* 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.
Stage #1: With potassium acetate; acetic anhydride In chloroform at 40℃; for 0.5 h; Stage #2: With isopentyl nitrate In chloroform at 80℃; for 12 h; Stage #3: With hydrogenchloride In methanol for 0.5 h;
A mixture of 5-fluoro-2-methylaniline (3g, 0.024mo1), potassium acetate (2.8 g, 0.028 mol) and acetic anhydride (6.8 mL, 0.072mo1) in chloroform (30 mL) was heated at 40 °C for 0.5 h. At this temperature isoamylnitrate (3.8 mL, 0.028mo1) was added and stined at 80 °C for 12 h. After completion of reaction, solvent was removed under reduced pressure, the residue wasbasified with sodium carbonate solution and was extracted with ethyl acetate. The organic layer was washed with water followed by brine solution and concentrated under reduced pressure to obtain crude compound. The residue was purified by column chromatography over silica gel (30 percent EtOAc:Hexane) to give the pure compound which was stined with methanolic HC1 (60 mL) for 30 mm. The reaction mixture was concentrated under reduced pressure, basified withaqueous sodium carbonate solution and extracted with ethyl acetate. The organic layer was washed with water, brine and was dried over anhydrous Na2SO4 and concentrated under reduced pressure to obtain crude compound. The crude compound was purified by columnchromatography (n-hexanel EtOAc 7:3) to give the title compound (2.0 g, 62 percent) as a pale yellow solid.
62%
Stage #1: With potassium acetate; acetic anhydride In chloroform at 40℃; for 0.5 h; Stage #2: With isopentyl nitrate In chloroform at 40 - 80℃; for 12 h; Stage #3: With hydrogenchloride In methanol for 0.5 h;
Synthesis of 6-fluoro-1H-indazole A mixture of 5-fluoro-2-methylaniline (3 g, 0.024 mol), potassium acetate (2.8 g, 0.028 mol) and acetic anhydride (6.8 mL, 0.072 mol) in chloroform (30 mL) was heated at 40° C. for 0.5 h. At this temperature isoamylnitrate (3.8 mL, 0.028 mol) was added and stirred at 80° C. for 12 h. After completion of reaction, solvent was removed under reduced pressure, the residue was basified with sodium carbonate solution and was extracted with ethyl acetate. The organic layer was washed with water followed by brine solution and concentrated under reduced pressure to obtain crude compound. The residue was purified by column chromatography over silica gel (30percent EtOAc:Hexane) to give the pure compound which was stirred with methanolic HCl (60 mL) for 30 min. The reaction mixture was concentrated under reduced pressure, basified with aqueous sodium carbonate solution and extracted with ethyl acetate. The organic layer was washed with water, brine and was dried over anhydrous Na2SO4 and concentrated under reduced pressure to obtain crude compound. The crude compound was purified by column chromatography (n-hexane/EtOAc 7:3) to give the title compound (2.0 g, 62percent) as a pale yellow solid. 1H NMR (400 MHz, DMSO-d6): δ 13.1 (bs, 1H), 8.10 (s, 1H), 7.82-7.84 (m, 1H), 7.33-7.30 (m, 1H), 7.02-6.97 (m, 1H). MS (ES) m/e: 135 (M-1)+.
Reference：
[1] Patent: WO2015/104662, 2015, A1, . Location in patent: Page/Page column 37; 38
[2] Patent: US2016/326151, 2016, A1, . Location in patent: Paragraph 0206
[3] Bioorganic and Medicinal Chemistry, 2008, vol. 16, # 4, p. 1966 - 1982
[4] Bioorganic and Medicinal Chemistry Letters, 2007, vol. 17, # 11, p. 3177 - 3180
[5] Bioorganic and Medicinal Chemistry, 2004, vol. 12, # 9, p. 2115 - 2137
2
[ 367-29-3 ]
[ 452-76-6 ]
Reference：
[1] Bulletin des Societes Chimiques Belges, 1960, vol. 69, p. 312 - 322
3
[ 372-19-0 ]
[ 593-53-3 ]
[ 443-86-7 ]
[ 367-29-3 ]
[ 452-77-7 ]
Reference：
[1] Journal of the American Chemical Society, 1985, vol. 107, p. 1556 - 1561
4
[ 367-29-3 ]
[ 13194-67-7 ]
Reference：
[1] Patent: US4243805, 1981, A,
5
[ 367-29-3 ]
[ 13194-67-7 ]
Reference：
[1] Collection of Czechoslovak Chemical Communications, 1979, vol. 44, # 7, p. 2108 - 2123
6
[ 367-29-3 ]
[ 656-35-9 ]
Reference：
[1] Bulletin des Societes Chimiques Belges, 1960, vol. 69, p. 312 - 322
7
[ 446-10-6 ]
[ 367-29-3 ]
Yield
Reaction Conditions
Operation in experiment
70%
With hydrogenchloride; iron In ethanol; water at 0℃; for 12 h; Reflux
4-Fluoro-1-methyl-2-nitrobenzene (2.50 g, 16 mmol) was dissolved in ethanol (50 mL).To this solution, iron powder (4.50 g, 81 mmol) and 0.25 ml of HC1 were added at 0 °C and the reaction mixture was refluxed for 12h. After completion of reaction, reaction mixture was cooled to room temperature, diluted with ethyl acetate, filtered through Celite® and washed with ethyl acetate. Filtrate was basified with sodium bicarbonate solution; organic layer was washed with water followed by brine solution. Organic layer was dried over anhydrous Na2SO4 andconcentrated under reduced pressure to obtain crude compound. The residue was purified by column chromatography (n-hexane/ EtOAc 1:1) to give the title compound (1.4 g, 70 percent) as a light brown solid.‘H NMR (400 MHz, DMSO-d6): ö 6.87 (t, J = 7.6 Hz, 1H), 6.38-6.34 (m, 1H), 6.22-6.18 (m, 1H), 5.11 (bs, 2H), 1.99 (s, 3H). MS (ES) mle: 126 (M+1).
70%
With hydrogenchloride; iron In ethanol; water at 0℃; for 12 h; Reflux
Synthesis of 5-fluoro-2-methylaniline 4-Fluoro-1-methyl-2-nitrobenzene (2.50 g, 16 mmol) was dissolved in ethanol (50 mL). To this solution, iron powder (4.50 g, 81 mmol) and 0.25 ml of HCl were added at 0° C. and the reaction mixture was refluxed for 12 h. After completion of reaction, reaction mixture was cooled to room temperature, diluted with ethyl acetate, filtered through Celite® and washed with ethyl acetate. Filtrate was basified with sodium bicarbonate solution; organic layer was washed with water followed by brine solution. Organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to obtain crude compound. The residue was purified by column chromatography (n-hexane/EtOAc 1:1) to give the title compound (1.4 g, 70percent) as a light brown solid. 1H NMR (400 MHz, DMSO-d6): δ 6.87 (t, J=7.6 Hz, 1H), 6.38-6.34 (m, 1H), 6.22-6.18 (m, 1H), 5.11 (bs, 2H), 1.99 (s, 3H). MS (ES) m/e: 126 (M+1)+.
Reference：
[1] Journal of Organic Chemistry, 1992, vol. 57, # 19, p. 5254 - 5255
[2] Patent: WO2015/104662, 2015, A1, . Location in patent: Page/Page column 37
[3] Patent: US2016/326151, 2016, A1, . Location in patent: Paragraph 0204
[4] Journal of the American Chemical Society, 1948, vol. 70, p. 439
[5] Journal of the Chemical Society, 1953, p. 3326
[6] Collection of Czechoslovak Chemical Communications, 1975, vol. 40, # 3, p. 719 - 737
[7] Collection of Czechoslovak Chemical Communications, 1979, vol. 44, # 7, p. 2108 - 2123
[8] Journal of the Chemical Society, 1960, p. 672 - 676
[9] Journal of the American Chemical Society, 1996, vol. 118, # 17, p. 4036 - 4048
[10] Bioorganic and Medicinal Chemistry Letters, 2007, vol. 17, # 11, p. 3177 - 3180
Reference：
[1] Angewandte Chemie - International Edition, 2010, vol. 49, # 24, p. 4071 - 4074
[2] Chemistry - A European Journal, 2013, vol. 19, # 6, p. 2131 - 2141
[3] Chemistry - A European Journal, 2010, vol. 16, # 6, p. 1983 - 1991
10
[ 446-33-3 ]
[ 367-29-3 ]
Reference：
[1] Patent: US3954852, 1976, A,
11
[ 372-19-0 ]
[ 593-53-3 ]
[ 443-86-7 ]
[ 367-29-3 ]
[ 452-77-7 ]
Reference：
[1] Journal of the American Chemical Society, 1985, vol. 107, p. 1556 - 1561
12
[ 119-32-4 ]
[ 367-29-3 ]
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2007, vol. 17, # 11, p. 3177 - 3180
13
[ 372-19-0 ]
[ 593-53-3 ]
[ 443-86-7 ]
[ 367-29-3 ]
[ 452-77-7 ]
Reference：
[1] Journal of the American Chemical Society, 1985, vol. 107, p. 1556 - 1561
14
[ 367-29-3 ]
[ 446-32-2 ]
Reference：
[1] Journal of the American Chemical Society, 1948, vol. 70, p. 439
15
[ 367-29-3 ]
[ 452-85-7 ]
Yield
Reaction Conditions
Operation in experiment
99%
Stage #1: With sulfuric acid; sodium nitrite In water at 0℃; for 0.916667 h; Stage #2: With sulfuric acid; sodium sulfate; urea In water at 130℃; for 0.25 h;
7 mL of a hot solution of concentrated sulfuric acid in 21 mL of water was added to 5-fluoro-2- METHYLPHENYLAMINE (5 g, 40 mmol). The mixture was cooled in an ice bath for 30 minutes and treated with a solution of sodium nitrite (3.38 g, 48 mmol) in 10 mL of water over a period of 10 minutes. After stirring at 0 C for 45 minutes, the reaction was diluted with 20 mL of cold water and treated with 0.3 g of urea. The resulting mixture was added to a stirred solution of 11 mL of concentrated sulfuric acid in 10 mL of water containing 15 g of anhydrous sodium sulfate at 130 C over 10 minutes. After an additional 5 minutes at 130 C, the reaction was allowed to cool to room temperature and was extracted with three 100 mL portions of dichloromethane. The combined organic layers were washed with two 50 ML portions of water and concentrated in vacuo. The reddish oil was dissolved in 250 mL of diethyl ether and washed with three 50 mL portions of 10percent aqueous sodium hydroxide. The combined aqueous sodium hydroxide extracts were washed with two 50 mL portions of diethyl ether. The basic layer was acidified with 1 N aqueous HC1 and extracted with three 100 mL portions of dichloromethane. The combined dichloromethane layers were washed with two 50 ML portions of brine, dried over sodium sulfate, filtered, and concentrated in vacuo to give a light reddish liquid. The crude was purified by chromatography on Si02 (10percent ethyl acetate in hexanes) to give 5 g of 5-fluoro-2-methylphenol as a light brownish oil (99percent yield). A stirred solution of 5-fluoro-2-methylphenol (640 mg, 5 mmol) in 20 mL of anhydrous acetonitrile was cooled to-30 C to-40 C and treated with nitronium tetrafluoroborate (740 mg, 5.5 mmol). After 45 minutes, the reaction mixture was diluted with 100 mL of cold water and extracted with three 50 ML portions of dichloromethane. The combined organic layers were washed with three 25 mL portions of water, dried over sodium sulfate, and concentrated in vacuo to give a reddish crystalline solid. Chromatography over SI02 (5percent ethyl acetate in hexanes) gave 0. 58 g of the title product as bright yellow solid (68percent yield). The title compound was converted to the corresponding trifluoromethane sulfonate according to the procedure described in Example 26.
With N-Bromosuccinimide In N,N-dimethyl-formamide at 25℃; for 12 h;
A mixture of NBS (14.22 g, 80 mmol), 5-fluoro-2-methylaniline (10 g, 80 mmol) and N,Ndimethylformamide (200 mL) was stirred at 2500 for 12 h. The mixture was then poured into water and the solid was filtered to afford the title compound (13 g, 71 percent yield) as yellow solid. L0-MS m/z 204 (M+H), 1 .68 mm (ret. time).
71%
With N-Bromosuccinimide In N,N-dimethyl-formamide at 25℃; for 12 h;
A mixture of NBS (14.22 g, 80 mmol), 5-fluoro-2-methylaniline (10 g, 80 mmol) and N,N- dimethylformamide (200 mL) was stirred at 25 °C for 12 h. The mixture was then poured into water and the solid was filtered to afford the title compound (13 g, 71 percent yield) as yellow solid. LC-MS m/z 204 (M+H)+, 1.68 min (ret. time).
With hydrogenchloride; iron; In ethanol; water; at 0℃; for 12h;Reflux;
4-Fluoro-1-methyl-2-nitrobenzene (2.50 g, 16 mmol) was dissolved in ethanol (50 mL).To this solution, iron powder (4.50 g, 81 mmol) and 0.25 ml of HC1 were added at 0 C and the reaction mixture was refluxed for 12h. After completion of reaction, reaction mixture was cooled to room temperature, diluted with ethyl acetate, filtered through Celite and washed with ethyl acetate. Filtrate was basified with sodium bicarbonate solution; organic layer was washed with water followed by brine solution. Organic layer was dried over anhydrous Na2SO4 andconcentrated under reduced pressure to obtain crude compound. The residue was purified by column chromatography (n-hexane/ EtOAc 1:1) to give the title compound (1.4 g, 70 %) as a light brown solid.?H NMR (400 MHz, DMSO-d6): oe 6.87 (t, J = 7.6 Hz, 1H), 6.38-6.34 (m, 1H), 6.22-6.18 (m, 1H), 5.11 (bs, 2H), 1.99 (s, 3H). MS (ES) mle: 126 (M+1).
70%
With hydrogenchloride; iron; In ethanol; water; at 0℃; for 12h;Reflux;
Synthesis of 5-fluoro-2-methylaniline 4-Fluoro-1-methyl-2-nitrobenzene (2.50 g, 16 mmol) was dissolved in ethanol (50 mL). To this solution, iron powder (4.50 g, 81 mmol) and 0.25 ml of HCl were added at 0 C. and the reaction mixture was refluxed for 12 h. After completion of reaction, reaction mixture was cooled to room temperature, diluted with ethyl acetate, filtered through Celite and washed with ethyl acetate. Filtrate was basified with sodium bicarbonate solution; organic layer was washed with water followed by brine solution. Organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to obtain crude compound. The residue was purified by column chromatography (n-hexane/EtOAc 1:1) to give the title compound (1.4 g, 70%) as a light brown solid. 1H NMR (400 MHz, DMSO-d6): delta 6.87 (t, J=7.6 Hz, 1H), 6.38-6.34 (m, 1H), 6.22-6.18 (m, 1H), 5.11 (bs, 2H), 1.99 (s, 3H). MS (ES) m/e: 126 (M+1)+.
7 mL of a hot solution of concentrated sulfuric acid in 21 mL of water was added to 5-fluoro-2- METHYLPHENYLAMINE (5 g, 40 mmol). The mixture was cooled in an ice bath for 30 minutes and treated with a solution of sodium nitrite (3.38 g, 48 mmol) in 10 mL of water over a period of 10 minutes. After stirring at 0 C for 45 minutes, the reaction was diluted with 20 mL of cold water and treated with 0.3 g of urea. The resulting mixture was added to a stirred solution of 11 mL of concentrated sulfuric acid in 10 mL of water containing 15 g of anhydrous sodium sulfate at 130 C over 10 minutes. After an additional 5 minutes at 130 C, the reaction was allowed to cool to room temperature and was extracted with three 100 mL portions of dichloromethane. The combined organic layers were washed with two 50 ML portions of water and concentrated in vacuo. The reddish oil was dissolved in 250 mL of diethyl ether and washed with three 50 mL portions of 10% aqueous sodium hydroxide. The combined aqueous sodium hydroxide extracts were washed with two 50 mL portions of diethyl ether. The basic layer was acidified with 1 N aqueous HC1 and extracted with three 100 mL portions of dichloromethane. The combined dichloromethane layers were washed with two 50 ML portions of brine, dried over sodium sulfate, filtered, and concentrated in vacuo to give a light reddish liquid. The crude was purified by chromatography on Si02 (10% ethyl acetate in hexanes) to give 5 g of 5-fluoro-2-methylphenol as a light brownish oil (99% yield). A stirred solution of 5-fluoro-2-methylphenol (640 mg, 5 mmol) in 20 mL of anhydrous acetonitrile was cooled to-30 C to-40 C and treated with nitronium tetrafluoroborate (740 mg, 5.5 mmol). After 45 minutes, the reaction mixture was diluted with 100 mL of cold water and extracted with three 50 ML portions of dichloromethane. The combined organic layers were washed with three 25 mL portions of water, dried over sodium sulfate, and concentrated in vacuo to give a reddish crystalline solid. Chromatography over SI02 (5% ethyl acetate in hexanes) gave 0. 58 g of the title product as bright yellow solid (68% yield). The title compound was converted to the corresponding trifluoromethane sulfonate according to the procedure described in Example 26.
With sodium nitrite; In sulfuric acid; water;
Preparation of 5-fluoro-2-methylphenol (Compound 26A) A mixture of 5-fluoro-2-methylphenylamine in concentrated sulfuric acid and water was heated until a clear solution was obtained, then cooled to 0 C., a solution of sodium nitrite in water was added dropwise over 15 minutes, then poured into boiled saturated copper sulfate solution and heated for 15 minutes, cooled and extracted with ethyl acetate washed with water, brine, dried over anhydrous sodium sulfate, and concentrated to give 26A in good purity. 400 MHz 1H NMR (CDCl3) delta7.05 (t, 1H), 6.56 (m, 2H), 4.92 (s, 1H), 2.19 (s, 3H).
47A Preparation 47A: N-(5-Fluoro-2-methylphenyl)acetamide
Preparation 47A: N-(5-Fluoro-2-methylphenyl)acetamide A solution of 5-fluoro-2-methylaniline (5g, 0.04 mol), Ac20 (4.08 g, 0.04 mol) and TEA (4.848 g, 0.048 mol) in DCM (20 mL) was stirred overnight at rt. H20 was added, extracted with DCM, dried, concentrated to afford the title copound (6 g, 90%). [M+H] Calc'd for C9Hi0FNO, 168; Found, 168.
89.8%
In toluene at 110℃; for 4h;
1 Step 1
j0623j A solution of 5-fluoro-2-methylaniline (XXIV) (100 g, 799 mmol, 1.0 eq) andAc20 (89 g, 879 mmol, 1.1 eq)intoluene (4.0 L)was stirred at 110°C for4 h. TLC (PE:EtOAc = 2:1) showed (XXIV) was consumed. The reaction mixture was cooled to 25°C. The precipitated solid was filtered, washed with petro ether. The solid was dried in vacuo to give N-(5-fluoro-2-methylphenyl)acetamide (XXV) as a white solid (120 g, 717.8 mmol, 89.8% yield), which was used in step 2 without further purification. ESIMS found C9H,0FNO mlz 168.1 (M+1).
89.8%
In toluene at 110℃; for 4h;
Step 1
[0623] A solution of 5-fluoro-2-methylaniline (XXIV) (100 g, 799 mmol, 1.0 eq) and Ac20 (89 g, 879 mmol, 1.1 eq) in toluene (4.0 L) was stirred at 110°C for 4 h. TLC (PE:EtOAc = 2: 1) showed (XXIV) was consumed. The reaction mixture was cooled to 25°C. The precipitated solid was filtered, washed with petro ether. The solid was dried in vacuo to give N-(5-fluoro-2- methylphenyl)acetamide (XXV) as a white solid (120 g, 717.8 mmol, 89.8% yield), which was used in step 2 without further purification. ESIMS found C9H10FNO mlz 168.1 (M+l).
89.8%
In toluene at 110℃; for 4h;
1 Step 1
A solution of 5-fluoro-2-methylaniline (XXIV) (100 g, 799 mmol, 1.0 eq) and Ac20 (89 g, 879 mmol, 1.1 eq) in toluene (4.0 L) was stirred at 110°C for 4 h. TLC (PE:EtOAc = 2: 1) showed (XXIV) was consumed. The reaction mixture was cooled to 25°C. The precipitated solid was filtered, washed with petro ether. The solid was dried in vacuo to give N-(5-fluoro-2- methylphenyl)acetamide (XXV) as a white solid (120 g, 717.8 mmol, 89.8% yield), which was used in step 2 without further purification. ESIMS found C9H10FNO mlz 168.1 (M+l).
89.8%
In toluene at 110℃; for 4h;
1 Step 1
A solution of 5-fluoro-2-methylaniline (XXIV) (100 g, 799 mmol, 1.0 eq) and Ac20 (89 g, 879 mmol, 1.1 eq) in toluene (4.0 L) was stirred at 110°C for 4 h. TLC (PE:EtOAc = 2: 1) showed (XXIV) was consumed. The reaction mixture was cooled to 25°C. The precipitated solid was filtered, washed with petro ether. The solid was dried in vacuo to give N-(5-fluoro-2- methylphenyl)acetamide (XXV) as a white solid (120 g, 717.8 mmol, 89.8% yield), which was used in step 2 without further purification. ESIMS found C9H10FNO mlz 168.1 (M+l).
89.8%
In toluene at 110℃; for 4h;
1 Step 1
A solution of 5-fluoro-2-methylaniline (XVI) (100 g, 799 mmol, 1.0 eq) and Ac2O (89 g, 879 mmol, 1.1 eq) in toluene (4.0 L) was stirred at 110° C. for 4 h. TLC (PE:EtOAc=2:1) showed (XVI) was consumed. The reaction mixture was cooled to 25° C. The precipitated solid was filtered, washed with petro ether. The solid was dried in vacuo to give N-(5-fluoro-2-methylphenyl)acetamide (XVII) as a white solid (120 g, 717.8 mmol, 89.8% yield), which was used in step 2 without further purification. ESIMS found C9H10FNO m/z 168.1 (M+1).
84%
In toluene at 10℃; for 2h; Reflux;
66.1 Step-i: Synthesis of N-(S-fluoro-2-methylphenyl)acetamide
j0620] To a stirred solution of S-fluoro-2-methylaniline (25 g, 200 mmol) in toluene was added acetic anhydride (25 mE) at iO° C., the contents were stirred at reflux temperature for 2 h. Afier completion of reaction (monitored by TEC), the reaction mixture was cooled to room temperature, solid obtained was filtered and washed with diethyl ether and hexane to obtain desired compound (28 g, 84%)
With pyridine at 20℃; for 4h;
176
To a solution of 5 g of 5-fluoro-2-methylaniline in 30 mL of pyridine was added 4.6 mL of acetic anhydride, and stirred at room temperature for 4 hours. After distilling off the pyridine under reduced pressure, the residue was dissolved in 250 mL of ethyl acetate, and washed successively with water, 1N hydrochloric acid, water, saturated aqueous sodium hydrogen carbonate and saturated brine. The solution was dried over anhydrous magnesium sulfate, allowed to pass though a silica gel pad, and then the solvent was evaporated. The residue was recrystallized from ethyl acetate -diethyl ether, to afford 5.34 g of the title compound as white needle crystals. The mother liquor was further concentrated, and triturated with diethyl ether, to afford 907 mg of the title compound as purple needle crystals.1H-NMR (400 MHz, CDCl3) δ 2.22 (3H, s), 6.76 (1H, ddd, J = 2.0, 7.2, 8.0 Hz), 7.00 (1H, bs), 7.11 (1H, t, J = 7.2 Hz), 7.77 (1H, dd, J = 2.0, 6.8 Hz).
for 1h; Heating / reflux;
41.A
Example 41; Preparation of Intermediate Compound 41 G; Step A - Synthesis of Compound 41B ; 41 A 41 B; A solution of 5-fluoro-2-methylaniline (41 A, 25 g, 200 mmol) in toluene (250 mL) was treated with acetic anhydride (25 mL. 226 mmol) heated at reflux for 1 h. The reaction mixture was cooled when a colorless solid precipitated out which was filtered and washed with a mixture of ether and hexanes. The colorless solid was taken in acetic acid (150 mL) and treated dropwise with a solution of bromine (9.6 mL, 186 mmol) in acetic acid (20 mL) and stirred at rt. for 12 h. The solution was diluted with water and the solid separating out was filtered and washed to yield N-(4-bromo-5-fluoro-2-methylphenyl)acetamide (41B, 40 g) as a colorless solid.
In toluene at 20℃; for 1h;
22.A
Example 22; Preparation of Intermediate Compound 22G; Step A - Synthesis of Compound 2B; 22A 22B; A solution of 5-fluoro-2-methylaniline (22A, 25 g, 200 mmol) in toluene (250 mL) was treated with acetic anhydride (25 mL. 226 mmol) heated at reflux for 1 h. The reaction mixture was cooled when a colorless solid precipitated out which was filtered and washed with a mixture of ether and hexanes. The colorless solid was taken in acetic acid (150 mL) and treated dropwise with a solution of bromine (9.6 mL, 186 mmol) in acetic acid (20 mL) and stirred at rt. for 12 h. The solution was diluted with water and the solid separating out was filtered and washed to yield N-(4-bromo-5-fluoro-2-methylphenyl)acetamide (22B, 40 g) as a colorless solid.
In toluene for 1h; Heating / reflux;
24.A
Example 24; Preparation of Intermediate Compound 24G; Step A - Synthesis of Compound 24B; 24A 24B; A solution of 5-fluoro-2-methylaniline (24A, 25 g, 200 mmol) in toluene (250 mL) was treated with acetic anhydride (25 mL. 226 mmol) heated at reflux for 1 hour. The reaction mixture was cooled when a colorless solid precipitated out which was filtered and washed with a mixture of ether and hexanes. The colorless solid was taken in acetic acid (150 mL) and treated dropwise with a solution of bromine (9.6 mL, 186 mmol) in acetic acid (20 mL) and stirred at rt. for 12 hours. The solution was diluted with water and the solid separating out was filtered and washed to yield N-(4-bromo-5-fluoro-2-methylphenyl)acetamide (24B, 40 g) as a colorless solid.
In toluene at 100℃; for 1h;
88
Jl§ starting material, 5-fluoro-2-methylbenzenamine (12.37g, 99 mmol), was dissolved in toluene (120 mL) and acetic anhydride was added (12.5 mL, 113 mmol). The mixture was heated to 100 °C for 1 h. All solvents were removed in vacuo, and the resulting solid (88a) was dissolved in acetic acid (70 mL) and then bromine (4.82 mL, 94 mmol) was added dropwise. The dark solution was allowed to stir at room temperature for 12 h, during which time a tan precipitate formed
In toluene for 1h; Reflux;
14 5.1.14 N-(4-Bromo-5-fluoro-2-methylphenyl)acetamide (17)
A solution of 5-fluoro-2-methylaniline (25 g, 200 mmol) in toluene (250 mL) was treated with Ac2O (25 mL, 226 mmol) and heated at reflux for 1 h. The reaction mixture was concentrated in vacuo when a colorless solid precipitated out which was filtered and washed with ether and hexanes. The colorless solid was taken in acetic acide (150 mL) and treated with a solution of Br2 (9.6 mL, 186 mmol) in acetic acid (20 mL) and stirred at rt for 12 h. The reaction mixture was diluted with water when a colorless solid 17 (40 g, 81.6%) precipitated out. It was filtered and extensively washed.
In toluene at 110℃; for 4h;
1
Step 1 (0806) A solution of 5-fluoro-2-methylaniline (XVI) (100 g, 799 mmol, 1.0 eq) and Ac2O (89 g, 879 mmol, 1.1 eq) in toluene (4.0 L) was stirred at 110° C. for 4 h. TLC (PE:EtOAc=2:1) showed (XVI) was consumed. The reaction mixture was cooled to 25° C. The precipitated solid was filtered, washed with petro ether. The solid was dried in vacuo to give N-(5-fluoro-2-methylphenyl)acetamide (XVII) as a white solid (120 g, 717.8 mmol, 89.8% yield), which was used in step 2 without further purification. ESIMS found C9H10FNO m/z 168.1 (M+1).
With N-iodo-succinimide; trifluoroacetic acid at 25℃; for 3h;
With iodine; urea hydrogen peroxide adduct In ethyl acetate at 50℃; for 3h;
C1.1 5-Fluoro-4-iodo-2-methylaiii]iiie
5-Fluoro-4-iodo-2-methylaiii]iiie To a 1 L round bottom flask is added 5-fluoro-2-methylaniline (26.4 g, 211 mmol), ethyl acetate (500 mL), iodine (27.0 g, 106 mmol), and urea peroxide (14.8 g, 158 mmol). The reaction mixture is stirred at 50 °C for 3 hrs. After cooled to room temperature, it was added an aqueous saturated sodium hydrosulfite solution (300 mL). The organic phase is isolated and concentrated to provide a brown liquid (53.0 g, 100%). It is used in next step without further purification. (MS: [M+l] 252)
A mixture of 5-fluoro-2-methylaniline (3g, 0.024mo1), potassium acetate (2.8 g, 0.028 mol) and acetic anhydride (6.8 mL, 0.072mo1) in chloroform (30 mL) was heated at 40 C for 0.5 h. At this temperature isoamylnitrate (3.8 mL, 0.028mo1) was added and stined at 80 C for 12 h. After completion of reaction, solvent was removed under reduced pressure, the residue wasbasified with sodium carbonate solution and was extracted with ethyl acetate. The organic layer was washed with water followed by brine solution and concentrated under reduced pressure to obtain crude compound. The residue was purified by column chromatography over silica gel (30 % EtOAc:Hexane) to give the pure compound which was stined with methanolic HC1 (60 mL) for 30 mm. The reaction mixture was concentrated under reduced pressure, basified withaqueous sodium carbonate solution and extracted with ethyl acetate. The organic layer was washed with water, brine and was dried over anhydrous Na2SO4 and concentrated under reduced pressure to obtain crude compound. The crude compound was purified by columnchromatography (n-hexanel EtOAc 7:3) to give the title compound (2.0 g, 62 %) as a pale yellow solid.
62%
Synthesis of 6-fluoro-1H-indazole A mixture of 5-fluoro-2-methylaniline (3 g, 0.024 mol), potassium acetate (2.8 g, 0.028 mol) and acetic anhydride (6.8 mL, 0.072 mol) in chloroform (30 mL) was heated at 40 C. for 0.5 h. At this temperature isoamylnitrate (3.8 mL, 0.028 mol) was added and stirred at 80 C. for 12 h. After completion of reaction, solvent was removed under reduced pressure, the residue was basified with sodium carbonate solution and was extracted with ethyl acetate. The organic layer was washed with water followed by brine solution and concentrated under reduced pressure to obtain crude compound. The residue was purified by column chromatography over silica gel (30% EtOAc:Hexane) to give the pure compound which was stirred with methanolic HCl (60 mL) for 30 min. The reaction mixture was concentrated under reduced pressure, basified with aqueous sodium carbonate solution and extracted with ethyl acetate. The organic layer was washed with water, brine and was dried over anhydrous Na2SO4 and concentrated under reduced pressure to obtain crude compound. The crude compound was purified by column chromatography (n-hexane/EtOAc 7:3) to give the title compound (2.0 g, 62%) as a pale yellow solid. 1H NMR (400 MHz, DMSO-d6): delta 13.1 (bs, 1H), 8.10 (s, 1H), 7.82-7.84 (m, 1H), 7.33-7.30 (m, 1H), 7.02-6.97 (m, 1H). MS (ES) m/e: 135 (M-1)+.
PREPARATION 14 N-(4-Fluoro-2-methylphenyl)acetamide In the manner of Preparation 5, 20 g (0.160 mol) of 5-fluoro-2-methylaniline was converted into the title compound: yield 25.0 g (94%); m.p. 131-132 C., [lit. m.p. 133.5-134 C.: E. A. Steck, L. T. Fletcher, J. Am. Chem. Soc. 70, 439-440 (1948)].
With hydrogenchloride; potassium iodide; sulfuric acid; sodium nitrite; In water;
2-Amino-4-fluorotoluene (68 g) is added dropwise to a stirred solution of 100 ml hydrochloric acid in 700 ml of water and after cooling to 0-5 C., a solution of 46 g sodium nitrite in 100 ml water was slowly added dropwise. The resultant ice-cold solution of the diasonium chloride was added over 1 hour with stirring to a solution of 157 g potassium iodide and 35 ml of sulfuric acid in 250 ml water at 20-25 C. The mixture was then stirred and heated for 2 hours at 100 C. After cooling, an oily product was separated and the remaining aqueous layer extracted with benzene. The separated product was dissolved in the benzene layer, the solution washed with a 5% sodium hydrogen sulfite solution, with water, 5% sodium hydroxide solution and again with water, dried with magnesium sulfate and filtered with charcoal. From the filtrate, benzene was evaporated under reduced pressure and the residue distilled. There were obtained 105.3 g of 2-iodo-4-fluorotoluene boiling at 92-95 C./17 Torr.
2 EXAMPLE 2
EXAMPLE 2 2-acetamido-4-fluorotoluene (2) 139 ml (150.4 g; 1.473 molecules) of acetic anhydride were added in one portion to a hot (35°) stirred mixture of 90.0 g (0.719 molecule) of 2-amino-4-fluorotoluene (1) in 513 ml of water. The temperature rose to 73° and a solid separated out (by precipitation). The mixture was cooled to ambient temperature and the solid was recovered on a filter, washed with water (525 ml), then dried in vacuo at 80°, yield: 115.7 g (96.2%); m.p.: 127°-128°. The material was still transformable.
C. 5-fluoro-o-toluidinylbromide Bromine (0.5 mole) is added over 1 hour to stirred 5-fluoro-o-toluidine (0.5 mole) at 100 C illuminated with a high wattage lamp. The crude benzyl bromide is used as prepared.
With calcium carbonate; In hydrogenchloride; dichloromethane; water;
(Step 6) Synthesis of 5-fluoro-2-methylphenyl isothiocyanate Under stirring at 0ØC, a solution of 5-fluoro-2-methylaniline (1.23 g, 9.84 mmol) in methylene chloride (10 ml) was added dropwise to a mixture of calcium carbonate (2.46 g, 24.6 mmol) and thiophosgene (750 æl, 9.84 mmol) in a methylene chloride/water (1/1, 40 ml) mixture. After completion of the dropwise addition, the reaction mixture was stirred further at 0ØC for 35 minutes. The reaction mixture was poured in ice-1N HCl, followed by extraction with chloroform. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and distilled under reduced pressure to remove the solvent to give 5-fluoro-2-methylphenyl isothiocyanate (1.45 g, 88%) as a brown oil. MS (ESI) m/z 167 (M+).
Stage #1: 3-fluoro-6-methylaniline; glycerol With sulfuric acid; sodium 3-nitrobenzenesulfonate for 5h; Heating / reflux;
Stage #2: With sodium hydroxide In diethyl ether
5.1
Step 1: 5-fluoro-8-methylquinolineA solution of 5-fluoro-2-methylaniline (1.1 M) and sodium 3-nitrobenzenesulfonate (1 eq.) in glycerol/sulphuric acid (1/4, v/v) was refluxed for 5 h. After cooling the reaction mixture to 00C, Et2O and water were carefully added followed by solid NaOH until basic pH. After filtering away the insoluble material, the organic layer was separated, washed with brine, and dried. Evaporation of the solvent afforded (85%) the title compound as a pale brown solid; MS (ES+) m/z 162 (M+H)+.
80%
With sulfuric acid; sodium iodide In water at 140 - 145℃; for 4h; Inert atmosphere;
With sulfuric acid; sodium iodide In water at 140 - 145℃; for 4h; Inert atmosphere; Schlenk technique;
With sulfuric acid; sodium iodide In water at 140 - 145℃; for 4h; Schlenk technique;
With sulfuric acid; sodium iodide In water at 140 - 145℃; for 2.5h; Inert atmosphere; Schlenk technique;
With sulfuric acid; sodium iodide at 140℃; for 6h;
With sulfuric acid; sodium iodide In water at 140 - 145℃; for 3.5h;
With sulfuric acid; sodium iodide at 140℃; for 24h; Inert atmosphere; Schlenk technique;
With sulfuric acid; sodium iodide at 140℃; for 6h;
With sulfuric acid; sodium iodide In water at 140 - 145℃; for 6h;
(70a) [1,1-Dimethyl-2-(5-fluoro-2-methylphenylamino)ethyl]carbamic acid t-butyl ester 6.9 g of sodium triacetoxyborohydride (32.5 mmol) was added to a solution of 5.08 g of (1,1-dimethyl-2-oxoethyl)carbamic acid t-butyl ester obtained in Reference Example 3 (27.1 mmol), 5 g of 5-fluoro-2-methylaniline (27.1 mmol) and 1.55 ml of acetic acid (27.1 mmol) in methylene chloride (270 ml) under ice-cooling, and the mixture was stirred at room temperature for 16 hours. A saturated sodium bicarbonate aqueous solution was added to the reaction mixture, followed by extraction with methylene chloride. Then, the organic layer was washed with brine and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: hexane/ethyl acetate = 8/1) to obtain 5.68 g of the title compound (yield: 71 %). Colorless solid. 1H NMR spectrum (CDCl3, 400 MHz), delta: 6.96-6.92 (m, 1H), 6.31-6.27 (m, 2H), 4.57 (br s, 2H), 3.25 (d, 2H, J = 5.5 Hz), 2.11 (s, 3H), 1.43 (s, 9H), 1.39 (s, 6H).
338.1 Step 1. 2-Chloro-N-(5-fluoro-2-methylphenyl) acetamide
Step 1. 2-Chloro-N-(5-fluoro-2-methylphenyl) acetamide A solution of 2-methyl-5-fluoroaniline (0.880 g, 7.03 mmol) and chloroacetyl chloride (1.12 mL, 14.1 mmol) in THF (10 mL) was stirred at room temperature for 20 h. The solvent was concentrated and dried under high vacuum to give 2-chloro-N-(5-fluoro-2-methylphenyl)acetamide (1.46 g, 100%) as a gray solid. 1H NMR (CDCl3, 400 MHz) δ 8.30 (br s, 1H), 7.86 (dd, 1H), 7.14 (dd, 1H), 6.81 (td, 1H), 4.24 (s, 2H), 2.27 (s, 3H); LC-MS (ESI) m/z 224.0 [M+Na]+.
With triethylamine In acetone at 0 - 20℃;
With sodium hydrogencarbonate In acetone at 20℃; for 1h;
With triethylamine In dichloromethane at 0 - 20℃; for 24h;
117 Preparation of N-(5-Fluoro-2-methyl-phenyl)-acetamide VI-e
Preparation of N-(5-Fluoro-2-methyl-phenyl)-acetamide VI-e To a solution of 5-Fluoro-2-methyl-phenylamine (12.5 g, 0.1 mmol) in DCM (600 mL) were successively added TEA (30.5 mL, 0.22 mmol) and dropwise at 0
With N-Bromosuccinimide; In N,N-dimethyl-formamide; at 25℃; for 12h;
A mixture of NBS (14.22 g, 80 mmol), 5-fluoro-2-methylaniline (10 g, 80 mmol) and N,Ndimethylformamide (200 mL) was stirred at 2500 for 12 h. The mixture was then poured into water and the solid was filtered to afford the title compound (13 g, 71 percent yield) as yellow solid. L0-MS m/z 204 (M+H), 1 .68 mm (ret. time).
71%
With N-Bromosuccinimide; In N,N-dimethyl-formamide; at 25℃; for 12h;
A mixture of NBS (14.22 g, 80 mmol), 5-fluoro-2-methylaniline (10 g, 80 mmol) and N,N- dimethylformamide (200 mL) was stirred at 25 °C for 12 h. The mixture was then poured into water and the solid was filtered to afford the title compound (13 g, 71 percent yield) as yellow solid. LC-MS m/z 204 (M+H)+, 1.68 min (ret. time).
Stage #1: 3-fluoro-6-methylaniline With hydrogenchloride; sodium nitrite In water at 0℃; for 1h;
Stage #2: With tin(ll) chloride In water at 20℃; for 2h;
337.1 Step 1. (5-Fluoro-2-methylphenyl)hydrazine hydrochloride
Step 1. (5-Fluoro-2-methylphenyl)hydrazine hydrochloride To a solution of 2-methyl-5-fluoroaniline (1.31 g, 10.5 mmol) in concentrated HCl(aq) (12 mL) was added a solution of sodium nitrite (1.08 g, 15.7 mmol) in water (4.0 mL) slowly at 0° C. After the reaction mixture was stirred at 0° C. for 1 h, a solution of tin(II) chloride (5.97 g, 31.5 mmol) in concentrated HCl(aq) (6.0 mL) was added. The solution was stirred for another 2 h at room temperature. The solids were collected by filtration and washed with cold water and n-hexane to give (5-fluoro-2-methylphenyl)hydrazine hydrochloride (1.34 g, 72%) as a yellow solid. 1H NMR (DMSO-d6, 400 MHz) δ 10.26 (br s, 2H), 8.06 (br s, 1H), 7.11 (dd, 1H), 6.75 (dd, 1H), 6.66 (ddd, 1H), 2.11 (s, 3H).
3-[(5-fluoro-2-methylphenyl)carbamoyl]pyrazine-2-carboxylic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
92%
General procedure: Pyrazine-2,3-dicarboxylic anhydride (1.0 g, 6.7 mmol) was dissolved in tetrahydrofuran (40 mL)in an Erlenmeyer flask and the corresponding substituted aniline (6.7 mmol, 1 equiv.) was added in one dose. The reaction mixture was stirred for 1 hour at laboratory temperature. Water (30 mL) was added into the mixture followed by the saturated aqueous solution of NaHCO3 until pH 6 to form thecorresponding 3-(phenylcarbamoyl)pyrazine-2-carboxylic acid 1-18. Obtained crystals were filtered off and washed with water. The progress of the procedure was monitored by TLC eluted with thesystem water/butanol/acetic acid 5:4:1.
tert-butyl 4-((5-fluoro-2-methylphenyl)carbamoyl)-4-methylpiperidine-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
32%
Preparation of tert-butyl 4-((5-fluoro-2-methylphenyl)carbamoyl)-4- methylpiperidine- 1 -carboxylate. To a solution of 5-fluoro-2-methylaniline (586 mg, 4.68 mmol) in toluene (12.0 mL) was treated with trimethylaluminum (2.3 mL, 4.68 mmol) was stirred for 15 min at ambient temperature. Then the solution was treated with 1 -(tert-butyl) 4- ethyl 4-methylpiperidine-l,4-dicarboxylate (635 mg, 2.341 mmol) and then stirred for 16 h at 70C. The reaction was cooled to ambient temperature and treated with 0.5 M NaK Tartrate and diluted with EtOAc. The organic solution was washed with water and brine. The organic extracts were dried over anhydrous Na2S04(S), filtered and concentrated in vacuo. The residue was purified by silica chromatography (5-75% EtOAc in Hexanes as the gradient eluent) to cleanly provide the title compound (266 mg, 32% yield) MS (apci) m/z= 349.2 (M-H).
N-(2’-methyl-5’-fluorophenyl)-3α,12α-dihydroxy-5β-cholan-24-amide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
57%
Stage #1: Deoxycholic acid With 4-methyl-morpholine; O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate In N,N-dimethyl-formamide at 20℃; for 0.5h; Inert atmosphere; Sealed tube;
Stage #2: 3-fluoro-6-methylaniline With 4-methyl-morpholine In N,N-dimethyl-formamide at 20℃; Inert atmosphere; Sealed tube;
General procedure: To a round bottom flask, chenodeoxycholic acid 2 (393 mg, 1.0 mmol) and HBTU (476 mg, 1.25 mmol) were placed and dissolved in anhydrous DMF (5.0 mL). NMM (0.14 mL) was added into above reaction flask and it was sealed with a rubber septum and purged with argon and the resulting solution was stirred for 30 min at room temperature. A solution of aniline (112 mg, 1.20 mmol) in 2 mL of DMF was added to the reaction followed by 0.14 mL of NMM and the reaction was stirred for 30 min and then left at room temperature for overnight. The DMF was removed from the solution using a vacuum rotary evaporator using hot bath, dry further on high vacuum pump, and the residue so obtained, was treated with 150 mL of 2% ice cold HCl and sonicated twice for 10 min each time. A white precipitate formed during the sonication step. The flask was removed from the sonicator bath and allowed the precipitate to settled down on the bottom of flask, the liquid layer (water soluble material) was decanted, and the procedure was repeated two additional times with 100 mL of 2% HCl. The solid was collected by filtration, washed with cold water and dried under high vacuum to give a white solid which was subjected to purification by column chromatography over silica gel when eluted from a mixture of CH2Cl2-MeOH (95:5; 90:10; 85:15; 80:20 and 50:50) to give 383 mg (82% yield) of a white solid.
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