product was then extracted with ethyl acetate. The combined organic layer was washed by IN HC1 solution followed by brine solution,dried over sodium sulfate,filtered and concentrated under reduced pressure to get crude product. The crude product thus obtained was purified by column chromatography on silica gel with a mixture of ethyl acetate and n-hexane as an eluent to obtain 0.17 g of the title compound 4-(lA-1-234)as light yellow solid. NMR(CDCI3): 8.41(bs,1H),8.06(t,J = 8.4 Hz,1H),6.92-6.85 (m,2H),4.77(s,2H),2.29(s,3H),2.27(s,3H),2.26(s,3H).
ethyl 5-(chlorocarbonyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-5,6-dihydropyrrolo[3,4-c]pyrazole-2(4H)-carboxylate[ No CAS ]
N-(2-fluoro-4-methylphenyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
76%
To a solution of 117 mg (0.266 mmol) of ethyl 5-(chlorocarbonyl)-6,6-dimethyl-3-[1 -(trimethylsilyl)cyclobutanecarboxamido]-5,6-dihydropyrrolo[3,4-c]pyrazole- 2(4H)-carboxylate synthesized in the same way as in Reference Example 4 in 2 ml of 1,4-dioxane, 0.23 ml (1.3 mmol) of DIPEA and 0.15 ml (1.3 mmol) of 2-fluoro-4- methylaniline were added at room temperature in a nitrogen atmosphere and reacted at 100° C. for 6.5 hours with stirring. Subsequently, the reaction solution was cooled to room temperature, and 0.15 ml (1.4 mmol) of N,N-dimethylethane-1 ,2-diamine was added at room temperature and then reacted at room temperature for 1.5 hours with stirring. j0649] After completion of the reaction, ethyl acetate was added to the reaction solution, followed by washing with a 5percent aqueous potassium bisulfate solution. After separation into an organic layer and an aqueous layer, the aqueous layer was subjected to extraction twice with ethyl acetate. The whole organic layer thus obtained was dried over anhydrous magnesium sulfate, then filtered, and concentrated under reduced pressure. The obtained concentration residue was subjected to preparative column chromatography (apparatus 2, DIOL silica gel, elution solvent: n-hexane:ethyl acetate=80:20?65:35?50:50 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure. The obtained concentration residue was subjected to preparative column chromatography (apparatus 2, silica gel, elution solvent: dichloromethane:methanol=100:0? 99:1?98:2 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure. The obtained concentration residue was dissolved in ethyl acetate, then n-hexane was added thereto, and the deposited solid was collected by filtration, washed with n-hexane, and then dried under reduced pressure to obtain 92.8 mg of the title compound (yield: 76percent) as a white solid.10650] Mass spectrum (CI, mlz): 458 [M+1].10651] ?H-NMR spectrum (400 MHz, DMSO-d5) oe: 12.26 & 11.75 (br s, total 1H), 9.60 (br s, 1H), 7.83-7.57 (m, 1H), 7.38 (br s, 1H), 7.03-6.96 (m, 1H), 6.94-6.88 (m, 1H), 4.60 (br s, 2H), 2.56-2.40 (m, 2H), 2.27 (s, 3H), 2.25-2.13 (m, 2H), 1.92-1.72 (m, 2H), 1.64 (br s, 6H), 0.09 (s, 9H).
2-fluoro-4-methylbenzene-1-sulfonyl chloride[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
36.1%
To a l000mL three necked flaskwas added 9OmL H20, to the stirred mixture was dropped SOC12(29.8g, 219.7mmol,5.Seq) under 0°C-5°C, then the reaction was stirred at room temperature overnight. CuC1 (0.1 5g) was added to the reaction mixture (solution A).To a 500mL three necked flask was added 5OmL HC1, to the stirred mixture was added 2-fluoro-4- methylaniline (5g, 39.9mmol, 1.Oeq) under 0°C-5°C, then the reaction mixture wasdropped NaNO2(3.59g, S2mmol, 1.Oeq) aqueous solution (25mL) under -5°C-0°C. Then the reaction mixture was stirred at 0°C for 1 hour (solution B). Solution B was dropped to solution A under 0°C-5°C, then the reaction mixture was stirred at room temperature overnight. The reaction mixture was poured onto 500mL ice water and stirred for 0.5h, extracted with EA (lOOmL*3). The combined organic layers werewashed with sat. NaHCO3 aqueous solution and dried over Na2504, filtered and concentrated in vacuum. The residue was purified by column chromatography on silica gel to yield the title product (3g, HPLC: 95percent) as a light yellow solid. (Yield:36. 1percent).
Multi-step reaction with 3 steps
1.1: tetrahydrofuran / 60 °C
2.1: sodium hydride / tetrahydrofuran / 0.5 h / 0 °C
2.2: 20 °C
3.1: hydrogenchloride / 1,4-dioxane / 1 h / 20 °C
With sodium hydrogencarbonate; In dichloromethane; water; at 0 - 20℃; for 1h;
To a solution of 2- fluoro-4-methylaniline (250 mg, 2.0 mmol) in DCM (6 mL) was added saturated NaHCCb aqueous solution (6 mL). After the mixture cooling to 0°C, triphosgene (238 mg, 7.97 mmol) was added in one portion. The resulting solution was stirred for 1 h at room temperature. The resulting aqueous phase was extracted with DCM several times after separation. The resulted organic phases were combined and washed with brine. The residue was concentrated under vacuum after dried over anhydrous sodium. This resulted in 240 mg (79percent) of the title compound as ayellowish oil. LCMS (ESI, m/z): [M+H]+ = 152.0.
2-fluoro-4-methyl-N-(2-nitrophenyl)benzenamine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
81%
To a solution of <strong>[452-80-2]2-fluoro-4-methylaniline</strong> (125 mg, 1.0 mmol) in THF (3 mL) was added sodium hydride (96 mg, 4.0 mmol) batchwise at 0°C. The mixture was stirred for 30 min at this temperature then l-fluoro-2 -nitrobenzene (141 mg, 1.0 mmol) was added. The resulting mixture was stirred for 3 h at room temperature. The reaction was then quenched by the addition of 3 mL of saturated NH4CI aqueous solution. The resulting solution was extracted with ethyl acetate several times. The resulted organic layers were combined and washed with brine. The mixture was dried over anhydrous magnesium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (25:75). This resulted in 200 mg (81percent) of the title compound as a yellow solid. LCMS (ESI, m/z): [M+H]+ = 247.1.
N<SUP>1</SUP>,N<SUP>3</SUP>-bis(2-fluoro-4-methylphenyl)-4-methoxybenzene-1,3-isophthalamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
78.1%
General procedure: The solution of 4-methoxy-1,3-benzenedichloride (6)(0.93 g, 4.0 mmol) in anhydrous THF (15 mL) was added to3-bromine-4-methylaniline (1.48 g, 8.0 mmol). This solutionwas stirred rapidly at room temperature for about 1 hand then pyridine (1 mL) was added. The solution wasrefluxed for 4-8 h. The residue was recrystallized frommethanol-water to terminal compound 1a (1.81 g, yield85.2%). The other compounds (1b-1i) were prepared with thesimilar method of preparing compound 1a.
N<SUP>1</SUP>,N<SUP>3</SUP>-bis(2-fluoro-4-methylphenyl)-4-methoxybenzene-1,3-disulfonamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
67.1%
With pyridine; In tetrahydrofuran; at 20℃; for 12h;Reflux;
General procedure: The solution of 4-methoxybenzene-1,3-disulfonyldichloride(8) (0.87 g, 2.9 mmol) in anhydrous THF (15 mL) wasadded to pyridine (1 mL) and 3-bromine-4-methylanilin(1.07 g,5.8 mmol). This solution was stirred rapidly at roomtemperature for about 2 h and then was refluxed for 10 h.The resulting solution was concentrated in vacuo and thesolvent was removed. The residue was recrystallized frommethanol-water to terminal compound 2a (1.20 g, yield68.5%).The other compounds (2b-2i) were prepared with thesimilar method of preparing compound 2a.
[2] 4,4'-dimethylazobenzene (105.2 mg, 0.5 mmol) was added to a closed reaction vessel.Palladium dichloride (8.9 mg, 0.05 mmol), N-fluorobisbenzenesulfonamide (0.315 g, 1 mmol), silver nitrate (34.0 mg, 0.2 mmol), ethyl acetate (2.5 mL).The reaction mixture was stirred at 55 C for 12 h. The reaction was stopped and the mixture was diluted with 10 mL ethyl acetate.After filtration, the solvent was removed under reduced pressure, and the residue was purified by column chromatography [ The developing agent is separated and purified by V (petroleum ether) / V (ethyl acetate) = 20/1].The eluate containing the product is collected, and the eluent is evaporated to remove the solvent.a mixture of 4,4'-dimethylazobenzene and 2-fluoro-4,4'-dimethylazobenzene. [3] All 4,4'-dimethylazobenzene obtained andThe mixture of 2-fluoro-4,4'-dimethylazobenzene was dissolved in 5 mL of ethanol, and sodium borohydride (56.7 mg, 1.5 mmol) was carefully added portionwise.With cuprous chloride (99.0 mg, 1.0 mmol), the mixture was stirred at room temperature for 10 min. The reaction solution was dehydrated under reduced pressure of ethanol, and the residue obtained was added to 10 mL of water.It was extracted with ethyl acetate (10 mL×3), and the organic phase was dried over anhydrous sodium sulfate and then evaporated to remove solvent, and column chromatography (eluent ratio:The petroleum ether was separated from ethyl acetate by a volume ratio of 20:1. The eluent containing the product was collected, and the solvent was evaporated to give 2-fluoro-4-methylaniline 43.1 mg (yield: 69%).
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