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Limited Quantity
USD 15-60
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USD 80+
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Structure of 461-82-5 * 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.
With sulfuric acid; sodium nitrite In water at 5 - 110℃; for 2 h;
The 4-(trifloromethoxy) aniline (75 g) was diazotized in 9N H2S04 (750 mL) and aqueous NaNO2 (31 g in 62 mL water) solution at temperature below 5°C.The formed diazonium saltwas decomposed in boiling 9N H2S04 solution (750 mL)at 110°C for 2hrs. The reaction mixture was cooled to 25°C. The bottom layer ofreaction mixture was separated. The remaining reaction mixture was extracted with dichloromethane. All organic layers were combined, dried over Na2SO4, filtered and evaporated to obtain the title compound.Yield: 50 gPurity: 99.5percent
Reference：
[1] Journal of Medicinal Chemistry, 1982, vol. 25, # 9, p. 1097 - 1101
[2] Patent: WO2016/125185, 2016, A2, . Location in patent: Page/Page column 9
2
[ 461-82-5 ]
[ 828-27-3 ]
[ 108-95-2 ]
Reference：
[1] Patent: US5171857, 1992, A,
[2] Patent: US4925839, 1990, A,
[3] Patent: US4983612, 1991, A,
3
[ 461-82-5 ]
[ 9005-25-8 ]
[ 828-27-3 ]
[ 108-95-2 ]
Reference：
[1] Patent: EP566567, 1997, B1,
4
[ 461-82-5 ]
[ 2252-44-0 ]
Yield
Reaction Conditions
Operation in experiment
37 %Chromat.
Stage #2: With bromine In acetic acid at 0 - 5℃;
EXAMPLE 5 (COMPARATIVE) Preparation of l-bromo-3-trifluoromethoxybenzene with Br2 in acetic acid. 60 g of acetic acid are placed in a 100 cc flask, then slowly 30 g of 4- trifluoromethoxyaniline are added; the mixture is brought to 0-5°C and 27 g of elementary bromine are metered, slowly. A gas chromatograph analysis is performed at the end of the reaction:20percent of 4-trifluoromethoxyaniline, 37percent of mono-bromo-derivative as per the title, >41 percent of di-bromo-derivative.
34 %Chromat.
With bromine In water at 35℃; for 2 h;
EXAMPLE 6 (COMPARATIVE) Preparation of l-bromo-3-trifluoromethoxybenzene with Br2 in water. 17.7 g of 4-trifluoromethoxyaniline and 53 g of water at room temperature are placed in a 100 cc flask, the mixture is brought to 35°C and 32 g of elementary bromine are metered slowly over a period of 2 hours. After 0.8 equivalents, a gas chromatograph analysis is performed:10percent of 4-trifluoromethoxyaniline, 34percent of mono-bromo-derivative as per the title, 54percent of di-bromo-derivative.
Reference：
[1] Russian Journal of Organic Chemistry, 2002, vol. 38, # 2, p. 269 - 271
[2] Patent: WO2016/125185, 2016, A2, . Location in patent: Page/Page column 8
[3] Patent: CN106083601, 2016, A, . Location in patent: Paragraph 0027-0030
[4] Patent: CN108383737, 2018, A, . Location in patent: Paragraph 0011; 0020-0026
6
[ 407-14-7 ]
[ 461-82-5 ]
Yield
Reaction Conditions
Operation in experiment
62%
Stage #1: With magnesium; ethylene dibromide In tetrahydrofuranInert atmosphere Stage #2: With C10H17NO In tetrahydrofuran; toluene at -20℃; for 2 h; Inert atmosphere
General procedure: To a flame-dried 25 mL round bottom flask was charged activated Mg (7.5 mmol, 1.5 eq.) and 5 mL anhydrous THF. To this suspension was added 2 drops of 1,2-dibromoethane. After 5 min, a solution of Aryl bromide (5 mmol, 1.0 eq.) in 5 mL anhydrous THF was slowly added to the suspension of Mg at room temperature. The reaction was mildly exothermic. The Grignard reagent was titrated and 1 mmol of this reagent was added to a flame-dried reaction vial. The solution was diluted with 3 mL anhydrous toluene and after cooling to the target temperature T, a solution of oxaziridine (1.2 mmol, 1.2 eq.) in 1 mL anhydrous toluene was added. The reaction was maintained at the targeted temperature T for time t before being quenched with saturated aqueous NH4Cl. (The actual temperature/reaction time is listed for each substrate.)
Reference：
[1] Chemistry - An Asian Journal, 2018, vol. 13, # 3, p. 255 - 260
9
[ 100-66-3 ]
[ 461-82-5 ]
Reference：
[1] Patent: WO2016/125185, 2016, A2,
10
[ 34888-05-6 ]
[ 461-82-5 ]
Reference：
[1] Patent: WO2016/125185, 2016, A2,
11
[ 456-55-3 ]
[ 461-82-5 ]
Reference：
[1] Patent: WO2016/125185, 2016, A2,
12
[ 456-71-3 ]
[ 461-82-5 ]
Reference：
[1] Zhurnal Obshchei Khimii, 1957, vol. 27, p. 518,522; engl. Ausg. S. 587, 591
13
[ 36823-89-9 ]
[ 461-82-5 ]
Reference：
[1] Zhurnal Obshchei Khimii, 1957, vol. 27, p. 518,522; engl. Ausg. S. 587, 591
14
[ 332-25-2 ]
[ 461-82-5 ]
Reference：
[1] Zhurnal Obshchei Khimii, 1957, vol. 27, p. 518,522; engl. Ausg. S. 587, 591
15
[ 100114-88-3 ]
[ 461-82-5 ]
Reference：
[1] Zhurnal Obshchei Khimii, 1957, vol. 27, p. 518,522; engl. Ausg. S. 587, 591
16
[ 330-11-0 ]
[ 461-82-5 ]
Reference：
[1] Zhurnal Obshchei Khimii, 1957, vol. 27, p. 518,522; engl. Ausg. S. 587, 591
17
[ 100-07-2 ]
[ 461-82-5 ]
Reference：
[1] Zhurnal Obshchei Khimii, 1957, vol. 27, p. 518,522; engl. Ausg. S. 587, 591
18
[ 874-90-8 ]
[ 461-82-5 ]
Reference：
[1] Zhurnal Obshchei Khimii, 1957, vol. 27, p. 518,522; engl. Ausg. S. 587, 591
19
[ 461-82-5 ]
[ 658-89-9 ]
Reference：
[1] Journal of Medicinal Chemistry, 2011, vol. 54, # 24, p. 8541 - 8554
20
[ 461-82-5 ]
[ 2267-23-4 ]
Reference：
[1] Journal of Medicinal Chemistry, 1995, vol. 38, # 10, p. 1786 - 1792
[2] Patent: WO2006/22954, 2006, A2, . Location in patent: Page/Page column 23
21
[ 461-82-5 ]
[ 109-77-3 ]
[ 370-86-5 ]
Reference：
[1] Chemical Communications, 2014, vol. 50, # 11, p. 1341 - 1343
[2] Tetrahedron, 2010, vol. 66, # 13, p. 2384 - 2389
22
[ 461-82-5 ]
[ 133840-96-7 ]
Reference：
[1] Journal of Medicinal Chemistry, 1999, vol. 42, # 15, p. 2828 - 2843
23
[ 461-82-5 ]
[ 103962-05-6 ]
Reference：
[1] Chemistry - A European Journal, 2018, vol. 24, # 55, p. 14622 - 14626
[2] Chinese Chemical Letters, 2015, vol. 26, # 10, p. 1307 - 1310
[3] Organic Letters, 2018, vol. 20, # 17, p. 5167 - 5171
24
[ 288-88-0 ]
[ 461-82-5 ]
[ 103962-05-6 ]
Reference：
[1] Patent: US4925863, 1990, A,
25
[ 103962-04-5 ]
[ 461-82-5 ]
[ 103962-05-6 ]
Reference：
[1] Patent: EP174769, 1991, B1,
26
[ 461-82-5 ]
[ 175203-85-7 ]
Reference：
[1] Bioorganic and Medicinal Chemistry, 1998, vol. 6, # 4, p. 389 - 399
27
[ 461-82-5 ]
[ 196811-90-2 ]
Reference：
[1] Journal of the American Chemical Society, 2012, vol. 134, # 30, p. 12466 - 12469
[2] Journal of the American Chemical Society, 2012, vol. 134, # 43, p. 18147 - 18147,1
28
[ 461-82-5 ]
[ 175278-17-8 ]
Yield
Reaction Conditions
Operation in experiment
83%
With N-bromosuccinamide In acetonitrile at 0 - 20℃; for 4 h;
N-Bromosuccinamide (3.62 g, 20.34 mmol) was added to a solution of commercially available 4-(trifluoromethoxy)aniline (3.00 g, 1 6.95 mmol) in acetonitrile (30 mL) at 0°C. The resulting mixture was allowed to warm to roomtemperature and stirred for 4 hours. The solvent was removed under reduced pressure to give the crude product which was purified by column chromatography eluting in 10percent ethyl acetat/hexane to afford the title compound as brown oil (3.6 gm, 83percent): 1 H NMR (400 MHz, CDCI3) ö: 4.11 (bs, 2 H), 6.73 (d, 1 H), 6.99 (dd, 1 H), 7.31 (d, 1 H). LC-Ms (m/z): [M-H] = 253.1.
40%
Stage #1: With bromine In acetic acid at 20℃; for 2.16667 h; Stage #2: With sodium hydroxide In water; acetic acid
4-Trifluoromethoxyaniline (1.0 g, 5.6 mmol) was dissolved in glacial acetic acid (10 mL). Bromine (585 μL, 11 mmol) dissolved in glacial acetic acid (2 mL) was added with stirring during 10 minutes at room temperature. The resulting mixture was stirred at room temperature for 2 hours and then poured into water (100 mL). The solid formed (2,5-dibromo-4-trifluoromethoxyaniline) was filtered off. The filtrate was made alkaline with solid sodium hydroxide and extracted with dichloromethane (100 mL), dried (MgSO4) and concentrated (30°C; 200 mBar) to afford 0.57 g (40percent) of 2-bromo-4-trifluoromethoxyaniline.1H NMR (DMSO-d6): δ 5.55 (2H, bs), 6.85 (1H, d), 7.10 (1H, dd), 7.37 (1H, d).
Reference：
[1] Patent: WO2015/100232, 2015, A2, . Location in patent: Page/Page column 102
[2] Journal of Medicinal Chemistry, 2007, vol. 50, # 1, p. 113 - 128
[3] Patent: EP1183229, 2005, B1, . Location in patent: Page/Page column 143-144
[4] Organic Letters, 2011, vol. 13, # 20, p. 5636 - 5639
[5] Journal of the American Chemical Society, 2016, vol. 138, # 40, p. 13147 - 13150
[6] Chinese Journal of Chemistry, 2018, vol. 36, # 9, p. 815 - 818
29
[ 302-17-0 ]
[ 461-82-5 ]
[ 169037-23-4 ]
Reference：
[1] Pharmaceutical Chemistry Journal, 2017, vol. 51, # 5, p. 366 - 374
[2] Bioorganic and Medicinal Chemistry Letters, 2007, vol. 17, # 20, p. 5630 - 5633
[3] European Journal of Medicinal Chemistry, 2016, vol. 124, p. 809 - 819
Reference：
[1] Organic and Biomolecular Chemistry, 2015, vol. 13, # 14, p. 4296 - 4309
32
[ 461-82-5 ]
[ 88149-49-9 ]
Yield
Reaction Conditions
Operation in experiment
99.2%
at 30 - 55℃; for 3 h;
A method for preparing 2,6-dibromo-4- (trifluoromethoxy) aniline,Including the following steps:The sodium sulfate was filtered off embodiment Example 4 156g crystallization mother liquor into 250mL 4-neck flask,Start stirring dropping 17.5 (0.175mol) sulfuric acid,Then, 36.5 g of sodium bromide (0.354 moL) was added and then 30 g (99percent, 0.168 mol) of 4-trifluoromethoxyaniline was added.Adjust the temperature to above 30 ,Start dropping 35percent hydrogen peroxide 38g,When dropping temperature rise,When the temperature rose to 50 ,By controlling the cooling liquid dripping temperature control between 50 ~ 55 ,Keep the temperature drops off,Drip finished insulation 3 hours,Cooling to about 30 ,filter,Filter cake drying,White crystals of 2,6-dibromo-4-trifluoromethoxyaniline 55.8 g, purity99.6percent (HPLC), yield 99.2percent.
Reference：
[1] Patent: CN106631839, 2017, A, . Location in patent: Paragraph 0022-0033
[2] Organic Letters, 2011, vol. 13, # 20, p. 5636 - 5639
33
[ 1193-21-1 ]
[ 714962-04-6 ]
[ 461-82-5 ]
[ 778270-11-4 ]
Reference：
[1] Patent: US2011/21524, 2011, A1,
34
[ 461-82-5 ]
[ 778270-11-4 ]
Reference：
[1] Journal of the American Chemical Society, 2012, vol. 134, # 22, p. 9138 - 9141
35
[ 870072-76-7 ]
[ 461-82-5 ]
[ 870544-59-5 ]
Reference：
[1] Journal of Medicinal Chemistry, 2013, vol. 56, # 4, p. 1704 - 1714
Synthesis Example 8 In a 500-ml round bottom glass flask equipped with a thermometer, a condenser and a stirrer, 180.7 g of p-trifluoromethoxyaniline in purity of 99.4% and 250 ml of glacial acetic acid were placed and heated to 55 C. in the liquid temperature. Then, 105 ml of acetic anhydride was added dropwise for 2 hours, then the temperature was maintained at 70 C. for 80 minutes. After the reaction, the contents were concentrated under reduced pressure and dried to give white crystals of p-trifluoromethoxyacetanilide in purity of 100% in an amount of 219.0 g (yield 99.9%), having a melting point of 113 C.
With benzyltrimethylazanium tribroman-2-uide; In acetonitrile; at 20℃; for 24h;
2-Amino-6-(trifluoromethoxyVbenzothiazoleTo a mixture of 4-trifluoromethoxyaniline (2.07 mmol) and ammonium thiocyanate (2 mmol) in acetonitrile, is added benzyltrimethylammonium tribromide, at room temperature. The reaction is left to proceed while stirring at room temperature for 24 <n="29"/>hours; it is then neutralised with NaHCO3 and extracted with CH2Cl2 . The combined organic extracts are washed with H2O, dried over Na2SO4, filtered and then evaporated under vacuum. The crude product is purified by chromatography through silica, eluting with petroleum ether/AcOEt (1:1), and a solid obtained that is recrystallised from hexane/ethyl ether to give 2-amino-6-(trifluoromethoxy)-benzothiazole as pale yellow flakes, with a yield of 80%.
61%
With bromine; acetic acid; at 0 - 20℃;
[190] Preparation 1. 6-trifluoromethoxybenzo[d]thiazol-2-amine[191] Ammonium thiocyanate (1.70 g, 22.30 mmol) was added to a solution of 4-(trifluoromethoxy)aniline (3.54 g, 20.00 mmol) in acetic acid (30 mL). The reaction mixture was cooled to 0?10 ?. A solution of bromine (1.10 mL, 22.00 mmol) in acetic acid (5 mL) was added dropwise to the reaction mixture, which was then stirred at room temperature overnight. The resulting solid was filtered, and then dissolved in water. The aqueous layer was basified to pH 11-12 with solid sodium carbonate. The resulting solid was filtered, washed with water, and then dried in vacuo to give the titled compound (2.84 g) as a white solid. The product was used in the subsequent step without further purification (Yield: 61%).
61%
With bromine; acetic acid; In water; at 0 - 20℃;
Preparation 1. 6-trifluoromethoxybenzo[d]thiazol-2-amine Ammonium thiocyanate (1.70 g, 22.30 mmol) was added to a solution of 4-(trifluoromethoxy)aniline (3.54 g, 20.00 mmol) in acetic acid (30 mL). The reaction mixture was cooled to 0-10 C. A solution of bromine (1.10 mL, 22.00 mmol) in acetic acid (5 mL) was added dropwise to the reaction mixture, which was then stirred at room temperature overnight. The resulting solid was filtered, and then dissolved in water. The aqueous layer was basified to pH 11-12 with solid sodium carbonate. The resulting solid was filtered, washed with water, and then dried in vacuo to give the titled compound (2.84 g) as a white solid. The product was used in the subsequent step without further purification (Yield: 61%).
With benzyltrimethylammonium tribromide; In acetonitrile; at 20℃; for 24h;
[00102] To a mixture of 4-trifluormethoxy aniline 1 (2. 1 mmol) and ammonium thiocvanate (2.0 mmol) in 15 ml of CH3CN was added benzyltrimethylammonium tribromide 2 (2.0 mmol) at room temperature. The reaction mixture was stirred at room temperatiife for 24 h, neutralized with aqueous NaHCOs and extracted with DCM. (2 10 ml). The combined organic layers were washed with water, dried over a2S04, filtered and evaporated in vacuo. The crude material was purified by flash column chromatography on silica gel eluiing with petether/ethyl acetate (l :l,v/v) mixture to give a solid 3 that after recrysialSi ation from hexane gave light yellow crystals
With benzyltrimethylammonium tribromide; In acetonitrile; at 20℃; for 24h;
Step-1: Synthesis of Compound 3: [0140] To a mixture of 4-trifluormethoxy aniline 1 (2.1 mmol) and ammonium thiocyanate (2.0 mmol) in 15 ml of CH3CN was added benzyltrimethylammonium tribromide 2 (2.0 mmol) at room temperature. The reaction mixture was stirred at room temperature for 24 h, neutralized with aqueous NaHCO3 and extracted with DCM. (2×10 ml). The combined organic layers were washed with water, dried over Na2SO4, filtered and evaporated in vacuo. The crude material was purified by flash column chromatography on silica gel eluting with petether/ethyl acetate (1:1,v/v) mixture to give a solid 3 that after recrystallization from hexane gave light yellow crystals
Potassium thiocyanate (40 mmol)was added to a solution of 4-(trifluoromethoxy)aniline (10 mmol)in glacial acetic acid (20 mL). After the mixture stirring for 20 minat r. t., the reaction was cooled down just to keep the solution liquid. The solutionof bromine (15 mmol) in glacial acetic acid (5 mL) was added dropwiseover the 30 min. The reaction was allowed to reach r. t. and stirred overnight.The mixture was diluted with H2O, alkalized with Na2CO3and extracted with ethyl acetate (3 x 50 mL). The combined organiclayers were dried over Na2SO4, filtered and the solventwas under reduced pressure to dryness. The residue was recrystallized from diethylether-petrol ether to yield 6-(trifluoromethoxy)benzo[d]thiazol-2-amine as light-yellow solid(94%). 1H and 13C NMR, melting point and analytical data werein agreement with those reported in literature.
86%
Ref.: J. Med. Chem., 42:2828 (1999). A mixture of 4-trifluoromethoxy aniline (10 g, 56.5 mmol) and potassium thiocyanate (22 g, 226 mmol) in acetic acid (90 mL) was stirred for 10 min. To this mixture was added a solution of bromine (9.03 g, 56.5 mmol) in acetic acid (20 mL) over a period of 15 min. The resulting mixture was stirred overnight, then was poured into cold water and basified with cone, ammonium hydroxide. The resulting yellow solid was collected by filtration and triturated in heptane. The product was filtered and dried under vacuum to give the title material (11.4 g, 86%) as a yellow solid. LCMS: Anal. Calcd. for C8H5F3N2OS: 234.01; found: 235.02 (M+1)+. 1H NMR (600 MHz, DMSO-d6) delta 7.74 (br d, 1H), 7.62 (s, 2H), 7.32 (d, J= 8.7 Hz, 1H), 7.14 (br dd, J= 8.7 Hz, 1H), 1.83 (br d, J= 3.7 Hz, 2H).
With bromine; acetic acid; at -10 - 0℃; for 4h;
General procedure: A mixture of substituted aniline (0.01mol) and potassium thiocyanate (0.01mol) in glacial acetic acid was cooled and stirred. To this solution, bromine (0.01mol) was added drop-wise at such a rate to keep the reaction temperature between 0 and -10 C throughout the addition. Stirring was continued for additional 4 h and the separated hydrochloride salt was filtered, washed with acetic acid and dried. The reaction was monitored using TLC (toluene: methanol, 8:2). It was dissolved in hot water and neutralized with aqueous ammonia solution (25 %). The precipitate obtained was filtered, washed with water, dried and re-crystallized with benzene to afford the substituted-1, 3-benzothiazol-2-amine (1a-j). Yield: 70 %, m. p.: 245-248 C, IR (KBr) upsilonmax (cm-1): 3240 (NH2), 3020 (Ar-CH), 1565 (C=N); 1H-NMR (delta) DMSO-d6: 7.89-8.16 (m, 3H, Ar- H), 9.70 (s, 2H, NH2, D2O exchangeable).
1.8 g
With bromine; acetic acid; at 20℃; for 16h;
4-Trifluoromethoxyaniline (2 g, 1 1 .3 mmol) and potassium thio- cyanate (4.38 g, 45.1 mmol) was solved in acetic acid (20 ml). Bromine (0.57 ml, 1 1 .3 mmol) in acetic acid (5 ml) was added dropwise. The resulting mixture was stirred at RT for 16 hours. After completion of the reaction, the reaction mixture was poured into ice water and neutralized with aqueous ammonia. The aqueous phase was extracted with ethyl acetate. The organic phase was washed with water and brine, dried over sodium sulphate and concentrated under reduced pressure. Yield of 6-(trifluoromethoxy)-1 ,3-benzothiazol-2- amine (IV-2) after flash chromatography (100-200 mesh size silica gel, 20% ethyl acetate in hexane) was 1 .8 g.
General procedure: Method I. Compounds 1a-1e and 3b were synthesized using a modified procedure.1 Substituted aniline (1.0 equiv.) was added to a round-bottom flask. The flask was fitted with a rubber septum and purged with nitrogen gas, and acetic anhydride (1M in CH2Cl2, 1.1 equiv.) was added at room temperature. The reaction was refluxed overnight and monitored by TLC. Upon completion the reaction mixture was quenched with H2O. The resulting mixture was extracted with CH2Cl2. The combined organic layers were washed with brine, dried over anh. Na2SO4, filtered, then concentrated in vacuo to give the product.
With hydrogenchloride; iron; In methanol; at 60 - 65℃; for 2h;
Nitro trifloromethoxybenzene (204 g) was added together with iron (185 g), concentrated HC1 (44 ml) in methanol (800 ml) at 60C to 65C. The reaction was stirred and monitored for completion. The iron sludge was filtered off from the reaction mass using celite bed and the filtrate was boiled off. The pH was adjusted to 9-10 to get the desired crude product. The crude product was taken in water anddichloromethane for inorganics removal. The organic layer was extracted and evaporated to obtain the crude title product.Yield: 155 g Purity: 88.3%
With hydrogen; In ethanol; at 40℃; for 0.833333h;Autoclave;
Example 2: Take 28.2ml Pd (NO3)2· 2H2O solution (0.01mol / L) and 2.6ml HAuCl4Aqueous solution (0.01mol / L), were weighed 0.965g of silicon carbide were mixed and stirred at room temperature for 12h, evaporated to dryness, and then dried at 110 deg.] C 12h, and finally placed in a tube furnace, under at 500 with H2/ Ar (5:95) reducing 5h, gas flow rate was 20mL / min, to obtain 1g of palladium loading of 3wt%, 0.5wt% gold metallic palladium supported silicon carbide - metal catalyst, wherein palladium - gold bimetallic nanoparticles particle diameter of 7 nm.3g of <strong>[713-65-5]p-nitro-trifluoromethoxybenzene</strong> and 10mL of anhydrous ethanol at a mass ratio of 0.38 After mixing, the catalyst was added 0.1g (mass ratio of catalyst to nitro-trifluoromethoxybenzene 0.033), to form a suspension was then transferred to an autoclave with Shi Ying window, the autoclave was sealed and flushed with hydrogen gas, to maintain the hydrogen flow rate was 20mL / min (total intake air amount in 50min under atmospheric conditions and of nitrilotriacetic molar ratio of fluorine-methoxybenzene 3.08), under stirring, the reaction system was heated to 40 , the intensity 1W / cm & lt2reaction under artificial light source simulated sunlight, the reaction time 50min.Wherein <strong>[713-65-5]p-nitro-trifluoromethoxybenzene</strong> conversion was 100%, amino-trifluoromethoxy benzene selectivity was 100%.
With hydrogen; at 85 - 95℃; under 18751.9 - 30003 Torr; for 6h;
The 5000 L reduction reactor was continuously purged 3 times with nitrogen (<1 MPa), and the purge gas was discharged through a vent tube. In the absence of solvent, 1000 kg of <strong>[713-65-5]1-nitro-4-(trifluoromethoxy)benzene</strong> was added to the reaction vessel, and 2 kg of Raney nickel catalyst was added to steam.The steam was heated to 85 C, hydrogen gas was introduced, and the hydrogenation reduction reaction was carried out for 6 hours under the conditions of holding pressure (85 to 95 C, 2.5 to 4.0 MPa). After the reaction is over,It was continuously purged three times with nitrogen (<1 MPa), and the catalyst was recovered by filtration at 85 C under normal pressure. The filtrate was subjected to vacuum distillation (0.09 MPa, 115-125 C) for 120 hours.The 4-(trifluoromethoxy)aniline can be obtained, and the rectification residue is qualified by a singleBit processing.
With hydrogen; In methanol; under 750.075 Torr;
In a fixed bed reactor by adding 50 mg nano porous palladium catalyst, the pump will be anhydrous methanol continuously adding to the fixed bed reactor filled with, heating up to 30 C, adjusting a hydrogen pressure of 0.1 mpa, the hydrogen flow rate is 10 ml/min, to be temperature pressure stabilizes, the mass fraction of the pump will be 3% of the 1 - nitro -4 - (three-methoxy) benzene and 97% methanol is fed into a continuous fixed bed reactor, adjust the nitrobenzene solution flow rate is 0.10 ml/min, when the reactant material in the sampling analysis, raw material conversion is 100%, selectivity of 100%. Material vacuum in addition to the solvent can be obtained 4 - trifluoro anisidine product.
With hydrogen; In methanol; under 750.075 Torr;
In a fixed bed reactor by adding 50 mg nano porous palladium catalyst, the pump will be anhydrous methanol continuously adding to the fixed bed reactor filled with, heating up to 30 C, adjusting a hydrogen pressure of 0.1 mpa, the hydrogen flow rate is 10 ml/min, to be temperature pressure stabilizes, the mass fraction of the pump will be 3% of the 1 - nitro -4 - (three-methoxy) benzene and 97% methanol is fed into a continuous fixed bed reactor, adjust the nitrobenzene solution flow rate is 0.10 ml/min, when the reactant material in the sampling analysis, raw material conversion is 100%, selectivity of 100%. Material vacuum in addition to the solvent can be obtained 4 - trifluoro anisidine product.
With bromine; In dichloromethane; water; for 3h;Reflux;
In a 250 mL four-necked flask equipped with a mechanical stirrer, a constant-pressure dropping funnel, a reflux condenser, and a thermometer, add 18 g of 4-trifluoromethoxyaniline,100 mL of dichloromethane and 100 mL of water, 400 mL of concentrated 4% bromine water was added dropwise with stirring at room temperature, and stirred at reflux for 3 h.Thin layer chromatography (TLC, dichloromethane: methanol volume ratio 3: 1) was followed to the end of the reaction. The organic phase after the reaction liquid was separated was concentrated to remove the organic solvent.The pink powdery solid product 4-trifluoromethoxy-2-bromoaniline was obtained with a yield of 95% and a purity of 97%.
83%
With N-bromosuccinamide; In acetonitrile; at 0 - 20℃; for 4h;
N-Bromosuccinamide (3.62 g, 20.34 mmol) was added to a solution of commercially available 4-(trifluoromethoxy)aniline (3.00 g, 1 6.95 mmol) in acetonitrile (30 mL) at 0C. The resulting mixture was allowed to warm to roomtemperature and stirred for 4 hours. The solvent was removed under reduced pressure to give the crude product which was purified by column chromatography eluting in 10% ethyl acetat/hexane to afford the title compound as brown oil (3.6 gm, 83%): 1 H NMR (400 MHz, CDCI3) oe: 4.11 (bs, 2 H), 6.73 (d, 1 H), 6.99 (dd, 1 H), 7.31 (d, 1 H). LC-Ms (m/z): [M-H] = 253.1.
40%
4-Trifluoromethoxyaniline (1.0 g, 5.6 mmol) was dissolved in glacial acetic acid (10 mL). Bromine (585 muL, 11 mmol) dissolved in glacial acetic acid (2 mL) was added with stirring during 10 minutes at room temperature. The resulting mixture was stirred at room temperature for 2 hours and then poured into water (100 mL). The solid formed (2,5-dibromo-4-trifluoromethoxyaniline) was filtered off. The filtrate was made alkaline with solid sodium hydroxide and extracted with dichloromethane (100 mL), dried (MgSO4) and concentrated (30C; 200 mBar) to afford 0.57 g (40%) of 2-bromo-4-trifluoromethoxyaniline.1H NMR (DMSO-d6): delta 5.55 (2H, bs), 6.85 (1H, d), 7.10 (1H, dd), 7.37 (1H, d).
General procedure: Substituted aniline (1 mmol), 1N HCl (1 mL), H2O (6 mL), hydroxylamine hydrochloride (226 mg, 3.25 mmol), and anhydrous Na2SO4 (900 mg) was added in 25 ml seal tube, heat to boiling, andthen added chloral hydrate (198 mg, 1.2 mmol), kept boiling for 40 min, cooled, and then extracted with Ethyl acetate. The Ethyl acetate extracts were dried (Na2SO4) and evaporated. The residuewas added to a stirred solution of concentrated H2SO4 (1 mL) and H2O (0.1 mL) during 10 min at 65 C. The mixture was then kept at 80 C for 10 min and then poured onto cracked ice. Then the mixture was extracted with Ethyl acetate, and, the organic phase was dried over sodium sulfate. The solvent was removed under reduced pressure to afford the substituted isatins as crude product,and then compound 11a-j was obtained by substituted isatins through the General procedure A.
With sodium hydroxide; water; In methanol; at 0 - 20℃; for 1h;
To a solution of 2-nitro-4-trifluoromethoxyacetylaniline (45 g, 170 mmol) in methanol (200 mL) at 0 to 100C, was added sodium hydroxide solution (NaOH, 8.5g, 220 mmol, in 45 mL water). The reaction mixture was stirred at room temperature for one hour and diluted with 300 mL of water. The slurry was stirred in an ice bath for two hours and filtered. The yellow solid was washed with 50 mL methanol: water (1:2) and dried under vacuum to obtain a yellow solid.
With triethylamine; In butan-1-ol; for 20h;Heating / reflux;Product distribution / selectivity;
A mixture of compound 4,6-dichloro-2-pbLenyl-pyrimidine (27 g, 112 mmol),4-trifluoromethoxy aniline (21 g, 119 mmol) and triethylamine (33 mL, 225 mmol) in n-butanol (300 mL) was refluxed for 20 hours under nitrogen atmosphere. The reaction mixture was then cooled to room temperature and concentrated under vacuum. The crude compound was passed through the silica gel by using 5-6percent ethylacetate in petroleum ether to afford the compound (6-chloro-2-phenyl-pyrimidin- 4-yl)-(4-trifluoromethoxy-phenyl)-amine (20 g, 46percent) as off-white solid.
1-cyclohexyl-amino-4-(trifluoromethoxy-anilino)-anthraquinone[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With potassium acetate; In ethanol;
EXAMPLE 6 28.8 parts of 1-cyclohexylamino-4-bromo-anthraquinone, 16.5 parts of para-trifluoromethoxyaniline, 7.8 parts of potassium acetate and 0.75 parts of copper acetate are introduced into 33 parts of 4-methyl-2-pentanol and heated at 130 C. for 24 hours. The mixture is cooled to 70 C., diluted with 30 parts of ethanol, filtered, washed with 2% hydrochloric acid, then with water until neutral and dried. 16.2 parts of 1-cyclohexyl-amino- 4-(trifluoromethoxy-anilino)-anthraquinone are obtained.
EXAMPLE 4 12.64 parts of 1-methylamino-4bromo-anthraquinone, 9.9 parts of para-trifluoromethoxyaniline, 6 parts of potassium acetate and 2 parts of copper acetate are introduced into 43 parts of 4-methyl-2-pertanol and the mixture is heated at 132 C. for 8 hours. The mixture is then cooled to 60 C., filtered, washed with water, then the precipitate is taken up in dilute caustic soda, filtered, washed and dried. 9.6 parts of 1-methylamino-4-(p-trifluoromethoxy-anilino)-anthraquinone are obtained.
a mixture of 17.7 g of 4-trifluoromethoxyaniline, 33.7 g of sodium 3-nitrobenzenesulphonate, 6 g of iron sulphate heptahydrate, 10 g of boric acid, 250 ml of glycerol and 60 ml of concentrated sulphuric acid is heated at a temperature close to 150 C. for 1 hour 20 minutes. The reaction mixture is then poured over ice, alkalinized with a concentrated sodium hydroxide solution and then extracted with three times 300 ml of dichloromethane. The organic phase is washed with 100 ml of water, dried over magnesium sulphate and then concentrated under reduced pressure (2 kPa). The evaporation residue is chromatographed on a silica gel column, eluding with a mixture of cyclohexane and ethyl acetate (70-30 by volume) to provide 15 g of 6-trifluoromethoxyquinoline in the form of a light-coloured oil [1H NMR spectrum in CDCl3, T=300K, delta in ppm (20 MHz): 7.40 (1H, dd, J=3 and 7 Hz, arom. CH), 7.55 (1H, d, J=8 Hz, arom. CH), 7.60 (1H, s, arom. CH), 8.10 (1H, dd, J=7 and 1 Hz, arom. CH), 8.12 (1H, d, J=8 Hz, arom. CH), 8.90 (1H, dd, J=3 and 1 Hz, arom. CH)].
With pyridine; In 1,1-dichloroethane; at 20℃; for 5h;
Example 68: 4-(5-Oxo-4,5,6,7,8,9-hexahydro-2H-1,2,7,9-tetraazabenz[f]inden-4-yl)-N-(4-trifluoromethoxy-phenyl)-benzenesulfonamide; compound with trifluoro-acetic acid Preparation of the aldehyde: to a mixture of 610 mg of 4-chlorosulfonylbenzaldehyde (3 mmoles) and 460 mg of 4-trifluoromethoxyaniline (3 mmoles) in 2 ml of dichloroethane is added 2 ml of pyridine (25 mmoles). The reaction mixture is stirred at room temperature for 5 hours and then poured into 100ml of 10% HCl solution. The mixture is extracted with twice 30 ml of DCM. The combined organic phases are washed with 30 ml of water; 30 ml of saturated solution of sodium bicarbonate and brine, the solution is dried over MgS04 and evaporated. The crude is purified on silica gel using DCM/AcOEt 90/10 as eluent. 0.48g of 4-formyl-N-(4-trifluoromethoxy-phenyl)-benzenesulfonamide is isolated as a white solid (yield=47%). ([M+H]+): 346. Ret. Time: 5.53 min (gradient 5 to 85 % acetonitrile in 7 min).
EXAMPLE 5 (COMPARATIVE) Preparation of l-bromo-3-trifluoromethoxybenzene with Br2 in acetic acid. 60 g of acetic acid are placed in a 100 cc flask, then slowly 30 g of 4- trifluoromethoxyaniline are added; the mixture is brought to 0-5C and 27 g of elementary bromine are metered, slowly. A gas chromatograph analysis is performed at the end of the reaction:20% of 4-trifluoromethoxyaniline, 37% of mono-bromo-derivative as per the title, >41 % of di-bromo-derivative.
34%Chromat.
With bromine; In water; at 35℃; for 2h;Product distribution / selectivity;
EXAMPLE 6 (COMPARATIVE) Preparation of l-bromo-3-trifluoromethoxybenzene with Br2 in water. 17.7 g of 4-trifluoromethoxyaniline and 53 g of water at room temperature are placed in a 100 cc flask, the mixture is brought to 35C and 32 g of elementary bromine are metered slowly over a period of 2 hours. After 0.8 equivalents, a gas chromatograph analysis is performed:10% of 4-trifluoromethoxyaniline, 34% of mono-bromo-derivative as per the title, 54% of di-bromo-derivative.
With caesium carbonate;palladium diacetate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; In toluene; at 150℃; for 0.5h;Microwave irradiation;
To a solution of 4-trifluoromethoxyphenylamine (0.5 mL, 3.72 mmol) and <strong>[111196-81-7]2-chloro-5-ethyl-pyrimidine</strong> (0.45 mL, 3.72 mmol) in toluene (5 mL) was added Pd(AcO)2 (251 mg, 0.37 mmol), rac-BINAP (347 mg, 0.56 mmol) and Cs2CO3 (1.8 g, 5.6 mmol). The resulting mixture was heated in a microwave oven at 150 C. for 30 min. After cooling to room temperature, the reaction mixture was purified by silica gel chromatography to give the desired product, 252 mg (24%) as a yellow solid. 1H NMR (400 MHz, CDCl3) delta 8.29 (s, 2H), 7.63 (d, 2H), 7.17 (d, 2H), 2.54 (q, 2H), 1.24 (t, 3H).
Stir <strong>[52771-21-8]3-(trifluoromethoxy)benzaldehyde</strong> (25.2 g, 132.4 mmol), 4-(trifluoromethoxy)aniline (39.4 mL, 291 mmol) and ethyl pyruvate (14.6 mL, 132.4 mmol) in glacial HOAc (97 mL) at ambient temperature for 18 hours. Concentrate under reduced pressure and dissolve the residue in Et2O. Let stand 18 hours at ambient temperature. Filter the <n="18"/>precipitate and dry under vacuum to afford the titled compound (24.8 g) as a yellow crystalline solid. Purify the filtrate by silica gel chromatography (5-45% dichloromethane-hexane) to afford additional product (33.4 g, 76%). LC-MS ESI m/z: 577 (M-I)", Tr = 5.73 min., method 1.
6-chloro-5-methyl-N-(4-(trifluoromethoxy)phenyl)pyrimidine-4-amine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
84%
With N-ethyl-N,N-diisopropylamine; In ethanol; for 4h;Reflux;
4,6-dichloro-5-methyl pyrimidine (534.6mg, 3.3mmol) and 4- Trifluoromethoxyaniline (661mg, 3.6mmol) and, EtOH and Was added to DIEA (625muL, 3.6mmol), it was refluxed and the resulting mixture for 4 h. Then the obtained reaction mixture was cooled, concentrated, and triturated in ethyl acetate. The resulting organic layer was separated and dried over Na2SO4. The resulting organic layer was concentrated, followed by silica gel column chromatography and purified (ethyl acetate / hexane) to give the title compound (800 mg, yield: 84%; MS m / z 304.14 (M + 1))
With DIEA; triphenylphosphine; In ethanol; sodium carbonate; acetonitrile;
Example 2 3-[6-(4-Trifluoromethoxy-phenylamino)-pyrimidin-4-yl]-benzamide (GNF-2) 4,6-dichloropyrimidine (1 g, 6.7 mmol) is dissolved with p-trifluoromethoxy aniline (1.2 g, 6.7 mmol) in 15 mL ethanol, then 1.75 mL DIEA (10 mmol) is added. Reaction is under reflux for 2 hours, and cooled down to room temperature. After evaporating the solvent, the crude product is purified by flash chromatography (EA/Hexane=3:7) to give (6-chloro-pyrimidin-4-yl)-(4-trifluoromethoxy-phenyl)-amine as a white solid. To a degassed solution of (6-chloropyrimidin-4-yl)-(4-trifluoromethoxyphenyl)-amine (73 mg, 0.25 mmol) and (3-aminocarbonylphenyl)-boronic acid (42 mg, 0.25 mmol) in 0.4 M sodium carbonate aqueous solution (1.3 mL) and acetonitrile (1.3 mL) is added PPh3 (15 mg, 0.01 mmol). After stirring at about 90 C. under N2 for 12 hours, the reaction mixture is partitioned between saturated NaHCO3 and CHCl3/2-propanol (4:1). The aqueous layer is extracted with additional CHCl3/2-propanol (4:1) and the combined organic layers are dried over MgSO4, filtered, and concentrated under reduced pressure. The resultant yellowish oil is purified by column chromatography (SiO2, ethyl acetate) to give 3-[6-(4-trifluoromethoxyphenyl-amino)-pyrimidin-4-yl]-benzamide as a white solid. MSm/z 375.10(M+1).
With dicyclohexyl-carbodiimide; 4-(dimethylamino)pyridinium tosylate; In dichloromethane; at 20℃;
In a reaction flask, retinoic acid of 0.5g, p-(trifluoromethoxy)aniline of 0.35g, 4-dimethylaminopyridine (DMAP) p-toluene sulphonate of 0.56g and dichloromethane of 5ml are added and stirred in the condition of ice bath with white insoluble substances generated; DDC of 0.4g and dichloromethane solution are added with the reaction liquid changed into orange red and stirred at the room temperature overnight; and saturated ammonium chloride solution is added to stop the reaction, followed by extraction by dichloromethane, washing by water, drying by anhydrous sodium sulphate, concentration, column chromatography (petroleum ether: 60-90 C), fraction collection, concentration, and recrystallization by methanol to obtain a yellow solid of 0.05g, mp 89.7-174.5.5 C 1H-NMR(CDCl3), delta(ppm): 0.96(s,6H); 1.64(s,3H); 1.94(s,3H); 2.35 (s,3H); 1.40.+1.55 (t,4H); 1.95 (m,2H); 5.70(s,1H); 6.05-6.23 (m,4H); 6.95 (m,1H); 7.51 (d,1H); 7.11 (d,1H); N-H 7.09 (s,1H) 13C-NMR(CDCl3), delta(ppm): 13.01; 13.86; 19.32; 21.83; 29.05; 33.21; 34.37; 39.72; 121.83; 128.86; 129.50; 130.13; 130.97; 135.11; 137.32; 137.82; 139.74; 151.59; 165.14; 120.64; 120.86; 137.04 High-resolution MS: m/z: 459.2379 (theoretical value: 459.2385) molecular formula: C27H32F3NO2
With dicyclohexyl-carbodiimide; 4-(dimethylamino)pyridinium tosylate; In dichloromethane; at 0 - 20℃;
Example 10 (4-trifluoromethoxyphenyl)-(all-trans)-3,7-dimethyl-9-(2,6,6-trimethyl-1-cyclohexen -1-yl)-2,4,6,8-nonatetraenoic acid amide (6a-01) In a reaction flask, retinoic acid of 0.5 g, p-(trifluoromethoxy)aniline of 0.35 g, 4-dimethylaminopyridine (DMAP) p-toluene sulphonate of 0.56 g and dichloromethane of 5 ml are added and stirred in the condition of ice bath with white insoluble substances generated; DDC of 0.4 g and dichloromethane solution are added with the reaction liquid changed into orange red and stirred at the room temperature overnight; and saturated ammonium chloride solution is added to stop the reaction, followed by extraction by dichloromethane, washing by water, drying by anhydrous sodium sulphate, concentration, column chromatography (petroleum ether: 60-90 C.), fraction collection, concentration, and recrystallization by methanol to obtain a yellow solid of 0.05 g, mp 89.7-174.5.5 C. 1HNMR (CDCl3), delta(ppm): 0.96 (s, 6H); 1.64 (s, 3H); 1.94 (s, 3H); 2.35 (s, 3H); 1.40+1.55 (t, 4H); 1.95 (m, 2H); 5.70 (s, 1H); 6.05-6.23 (m, 4H); 6.95 (m, 1H); 7.51 (d, 1H); 7.11 (d, 1H); N-H 7.09 (s, 1H) 13CNMR (CDCl3), delta(ppm): 13.01; 13.86; 19.32; 21.83; 29.05; 33.21; 34.37; 39.72; 121.83; 128.86; 129.50; 130.13; 130.97; 135.11; 137.32; 137.82; 139.74; 151.59; 165.14; 120.64; 120.86; 137.04 High-resolution MS: m/z: 459.2379 (theoretical value: 459.2385) molecular formula: C27H32F3NO2
1-[(4-Methylphenyl)sulfonyl]-4-piperidinecarboxylic acid (0.283 g) and 2-chloro-4,6-dimethoxy-1,3,5-triazine (CDMT) in acetonitrile (40 ml) were treated at RT and under an argon atmosphere with N-methyl-morpholine (0.2 g) and the mixture was stirred for 2 h at RT. 4-trifluoromethoxy-aniline (0.176 g) was then added and stirring was continued for 20 h at RT until completion of the reaction. The reaction mixture was partitioned between ethyl acetate and aqueous 1M HCl, the layers were separated and the organic layer washed with 2M aqueous KHCO3 then dried over Na2SO4. The solvent was evaporated off, the residue purified by flash chromatography (AcOEt/heptane, gradient from 0 to 30%) to give 1-(toluene-4-sulfonyl)-piperidine-4-carboxylic acid (4-trifluoromethoxy-phenyl)-amide (0.298 g) as a white solid. MS (ESI): 443.1 (MH+).
l-[(4-Methylphenyl)sulfonyl]-4-piperidinecarboxylic acid (0.283 g) and 2-chloro-4,6- dimethoxy-l,3,5-triazine (CDMT) in acetonitrile (40 ml) were treated a RT and under an argon atmosphere with N-methyl-morpholine (0,2 g) and the mixture was stirred for 2 h at RT. 4-trifluoromethoxy-aniline (0.176 g) was then added and stirring was continued for 20 h at RT until completion of the reaction. The reaction mixture was partitioned between ethyl acetate and aqueous 1M HCl, the layers were separated and the organic layer washed with 2M aqueous KHCO3 then dried over Na2S04. The solvent was evaporated off, the residue purified by flash chromatography (AcOEt/heptane, gradient from 0 to 30%) to give l-(toluene-4-sulfonyl)-piperidine-4-carboxylic acid (4-trifiuoromethoxy-phenyl)- amide (0.298 g) as a white solid. MS (ESI): 443.1 (MH+).
With pyridine; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; at 60℃; for 1.3h;
Reference Production Example 3A mixture of 1.69 g of 4-trifluoromethoxyaniline, 1.50 g of 3-chloroisonicotic acid, 2.37 g of WSC and 10 ml of pyridine was stirred at 60C for 1.3 hours. The reaction mixture was cooled down to room temperature. The reaction mixture was poured into water. This mixture was extracted with ethyl acetate twice. The combined organic layers were washed with water and saturated saline, dried over magnesium sulfate, then, concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, to obtain 2.87 g of 3-chloro-N- [ ( 4- trifluoromethoxy) phenyl] isonicotinamide .1 H-N R (CDC13) delta: 8.71 (s, 1H) , 8.63 (d, J=5.1 Hz, 1H) , 8.14 (br s, 1H) , 7.68 (d, J=8.8 Hz, 2H) , 7.65 (d, J=5.1 Hz, 1H) , 7.26 (d, J=8.8 Hz, 2H)
With sulfuric acid; dihydrogen peroxide; sodium bromide; at 30 - 55℃; for 3.0h;
A method for preparing 2,6-dibromo-4- (trifluoromethoxy) aniline,Including the following steps:The sodium sulfate was filtered off embodiment Example 4 156g crystallization mother liquor into 250mL 4-neck flask,Start stirring dropping 17.5 (0.175mol) sulfuric acid,Then, 36.5 g of sodium bromide (0.354 moL) was added and then 30 g (99percent, 0.168 mol) of 4-trifluoromethoxyaniline was added.Adjust the temperature to above 30 ,Start dropping 35percent hydrogen peroxide 38g,When dropping temperature rise,When the temperature rose to 50 ,By controlling the cooling liquid dripping temperature control between 50 ~ 55 ,Keep the temperature drops off,Drip finished insulation 3 hours,Cooling to about 30 ,filter,Filter cake drying,White crystals of 2,6-dibromo-4-trifluoromethoxyaniline 55.8 g, purity99.6percent (HPLC), yield 99.2percent.
90%
With bromine chloride; triethylamine; In chloroform; at 35℃; for 12.0h;
208 g of chloroform, 43.3 g of bromine was added to a 250 ml four-necked flask, and the temperature was lowered to -5 ° C, and 17.5 g of chlorine gas was introduced.The obtained chlorobromide in chloroform solution was added dropwise at 35 ° C to hold 44.6 g of p-trifluoromethoxyaniline and 25.4 g of triethylamine.In the reactor of the amine, after stirring for 12 hours, the solvent was removed by filtration and distillation to obtain 2,6-dibromo-4-trifluoromethoxyaniline.76g. (yield 90percent)
With ferrous(II) sulfate heptahydrate; sulfuric acid; boric acid; In water; glycerol; at 0 - 150℃;
To a stirred solution of 4-(trifluoromethoxy)aniline (1.0 g, 5.6 mmol), sodium-3-nitrobenzene sulfonate (1.89 g, 8.4 mmol), boric acid (0.55 g, 8.9 mmol) and iron(II) sulfate heptahydrate (FeSO4.7H2O; 0.31 g, 1.1 mmol) in glycerol (14 mL) was added concentrated sulfuric acid (H2SO4; 3.4 mL) dropwise at 0 C. The reaction mixture was gradually heated to 150 C. and stirred for 5 h. After completion of the reaction (monitored by TLC), the reaction mixture was poured into ice-cold H2O (100 mL), made basic with 50% aq sodium hydroxide (NaOH) solution (10 mL) and extracted with Et2O (4*25 mL). The separated organic layer was washed with H2O (50 mL) and brine (50 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure to obtain the crude material. Purification by silica gel column chromatography (eluting with 12% EtOAc/hexane) afforded the quinoline K (0.95 g, 4.42 mmol, 79%) as a colorless liquid. 1H NMR (200 MHz, CDCl3): delta 8.96-8.94 (m, 1H), 8.16 (d, J=8.2 Hz, 2H), 7.65-7.56 (m, 2H), 7.47 (dd, J=8.2, 4.2 Hz, 1H). MS (ESI): m/z 214 [M+H]+.
With hydrogen;palladium 10% on activated carbon; In ethanol; water; under 760.051 Torr; for 31h;Inert atmosphere;
Step 1. (2,2-Dimethoxyethyl)-(4-trifluoromethoxyphenyl) amine. To a stirred solution of 4-trifluoromethoxyaniline (1 mL, 7.46 mmol) and glyoxaldehyde dimethyl acetal (60% v/v in water; 8.95 mmol, 1.6 mL) in EtOH (37 mL) was added 10% Pd/C (300 mg). The mixture was evacuated and flushed with nitrogen three times. Hydrogen was then added in a balloon apparatus and the mixture was stirred under 1 atm of hydrogen for 31 h. The mixture was filtered through a pad of Celite and the pad was washed with EtOH (25 mL). The ethanol was removed under reduced pressure and the residue was diluted with CH2Cl2 (30 mL). The layers were separated and the organic phase was dried over MgSO4, filtered and concentrated to give (2,2-dimethoxyethyl)-(4-trifluoromethoxyphenyl) amine (1.7 g, 86%): 1H NMR (400 MHz, CDCl3) delta 7.04 (d, J = 8.9 Hz, 2H), 6.59 (d, J = 8.9 Hz, 2H), 4.56 (t, J = 5.4 Hz, IH), 3.92 (br s, IH), 3.51 (d, J= 5.4 Hz, 2H), 3.42 (s, 6H); EIMS m/z 265 (M+).
General procedure: To a flame-dried 25 mL round bottom flask was charged activated Mg (7.5 mmol, 1.5 eq.) and 5 mL anhydrous THF. To this suspension was added 2 drops of 1,2-dibromoethane. After 5 min, a solution of Aryl bromide (5 mmol, 1.0 eq.) in 5 mL anhydrous THF was slowly added to the suspension of Mg at room temperature. The reaction was mildly exothermic. The Grignard reagent was titrated and 1 mmol of this reagent was added to a flame-dried reaction vial. The solution was diluted with 3 mL anhydrous toluene and after cooling to the target temperature T, a solution of oxaziridine (1.2 mmol, 1.2 eq.) in 1 mL anhydrous toluene was added. The reaction was maintained at the targeted temperature T for time t before being quenched with saturated aqueous NH4Cl. (The actual temperature/reaction time is listed for each substrate.)
3-bromo-4-fluoro-N-(4-(trifluoromethoxy)phenyl)benzamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
Stage 1.3: 3-Bromo-4-fluoro-N-(4-(trifluoromethoxy)phenyl)benzamide [0354] SOCl2 (2.92 mL, 40.0 mmol) and DMF (0.5 mL) were added dropwise to a suspension of <strong>[1007-16-5]3-bromo-4-fluorobenzoic acid</strong> (1.752 g, 8 mmol) in toluene (20 mL) and the RM was stirred at 80 C. for 1 h The solvent was evaporated off under reduced pressure and the residue was diluted with THF (15 mL). DIPEA (2.79 mL, 16.00 mmol) was added and the mixture was cooled to 0 C., treated with a solution of 4-trifluoromethoxyaniline (1.181 mL, 8.80 mmol) in THF (5 mL) and stirred for 1 h. The RM was treated with aq. 1 M HCl (50 mL), and extracted with TBME. The combined extracts were washed with aq. 1 M HCl, aq. 1 M NaOH and brine, dried over MgSO4 and the solvent was evaporated off under reduced pressure to give a residue was crystallized from n-heptane/DCM to afford the title compound as a white solid. UPLC-MS (Condition 1) tR=3.18 min, m/z=377.9/379.9 [M+H]+, m/z=375.9/377.9 [M-H]-; 1H-NMR (400 MHz, DMSO-d6) delta ppm 7.38 (d, J=8.6 Hz, 2H) 7.56 (t, J=8.7 Hz, 1H) 7.87 (d, J=9.0 Hz, 2H) 8.00-8.06 (m, 1H) 8.32 (dd, J=6.6, 2.2 Hz, 1H) 10.50 (s, 1H).
SOCl2 (2.92 mL, 40.0 mmol) and DMF (0.5 mL) were added dropwise to a suspension of <strong>[1007-16-5]3-bromo-4-fluorobenzoic acid</strong> (1.752 g, 8 mmol) in toluene (20 mL) and the RM was stirred at 80C for 1 h The solvent was evaporated off under reduced pressure and the residue was diluted with THF (15 mL). DIPEA (2.79 mL, 16.00 mmol) was added and the mixture was cooled to 0C, treated with a solution of 4-trifluoromethoxyaniline (1.181 mL, 8.80 mmol) in THF (5 mL) and stirred for 1 h. The RM was treated with aq. 1 M HC1 (50 mL), and extracted with TBME. The combined extracts were washed with aq. 1 M HC1, aq. 1 M NaOH and brine, dried over MgS04 and the solvent was evaporated off under reduced pressure to give a residue was crystallized from n-heptane / DCM to afford the title compound as a white solid. UPLC-MS (Condition 1) tR = 3.18 min, m/z = 377.9/379.9 [M+H]+, m/z = 375.9/377.9 [M-H]"; XH-NMR (400 MHz, DMSO-de) delta ppm 7.38 (d, J = 8.6 Hz, 2 H) 7.56 (t, J = 8.7 Hz, 1 H) 7.87 (d, J = 9.0 Hz, 2 H) 8.00 - 8.06 (m, 1 H) 8.32 (dd, J = 6.6, 2.2 Hz, 1 H) 10.50 (s, 1 H).
6-chloro-5-iodo-N-(4-(trifluoromethoxy)phenyl)nicotinamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
Stage 4.2: 6-Chloro-5-iodo-N-(4-(trifluoromethoxy)phenyl)nicotinamide DMF (0.13 mL) and SOCl2 (0.734 mL, 10.05 mmol) were added to a mixture of <strong>[59782-87-5]6-chloro-5-iodonicotinic acid</strong> (1.00 g, 3.35 mmol) and 4-(trifluoromethoxy)aniline (0.623 mg, 3.52 mmol) in toluene (7 mL) and the RM was stirred at 80 C. for 1 h. The solvent was evaporated off under reduced pressure and under argon the residue was dissolved in THF (7.00 mL) and DIPEA (1.17 mL, 6.7 mmol), cooled to -15 C. treated dropwise with a solution of 4-(trifluoromethoxy)aniline (0.476 mL, 3.52 mmol) in THF (7.00 mL) and stirred at RT for 1 h. The solvent was evaporated off under reduced pressure and the residue treated with aq. 1N HCl (30 mL) and extracted with TBME (100 mL). The combined extracts were washed with sat. aq. Na2CO3 (30 mL) and brine (30 mL), dried over Na2SO4 and the solvent was evaporated off under reduced pressure until crystallization commenced. The product was triturated with n-heptane, filtered and dried to afford the title compound as an off-white solid. HPLC (Condition 4) tR=6.36 min, UPLC-MS (Condition 3) tR=1.23 min, m/z=441.1 [M-H]-.
[00679] DMF (0.014 mL, 0.176 mmol) and oxalyl chloride (2.316 mL, 26.5 mmol) were added to a solution of <strong>[59782-87-5]6-chloro-5-iodonicotinic acid</strong> (5 g, 17.64 mmol) in DCM (80 mL) and the RM was stirred for 2 h at RT under a nitrogen atmosphere. The solvent was evaporated off under reduced pressure and the residue was dissolved in THF (60 mL). DIPEA (9.24 mL, 52.9 mmol) was added and the mixture was cooled down to 5C, treated dropwise with a solution of 4- (trifluoro methoxy)aniline (2.62 mL, 19.40 mmol) in DCM (20 mL) and stirred at 5C for 30 min and at RT for 1 h. The solvent was off under reduced pressure and the residue was treated with aq. 10 % citric acid (70 mL) and extracted with EtOAc. The combined extracts were washed with sat. aq. Na2C03 and brine, dried over Na2S04 and the solvent was evaporated off under reduced pressure to give the crude product was suspended in n-hexane, and filtered to afford the title compound as a beige solid. UPLC-MS (Condition 3) tR = 1.22 min, 440.9/442.9 [M-H]~.
5-bromo-N-(4-(trifluoromethoxy)phenyl)nicotinamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 0℃; for 2h;Inert atmosphere;
SOCl2 (10.84 mL, 148.5 mmol) was added to a suspension of 5-bromonicotinic acid (5 g, 24.75 mmol) in DCM (60 mL) and the RM was stirred at RT overnight. The solvent was evaporated off under reduced pressure and the residue was dissolved in DCM (40 mL), the mixture was cooled to 0C under a nitrogen atmosphere, DIPEA (8.65 mL, 49.5 mmol) was added dropwise, followed with a solution of 4-trifluoromethoxyaniline (3.65 mL, 27.2 mmol) in DCM (20 mL). The RM was stirreSOCl2 (10.84 mL, 148.5 mmol) was added to a suspension of 5-bromonicotinic acid (5 g, 24.75 mmol) in DCM (60 mL) and the RM was stirred at RT overnight. The solvent was evaporated off under reduced pressure and the residue was dissolved in DCM (40 mL), the mixture was cooled to 0C under a nitrogen atmosphere, DIPEA (8.65 mL, 49.5 mmol) was added dropwise, followed with a solution of 4-trifluoromethoxyaniline (3.65 mL, 27.2 mmol) in DCM (20 mL). The RM was stirred for 2 h, treated with sat. aq. Na2CC>3 (100 mL), and extracted EtOAc. The combined extracts were washed with sat. solution of KH2P04 (pH = 4), brine, dried over MgS04 and the solvent was evaporated off under reduced pressure to give a residue which was recrystallized from n-heptane / EtOAc to afford the title compound as beige needles. UPLC- MS (Condition 1) tR = 2.71 min, m/z = 360.9-362.9 [M+H]+, m/z = 358.9-361.0 [M-H]"; XH-NMR (400 MHz, DMSO-d6) delta ppm 7.40 (d, J=8.3 Hz, 2 H) 7.87 (d, 2 H) 8.55 (t, J=2.1 Hz, 1 H) 8.93 (d, J=2.2 Hz, 1 H) 9.07 (d, J=1.7 Hz, 1 H) 10.67 (s, 1 H).d for 2 h, treated with sat. aq. Na2CC>3 (100 mL), and extracted EtOAc. The combined extracts were washed with sat. solution of KH2P04 (pH = 4), brine, dried over MgS04 and the solvent was evaporated off under reduced pressure to give a residue which was recrystallized from n-heptane / EtOAc to afford the title compound as beige needles. UPLC- MS (Condition 1) tR = 2.71 min, m/z = 360.9-362.9 [M+H]+, m/z = 358.9-361.0 [M-H]"; XH-NMR (400 MHz, DMSO-d6) delta ppm 7.40 (d, J=8.3 Hz, 2 H) 7.87 (d, 2 H) 8.55 (t, J=2.1 Hz, 1 H) 8.93 (d, J=2.2 Hz, 1 H) 9.07 (d, J=1.7 Hz, 1 H) 10.67 (s, 1 H).
3-bromo-2-fluoro-N-(4-(trifluoromethoxy)phenyl)benzamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
A solution of oxalyl chloride (0.657 mL, 7.50 mmol) in DCM (10 mL) and of DMF (0.01 mL) were added to a suspension of <strong>[161957-56-8]3-bromo-2-fluorobenzoic acid</strong> (1.095 g, 5 mmol) in DCM (10 mL) and the RM was stirred for at RT for 2 h. The solvent was evaporated off under reduced pressure. The residue was dissolved in DCE (10 mL), treated dropwise with a solution of 4-(trifluoromethoxy)aniline (0.744 mL, 5.50 mmol) and DIPEA (1.747 mL, 10.00 mmol) and the RM was stirred for at RT for 1 h. The RM was treated with an aq. NaHCC and extracted with DCM. The combined extracts were washed with water, dried over Na2S04 and the solvent was evaporated off under reduced pressure to give the crude product which was purified by flash chromatography (Silica gel column, 100 g, n- hexane / EtOAc 2: 1) to afford the title compound as beige crystals. UPLC-MS (Condition 2) tR= 1.22 min, m/z = 375.9/378.0 [M-H-]
With hydrogenchloride; In ethanol; water; for 3h;Reflux;
General procedure: To a solution of intermediate 5a (5.00 g, 17 mmol) and 3-fluorobenzenamine (6a, 1.89 g, 17 mmol) in ethanol (80 mL) was added concentrated HCl (2.0 mL). The mixture was heated to reflux for 3 h. After cooling to rt, the reaction mixture was filtered to give 7a as an off-white solid (4.86 g, 79.1%).
With N-ethyl-N,N-diisopropylamine; In toluene; at 90℃; for 18h;
General procedure: A mixture of asubstituted aniline (33aem) (5.5 mmol), N-ethyldiisopropylamineand alkyl halide (34aec) or ethyl sulfate (34d) in the molar ratio of1:1:1 in toluene (21 ml) was stirred and heated at 90∘C for 18 h. Inthe cases listed below it was necessary to vary the conditions of reaction as summarized in Table 1.The resulting suspension was taken up with ethyl acetate. The organic phase was washed with water then dried over anhydrous sodium sulfate. On evaporation of the solvent, in most cases a solidor an oily residuewas obtained. Purification was performed by flash chromatography on a silica gel column eluting with the following mixture of solvents: ethyl acetate/petrol ether 40-60∘, in the ratio of 6:4 (35, 42); 7:3 (52); 8:2 (41, 43, 48, 51, 53, 62, 65); 9:1 (38, 39,45, 46, 47, 50); 95:5 (36, 37, 44, 55, 56, 57, 58, 59, 60, 61); 98:2 (64);petrol ether 40-60∘/diethyl ether 9:1 (49); toluene/ethyl acetate 95:5 (63); chloroform/methanol 95:5 (54), chloroform/methanol 98:2 (66).
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%).
With benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 25℃; for 16h;
To a solution of <strong>[37972-69-3]6-oxo-1,6-dihydropyridazine-3-carboxylic acid</strong> (500 mg, 3.16 mmol) in DMF (5 mL) at 25 C 4-(trifluoromethoxy)aniline ( 616 mg, 3.48 mmol), DIEA ( 1.1 mL, 6.3 mmol) and PyBOP (1.643 g, 3.16 mmol) were added. The resulting mixture was stirred at 25 C for 16 h, then diluted EtOAc and washed with brine. The organic layer was dried (Na2S04), concentrated under reduced pressure and the residue was triturated with a 1/1 v/v mixture of Et20/DCM to give the title compound as a white solid (415 mg, 44%); MS (ES+) C12H8F3N303 requires: 299, found: 300 [M+H]+.
Stage #1: diethyl oxalpropionate; 4-(trifluoromethoxy)aniline With acetic acid In toluene at 110℃; Dean-Stark;
Stage #2: In diphenylether at 250℃;
General procedure: In a 250ml round-bottom flask (RBF) attached with a Dean-Stark trap and a reflux condenser was charged with diethyl oxalpropionate (β-ketoester) (0.045mol), toluene (20ml), glacial acidic acid (1ml) and corresponding p-substituted anilines (1a-h) (0.045mol). The reaction mixture was refluxed at 110°C until no more water was separated (3-18h) to afford corresponding Schiff bases. Toluene was distilled under reduced pressure, and resulting crude intermediates were than used in the next step (thermal cyclisation). Biphenyl ether (25ml) was stirred and heated at reflux, while crude intermediates were added rapidly through the dropping funnel. Stirring and refluxing continued for 10-15min until no more ethanol separated within Dean-Stark trap. The mixture was then allowed to cool at room temperature while precipitation arose. Solids were filtered off and washed. 6-Substituted-4-hydroxyquinoline-2-carboxylicethylesters (2a-h) were dissolved in required amount of tetrahydrofuran. Lithium hydroxide (0.0031mol) and water (0.012)mol were added, reaction mixture was allowed to stir for 4-6h. Reaction mixture was neutralized to pH 6.5 by addition of 1% HCl. Obtained precipitates were filtered, washed, and recrystallized from ethanol.
With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In N,N-dimethyl-formamide; at 20℃;
Step 1: A scintillation vial was charged 2-amino-4-trifluoromethyl-benzoic acid (410 mg, 2.0 mmol), 4-trifluoromethoxy-phenylamine (531 mg, 3.0 mmol), diisopropylethylamine (1.0 ml_, 6.0 mmol) and dry dimethyl formamide (10 ml). To this mixture was added HATU (760 mg, 2.0 mmol) and the reaction was stirred at room temperature overnight. The reaction mixture was poured into water and the precipitate was filtered, washed with water and dried under vacuum to give 2-amino- N-(4-trifluoromethoxy-phenyl)-4-trifluoromethyl-benzamide (65 mg; 90%) as a white solid; LCMS (ESI) 365 (M+H); 1H NMR (CHLOROFORM-d) delta: 7.77 (br.s., 1 H), 7.62 (d, J=8.9 Hz, 1 H), 7.57 (d, J=8.2 Hz, 1 H), 7.24 (s, 2H), 6.92 - 7.00 (m, 1 H), 5.70 (br.s., 1 H).
With caesium carbonate; at 125℃; for 12h;Schlenk technique;
General procedure: To an oven-dried, 25 mL Schlenk tube were added amines (0.5 mmol), methanol (1.5 mL), Cp*Ir(at)CTF (15.0 mg, 0.0025 mmol,0.5 mol %), Cs2CO3 (163 mg, 0.5 mmol). The mixture of reaction was heated at 125 C in an oil bath for 12 h. The reaction mixture was cooled to ambient temperature, concentrated in vacuo and purified by flash column chromatography with hexanes/ethyl acetate to afford the corresponding product.
tert-butyl (4-((4-(trifluoromethoxy)phenyl)carbamoyl)thiazol-2-yl)carbamate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
69.6%
General procedure: A solution of compound 3 (0.5 g, 2.0mmol), EDCI (0.45 g, 2.34 mmol), HOBT (0.28 g, 2.05 mmol) in anhydrous CH2Cl2 (20 mL) was stirred for 1 h at room temperature under nitrogen atmosphere, followed adding various amines or alcohols (1.95 mmol) and Et3N(0.24 g, 2.34 mmol). The reaction mixture was then stirred overnight at room temperature. After completion of the reaction, the mixture was washed with H2O (20mL), saturated NaHCO3 (20 mL) and brine (20 mL), the organic layer was dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude product was purified by column chromatograph on silica gel (200-300 mesh) by ethyl acetate and petroleum ether (v/v = 1:41:1) as eluent to afford target compounds (yield 50.1%-86.4%).
General procedure: A mixture of 4-methylaniline (8 g, 74.77mmol) and water was stirred at 35 C, before 98% sulfuric acid was added gradually. The reaction mixture was continue stirring for 35 minutes and then cooled to 0 C. Sodium nitrite solution (5.42 g, 80 mmol) was added and stirred for 2 hours. Then, dichloromethane and potassium iodide solution (13.03 g, 78.50 mmol) were added to the diazonium salt. The mixture was stirred for 6 hours at 0C and kept stirring at room temperature for 10 hours. The organic phase was separated, washed with sodium bisulfate solution, saturated sodium chloride solution, saturation sodium solution and then were dried by sodium sulfate solution. The mixture was filtered and the filtrate was concentrated in vacuum to give crude product. The crude productwas purified by column chromatography of silica gel, eluted with petroleum ether /ethyl acetate (3:1, V/V) to give 5a-d as yellow solids.
3-((4-(trifluoromethoxy)phenyl)carbamoyl)-7-oxabicyclo[2.2.1]heptane-2-carboxylic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
47%
With triethylamine; In tetrahydrofuran; at 20℃; for 14h;
General procedure: To a solution of NCTD (1, 1.0 g, 5.95 mmol) dissolved in tetrahydrofuran (THF, 10 mL)accompanied by triethylamine (TEA, 0.5 mL) as the acid-binding agent was added the correspondingaromatic amine (1 equiv., 5.95 mmol). When the reaction was complete after 14 h as checkedby TLC analysis, the solution was concentrated under reduced pressure and diluted with acetone(100 mL). The resulting filter cake was either recrystallized from methanol or purified by columnchromatography (MeOH/CH2Cl2, 1: 4, v/v) to afford the desired products II (1-36). The yields,physical properties, 1H-NMR, 13C-NMR, and HRMS-ESI of the target compounds II were as follows.
methyl 2,3-bis([4-(trifluoromethoxy)phenyl]amino})quinoxaline-6-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With hydrogenchloride; In water; isopropyl alcohol; at 60℃;
The compounds of this invention can be prepared by the above synthetic scheme III obtained synthetic schemes see specific description of the embodiments.In the synthesis of Scheme III, the first four positions have a modified-phenylenediamine was dissolved in 2mL of concentrated HCl and heated to 180 deg.] C overnight, the mixture was filtered and the precipitated intermediate product obtained after drying by water b.The intermediate product is then dissolved to b of POCl3and heated to 110 3 hours.After the reaction mixture was cooled to room temperature, poured into ice water and a precipitate, the precipitate was dried in an oven to obtain an intermediate product c.And c aniline intermediate product was dissolved in IPA, followed by addition of 2 drops of concentrated HCl, then the mixture was heated to 60 deg.] C overnight.The mixture was filtered utilizing IPA to produce a precipitate, the precipitate was further purified using chromatography to give TD-83 to TD-95, ITRI TD-602 to ITRI TD-604, ITRI TD- 607, ITRI TD-608, compound ITRI TD-613 to ITRI TD-618, ITRI TD- 620to ITRI TD-624, ITRI TD- 629and so on.
1) Add 1 mol of trifluoromethoxybenzene and anhydrous DMSO to the reaction vessel under argon and vigorous stirring. Then add sodium ferrate and sodium bromide as auxiliary reaction mixture, heat to 95 C for 4 h, then add sodium amide, The temperature was raised to 155 C, the reaction pressure was raised to 4 atm, and the reaction was continued for 10 h; The ratio of trifluoromethoxybenzene to sodium amide is 1:4.5, The ratio of the amount of the trifluoromethoxybenzene to the auxiliary reaction mixture was 1:1.4. The ratio of sodium ferrate to sodium bromide is 1:1. 2) After cooling the system, pour it into 8 volumes of water. The extract was extracted with 4 times the original reaction volume of chloroform, and the extract was washed with water and dried over anhydrous sodium sulfate. Then concentrated to give the product in a molar yield of 98.2%, HPLC purity 97.7%
5-amino-1-(4-trifluoromethoxyphenyl)-3-cyano-1H-pyrazole[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
77.4%
In a 250 mL round bottom three-necked flask0.01 mol of 4-trifluoromethoxyaniline and a small amount of ethanol,3.0 mL (0.035 mol) of concentrated hydrochloric acid was added dropwise under ice-cooling with stirring.0.018 mol of sodium nitrite was dissolved in 10 mL of water,Slowly dropping into the flask,After the reaction was completed 0.5h yellow diazonium salt solution.0.01 mol of <strong>[40497-11-8]ethyl 2,3-dicyanopropionate</strong> was added to a three-necked flask,The prepared diazonium salt solution was dropped into the flask,After dropping the reaction 2 h.Adding ammonia,Adjust the pH to 9-10,Reaction at room temperature for 2h.After completion of the reaction, the reaction mixture was extracted with 40 mL of dichloromethane,The organic layer was washed with water (2 x 30 mL)Washed with saturated sodium chloride solution (1 x 40 mL)Dried over anhydrous magnesium sulfate,A portion of the solvent was evaporated under reduced pressure to crystallize to yield 2.06 g of product,The yield was 77.4%
With 1,1'-bis-(diphenylphosphino)ferrocene; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium tert-butylate; In toluene; at 120℃; for 5h;Inert atmosphere;
Compound 1 (4-trifluoromethoxybromobenzene) (24.10 g, 0.1 mol) and compound 2 (4-trifluoromethoxyphenylamine) (17.71 g, 0.1 mol) were added to dry toluene solution (300 mL). 1,10-Bis(diphenylphosphino)ferrocene (DPPF) (6.65 g, 12 mmol), [1,10-bis(diphenylphosphino)ferrocene]palladium(II) dichloride dichloromethane adduct [(DPPF)PdCl2.CH2Cl2] (0.33 g, 0.4 mmol) and potassium tert-butoxide (KOtBu) (9.61 g, 0.1 mol) were added to the reaction mixture under nitrogen atmosphere. The reaction was stirred for 5 h at 120 C. After completing the reaction, the mixture was poured into water (100 mL); the organic layer was extracted with ethyl acetate and distilled water. The obtained organic layer was isolated by silica gel column chromatography using the ethyl acetate:petroleum ether (1: 9) to get the oily product. Yield 67%. 1H NMR (300 MHz, Chloroform-d) delta = 7.15 (d, J = 8.4 Hz, 4H), 7.04 (d,J = 9.0 Hz, 4H), 5.72 (s, 1H). 13C NMR (126 MHz, Chloroform-d) delta = 143.65, 142.07, 122.79, 119.09.
3. Preparation of (8-chloro-quinolin-2-yl)-(4-trifluoromethoxyphenyl)-amine (free base) without a Palladium-Catalyst 2,8-Dichloroquinoline (125 g; 0.63 mol) was slurried in 4-(trifluoromethoxy)aniline (280 g; 1 .58 mol) and isopropanol (240 ml_) and the mixture was heated to 90C. The mixture was stirred for 3-4 h when HPLC indicated complete conversion of dichloroquinoline. Thereafter, additional isopropanol (730 ml_) was added and the mixture cooled to approx. 40C. Water (2.5 L) was added slowly and the resulting precipitate was collected by suction filtration. The filter cake was dried under reduced pressure and afterwards recrystallized from boiling cyclohexane (1 .5 L) in order to yield pure product as an off-white solid. Yield: 203 g (95%) Chemical purity: 99.9% (peak area at lambda=254 nm). The identity of (8-chloro-quinolin-2-yl)-(4-trifluoromethoxyphenyl)-amine was verified by 1 H-NMR (Fig. 1 ); FT-IR (Fig. 2) and GC-MS (Fig. 3). The NMR spectrum was characterized by the following signals: 1 H NMR (400 MHz, CDCI3) delta ppm 6.87 (m, 2 H); 7.23 (m, 3 H); 7.55 (dd, J=8.01 , 1 .28 Hz, 1 H); 7.72 (dd, J=7.52, 1 .28 Hz, 1 H); 7.90 (m, 3 H). The IR-spectrum was characterized by the following signals: 3406; 1626; 1606; 1535; 1506; 1475; 1425; 1392; 1257; 1217; 1 146; 1001 ; 849; 822; 795; 754; 719; 673; 663; 631 cm"1. The solid state characteristics were investigated by means of DSC and XRPD and is as follows: The DSC thermogram (Fig. 4) is characterized by a single endotherm with an onset temperature of 120C (± 2C) and a peak temperature of 121 (± 2C). A characteristic x-ray powder diffractogrann is given in Fig. 5 and its characteristic signals are summarized in the following table: Major peaks can be seen at angles 7.3, 14.6 and 18.3 with relative intensities of 100.0%, 86.4% and 18.3%, respectively. Further prominent peaks can be seen at angles 23.0 and 24.8 with relative intensities of 18.1 % and 35.1 %, respectively. Additional prominent peaks can be seen at angles 28.3 and 29.5 with relative intensities of 13.8% and 1 1 .2%. Finally, remarkable peaks can be seen at angles 18.6, 22.3, 24.1 , 29.0 and 42.6 with relative intensities of 8.2%, 8.0%, 7.1 %, 8.6% and 7.4%, respectively.
54%
General procedure: A mixture of substrate 2 (0.5 mmol), 1 (0.6 mmol), Pd(OAc)2 (2 mol%), Xphos (4 mol%), NaOtBu (2.0 equiv.) and Na2SO4 (2.0 g) were added to the 25 mL screw-capped stainless-steel vessel, along with two stainless steel balls ( = 1.4 cm). After that, the vessel was placed in the mixer mill, and the contents were ball milled at 30 Hz for 60 min. At the end of the reaction, small portion (3 mL) ethyl acetate and (3 mL) H2O were added in to the vessel and grinding for another 2 min at 30 Hz. Then, after the washing by brine, the organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo to give a residue, which was purified by flash column chromatography on silica gel to give the desired product.
With palladium diacetate; caesium carbonate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In tert-butyl alcohol; at 90℃; for 20h;Inert atmosphere;
2. Preparation of (8-chloro-quinolin-2-yl)-(4-trifluoromethoxyphenyl)-amine (Comperative Example) 2,8-Dichloroquinoline (984mg) is placed in 20 ml tert-butanol. 4- (trifluoromethoxy)aniline (743 muIota_) is then added in presence of 4.6g Cs2CO3, in the presence of 58mg Xantphos (4,5-Bis(diphenylphosphino)-9,9- dimethylxanthene), and in the presence of 22mg Pd(OAc)2. The reaction mixture is then heated at 90C and stirred during 20 hours under argon. The reaction mixture is concentrated under reduced pressure and the resulting residue is diluted with ethyl acetate. The organic phase is then washed twice with water, dried on magnesium sulphate, filtered and concentrated under reduced pressure.
2-methyl-propane-2-sulfinic acid [3-(4-trifluoromethoxy-phenylamino)-oxetan-3-yl]-amide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
78%
In methanol; at 60℃; for 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.
5-nitro-N-(4-(trifluoromethoxy)phenyl)pyrimidine-2-amine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
90%
In acetonitrile;Inert atmosphere;
The first step: a vacuum 50mL reaction bottle is vacuumed three times, then added to the reaction bottle4-(trifluoromethoxy)aniline (177 mg, 1.0 mmol, 1.0 equiv), add 10.0 mL of dry acetonitrile and stir to 4-(Trifluoromethoxy) aniline was completely dissolved, 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-(trifluoroMethoxy)phenyl)pyrimidine-2-amine (270 mg, 90% yield).
5-bromo-4-methyl-N-[4-(trifluoromethoxy)phenyl]pyrimidin-2-amine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
52%
With hydrogenchloride; water; In isopropyl alcohol; at 100℃; for 4h;
A mixture of <strong>[633328-95-7]5-bromo-2-chloro-4-methyl-pyrimidine</strong> (2 g), 4-Trifluoromethoxyaniline (2.04 g), concentrated Hydrochloric acid solution (0.2 mL) in in 2-propanol (20 mL) was heated at 100 00 for 4 h. The mixture was subsequently cooled to room temperature, poured into ice and basified with a saturated solution Sodium bicarbonate solution and precipitated solids were filtered. The filteredsolid was subjected to Silica gel flash column chromatography eluting with a gradient of Ethyl acetate and n-Heptane to afford the desired product (1 .75 g, 52 %) as an off-white solid. LCMS:Rt: 2.20 min; MS: mz = 346.1 (M-1); IH NMR (300 MHz, CDCI3) 68.32(s, IH), 7.88 (5, IH), 7.63-7.51 (m, 2H), 7.19 -7.07 (m, 2H), 2.50 (5, 3H).
4-[4-(trifluoromethoxy)anilino]pyridine-3-carbonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
65.9%
With palladium diacetate; caesium carbonate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; In 1,4-dioxane; at 100℃; for 15h;
[00428] To a solution of 79-1 (300.0 mg, 2.2 mmol, 1.0 eq), 79-2 (384.4 mg, 2.2 mmol, 0.29 mL, 1.0 eq) and palladium acetate (48.7 mg, 0.22 mmol, 0.1 eq) in dioxane (8.0 mL) was added BINAP (135.1 mg, 0.22 mmol, 0.1 eq) and Cs2C03 (707.0 mg, 2.2 mmol, 1.0 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 product 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 give 79-3 (400.0 mg, 1.4 mmol, 65.9% yield). LCMS (ESI): RT = 0.573 min, mass calc. for Ci3H8F3N30 279.06, m/z found 279.9 [M+H]+.
Add a solution of trimethylaluminum in toluene (2 mol/L, 6 mL, 12 mmol) to a solution of 4-trifluoromethoxyaniline (ie compound 5, 1.77 g, 10 mmol) in toluene (20 mL). in. Stir at room temperature for 16 hours.Methyl 5-aminothiophene-3-carboxylate (i.e. Compound 4, 1.58 g, 10 mmol) was then added. The reaction solution was stirred and refluxed under a nitrogen atmosphere for 24 hours.Then, the reaction solution was cooled to room temperature, and a saturated sodium hydrogen carbonate aqueous solution (20 mL) was added dropwise, and the mixture was stirred at room temperature for 30 minutes.It was extracted three times with dichloromethane, and the organic layer was combined.An oil is obtained, and then an ethane/ethyl acetate mixture is added.It was ground to precipitate a brown solid which was Intermediate 6. Yield: 65%.
General procedure: A solution of <strong>[93683-65-9]6-chloro-3-nitropicolinonitrile</strong> (25) (0.60 g, 2.7 mmol) and an appropriate aniline was heated at 130 C in isopropanol. After 3-16 h, the solution was concentrated under reduced pressure. The precipitate obtained was neutralized with solution of ammonia in methanol to afford 26-38 as a crude product. The next step was carried out without any purification. To a suspension of 26-38 in methanol (20 mL) and concentrated hydrochloric acid (36%, 2 - 4.0 mL) was added iron powder. The mixture was refluxed until all the starting material had reacted (monitored on TLC). The hot reaction mixture was poured into water (20 mL) and stirred for 5 min. The unreacted iron was removed using a stirring bar retriever, and the aqueous solution was neutralized with ammonium hydroxide to pH 4. The solution was then extracted with chloroform (3 × 20 mL), and the combined organic layer was washed with water (2 × 5.0 mL), sodium bicarbonate solution (5.0 mL), and brine (5.0 mL) and dried over anhydrous sodium sulfate. The product (39-52) was obtained as a gummy brown semi-solid. The next step was carried out without any purification and characterization. Mixture of 39-52, chloroformamidine hydrochloride (1 g), and dimethyl sulfone (4.0 g) was heated in an oil bath at 140 C under nitrogen for 15 min. The oil bath was removed, and water (10 mL) was added slowly to the hot reaction mixture. The aqueous solution was cooled to room temperature and extracted with chloroform (3 × 5 mL) to remove dimethyl sulfone. The aqueous phase was made basic to pH 10 with ammonium hydroxide, followed by removal of water under reduced pressure. The residue was dissolved in a mixture of 50:50 methanol-acetone (v/v), and silica gel was added (3.0 g). After the removal of solvent with a rotary evaporator, the silica gel plug was loaded onto a column and eluted with 1:5 MeOH-CHCl3 (v/v). The fractions containing the required compound were evaporated under reduced pressure to afford the targeted compounds.
With iron(III) chloride; N-chloro-succinimide; In dichloromethane; for 3h;Reflux;
Into a 250mI four-necked flask equipped with a mechanical stirrer, a constant pressure dropping funnel, a reflux condenser and a thermometer, add 18g of 4-trifluoromethoxyaniline,5 g of ferric chloride and 100 mL of dichloromethane, dissolve 18 g of chlorosuccinimide (NCS) in 100 mL of dichloromethane,Add dropwise into the 4-trifluoromethoxyaniline solution while stirring at room temperature and stir at reflux for 3h. Thin layer chromatography (TLC, dichloromethane: methanol volume ratio 3: 1) is tracked to the end of the reaction.The reaction solution was concentrated to remove the organic solvent, and the residue was collected under reduced pressure at 107-109 C (10 kPa) to obtain 18 g of 4-trifluoromethoxy-2-chloroaniline as a dark blue oily product with a yield of 85% and a content of 99%.
2-((E)-(4-(trifluoromethoxy)phenylimino)methyl)-3,5-dimethoxyphenol[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
83%
In methanol at 40 - 50℃; for 2h;
2.2. Synthesis of schiffbase ligands
General procedure: The Schiffbase ligands ( HL 1-3 ) were synthesized by adding 25 ml of a methanolic solution of 3-Chloro-5-fluo- rosalicylaldehyde/4,6-Dimethoxysalicylaldehyde/4-(Diethylamino) salicylaldehyde (10 mmol) was added to 25 ml of a methanolic solution of 4-trifluoromethoxy aniline (10 mmol) (1:1 M ratio ( Scheme 1 )) drop wise with stirring and the resulting solution was refluxed for 2 h. The solution was cooled at room temperature and this liquid Schiffbase ligand was used without further purification.
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