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Limited Quantity
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Structure of 455-14-1 * 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 Medicinal Chemistry, 2016, vol. 59, # 21, p. 9814 - 9824
5
[ 455-14-1 ]
[ 26893-12-9 ]
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2004, vol. 14, # 6, p. 1577 - 1580
[2] European Journal of Medicinal Chemistry, 2015, vol. 103, p. 1 - 16
6
[ 455-14-1 ]
[ 87-13-8 ]
[ 26893-12-9 ]
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 1998, vol. 8, # 19, p. 2629 - 2634
[2] Bioorganic and Medicinal Chemistry Letters, 2003, vol. 13, # 8, p. 1487 - 1490
7
[ 455-14-1 ]
[ 821-48-7 ]
[ 30459-17-7 ]
Reference：
[1] European Journal of Pharmaceutical Sciences, 2016, vol. 88, p. 166 - 177
8
[ 455-14-1 ]
[ 400-98-6 ]
Reference：
[1] Journal of Medicinal Chemistry, 1995, vol. 38, # 10, p. 1786 - 1792
[2] Organic and Biomolecular Chemistry, 2016, vol. 14, # 9, p. 2645 - 2650
[3] Patent: CN107032965, 2017, A,
9
[ 455-14-1 ]
[ 49713-56-6 ]
Reference：
[1] Journal of Medicinal Chemistry, 2013, vol. 56, # 19, p. 7679 - 7690
10
[ 1616514-66-9 ]
[ 579-66-8 ]
[ 455-14-1 ]
[ 1616514-74-9 ]
[ 1616514-80-7 ]
[ 1616514-86-3 ]
Yield
Reaction Conditions
Operation in experiment
16%
With hydrogenchloride In ethanol for 2 h; Inert atmosphere; Reflux
General procedure: To a round bottom flask were charged with an N,N′-diaryl hydrazine (9 or 15, 1 mmol), 95percent ethanol (10 mL), and conc. HCl (0.5 mL) under nitrogen at room temperature. The reaction mixture was refluxed for 2 h, then cooled to room temperature, neutralized with solid NaHCO3, filtered, concentrated. The residue was purified by flash column chromatography.
Reference：
[1] Organic and Biomolecular Chemistry, 2014, vol. 12, # 27, p. 4952 - 4963
[2] Tetrahedron, 2016, vol. 72, # 17, p. 2186 - 2195
11
[ 455-13-0 ]
[ 1639128-66-7 ]
[ 579-66-8 ]
[ 455-14-1 ]
[ 1616514-80-7 ]
[ 1616514-86-3 ]
Reference：
[1] Organic and Biomolecular Chemistry, 2014, vol. 12, # 27, p. 4952 - 4963
12
[ 455-14-1 ]
[ 7657-08-1 ]
Reference：
[1] Journal of Organic Chemistry, 1977, vol. 42, p. 2426 - 2431
13
[ 108-22-5 ]
[ 455-14-1 ]
[ 713-45-1 ]
Reference：
[1] Green Chemistry, 2018, vol. 20, # 6, p. 1290 - 1296
[2] Journal of the American Chemical Society, 2015, vol. 137, # 28, p. 8892 - 8895
14
[ 1616514-65-8 ]
[ 455-14-1 ]
[ 24549-06-2 ]
[ 1616514-73-8 ]
[ 1616514-79-4 ]
[ 1616514-85-2 ]
Yield
Reaction Conditions
Operation in experiment
18%
With hydrogenchloride In ethanol for 2 h; Inert atmosphere; Reflux
General procedure: To a round bottom flask were charged with an N,N′-diaryl hydrazine (9 or 15, 1 mmol), 95percent ethanol (10 mL), and conc. HCl (0.5 mL) under nitrogen at room temperature. The reaction mixture was refluxed for 2 h, then cooled to room temperature, neutralized with solid NaHCO3, filtered, concentrated. The residue was purified by flash column chromatography.
Reference：
[1] Organic and Biomolecular Chemistry, 2014, vol. 12, # 27, p. 4952 - 4963
[2] Tetrahedron, 2016, vol. 72, # 17, p. 2186 - 2195
15
[ 455-13-0 ]
[ 1639128-65-6 ]
[ 455-14-1 ]
[ 24549-06-2 ]
[ 1616514-73-8 ]
[ 1616514-85-2 ]
Reference：
[1] Organic and Biomolecular Chemistry, 2014, vol. 12, # 27, p. 4952 - 4963
16
[ 455-14-1 ]
[ 2991-42-6 ]
Reference：
[1] Liebigs Annales, 1997, # 1, p. 141 - 154
[2] Journal of Medicinal Chemistry, 2013, vol. 56, # 13, p. 5261 - 5274
EXAMPLE 163 STR185 Step 1. Preparation of N-(4-trifluoromethylphenyl)-2,2-dimethylpropanamide. A solution of dichloromethane (200 mL), 4-aminobenzotrifluoride (32.0 g, 199 mmol) and triethylamine (40 g, 396 mmol) was cooled to 0° C. under a dry nitrogen atmosphere. Trimethylacetyl chloride (32.9 g, 273 mmol) was added drop-wise over 2 hours, maintaining the temperature below 10° C. After the addition, the contents were allowed to warm to room temperature for 2 hours. The reaction was washed with water (2*200 mL), saturated ammonium chloride solution (2*200 mL), dried over sodium sulfate and filtered. The solvent was removed in vacuo to afford a white solid, N-(4-trifluoromethylphenyl)-2,2-dimethylpropanamide (48.0 g, 98percent): mp 157-159° C. 1 H NMR (CDCl3 /300 MHz) 7.61 (ab, 4H, J=8.7, Δν=28.6 Hz), 7.47 (br s, 1H), 1.33 (s, 9H). ESHRMS m/z 246.1123 (M+H+, Calc'd 246.1106). Anal. Calc'd for C12 H14 F3 NO: C, 58.77; H, 5.75; N, 5.71. Found: C, 58.28; H, 5.79; N, 5.65.
98%
With triethylamine In dichloromethane
Step 1. Preparation of N-(4-trifluoromethylphenyl)-2,2-dimethylpropanamide A solution of dichloromethane (200 mL), 4-aminobenzotrifluoride (32.0 g, 199 mmol) and triethylamine (40 g, 396 mmol) was cooled to 0° C. under a dry nitrogen atmosphere. Trimethylacetyl chloride (32.9 g, 273 mmol) was added drop-wise over 2 hours, maintaining the temperature below 10° C. After the addition, the contents were allowed to warm to room temperature for 2 hours. The reaction was washed with water (2*200 mL), saturated ammonium chloride solution (2*200 mL), dried over sodium sulfate and filtered. The solvent was removed in vacuo to afford a white solid, N-(4-trifluoromethylphenyl)-2,2-dimethylpropanamide (48.0 g, 98percent): mp 157-159° C. 1 H NMR (CDCl3 /300 MHz) 7.61 (ab, 4H, J=8.7, Δν=28.6 Hz), 7.47 (br s, 1H), 1.33 (s, 9H). ESHRMS m/z 246.1123 (M+H+, Calc'd 246.1106). Anal. Calc'd for C12 H14 F3 NO: C, 58.77; H, 5.75; N, 5.71. Found: C, 58.28; H, 5.79; N, 5.65.
97%
With pyridine In dichloromethane
EXAMPLE 65 4'-Trifluoromethyl-2,2-dimethylpropionanilide To a stirred solution of 4-trifluoromethylaniline (25 g, 0.155 mol) and pyridine (62 ml, 0.775 mol) in dichloromethane (300 ml) cooled to 0° C. under nitrogen was added dropwise pivaloyl chloride (19 ml, 0.155 mol). The reaction mixture was stirred at room temperature for 3.5 hr, then diluted with dichloromethane (300 ml). The resulting solution was washed sequentially with 1N aqueous hydrochloric acid solution (2*), saturated aqueous sodium bicarbonate solution, water and brine, dried (anhydrous sodium sulfate)and concentrated in vacuo to yield the title compound as a white solid (37 g, 97percent yield). 1 H NMR (250 MHz, CDCl3) δ 1.33 (s, 9H); 7.74 (b, 1H); 7.57 (d, 2H); 7.67 (d, 2H).
Reference：
[1] Patent: US6034256, 2000, A,
[2] Patent: US6077850, 2000, A,
[3] Patent: US5770594, 1998, A,
[4] Journal of Labelled Compounds and Radiopharmaceuticals, 2010, vol. 53, # 3, p. 141 - 147
[5] Journal of Medicinal Chemistry, 1988, vol. 31, # 6, p. 1215 - 1220
[6] Patent: US2005/54627, 2005, A1, . Location in patent: Page/Page column 38
[7] Patent: US2005/54626, 2005, A1, . Location in patent: Page/Page column 34
[8] European Journal of Medicinal Chemistry, 2010, vol. 45, # 7, p. 2726 - 2732
[9] Journal of Fluorine Chemistry, 2010, vol. 131, # 7, p. 800 - 804
[10] Angewandte Chemie - International Edition, 2015, vol. 54, # 47, p. 14103 - 14107[11] Angew. Chem., 2015, vol. 127, # 47, p. 14309 - 14313,5
[12] Angewandte Chemie - International Edition, 2018, vol. 57, # 29, p. 9108 - 9112[13] Angew. Chem., 2018, vol. 130, p. 9246 - 9250,5
With 1,8-diazabicyclo[5.4.0]undec-7-ene In 1-methyl-pyrrolidin-2-one at 250℃; for 0.2 h; Flow reactor
General procedure: Selective N-monomethlyation reactions were performed in a Vapourtec E-series continuous flow system equipped with a high temperature tube reactor (10 mL, stainless steel, 0.03'' i.d., Fig. 2 ) and a membrane back pressure regulator (Zaiput). Stock solutions of aniline (20 mmol, 1.0 equiv, 2 M), DMC (5.05 mL, 60 mmol, 3.0 equiv, 6 M), and DBU (4.47 mL, 30 mmol, 1.5 equiv, 3 M) were prepared in oven-dried 10 mL volumetric flasks using NMP as the solvent. The solutions were transferred to screw-thread vials with septum caps and reagents were pumped directly from the vials. After the high temperature coiled tube reactor was heated to 250 °C, peristaltic pumps (Vapourtec V-3) were used to pump the reactant solutions into the system (0.277 mL/min each for a 12 min residence time). The solutions were mixed with a cross-mixer (0.4″ i.d.), passed though the high temperature coiled tube reactor. Upon exiting the reactor, the reaction stream was passed through a short segment of stainless steel tubing to enable the reaction to cool and then exited the system by passage through the back pressure regulator (Note: PFA fittings should not be used at the exit of the reactor as they will deform due to the high temperature of the reaction stream and cause leaks in the system. Stainless steel connectors and tubing (12'') were used in our system.). After the flow system was equilibrated for 18 min, the product stream was collected for 5 min (2.77 mmol of aniline). The crude mixture was dissolved in ethyl acetate and washed with brine. The combined organic layers were dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (Biotage 25 g Ultra-sil, 3–15percent ethyl acetate in hexanes) to afford the desired product.
With pyridine; copper diacetate In 1,4-dioxane for 6 h; Reflux
Intermediate 1: N-Methyl-4-(trifluoromethyl) aniline To a mixture of 4-trifluoromethylaniline (196 mg, 1.2 mmol), copper acetate (550 mg, 3.0 mmol) and pyridine (0.34 mL, 4.2 mmol) in dioxane (6 mL) was added methylboronic acid (181 mg, 3.0 mmol, Aldrich, Catalog number: 165335). The mixture was heated with stirring under reflux for 6 hours. The resulting mixture was filtered. The filtrate was concentrated under vacuum and purified by column chromatography to afford N-methyl-4-(trifluoromethyl)-aniline (150 mg, 70 percent). MS obsd. (ESI+) [(M+H)+]: 176
Reference：
[1] Advanced Synthesis and Catalysis, 2017, vol. 359, # 24, p. 4278 - 4283
[2] Inorganic Chemistry, 2015, vol. 54, # 11, p. 5079 - 5084
28
[ 329-17-9 ]
[ 455-14-1 ]
[ 22864-65-9 ]
Reference：
[1] Chemical Communications, 2000, # 5, p. 393 - 394
29
[ 592489-19-5 ]
[ 455-14-1 ]
[ 623-08-5 ]
[ 22864-65-9 ]
Reference：
[1] Bulletin of the Chemical Society of Japan, 2003, vol. 76, # 5, p. 1063 - 1070
30
[ 455-14-1 ]
[ 22864-65-9 ]
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2006, vol. 16, # 10, p. 2621 - 2627
31
[ 455-14-1 ]
[ 149-73-5 ]
[ 22864-65-9 ]
Reference：
[1] Journal of Medicinal Chemistry, 1991, vol. 34, # 11, p. 3295 - 3301
32
[ 455-14-1 ]
[ 598-21-0 ]
[ 3823-19-6 ]
Reference：
[1] Journal of Medicinal Chemistry, 2016, vol. 59, # 24, p. 11148 - 11160
[2] Journal of the American Chemical Society, 1970, vol. 92, p. 2114 - 2118
[3] RSC Advances, 2017, vol. 7, # 54, p. 34005 - 34011
33
[ 22118-09-8 ]
[ 455-14-1 ]
[ 3823-19-6 ]
Reference：
[1] Journal of Medicinal Chemistry, 2014, vol. 57, # 24, p. 10544 - 10550
[2] Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 5, p. 1985 - 1988
[3] ACS Medicinal Chemistry Letters, 2016, vol. 7, # 3, p. 235 - 239
34
[ 455-14-1 ]
[ 372-09-8 ]
[ 24522-30-3 ]
Yield
Reaction Conditions
Operation in experiment
95%
Stage #1: With 4-methyl-morpholine In tetrahydrofuran at 0 - 10℃; for 1 h; Industry scale Stage #2: With isopropyl chloroformate In tetrahydrofuran at 0 - 10℃; for 2 - 3 h; Industry scale
Example 1 Preparation of 4-trifluoromethyl cyanoacetoanilide (compound (IV)) In 700 L of tetrahydrofuran, 63.4 kg of cyanoacetic acid was dissolved with stirring in nitrogen atmosphere at room temperature. This solution was cooled to 0 to 10°C, and then N-methylmorpholine was added dropwise with stirring at the same temperature in about an hour. Then, 100.0 kg of 4-trifluoromethylaniline was added dropwise. To this reaction mixture, 91.3kg of isopropyl chlorocarbonate was added dropwise with stirring at the same temperature in about an hour. Further, the stirring was continued for 1 to 2 hours. After the reaction was finished, 200 L of water was added to the reaction mixture, which was stirred and then allowed to stand for separation. An organic layer (upper layer) was washed with 16.7 percent brine, and then 400 L of isopropyl alcohol was added thereto, which was concentrated under reduced pressure until the liquid amount became 400 L. To the condensed solution, 400 L of isopropyl alcohol was added, which was concentrated again under reduced pressure until the liquid amount became 400 L. To the condensed solution, 100 L of isopropyl alcohol was added at 20 to 30°C with stirring, and then 500 L of water was added dropwise in about an hour. Then, the stirring was further continued for an hour at the same temperature. This mixture was cooled to 0 to 10°C with stirring, and then stirred at the same temperature for an hour. Precipitated crystals were collected by filtration and dried, to give 134.5 kg of the title compound (IV) in a yield of 95.0 percent.
88.15%
With dicyclohexyl-carbodiimide In ethyl acetate at 25 - 30℃; for 2 h; Inert atmosphere
In a 500-ml., four-necked, round-bottomed flask fitted with a mechanical stirrer, a 125-ml dropping funnel, and a thermometer were placed 8.34g. (0.098 moles) of cyanoacetic acid (7) and 165- ml., of ethyl acetate and the mixture was stirred for 10 minutes under nitrogen atmosphere and then added 10.0 g. ( 0.62 moles) of 4-trifluoromethyl aniline (3). From a clean dropping funnel 14.1 g. (0.068 moles, dissolved in ethyl acetate 85mL) of dicyclohexylcarbodiimide was added dropwise over a period of about 1 hour at the same temperature. The reaction mixture was stirred for additional 1.0 hour at 25-30°C. After completion of the reaction precipitated urea was filtered and slurry washed successively with two 50-ml. portions of ethyl acetate and filtered. The organic extracts were combined and washed successively with two 50-ml. portions of 5percent sodium bicarbonate solution, 25-ml.of 5percent hydrochloric acid solution, and again with 50-ml. of 5percent sodium chloride solution. Separated organic layer was evaporated under reduced pressure to yield solid material. To the solid 170-ml isopropyl alcohol was added and the mixture was heated to70-75°C, obtained clear solution and filtered. The filtrate was concentrated to 10 volumes and cooled to 15-20°C. The separated product was filtered and dried in a vacuum oven. Yield =12.5. g (88.15percent), HPLC Purity: 99.6percent
Reference：
[1] Patent: EP1609778, 2005, A1, . Location in patent: Page/Page column 5; 8-9
[2] Patent: WO2017/103942, 2017, A1, . Location in patent: Page/Page column 5; 7
[3] Journal of Medicinal Chemistry, 1996, vol. 39, # 23, p. 4608 - 4621
[4] Journal of Medicinal Chemistry, 2017, vol. 60, # 11, p. 4626 - 4635
[5] Journal of Medicinal Chemistry, 1991, vol. 34, # 11, p. 3295 - 3301
[6] Journal of Labelled Compounds and Radiopharmaceuticals, 2003, vol. 46, p. S119 - S119
[7] Patent: US5714514, 1998, A,
[8] Bioorganic and Medicinal Chemistry, 2009, vol. 17, # 3, p. 1079 - 1087
[9] Patent: EP1609778, 2005, A1, . Location in patent: Page/Page column 5; 10
[10] Journal of Heterocyclic Chemistry, 2011, vol. 48, # 4, p. 901 - 906
35
[ 455-14-1 ]
[ 16130-58-8 ]
[ 24522-30-3 ]
Reference：
[1] Helvetica Chimica Acta, 1998, vol. 81, # 7, p. 1319 - 1328
[2] Journal of Medicinal Chemistry, 2009, vol. 52, # 9, p. 2683 - 2693
36
[ 455-14-1 ]
[ 105-56-6 ]
[ 24522-30-3 ]
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2007, vol. 17, # 5, p. 1369 - 1375
[2] Bioorganic and Medicinal Chemistry Letters, 2009, vol. 19, # 4, p. 1195 - 1198
[3] Indian Journal of Heterocyclic Chemistry, 2012, vol. 21, # 3, p. 225 - 228
37
[ 455-14-1 ]
[ 36140-83-7 ]
[ 24522-30-3 ]
Reference：
[1] Archiv der Pharmazie, 2018, vol. 351, # 7,
38
[ 887144-94-7 ]
[ 455-14-1 ]
[ 367-71-5 ]
Yield
Reaction Conditions
Operation in experiment
82%
With potassium carbonate; nickel(II) hydroxide In dimethyl sulfoxide at 35℃; for 2 h;
In the preparation method of the trifluoromethyl aromatic amine of the present embodiment, the aromatic amine is p-trifluoromethylaniline, and other reactions and post-treatment processes are the same as in the embodiment 28. The preparation method of the trifluoromethyl aromatic amine of the present embodiment, the aromatic amine is aniline, and the nickel compound is nickel hydroxide.The base is potassium carbonate, and the reaction process parameters are: 1-trifluoromethyl-1,2-phenyliodo-3(H)-one (0.5 mmol, 1.0 eq).Aromatic amine (1.5 mmol, 3.0 eq), nickel hydroxide 10 molpercent, potassium carbonate (1.5 mmol, 3.0 eq),DMSO (2 mL) was reacted at 35 ° C for 2 h, and the other reactions and workup procedures were the same as in Example 1.
Reference：
[1] Organic Letters, 2018, vol. 20, # 13, p. 3732 - 3735
[2] Patent: CN108503552, 2018, A, . Location in patent: Paragraph 0142-0146
39
[ 455-14-1 ]
[ 2314-97-8 ]
[ 367-71-5 ]
Yield
Reaction Conditions
Operation in experiment
89%
With fac-tris(2-phenylpyridinato-N,C2')iridium(III); potassium carbonate In 1,2-dichloro-ethane at 20℃; for 24 h; Inert atmosphere; Schlenk technique; Irradiation
General procedure: A 25 mL of Schlenk tube equipped with a magnetic stir bar were charged with aniline (1.2 mmol, 3.0 equiv) or heterocycles (0.8 mmol, 2.0 equiv), K2CO3 (0.8 mmol, 2.0 equiv) and fac-Ir(ppy)3 (2.6 mg, 0.004 mmol, 1 mol percent), under air. The vessel was evacuated and backfilled with Ar (3 times), CF3I stock solution (0.56 mL, 0.71 mmol/mL in 1,2-chloroethane or 0.36 mL, 1.11 mmol/mL in DMSO, 1.0 equiv), anhydrous 1,2-dichloroethane (3 mL) were then added. The tube was screw capped and stirred at room temperature under irradiation of blue LEDs (12 W) for 24 hours. The reaction S15 mixture was filtered through a pad of Celite and washed with ethyl acetate (3×5 mL). The filtrate was concentrated. The residue was subjected to column chromatography on silica gel to afford the pure product.
Reference：
[1] Journal of Organic Chemistry, 2014, vol. 79, # 19, p. 8984 - 8989
41
[ 455-14-1 ]
[ 128796-39-4 ]
Yield
Reaction Conditions
Operation in experiment
62%
Stage #1: With hydrogenchloride; sodium nitrite In methanol; water at 0 - 5℃; for 0.5 h; Stage #2: With tetrahydroxydiboron In methanol; water at 20℃; for 1 h;
General procedure: To a solution of arylamine (0.5 mmol, 1.0 equiv) in MeOH(1.0 mL) was added HCl (0.5 mL, 1.5 mmol, 3.0 equiv), followed by H2O (0.5 ml). This mixture was stirred 2 min,and the NaNO2 solution (0.25 mL) was then added. The NaNO2 solution was prepared by dissolving 35 mg ofNaNO2 in H2O (0.25 mL). This mixture was stirred 30 minat 0–5 °C, followed by HCl (135 mg, 1.5 mmol, 3.0 equivalents) in MeOH (1.0 mL). This mixture was stirred 60min. H2O (10 mL) was added to reaction mixture, then extracted with CH2Cl2 (50 mL, 3×). The combined organic layer was dried over Na2SO4, followed by evaporation to give the products.
With chlorine In chlorobenzene at 110℃; for 6.5 h;
12 140 kg of pure monochlorobenzene are charged to a 20 m3 jacketed reactor rendered inert with nitrogen. The solvent heel is subsequently brought to 110C by heating the jacket. The reactor is subsequently fed with a 70percent solution of para-trifluoromethylaniline in monochlorobenzene at a flow rate of 792 kg/h for 6 h 30 and with Cl at a flow rate of 488 kg/h. The temperature is maintained at 110C by cooling the jacket. Once feeding is complete, the residual content of para-trifluoromethylaniline or of monochloro derivative is monitored. If one of these compounds remains, it is then advisable to adjust the amount of chlorine in order to consume the residual product. At the end of the reaction, the monochlorobenzene is distilled off by placing the reactor under gradually increasing vacuum through a distillation column. After removal of the solvent, the 2,6-dichloro-para-trifluoromethylaniline is cooled to 60C before emptying the reactor to the storage tank.
With sodium hydrogencarbonate In N,N-dimethyl acetamide; toluene
c) 4-Trifluoromethylaniline (5.75 g, 35.7 mm) was dissolved in a mixture of NaHCO3 (3.16 g, 37.6 mm), N,N-dimethylacetamide (0.7 ml, 7.5 mm) and toluene (70 ml). The mixture was warmed to 40° C. and 5-methylisoxazole-4-carboxylic acid chloride (5 g, 34.4 mm) was added dropwise over 20 min. The mixture was stirred at this temperature for another 3 h. and then it was heated to reflux temperature. The hot mixture was washed with water (3*10 ml). The organic phase was allowed to cool to ambient temperature, which induced leflunomide to precipitate as a white powder. The powder was isolated by filtration and then dried at 60° C. to give leflunomide (8.0 g, 86percent) in 99.5percent purity.
Reference：
[1] Farmaco, 1991, vol. 46, # 6, p. 789 - 802
[2] Patent: US2002/22646, 2002, A1,
[3] Chemistry - A European Journal, 2014, vol. 20, # 31, p. 9514 - 9518
[4] Patent: US2002/22646, 2002, A1,
[5] Patent: US5494911, 1996, A,
[6] Patent: US5504084, 1996, A,
[7] Patent: US5547971, 1996, A,
[8] Patent: US5519042, 1996, A,
[9] Patent: US4284786, 1981, A,
[10] Patent: WO2016/203410, 2016, A1, . Location in patent: Page/Page column 15; 16; 19
45
[ 455-14-1 ]
[ 75706-12-6 ]
Yield
Reaction Conditions
Operation in experiment
62.34%
Stage #1: With thionyl chloride In toluene at 25 - 70℃; for 6 h; Stage #2: at 0 - 30℃; for 6 h;
N-(4'-trifluoromethyIp)-5-methylisoxazole-4-carboxamide:5-Methylisoxazole~4-carboxylic acid 25.0 g (0.197 mol) was taken in toluene (312.5 ml), heated to reflux arid 62.5 ml toluene was distilled off. The solution was cooled to 25-30 0C. To this solution N, N-Dimethylformamide (0.16 ml) and thionyl chloride 25.68 g (0.216 mol) was added at 25-30 C and heated to 65 to 70 0C for 6 hours. Then the reaction mass was cooled to 0 0C and 4-trifluoromethylaniline 30.07 g (0.199 mol) was added drop wise at this temperature. The resulted reaction mixture was stirred at the same temperature for 2 hours, allowed to come to 25-30 0C and stirred for 4 hours. Water (125 ml) was added to the ' reaction mixture and stirred for 2 hours. The solid was separated out, which was filtered and washed with water (250 ml), dried under vacuum at 80 0C to obtain 40.25 g off white solid which was purified with toluene to give 33.15 g (62.34 percent) leflunomide with 99.9percent HPLC purity and any individual impurity less than 0.1percent.
Reference：
[1] Journal of Organic Chemistry, 1985, vol. 50, # 23, p. 4576 - 4582
49
[ 455-14-1 ]
[ 2923-56-0 ]
Reference：
[1] Journal of Organic Chemistry, 1995, vol. 60, # 8, p. 2411 - 2422
[2] Journal of Agricultural and Food Chemistry, 2014, vol. 62, # 2, p. 381 - 390
[3] Advanced Synthesis and Catalysis, 2014, vol. 356, # 7, p. 1571 - 1576
[4] Advanced Synthesis and Catalysis, 2015, vol. 357, # 4, p. 761 - 766
[5] Journal of the Chinese Chemical Society, 2018, vol. 65, # 5, p. 538 - 547
50
[ 455-14-1 ]
[ 163444-17-5 ]
Yield
Reaction Conditions
Operation in experiment
97%
With Iodine monochloride In methanol; dichloromethane at 0 - 20℃;
Step 2 2-Iodo-4-(trifluoromethyl)aniline A 500 mL 3-necked round bottom flask was charged with 4-(trifluoromethyl)aniline (22.5 g, 0.14 mol) and MeOH (100 mL). To the above was added dropwise a solution of IC1 (25 g, 0.15 mol) in CH2Cl2 (100 mL) at 0° C. The resulting mixture was stirred at room temperature for 1 h. Reaction progress was monitored by TLC (EtOAc/Petroleum ether=1:10, Rf=0.5). Work-up: the mixture was concentrated in vacuo. The residue was re-dissolved in CH2Cl2, washed with water, dried over anhydrous Na2SO4 and concentrated in vacuo, to give 37.8 g (97percent) of the product. 1H NMR (300 MHz, CDCl3) δ: 7.86 (d, J=1.2 Hz, 1H), 7.36 (dd, J=8.4, 1.8 Hz, 1H), 6.73 (d, J=8.7 Hz, 1H), 4.41 (br, 2H).
97%
With Iodine monochloride In methanol; dichloromethane at 0 - 20℃; for 1 h;
A 500 mL 3-necked round bottom flask was charged with 4- (trifluoromethyl)aniline (22.5 g, 0.14 mol) and MeOH (100 mL). To the above was added dropwise a solution of ICl (25 g, 0.15 mol) in CH2C12 (100 mL) at 0 °C. The resulting mixture was stirred at room temperature for 1 h. Reaction progress was monitored by TLC (EtO Ac/Petroleum ether = 1 : 10, Rf = 0.5). Work-up: the mixture was concentrated in vacuo. The residue was re-dissolved in CH2C12, washed with water, dried over anhydrous Na2S04 and concentrated in vacuo, to give 37.8 g (97percent) of the product. *H NMR (300 MHz, CDC13) δ: 7.86 (d, J = 1.2 Hz, 1H), 7.36 (dd, J = 8.4, 1.8 Hz, 1H), 6.73 (d, J = 8.7 Hz, 1H), 4.41 (br, 2H).
89%
With N-iodo-succinimide; [bis(trifluoromethanesulfonyl)imidate](triphenylphosphine)gold(I) In 1,2-dichloro-ethane; toluene at 85℃; for 14 h;
General procedure: To a stirred solution of the substrate (1 mmol) in CH2Cl2 or (CH2Cl)2 (0.1 M) were added Ph3PAuNTf2 (0.025 mmol, 19 mg; complex Ph3PAuNTf2 toluene, 2:1) followed by N-iodosuccinimide (1.1 mmol, 248 mg). The resulting solution was stirred at r.t. or under reflux until complete conversion of the starting material. After removal of the solvent under reduced pressure, the crude material was purified by flash column chromatography using different gradients of hexanes and EtOAc to obtain the pure desired products.
75%
With N,N,N-trimethylbenzenemethanaminium dichloroiodate; calcium carbonate In methanol; dichloromethane at 20℃; for 24 h;
PREPARATION 4; 2-Iodo-4-(trifluoromethyl)aniline; A solution of 5 g (31 mM) of 4-(trifluoromethyl)aniline in 90 ml of methanol and 30 ml of dichloromethane is prepared and 3.56 g (35.6 mM) of calcium carbonate are added. 14.9 g (42.7 mM) of trimethylbenzylammonium dichloroiodide are then added in portions at room temperature, with stirring. The reaction medium is stirred for 24 hours at room temperature and then filtered to remove the mineral salts. The filtrate is concentrated under reduced pressure and the crude product is purified by chromatography on silica gel using a cyclohexane/ethyl acetate mixture (8/2; v/v) as the eluent to give 6.65 g of the expected compound in the form of an orange oil (yield=75percent).1H NMR (CDCl3, 300 MHz) δ=5.0 (s, 2H), 6.82 (d, J=5.5 Hz, 1H), 7.38 (dd, J=5.5 Hz, 1.3 Hz, 1H), 7.79 (d, J=1.3 Hz, 1H).
70%
With Iodine monochloride In methanol; dichloromethane at 20℃;
To a solution of 4-(trifluoromethyl)benzenamine (10.0 g, 0.0617 mol) in dry methanol (200 ml) was added iodine monochloride (10.49 g, 0.148 mol) in dry MDC (40 ml) at RT slowly. Reaction mixture was stirred at RT over night. The reaction mixture was concentrated, water was added and extracted with ethyl acetate (2.x.100 ml). The organic layer was washed with water, brine (2.x.50 ml), dried over Na2SO4 and concentrated. The crude product was purified by column chromatography using 6percent ethyl acetate in pet-ether to get 2-iodo-4-(trifluoromethyl)benzenamine (12.5 g, 70percent) as pale yellow liquid. 1H NMR (400 MHz, CDCl3) δ 4.42 (bs, 2H), 6.75 (d, 1H), 7.38 (d, 1H), 7.87 (s, 1H).
61%
With iodine; silver sulfate In ethanol at 20℃; for 18 h;
Method DSynthesis of substituted 2-(1 H-indol-3-yl)ethanamineStep I: substituted 2-iodo-aniline Iodine (1 eq) was added to a stirred mixture of silver sulphate (1 eq) and an aniline (1 eql) in ethanol (6.21 mL/mmol). The reaction mixture was then stirred at room temperature for 18 hours and filtered over celite. The solution was concentrated under reduced pressure and the residue was partitioned between ethyl acetate and a saturated aqueous solution of sodium thiosulphate. The organic layer was washed with brine, dried with magnesium sulphate and concentrated under reduced pressure. The crude residue was purified by flash chromatography on silica gel to yield a substituted 2-iodo-aniline; INTERMEDIATE 10 - PREPARATION of 2-iodo-4-(trifluoromethyl)aniline. 2-iodo-4-(trifluoromethyl)aniline was prepared according to method D Step I with iodine (1.58 g; 6.21 mmol), silver sulphate (1.94 g; 6.21 mmol) and 4-(trifluoromethyl)aniline (0.8 mL; 6.21 mmol) in ethanol (40 mL). The crude residue was purified by flash chromatography on silica gel (eluent 2 to 40 percent ethyl acetate in heptane) to afford 1.08 g (61 percent) of 2-iodo-4-(trifluoromethyl)aniline as a red oil.1 H NMR (DMSO-d6) δ 7.80 (s, 1 H), 7.38 (d, 1 H), 6.82 (d, 2H), 5.93 (s, 2H).
61%
With iodine; silver sulfate In ethanol at 20℃; for 18 h;
INTERMEDIATE 40 - PREPARATION of 2-lodo-4-(trifluoromethyl)aniline. Iodine (1.58 g; 6.21 mmol) was added to a stirred mixture of silver sulphate (1.94 g; 6.21 mmol) and 4-(trifluoromethyl)aniline (0.8 mL; 6.21 mmol) in ethanol (40 mL). The reaction mixture was then stirred at room temperature for 18 hours and filtered over celite. The volatiles were removed under reduced pressure and the residue was partitioned between ethyl acetate and a saturated aqueous solution of sodium thiosulfate. The organic layer was washed with brine, dried and concentrated under reduced pressure. The crude residue was purified by flash chromatography on silica gel (eluent 2 to 40 percent ethyl acetate in heptane) to afford 1.08 g (61 percent) of the title compound as a red oil.1 H NMR (DMSO-d6) δ 7.80 (s, 1 H), 7.38 (d, 1 H), 6.82 (d, 2H), 5.93 (s, 2H).
61%
With iodine; silver sulfate In ethanol at 20℃; for 18 h;
Iodine (1.58 g; 6.21 mmol) was added to a stirred mixture of silver sulphate (1.94 g; 6.21 mmol) and 4-(trifluoromethyl)aniline (0.8 mL; 6.21 mmol) in ethanol (40 mL). The reaction mixture was then stirred at room temperature for 18 hours and filtered over celite. The volatiles were removed under reduced pressure and the residue was partitioned between ethyl acetate and a saturated aqueous solution of sodium thiosulfate. The organic layer was washed with brine, dried and concentrated under reduced pressure. The crude residue was purified by flash chromatography on silica gel (eluent 2 to 40percent ethyl acetate in heptane) to afford 1.08 g (61percent) of the title compound as a red oil. [0628] 1H NMR (DMSO-d6) δ 7.80 (s, 1H), 7.38 (d, 1H), 6.82 (d, 2H), 5.93 (s, 2H).
61%
With iodine; silver sulfate In ethanol at 20℃; for 18 h;
Iodine (1 eq) was added to a stirred mixture of silver sulphate (1 eq) and an aniline (1 eql) in ethanol (6.21 mL/mmol). The reaction mixture was then stirred at room temperature for 18 hours and filtered over celite. The solution was concentrated under reduced pressure and the residue was partitioned between ethyl acetate and a saturated aqueous solution of sodium thiosulphate. The organic layer was washed with brine, dried with magnesium sulphate and concentrated under reduced pressure. The crude residue was purified by flash chromatography on silica gel to yield a substituted 2-iodo-aniline. 2-iodo-4-(trifluoromethyl)aniline was prepared according to method D Step I with iodine (1.58 g; 6.21 mmol), silver sulphate (1.94 g; 6.21 mmol) and 4-(trifluoromethyl)aniline (0.8 mL; 6.21 mmol) in ethanol (40 mL). The crude residue was purified by flash chromatography on silica gel (eluent 2 to 40percent ethyl acetate in heptane) to afford 1.08 g (61percent) of 2-iodo-4-(trifluoromethyl)aniline as a red oil. [0533] 1H NMR (DMSO-d6) δ 7.80 (s, 1H), 7.38 (d, 1H), 6.82 (d, 2H), 5.93 (s, 2H).
61%
With iodine; silver sulfate In ethanol at 20℃; for 18 h;
INTERMEDIATE 132 - PREPARATION of 2-iodo-4-(trifluoromethyl)aniline; Iodine (1.58 g; 6.21 mmol) was added to a stirred mixture of silver sulphate (1.94 g; 6.21 mmol) and 4-(trifluoromethyl)aniline (0.8 ml 6.21 mmol) in ethanol (40 ml_). The reaction mixture was then stirred at room temperature for 18 hours and filtered through celite. The volatiles were removed under reduced pressure and the residue was partitioned between ethyl acetate and a saturated aqueous solution of sodium thiosulphate. The organic layer was washed with brine, dried and concentrated under reduced pressure. The crude residue was purified by flash chromatography on silica gel (eluent 2 to 40 percent ethyl acetate in heptane) to afford 1.08 g (61 percent) of 2-iodo-4-(trifluoromethyl)aniline as a red oil. 1H NMR (DMSO-de) δ 7.80 (s, 1 H), 7.38 (d, 1 H), 6.82 (d, 2H), 5.93 (s, 2H)
2.3 g
With iodine; silver sulfate In ethanol at 20℃; for 1 h;
A mixture of 2.5 g of 4-trifluoromethylaniline, 3.9 g of iodine, 4.8 g of silver (I) sulfate, and 300 ml of ethanol was stirred for 1 hour at room temperature. The reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure. The residues were subjected to silica gel column chromatography, thereby obtaining 2.3 g of 2-iodo-4-trifluoromethylaniline.1H-NMR (CDC13) ö: 7.88-7.85 (m, 1H), 7.40-7.35 (m, 1H), 6.74 (d, 1H, J=8.3 Hz), 4.42 (br s, 2H)
Reference：
[1] Heterocycles, 2002, vol. 57, # 3, p. 465 - 476
[2] Patent: US2010/120741, 2010, A1, . Location in patent: Page/Page column 91
[3] Patent: WO2011/112731, 2011, A2, . Location in patent: Page/Page column 196
[4] Synthesis, 2004, # 11, p. 1869 - 1873
[5] Synlett, 2014, vol. 25, # 3, p. 399 - 402
[6] Bioorganic and Medicinal Chemistry Letters, 2010, vol. 20, # 9, p. 2722 - 2725
[7] Patent: US2008/153816, 2008, A1, . Location in patent: Page/Page column 7
[8] Organic Letters, 2011, vol. 13, # 12, p. 3242 - 3245
[9] Patent: US2005/54626, 2005, A1, . Location in patent: Page/Page column 34
[10] Tetrahedron, 1994, vol. 50, # 25, p. 7343 - 7366
[11] Patent: WO2012/80220, 2012, A1, . Location in patent: Page/Page column 71; 75
[12] Patent: WO2012/80221, 2012, A1, . Location in patent: Page/Page column 84-85
[13] Patent: US2013/274260, 2013, A1, . Location in patent: Paragraph 0627-0628
[14] Patent: US2013/289033, 2013, A1, . Location in patent: Paragraph 0510; 0532-0533
[15] Patent: WO2010/142801, 2010, A1, . Location in patent: Page/Page column 187
[16] Arzneimittel-Forschung/Drug Research, 2000, vol. 50, # 12, p. 1084 - 1092
[17] Bioorganic and Medicinal Chemistry Letters, 2003, vol. 13, # 24, p. 4385 - 4388
[18] Organic Letters, 2005, vol. 7, # 10, p. 2043 - 2046
[19] Synlett, 2006, # 1, p. 65 - 68
[20] Journal of Organic Chemistry, 2006, vol. 71, # 18, p. 7079 - 7082
[21] Journal of Organic Chemistry, 2009, vol. 74, # 17, p. 6631 - 6636
[22] Patent: WO2005/13985, 2005, A1, . Location in patent: Page/Page column 47-49
[23] Bioorganic and Medicinal Chemistry Letters, 2013, vol. 23, # 5, p. 1351 - 1357
[24] Patent: US2015/289512, 2015, A1, . Location in patent: Paragraph 1208; 1209
[25] Journal of Organic Chemistry, 2016, vol. 81, # 22, p. 10987 - 10999
Reference：
[1] Journal of Medicinal Chemistry, 1998, vol. 41, # 10, p. 1598 - 1612
53
[ 455-14-1 ]
[ 100846-24-0 ]
Reference：
[1] Heterocycles, 2002, vol. 57, # 3, p. 465 - 476
[2] Heterocycles, 2002, vol. 57, # 3, p. 465 - 476
[3] Journal of Medicinal Chemistry, 1998, vol. 41, # 10, p. 1598 - 1612
54
[ 455-14-1 ]
[ 87-13-8 ]
[ 175203-85-7 ]
Reference：
[1] Patent: US6093732, 2000, A,
55
[ 455-14-1 ]
[ 57946-63-1 ]
Yield
Reaction Conditions
Operation in experiment
50%
With N-Bromosuccinimide In dichloromethane
Add 200 mL of distilled CH2Cl 2 and 4- (trifluoromethyl) aniline (20 g, 124.13 mmol) to a two neck flask. Slowly dropwise N-bromosuccinimide (24.3 g, 136.5 mmol) dissolved in CH2Cl2. When the reaction is complete, extract with CH2Cl2. Purification by column separation (EA: Hx = 1: 4) (yield: 50percent)
Reference：
[1] Journal of Organic Chemistry, 2018, vol. 83, # 2, p. 930 - 938
[2] Patent: KR2018/50795, 2018, A, . Location in patent: Paragraph 0086; 0087; 0104-0106
[3] Patent: US3946025, 1976, A,
[4] Chinese Journal of Chemistry, 2018, vol. 36, # 9, p. 815 - 818
[5] Patent: US3995042, 1976, A,
With sodium acetate; acetic acid; at 5 - 20℃; for 2h;
4-trifluoromethylaniline (5.54 g, 34.4 mmol) was added to 12.5 mL of a saturated sodium acetate solution, An additional 12.5 mL of acetic acid solution was added to form a suspension. The suspension was placed in an ice bath, and bromoacetyl bromide (2.75 mL, 34.4 mmol) was added dropwise when the temperature was lower than 5 C. After the dripping was completed, the ice bath was taken out and stirred at room temperature for 2 hours. The precipitate was filtered, washed with distilled water (2 × 5 mL), and dried under vacuum to obtain the crude compound 4e, which was recrystallized from absolute ethanol. White solid; Yield: 88%;
EXAMPLE 163 STR185 Step 1. Preparation of N-(4-trifluoromethylphenyl)-2,2-dimethylpropanamide. A solution of dichloromethane (200 mL), 4-aminobenzotrifluoride (32.0 g, 199 mmol) and triethylamine (40 g, 396 mmol) was cooled to 0 C. under a dry nitrogen atmosphere. Trimethylacetyl chloride (32.9 g, 273 mmol) was added drop-wise over 2 hours, maintaining the temperature below 10 C. After the addition, the contents were allowed to warm to room temperature for 2 hours. The reaction was washed with water (2*200 mL), saturated ammonium chloride solution (2*200 mL), dried over sodium sulfate and filtered. The solvent was removed in vacuo to afford a white solid, N-(4-trifluoromethylphenyl)-2,2-dimethylpropanamide (48.0 g, 98%): mp 157-159 C. 1 H NMR (CDCl3 /300 MHz) 7.61 (ab, 4H, J=8.7, Deltanu=28.6 Hz), 7.47 (br s, 1H), 1.33 (s, 9H). ESHRMS m/z 246.1123 (M+H+, Calc'd 246.1106). Anal. Calc'd for C12 H14 F3 NO: C, 58.77; H, 5.75; N, 5.71. Found: C, 58.28; H, 5.79; N, 5.65.
98%
With triethylamine; In dichloromethane;
Step 1. Preparation of N-(4-trifluoromethylphenyl)-2,2-dimethylpropanamide A solution of dichloromethane (200 mL), 4-aminobenzotrifluoride (32.0 g, 199 mmol) and triethylamine (40 g, 396 mmol) was cooled to 0 C. under a dry nitrogen atmosphere. Trimethylacetyl chloride (32.9 g, 273 mmol) was added drop-wise over 2 hours, maintaining the temperature below 10 C. After the addition, the contents were allowed to warm to room temperature for 2 hours. The reaction was washed with water (2*200 mL), saturated ammonium chloride solution (2*200 mL), dried over sodium sulfate and filtered. The solvent was removed in vacuo to afford a white solid, N-(4-trifluoromethylphenyl)-2,2-dimethylpropanamide (48.0 g, 98%): mp 157-159 C. 1 H NMR (CDCl3 /300 MHz) 7.61 (ab, 4H, J=8.7, Deltanu=28.6 Hz), 7.47 (br s, 1H), 1.33 (s, 9H). ESHRMS m/z 246.1123 (M+H+, Calc'd 246.1106). Anal. Calc'd for C12 H14 F3 NO: C, 58.77; H, 5.75; N, 5.71. Found: C, 58.28; H, 5.79; N, 5.65.
97%
With pyridine; In dichloromethane;
EXAMPLE 65 4'-Trifluoromethyl-2,2-dimethylpropionanilide To a stirred solution of 4-trifluoromethylaniline (25 g, 0.155 mol) and pyridine (62 ml, 0.775 mol) in dichloromethane (300 ml) cooled to 0 C. under nitrogen was added dropwise pivaloyl chloride (19 ml, 0.155 mol). The reaction mixture was stirred at room temperature for 3.5 hr, then diluted with dichloromethane (300 ml). The resulting solution was washed sequentially with 1N aqueous hydrochloric acid solution (2*), saturated aqueous sodium bicarbonate solution, water and brine, dried (anhydrous sodium sulfate)and concentrated in vacuo to yield the title compound as a white solid (37 g, 97% yield). 1 H NMR (250 MHz, CDCl3) delta 1.33 (s, 9H); 7.74 (b, 1H); 7.57 (d, 2H); 7.67 (d, 2H).
With triethylamine; In benzene; at 0 - 20℃;
Synthesis of 5-(trifluoromethyl)-2-(trifluoromethylsulfonamido)benzoic acid Preparation B6, Step 1: To a solution of 4-trifluoromethylaniline (5 g, 0.031 mol) in 50 ml of dry benzene was added triethylamine (6.26 g, 8.63 ml, 0.06 mol) at 0 C. Pivaloyl chloride (4.5 g, 0.04 mol) was added slowly and stirred at RT over night. The RM was quenched with water and extracted with ethyl acetate. The organic layer was washed with water, brine and concentrated. To the solid was triturated with pet-ether and filtered to give N-(4-(trifluoromethyl)phenyl)-pivalamide (6.7 g) as white solid.
With triethylamine; In benzene; at 0 - 20℃;
Preparation B6: Synthesis of 5-(trifluoromethyl)-2-(trifluoromethylsulfonamido)benzoic Acid Preparation B6, Step 1: To a solution of 4-trifluoromethylaniline (5 g, 0.031 mol) in 50 ml of dry benzene was added triethylamine (6.26 g, 8.63 ml, 0.06 mol) at 0 C. Pivaloyl chloride (4.5 g, 0.04 mol) was added slowly and stirred at RT over night. The RM was quenched with water and extracted with ethyl acetate. The organic layer was washed with water, brine and concentrated. To the solid was triturated with pet-ether and filtered to give N-(4-(trifluoromethyl)phenyl)-pivalamide (6.7 g) as white solid.
General procedure: A mixture of 0.1 mol of 4?substituted aniline and 0.1 mol ofPotassium thiocyanate (KCNS) in 100 ml glacial acetic acid (AcOH) was cooled inan ice bath and stirred for 10 to 20 min, and then 0.1 mol bromine in glacialacetic acid was added dropwise at such a rate to keep the temperature below 10C throughout the addition. Theprogress of the reaction was monitored by Thin Layer Chromatography usingtoluene: acetone (8:2) solvent system. The reaction mixture was stirredat room temperature for 2 to 4 hrs, the hydrobromide (HBr) salt thus separatedout was filtered, washed with acetic acid, dried, dissolved in hot water and basified to pH 11.0 with ammonia solution (NH4OH)and the resulting precipitate was filtered, washed with water and dried to getthe desired product 2a-q.
With chlorine; In chlorobenzene; at 110℃; for 6.5h;
12 140 kg of pure monochlorobenzene are charged to a 20 m3 jacketed reactor rendered inert with nitrogen. The solvent heel is subsequently brought to 110C by heating the jacket. The reactor is subsequently fed with a 70percent solution of para-trifluoromethylaniline in monochlorobenzene at a flow rate of 792 kg/h for 6 h 30 and with Cl at a flow rate of 488 kg/h. The temperature is maintained at 110C by cooling the jacket. Once feeding is complete, the residual content of para-trifluoromethylaniline or of monochloro derivative is monitored. If one of these compounds remains, it is then advisable to adjust the amount of chlorine in order to consume the residual product. At the end of the reaction, the monochlorobenzene is distilled off by placing the reactor under gradually increasing vacuum through a distillation column. After removal of the solvent, the 2,6-dichloro-para-trifluoromethylaniline is cooled to 60C before emptying the reactor to the storage tank.
With hydrogen iodide; In 1,4-dioxane; water; at 130℃; for 0.166667h;Microwave irradiation;
C. 7-Benzyl-N- (4- (trifluoromethyl) phenyl) -5,6, 7,8-tetrahydropyrido [3,4-d] pyrimidin-4-amine [00229] 7-Benzyl-4-chloro-5, 6,7, 8-tetrahydro-pyrido [3, 4-d] pyrimidine (0.6g, 2.3mmol) was dissolved in anhydrous dioxane (2mL) and 4- (trifluoromethyl) aniline was added (0. 43mL, 3.45 mmol), followed by HI/H20 (0. 2ml, 47%). The mixture was heated at 130C in a sealed tube for 10 min in a microwave (Smith creator model, Personal Chemistry). The solvents were removed under vacuum and the residue was dissolved in ethyl acetate and washed with sat. NaHC03 and brine. The organic layer was dried over Na2SO4, filtered and evaporated to give the desired compound as a yellow solid (800mg, 91%) which was used as such for the next step.
With sodium t-butanolate;bis-triphenylphosphine-palladium(II) chloride; In N,N-dimethyl-formamide; at 120℃;
To a solution of 7-benzyl4-chloro-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine (1 g, 4 mmol.) in 10 ml of N,N-dimethylformamide dichlorobis(triphenylphosphine)palladium(II) (100 mg), 4-trifluoromethylaniline (1.2 eq) and sodium tert-butoxide (2 eq) were added. The reaction mixture was heated to 120 C. overnight and cool to room temperature. The reaction was quenched with water and extracted with ethyl acetate (3*50 mL) to give dark brown crude material. The crude material was chromatographed on silica gel, eluding with methanol/dichloromethane to afford the title product.
With HI; sodium iodide; In hexane; water; ethyl acetate; acetonitrile;
C. 7-Benzyl-N-(4-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-amine 7-Benzyl-4-chloro-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine (12.0 g, 46.3 mmol) was dissolved in 20 mL of anhydrous acetonitrile and 4-(trifluoromethyl)aniline was added (7.0 mL, 55.6 mmol), followed by 47% HI/H2O (2.0 L) and sodium iodide (10.3 g, 69.5 mmol). The mixture was heated at refluxed overnight and solvents were removed under vacuum. The residue was dissolved in ethyl acetate and washed with sat. NaHCO3 and brine. The organic layer was dried over Na2SO4, filtered and evaporated to a yellow solid which was purified by silica gel flash chromatography using a gradient of ethyl acetate:hexane (0-100%) to give the desired compound as a brown oil (15 g). MS: M+H=385.
With 2-methoxy-ethanol; at 150℃; for 3h;
A mixture of <strong>[192869-80-0]7-benzyl-4-chloro-5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidine</strong> (233 mg, 0.9 mmol, prepared according to the procedure described in WO2003076427), 4-trifluoromethyl-phenylamine (188 mg, 1.17 mmol, Aldrich) and 2-methoxyethanol (0.5 mL) was heated at 150 C. in a sealed glass tube with stirring for 3 h. The reaction mixture was cooled to room temperature and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (gradient, 60 to 90% EtOAc/hexane) to provide the title compound as a brown amorphous solid. MS (ESI, pos. ion.) m/z: 385 (M+1).
Step D; Methyl 2-Nitro-3r (4-trifluoromethylphenYlimino) methyllbenzoate; Heat a mixture of <strong>[138229-59-1]methyl 3-formyl-2-nitrobenzoate</strong> (4.03 g, 19. 27 mmol) and 4- trifluoromethyl-phenylamine (3.26 g, 20.23 mmol) in ethanol (15 mL) at reflux under nitrogen for 2 h and cool the mixture to room temperature. Dilute the mixture with hexanes (75 mL), stir for 2.5 h and collect the solids by vacuum filtration, washing with hexanes (10 mL) to provide methyl 2-nitro-3- [ (4- trifluoromethylphenylimino) methyllbenzoate as a white solid (5.35 g, 79%) : 1H NMR (CDC13) 8 3.95 (s, 1H), 7.26 (d, 2H), 7.67 (d, 2H), 7.73 (d, 1H), 8.16 (dd, 1H), 8.36 (s, 1H), 8. 51 (dd, 1H); APCI MS mAz 353 [Cl6HlIF3N204 + H1+.
Preparation of ethyl 1-(4-trifluoromethylphenylaminocarbonyl)cyclopropanecarboxylate 1-Carboethoxycyclopropanecarboxylic acid (9.81 grams, 0.06 mole), ethyl chloroformate (6.73 grams, 0.06 mole) and 4-aminobenzotrifluoride (10.0 grams, 0.06 mole) were reacted sequentially in the presence of triethylamine (6.28 grams, 0.06 mole) in a manner similar to that described in Example XXXIII to give 10.25 grams (0.03 mole) of ethyl 1-(4-trifluoromethylphenylaminocarbonyl)cyclopropanecarboxylate having a melting point of 80.5 C.-82.0 C. Elemental analysis of the product indicated the following: Analysis: C14 H14 F3 NO3 Calculated: C, 55.82; H, 4.68; N, 4.65; Found: C, 55.53; H, 5.01; N, 4.43.
triethylamine;
Preparation of ethyl 1-(4-trifluoromethylphenylaminocarbonyl)cyclopropanecarboxylate 1-Carboethoxycyclopropanecarboxylic acid (9.81 grams, 0.06 mole), ethyl chloroformate (6.73 grams, 0.06 mole) and 4-aminobenzotrifluoride (10.0 grams, 0.06 mole) were reacted sequentially in the presence of triethylamine (6.28 grams, 0.06 mole) in a manner similar to that described in Example XXXIII to give 10.25 grams (0.03 mole) of ethyl 1-(4-trifluoromethylphenylaminocarbonyl)cyclopropanecarboxylate having a melting point of 80.5 C.-82.0 C. elemental analysis of the product indicated the following: Analysis: C14 H14 F3 NO3: Calculated: C, 55.82; H, 4.68; N, 4.65. Found: C, 55.53; N, 5.01; N, 4.43.
PREPARATION 37 4-Trifluoromethyl-N-pivaloylaniline To a solution of 6.87 g (0.043 mol) of 4-trifluoromethylaniline in 110 ml of dichloromethane was added 5.25 ml (0.043 mol) of pivaloylchloride. After stirring for 1.5 hours, 190 ml of a saturated solution of aqueous sodium bicarbonate was added. The reaction proceeded an additional 2 hours and the organic layer was separated and dried over anhydrous magnesium sulfate. The solution was filtered and the solvent removed to give the title compound, yield 9.16 g (88percent), m.p. 154°-158° C.
N-[5-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-acetoxybenzoyl]-4-trifluoromethylaniline[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With triethylamine; In dichloromethane;
Example 112 N-[5-(5,6-Dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-acetoxybenzoyl]-4-trifluoromethylaniline 4-Trifluoromethylaniline (0.258 g, 1.60 mmol), triethylamine (0.162 g, 1.60 mmol) and <strong>[37091-73-9]2-chloro-1,3-dimethylimidazolinium chloride</strong> (0.271 g, 1.60 mmol) were added to a methylene chloride solution (20 ml) of 5-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-acetoxybenzoic acid (0.200 g, 0.535 mmol) and the resulting solution was stirred at room temperature for 12 hours. The reaction solution was poured into ice water and then extracted with methylene chloride. The extract was washed with water and then dried, and the solvent was removed by distillation. The obtained residue was purified by preparative thin-layer chromatography (hexane: ethyl acetate = 1:2) to obtain the titled compound (0.123 g, 0.238 mmol, 44percent).
N-[3-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-acetoxybenzoyl]-4-trifluoromethylaniline[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With triethylamine; In dichloromethane;
Example 165 N-[3-(5,6-Dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-acetoxybenzoyl]-4-trifluoromethylaniline 4-Trifluoromethylaniline (0.159 g, 1.604 mmol), triethylamine (0.162 g, 1.604 mmol) and <strong>[37091-73-9]2-chloro-1,3-dimethylimidazolinium chloride</strong> (0.271 g, 1.604 mmol) were added to a methylene chloride solution (50 ml) of 3-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-acetoxybenzoic acid (0.200 g, 0.535 mmol) and the resulting solution was stirred at room temperature for 12 hours. The reaction solution was poured into ice water and then extracted with methylene chloride. The extract was washed with water and then dried, and the solvent was removed by distillation. The obtained residue was purified by preparative thin-layer chromatography (hexane: ethyl acetate = 1:1) and then recrystallized from ether to obtain the titled compound (0.140 g, 0.271 mmol, 51percent).
N-[5-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-(pyridin-3-ylmethyloxy)benzoyl]-4-trifluoromethylaniline[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With triethylamine; In dichloromethane;
Example 172 N-[5-(5,6-Dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-(3-pyridylmethyloxy)benzoyl]-4-trifluoromethylaniline 4-Trifluoromethylaniline (0.242 g, 1.500 mmol), triethylamine (0.152 g, 1.500 mmol) and <strong>[37091-73-9]2-chloro-1,3-dimethylimidazolinium chloride</strong> (0.254 g, 1.500 mmol) were added to a methylene chloride solution (100 ml) of 5-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-(3-pyridylmethyloxy)benzoic acid (0.215 g, 0.500 mmol) and the resulting solution was stirred at room temperature for 12 hours. The reaction solution was poured into ice water and then extracted with methylene chloride. The extract was washed with water and then dried, and the solvent was removed by distillation. The obtained residue was purified by preparative thin-layer chromatography (chloroform: methanol = 10:1) and then recrystallized from ether to obtain the titled compound (0.035 g, 0.0618 mmol, 12percent).
N-[5-(3,5,6-trimethyl-1,4-benzoquinon-2-yl)methyl-2-acetoxybenzoyl]-4-trifluoromethylaniline[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With triethylamine; In hexane; dichloromethane; ethyl acetate;
Example 234 N-[5-(3,5,6-Trimethyl-1,4-benzoquinon-2-yl)methyl-2-acetoxybenzoyl]-4-trifluoromethylaniline 4-Trifluoromethylaniline (0.176 g, 1.096 mmol), triethylamine (0.111 g, 1.096 mmol) and <strong>[37091-73-9]2-chloro-1,3-dimethylimidazolinium chloride</strong> (0.185 g, 1.096 mmol) were added to a methylene chloride solution (100 ml) of 5-(3,5,6-trimethyl-1,4-benzoquinon-2-yl)methyl-2-acetoxybenzoic acid (0.250 g, 0.730 mmol) and the resulting solution was stirred at room temperature for 12 hours. The reaction solution was poured into ice water and then extracted with methylene chloride. The extract was washed with water and then dried, and the solvent was removed by distillation. The obtained residue was purified by preparative thin-layer chromatography (chloroform: methanol = 10:1) and then recrystallized from a mixed solvent of ethyl acetate and hexane (1:2) to obtain the titled compound (0.220 g, 0.453 mmol, 62percent).
With pyridine; copper diacetate; In 1,4-dioxane; for 6h;Reflux;
Intermediate 1: N-Methyl-4-(trifluoromethyl) aniline To a mixture of 4-trifluoromethylaniline (196 mg, 1.2 mmol), copper acetate (550 mg, 3.0 mmol) and pyridine (0.34 mL, 4.2 mmol) in dioxane (6 mL) was added methylboronic acid (181 mg, 3.0 mmol, Aldrich, Catalog number: 165335). The mixture was heated with stirring under reflux for 6 hours. The resulting mixture was filtered. The filtrate was concentrated under vacuum and purified by column chromatography to afford N-methyl-4-(trifluoromethyl)-aniline (150 mg, 70 %). MS obsd. (ESI+) [(M+H)+]: 176
To a solution of p-trifluoromethylaniline (80.6 g) in concentrated HCl (152.1 g) and water (200 mL) cooled at 0° C. was added drop wise a solution of NaNO2 (39.7 g) in water (90 mL) over a 30-minute period. The temperature was kept at 0-5° C. during the addition of NaNO2 solution. After stirring at 0~5° C. for an hour, the cold reaction mixture was filtered to remove an insoluble yellow solid. The filtrate was then treated with urea until KI-starch paper not turning blue, followed by adding an aqueous KI (124.5 g) solution over a 1~1.5 hour period. The reaction mixture was stirred for an additional hour, decolorized by adding saturated NaHSO3 solution, then extracted 3 times with petroleum ether. The combined petroleum ether solution was dried and concentrated. The residue was purified by column chromatography to give 75.7 g of intermediate VII-A48 as a red oil.
To 3-(chlorosulfonyl)benzoyl chloride (0.36 g 1.5 mmol) in anhydrous dichloromethane (50 mL) was added octahydro-lH-pyrido[l,2-alpha]pyrazine (0.21 g, 1.5 mmol) in dichloromethane (4 mL) slowly over 10 minutes at room temperature. Then sodium carbonate (0.32 g, 3 mmol) was added. The mixture was stirred at room temperature for 5 hours. Then 3 -(trifluoromethyl)aniline (2.9 g, 18 mmol) was added. The mixture was stirred at room temperature for 5 days, then sodium carbonate(0.32 g, 3 mmol) and methanol (5 mL) were added, the mixture was stirred for 20 minutes, then filtered, and concentrated. The residue was purified by chromatography on silica gel (methanol/ethyl acetate = 1 : 10) to give the titled compound: 1U NMR (400 MHz, DMSO-J6) delta ppm 1.00-1.27 (m, 3H), 1.42-2.10 (m, 7H), 2.70-3.40 (m, 4H), 4.25-4.40 (m, IH), 7.40 (m, 3H), 7.50 (m, IH), 7.70 (m, 3H), 7.85 (m, IH), 10.80 (br s, IH); MS (ESI) m/z 468 (M+H)+.
With sodium tris(acetoxy)borohydride; acetic acid; In 1,2-dichloro-ethane; at 20℃; for 2h;
To a mixture of <strong>[619-12-5]4-formyl-3-hydroxy-benzoic acid</strong> (206 mg, 1.20 mmol), 4-(trifluoromethyl)aniline (124 uL, 1.00 mmol), acetic acid (114 uL, 2.0 mmol) in 1,2-dichloroethane (5 mL) was added sodium triacetoxyborohydride (318 mg, 1.50 mmol). The reaction mixture was stirred at room temperature for 2 hr. To the above mixture was added isovaleraldehyde (1.30 uL, 1.20 mmol), sodium triacetoxyborohydride (318 mg, 1.50 mmol), and acetic acid (114 uL, 2.0 mmol). The reaction mixture was stirred at room temperature overnight. Added more Isovaleraldehyde (65 uL, 0.60 mmol), sodium triacetoxyborohydride (160 mg, 0.75 mmol) and 1,2-dichloroethane (1 mL)., and stirred at room temperature overnight. LC-MS shows mainly desired product, plus trace of intermediate. The reaction mixture was partitioned between EtOAc and water. The organic phase was washed with brine, dried over MgSO4, filtered and concentrated to get 440 mg crude acid as a yellow oil.
With dmap; In dichloromethane; at 0 - 20℃; for 4.5h;
General procedure: Different para-substituted aromatic amine (4.1 mmol) and N,N-dimethylpyridin-4-amine (0.15 g, 1.2 mmol) were added to anhydrousdichloromethane (20 mL) at 0 C. Then, 15a (0.8 g, 5.1 mmol) dissolvedin 5 mL of dichloromethane was added. The ice bath was removed after0.5 h and the mixture was stirred for an additional 4 h at room temperature(monitored by TLC). Then the dichloromethane (50 mL) waspoured into the reaction mixture. The organic phase was washed with1 N hydrochloric acid solution, saturated sodium bicarbonate solutionand saturated sodium chloride solution, and dried over anhydrousNa2SO4, subsequently. The obtained crude product was purified byflash column chromatography to afford the intermediates 16a-e.
Production Example 16 N-[(1-methyl-1H-pyrazol-5-yl)methyl]-4-(trifluoromethyl)aniline Acetic acid (0.87 mL) was added to a chloroform (10 mL) solution that contained <strong>[27258-33-9]1-methyl-1H-pyrazol-5-carbaldehyde</strong> (1.00 g) and 4-aminobenzotrifluoride (1.76 g) at a room temperature, and the obtained solution was then stirred for 10 minutes. Thereafter, sodium triacetoxyborohydride (2.89 g) was added to the reaction solution, and the obtained mixture was then stirred for 5.5 hours. Thereafter, a saturated sodium hydrogencarbonate aqueous solution was added to the reaction solution, and the obtained mixture was then extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate, and was then concentrated under a reduced pressure. The obtained solid was washed with diisopropyl ether, so as to obtain the title compound (1.88 g) in the form of a light yellow solid. 1H NMR (600 MHz, CHLOROFORM-d) delta ppm 3.87 (s, 3H) 4.08-4.17 (m, 1H) 4.35 (s, 2H) 6.21 (d, J=1.83 Hz, 1H) 6.67 (d, J=8.71 Hz, 2H) 7.42 (d, J=1.83 Hz, 1H) 7.44 (d, J=8.71 Hz, 2H); MS (ESI pos.) m/z: 256 [M+H]+
1.88 g
Production Example 9 N-[(1-methyl-1H-pyrazol-5-yl)methyl]-4-(trifluoromethyl)aniline Acetic acid (0.87 mL) was added to a chloroform (10 mL) solution that contained <strong>[27258-33-9]1-methyl-1H-pyrazol-5-carbaldehyde</strong> (1.00 g) and 4-aminobenzotrifluoride (1.76 g) at a room temperature, and the obtained solution was then stirred for 10 minutes. Thereafter, sodium triacetoxyborohydride (2.89 g) was added to the reaction solution, and the obtained mixture was then stirred for 5.5 hours. Thereafter, a saturated sodium hydrogencarbonate aqueous solution was added to the reaction solution, and the obtained mixture was then extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate, and was then concentrated under a reduced pressure. The obtained solid was washed with diisopropyl ether, so as to obtain the title compound (1.88 g) in the form of a light yellow solid. 1H NMR (600 MHz, CHLOROFORM-d) delta ppm 3.87 (s, 3H) 4.08-4.17 (m, 1H) 4.35 (s, 2H) 6.21 (d, J=1.83 Hz, 1H) 6.67 (d, J=8.71 Hz, 2H) 7.42 (d, J=1.83 Hz, 1H) 7.44 (d, J=8.71 Hz, 2H); MS (ESI pos.) m/z: 256 [M+H]+
methyl 2-[(9H-fluoren-9-ylmethoxy)carbonyl]amino}-3-[(5-methoxypyridin-2-yl)carbamoyl]propanoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
75%
c) Methyl 2-{ r(9H-fluoren-9-ylmethoxy)carbonyllamino|-3T(5- methoxypyridin-2-yl)carbamoyllpropanoate (1-48). HATU (1.27 g; 3.34 mmol; 1.2 eq) and DIPEA (1.41 mL; 8.1 mmol; 3 eq) were added to a solution of 3-{ [(9H-fluoren-9-ylmethoxy)carbonyl]amino}-4-methoxy-4- oxobutanoic acid (1-47) (1.03 g; 2.7 mmol; 1 eq) in dimethylformamide (51 mL). After 20 minutes, 5-methoxypyridin-2-amine (415.5 mg; 3.34 mmol; 1.2 eq) was added and the reaction mixture was stirred at room temperature overnight. Water (50 mL) and ethyl acetate (50 mL) were added and the aqueous layer was extracted with ethyl acetate (3 x 30 mL). The combined organic layers were washed with saturated sodium chloride (3 x 50 mL), dried over sodium sulfate, filtered and concentrated to dryness. The crude was purified on silica gel using dichloromethane/ethyl acetate (90/10 to 50/50) as an eluent. After washing in ethyl acetate and saturated sodium chloride, the title compound methyl 2-{ [(9H-fluoren-9-ylmethoxy)carbonyl]amino}- 3-[(5-methoxypyridin-2-yl)carbamoyl]propanoate was obtained in 75percent yield (1.00 g). 1H-NMR (CDC13): delta (ppm) 2.97 (m, 1Eta), 3.19 (d, 1Eta), 3.78 (s, 3Eta), 3.82 (s, 3Eta), 4.23 (m, 1Eta), 4.37 (m, 2Eta), 4.69 (m, 1Eta), 6.04 (m, 1Eta), 7.30 (m, 2Eta), 7.38 (m, 3Eta), 7.59 (m, 2Eta), 7.76 (m, 2Eta), 7.95 (m, 2Eta), 8.07 (d, 1Eta).
General procedure: To a solution of anilines (1.2 eq.) in acetonitrile (15 mL) was added compound 5 (1.0 eq.) and the mixture stirred atroom temperature for 16 h. The solid formed was filtered and washed with acetonitrile (5 mL). The filtrate was concentrated to afford residue was subjected to column chromatography on silica gel to yield compound 7 (Yield: 47-78%).
3-fluoro-4-(((4-(trifluoromethyl)phenyl)amino)methyl)benzonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
28%
With N-ethyl-N,N-diisopropylamine; In acetonitrile; at 20℃; for 16h;
(Formula 6-2: 3-fluoro-4-((4-trifluoromethyl)phenylamino)methyl)benzonitrile)[1580][1581]Compound ofFormula 6-1(<strong>[105942-09-4]4-(bromomethyl)-3-fluorobenzonitrile</strong>; 1.10 g, 5.06 mmol) was dissolved in acetonitrile (60 mL), and then 4-(trifluoromethyl)benzenamine (0.39 mL, 4.30 mmol) and N,N-diisopropylethylamine (1.14 mL, 6.45 mmol) were added at room temperature and stirred at the same temperature for 16 hours. Then, saturated sodium hydrogen carbonate aqueous solution was poured into the reaction mixture, and the organic layer was extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride aqueous solution, dehydrated with anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was purified and concentrated by column chromatography (silica; ethyl acetate/hexane=10-30%) to give the desired compound ofFormula 6-2(0.11 g, 28%) in the form of a colorless oil.
3-chloro-N-(4-trifluoromethylphenyl)picolinamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
1.34 g
With pyridine; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; at 20℃; for 2h;
Production Example 8 (1) [0716] A mixture of 0.80 g of 4-trifluoromethylaniline, 0.78 g of <strong>[57266-69-0]3-chloropicolinic acid</strong>, 1.15 g of EDCI hydrochloride, 0.06 g of HOBt and 10 mL of pyridine was stirred at room temperature for 2 hours. A saturated aqueous sodium bicarbonate solution was poured to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure, and the resulting solid was washed with hexane and dried to obtain 1.34 g of 3-chloro-N-(4-trifluoromethylphenyl)picolinamide. 3-Chloro-N-(4-trifluoromethylphenyl)picolinamide 1H-NMR (CDCl3) delta: 10.16 (1H, s), 8.55 (1H, d), 7.95-7.87(3H, m), 7.64(2H, d), 7.47 (1H, dd).
N<SUP>2</SUP>-(4-(trifluoromethyl)phenyl)pyrazine-2,6-diamine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
26%
With potassium phosphate; tris-(dibenzylideneacetone)dipalladium(0); XPhos; In 1,2-dimethoxyethane; at 110℃; for 0.5h;
Step 1. To 6-chloropyrazin-2-amine (1.05 g, 8 mmol) was added K3PO4 (3.4 g, 16 mmol), XPhos (191 mg, 0.4 mmol), Pd2dba3 (183 mg, 0.2 mmol), 4-(trifluoromethyl)aniline (1.99 mL, 16 mmol) and DME (20 mL). The reaction mixture was heated at 110 °C for 30 minutes, then partitioned between EtOAc and NH4CI (aqueous solution). The organic layer was purified by chromatography on silica gel (gradient from ethyl acetate:hexane 1:2 to EtOAc:MeOH 4:0) and washed with hexane to provide N2-(4- (trifluoromethyl)phenyl)pyrazine-2,6-diamine as a brown solid (530 mg, 26 percent). ]H NMR (DMSO-i delta 9.39 (s, 1H), 7.87 (dist. d, J = 8.5 Hz, 2H), 7.54 (dist. d, J = 8.8 Hz, 2H), 7.39 (s, 1H), 7.31 (s, 1H), 6.24 (s, 2H); MS m/z 255 (ESI) [M+H]+.
With N-[(dimethylamino)-1H-1,2,3-triazolo-[4,5-b]pyridin-1-ylmethylene]-N-methylmethanaminium hexafluorophosphate N-oxide; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 25℃;Inert atmosphere;
[00954] A solution of 3 (1.00 mg, 7.09 mmols, 1.0 eq), 20 (1.14 g, 7.09 mmols, 1.0 eq), HATU (5.39 g, 14.2 mmols, 2.0 eq) and DIPEA (2.74 g, 21.3 mmols, 3.0 eq) in DMF (25 mL) was stirred at 25 °C overnight under nitrogen. The mixture was diluted with water and extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel chromatography (petroleum ether/ethyl acetate, 2 / 1) to give the desired product 21 (800 mg, 2.82 mmols, 3 8.1percent) as a white solid.
With palladium diacetate; caesium carbonate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; In 1,4-dioxane; at 100℃;Inert atmosphere;
General procedure: To a solution of benzoic acid methyl ester (3, 4a,b) (500 mg), the respective arylamine compounds (2.4 equiv for 3, 1.2 equiv for 4a,b), Cs2CO3 (2.8 equiv for 3, 1.4 equiv for 4a,b), BINAP (0.08 equiv) in 1,4-dioxane (5 mL) was added Pd(OAc)2 (5 mol percent) under nitrogen. And the reaction mixture was stirred at 100 °C for 10?24 h. The reaction mixture was cooled to room temperature, and then H2O was added. The mixture was extracted with ethyl acetate, and then the organic layers were combined, dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude product was purified by column chromatography.
6-bromo-2-chloro-N-[4-(trifluoromethyl)phenyl]-3-amino-quinoxaline[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
40%
In N,N-dimethyl-formamide; for 24h;Reflux;
To a solution of compound 1 (2.78 g, 0.01 mol) in DMF (50 mL), 4-(trifluoromethyl)aniline (1.61 g, 0.01 mol) was added. The reaction mixture was refluxed for 24 h. After completion of the reaction, the reaction mixture was poured onto crushed ice with stirring. Then, the solid residue that formed was filtered, washed with water, dried and crystallized from petroleum ether (80-100C) to give 4. Yield: 40%; (brown powder): m.p. 157-159 O C;IR (KBr, cm -1 ): 3158 (NH), 1603 (C=N). 1 H NMR(DMSO-d 6 , delta , ppm): 7.25-7.82 (m, 7H, Ar-H), 9.71(s, br, 1H, NH; exchangeable with D 2 O). 13 C NMR(DMSO-d 6 , delta , ppm): 121.15-147.09 (12Ar-C, CF 3 ),152.69, 152.86 (2C=N). MS (m/z), 336 (M + -C 2 H 3 F 2 ; 100%), 401 (M + ; 88%), 402 (M + + 1; 60%),403 (M + + 2; 57%), 404 (M + + 3; 62%), 405 (M + + 4;52%). Analysis: calcd. for C 15 H 8 BrClF 3 N 3 (402.60):C, 44.75; H, 2.00; N, 10.44%; found: C, 44.61; H,2.26; N, 10.69%.
2-methyl-propane-2-sulfinic acid [3-(4-trifluoromethyl-phenylamino)-oxetan-3-yl]-amide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
71%
In methanol; at 60℃; for 5.6h;Inert atmosphere;
General procedure: To a stirred solution of substituted aniline (1 eq) in methanol (3 mL), <strong>[1158098-73-7]oxetan-3-tert-butylsulfinimine</strong> (1.5 eq) was added under argon atmosphere. Reaction mixture was heated at 60 C for appropriate time (Table 2). After the completion of reaction (TLC), reaction mixture was then concentrated. To the resulting residue water was added and then extracted with ethyl acetate (2 X 3 mL). Organic layer was then dried over anhydrous sodium sulphate and filtered. Solvent was removed under reduced pressure. The resulting products were then purified by chromatography using n-hexane-ethyl acetate (7:3) to afford pure 2-methyl-N-[(3-phenylamino)oxetan-3-yl]-2-propanesulfinamide derivatives. All synthesized compounds were characterized by IR, 1H-NMR, HRMS and 13C-NMR spectroscopic techniques.
With 1,4-diaza-bicyclo[2.2.2]octane; palladium diacetate; N-ethyl-N,N-diisopropylamine; sodium iodide; at 50℃; under 760.051 Torr; for 24h;
Compound 19: A 25 mL reaction flask was sequentially charged with palladium acetate (0.001 mmol), amine 1s (0.5 mmol), amine 1s'(2.0 mmol), triethylenediamine (0.1 mmol), diisopropylethylamine (0.1 mmol), sodium iodide (0.25 mmol) and polyethylene glycol-400 (2.0 g) and introduced with one atmosphere of carbon monoxide and air (1: 1) at 50 C for 24 h. Cool to room temperature and extractAfter removal of the solvent by distillation under reduced pressure, the product was isolated by column chromatography to yield 97%.
With 1,8-diazabicyclo[5.4.0]undec-7-ene; In 1-methyl-pyrrolidin-2-one; at 250℃; for 0.2h;Flow reactor;
General procedure: Selective N-monomethlyation reactions were performed in a Vapourtec E-series continuous flow system equipped with a high temperature tube reactor (10 mL, stainless steel, 0.03'' i.d., Fig. 2 ) and a membrane back pressure regulator (Zaiput). Stock solutions of aniline (20 mmol, 1.0 equiv, 2 M), DMC (5.05 mL, 60 mmol, 3.0 equiv, 6 M), and DBU (4.47 mL, 30 mmol, 1.5 equiv, 3 M) were prepared in oven-dried 10 mL volumetric flasks using NMP as the solvent. The solutions were transferred to screw-thread vials with septum caps and reagents were pumped directly from the vials. After the high temperature coiled tube reactor was heated to 250 C, peristaltic pumps (Vapourtec V-3) were used to pump the reactant solutions into the system (0.277 mL/min each for a 12 min residence time). The solutions were mixed with a cross-mixer (0.4? i.d.), passed though the high temperature coiled tube reactor. Upon exiting the reactor, the reaction stream was passed through a short segment of stainless steel tubing to enable the reaction to cool and then exited the system by passage through the back pressure regulator (Note: PFA fittings should not be used at the exit of the reactor as they will deform due to the high temperature of the reaction stream and cause leaks in the system. Stainless steel connectors and tubing (12'') were used in our system.). After the flow system was equilibrated for 18 min, the product stream was collected for 5 min (2.77 mmol of aniline). The crude mixture was dissolved in ethyl acetate and washed with brine. The combined organic layers were dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (Biotage 25 g Ultra-sil, 3-15% ethyl acetate in hexanes) to afford the desired product.
5-nitro-N-(4-(trifluoromethyl)phenyl)pyrimidine-2-amine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
88%
Inert atmosphere;
The first step: a vacuum 50mL reaction bottle is vacuumed three times, then added to the reaction bottle4-(Trifluoromethyl)aniline (161 mg, 1.0 mmol, 1.0 equiv), add 10.0 mL of dry acetonitrile and stir to 4- (3)The fluoromethyl)aniline was completely dissolved, and then <strong>[10320-42-0]2-chloro-5-nitropyrimidine</strong> (0.1593 g, 1.0 mmol, was added to the reaction jar).1.0equiv). The entire mixture was reacted under nitrogen pressure for 4-5 hours. The reaction is detected by TLC to detect the progress of the reaction.The reaction can be stopped by the complete reaction of the aniline. The experimental treatment is to drain the solution in the reaction; the reaction is carried out with ethyl acetate.The solute in the jar was dissolved and transferred to a 100 mL round bottom flask. 2 mL (200-300 mesh) of silicon was added to the round bottom flask.The gel was spin-dried (petroleum ether and ethyl acetate) over silica gel on a column. Wait until the intermediate product is pale yellow crystal 5-nitro-N-(4-(trifluoroMethyl)phenyl)pyrimidine-2-amine (249 mg, 88% yield).
With p-toluenesulfonic acid monohydrate; In 1-methyl-pyrrolidin-2-one; at 60℃; for 2h;
Compound (III-11) (120 mg, 0.620 mmol) and compound (IIb-2) (150 mg, 0.931 mmol) were dissolved in NMP (2.0 mL), And p-toluenesulfonic acid monohydrate(118 mg, 0.620 mmol) was added,Followed by stirring at 60 C. for 2 hours. The reaction solution was allowed to cool,Water was added and extracted with ethyl acetate.The organic layer was dried over anhydrous sodium sulfate,It was filtered. After distilling off the solvent under reduced pressure,The residue was purified by silica gel column chromatography (n-hexane: ethyl acetate)Compound (IV-122)(Yield 100 mg, Yield 51%)Was obtained.
51%
With toluene-4-sulfonic acid; In 1-methyl-pyrrolidin-2-one; at 60℃; for 2h;
Compound (III-11) (120 mg, 0.620 mmol) and compound (IIb-2) (150 mg, 0.931 mmol) were dissolved in NMP(2.0 mL), p-toluenesulfonic acid monohydrate (118 mg, 0.620 mmol) was added and the mixture was stirred at 60C for2 hr. The reaction mixture was allowed to cool, water was added, and the mixture was extracted with ethyl acetate. Theorganic layer was dried over anhydrous sodium sulfate, and filtered. The solvent was evaporated under reduced pressure,and the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate) to give compound (IV-122)(yield 100 mg, 51%)
7-nitro-N-[4-(trifluoromethyl)phenyl]quinolin-8-amine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
37%
With sodium hydride; In dimethyl sulfoxide; mineral oil; at 20℃; for 1.0h;
General procedure: Sodium hydride (60 % suspension in paraffin oil, 40 mg, 1.0 mmol) and the appropriate nitroquinoline 1, 5, 9, or 11 (87 mg, 0.5 mmol) were added to a solution of arylamine (1.0 mmol) in anhydrous DMSO (2.0 ml) at room temperature. The mixture was vigorously stirred at room temperature for 1 hand then poured into saturated NaCl solution that wa scooled to 5 . The obtained precipitate was filtered off, washed with water, and dried. The obtained mixture was separated into individual compounds by dry silica gel flash chromatography
4-[4-(trifluoromethyl)anilino]pyridine-3-carbonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
65.3%
With palladium diacetate; caesium carbonate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; In 1,4-dioxane; at 100℃; for 15h;Inert atmosphere;
[00425] To a solution of 78-1 (500.0 mg, 3.6 mmol, 1.0 eq), 78-2 (581.5 mg, 3.6 mmol, 0.45 mL, 1.0 eq) and Cs2C03 (1.2 g, 3.6 mmol, 1.0 eq) in dioxane (10.0 mL) was added BINAP (224.7 mg, 0.36 mmol, 0.1 eq) and palladium acetate (81.0 mg, 0.36 mmol, 0.1 eq). The resulting mixture was stirred at 100 C under N2 for 15 hour. LCMS showed the desired compound was formed and the starting material was consumed completely. TLC (30% ethyl acetate in petroleum ether, Rf = 0.4) showed the starting material was consumed and a new spot appeared. The reaction mixture was concentrated. The crude residue was dissolved in CH2C12 (25 ml) and washed with water (2 x 15 mL). After drying over anhydrous Na2S04, the solvent was removed under reduced pressure to afford the crude product. The crude product was purified by column chromatography over silica gel to provide 78-3 (620.0 mg, 2.4 mmol, 65.3% yield). LCMS (ESI): RT = 0.575 min, mass calc. for Ci3H8F3N3 263.07, m/z found 263.8 [M+H]+.
With tert.-butylnitrite; sodium acetate; tetra-(n-butyl)ammonium iodide; dibenzoyl peroxide; In acetonitrile; at 80℃;Schlenk technique; Inert atmosphere;
General procedure: In air, Bpin-B(dan) (0.1 mmol, 1.0 eq.), aryl amide (0.2 mmol, 2.0 eq.), TBAI (0.01 eq.),NaOAc (0.15 eq.), and BPO (0.01 eq.) were sequentially weighed and added to a screw-cappedSchenk tube containing a magnetic stir bar. The vessel was evacuated and refilled with nitrogen forthree times. t-BuONO (0.2 eq.) and MeCN (0.6 mL) were added in turn under N2 atmosphere usingsyringes through a septum which was temporarily used to replace the screw cap. The reaction mixturewas then vigorously stirred at 80 C for the indicated time. The resulting mixture was filtered through a pad of Celite, and the filter cake was washed with ethyl acetate (3 mL x 2). The combined filtratewas evaporated under vacuum to dryness and the residue was purified by column chromatography toyield the desired product.
With sodium tris(acetoxy)borohydride; acetic acid; In dichloromethane; at 20℃; for 4h;
Compound 3 (523 mg, 2.5 mmol, 1.0 eq), Compound 4 (400 mg, 2.5 mmol, 1.0 eq) was dissolved in 15 mL of dichloromethane and 0.15 mL of acetic acid at room temperature, stirred for 1 hour, and the reaction was cooled to 0 C. NaBH(OAc)3 (733 mg, 3.5 mmol, 1.4 eq) was added portionwise, and the mixture was reacted for 4 hours. The TLC shows that there are new points generated. 25 mL of water and 30 mL of ethyl acetate were added to the mixture, and the organic layer was dried over anhydrous sodium sulfate. The column (PE/EA = 1:0-200:1) gave a purple solid compound 5 (85 mg, yield: 10%).
General procedure: The residue mentioned above was dissolved in toluene, followed by added catalytic amounts of DMF, dropwise added SOCl2 at 0 C. After that, the reaction mixture was heated to 80 C and stirred for 12 h. The solvent was evaporated to dryness, and the residue was dissolved in toluene. The phenylamine dissolved in toluene (30 ml) was dropwise added to the resulting solution, and then the reaction mixture was stirred overnight. Then the mixture was filtered, and the filtration was washed by water for three times, which was further purified by recrystallization from toluene to give the title compound 34a as white solid (7.83g, 67% in three step).
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃; for 4h;
General procedure: A solution of 1-(methoxycarbonyl)cyclopropane-1- carboxylic acid(0.92 g, 6.40 mmol), aniline (0.89 g, 9.60 mmol), 3-(ethyliminomethyleneamino)-N,N-dimethyl-propan-1-amine (1.48 g, 9.6 mmol), and 1-Hydroxybenzotriazole (1.29 g, 9.6 mmol) in 20 mL dichloromethane,was stirred at room temperature for 4 h. The solvent was then removedunder reduced pressure. The residue was dissolved in ethyl acetate(40 mL) and then was washed with saturated sodium carbonate (40 mL)and acid water (40 mL) successively, and dried over anhydrous sodiumsulfate, evaporated to give the product (3a-k).
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