* 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 Example 95 tert-butyl (3R*,4R*)-4-[[3-chloro-5-(trifluoromethyl)benzyl](methyl)amino]carbonyl}-3-(4-fluoro-2-methylphenyl)piperidine-1-carboxylate(Step 1)To a solution of 3-trifluoromethylbenzoic acid (203.4 g) in concentrated sulfuric acid (880 mL) was added 90percent fuming nitric acid (210 mL) at 0° C. over 1 hr. The mixture was stirred at 35° C. for 3 hr, and slowly poured onto ice (about 1 kg). The precipitate was filtrated with water (500 mL), and dissolved in ethyl acetate (500 mL). The ethyl acetate solution was washed with water and dried, and the solvent was evaporated under reduced pressure to give 3-nitro-5-(trifluoromethyl)benzoic acid (232.5 g, 92percent) as a white powder. 1H-NMR (300 MHz, CDCl3):δ 8.69 (1H, s), 8.74 (1H, s), 9.1 (1H, s)
87%
at 20℃; for 3 h;
Fuming nitric acid (5.5 mL) was added dropwise into a mixtureof 3-trifluoromethylbenzoic acid (5 g, 0.026 mol) and concentratedsulfuric acid (23 mL) under vigorous stirring. The reaction mixturewas stirred for 3 h at rt and then poured on ice. The crude productwas filtered, dissolved in EtOAc (30 mL) and washed with water(2 x 25 mL) and brine (1 x 25 mL). The organic layer was dried overanhydrous Na2SO4 and evaporated under reduced pressure. Yield:87percent as a light yellow solid; mp 128-130 °C. 1H NMR (500 MHz,acetone) δ 9.00 (t, J = 1.8 Hz, 1H), 8.78 (t, J = 1.9 Hz, 1H), 8.66 (t,J = 1.7 Hz, 1H). 13C NMR (126 MHz, acetone) δ 164.52,149.77,134.72,132.76 (q, J = 34.2 Hz), 132.37 (q, J = 3.6 Hz), 128.46, 125.20 (q,J = 3.9 Hz), 123.72 (q, J =272.4 Hz).
80%
With sulfuric acid; nitric acid In water at 0 - 90℃; for 75 h;
Step 1 : 3-Nitro-5-(trifluoromethyl)benzoic acid To a mixture of 3-(trifluoromethyl)benzoic acid (5 g, 26.3 mmol) in H2SO4 (50 mL, 938 mmol) was added nitric acid (3.53 mL, 79 mmol). The mixture was stirred at 0 °C for 15 min and warmed to 90 °C over 1 h. Then the mixture was added to ice water dropwise. The mixture was filtered to give a white solid of 3-nitro-5-(trifluoromethyl)benzoic acid (5.2 g, 21.01 mmol, 80.0percent): lH NMR (400 MHz, CD3OD) δ 8.99 (s, IH), 8.72 (s, IH), 8.61 (s, IH).
77%
at 0 - 90℃; for 1.08333 h;
To a mixture of 3- (trifluoromethyl) benzoic acid (5 g 26.3 mmol) in sulfuric acid (50 ml 938 mmol) was added nitric acid (3.53 ml 79 mmol) . The mixture was stirred at 0 for 15min and warmed to 90 over 1 hour. Then the mixture was added to ice water dropwise. The mixture was then filtered to give a white solid of 3-nitro-5- (trifluoromethyl) benzoic acid (5 g 20.20 mmol 77yield) 1HNMR(400 MHz METHANOL-d4) δ 8.99 (s 1H) 8.72 (s 1H) 8.61 (s 1H)
Reference：
[1] Patent: US2008/275085, 2008, A1, . Location in patent: Page/Page column 45
[2] Journal of the American Chemical Society, 2017, vol. 139, # 43, p. 15308 - 15311
[3] Journal of Medicinal Chemistry, 2016, vol. 59, # 6, p. 2362 - 2380
[4] Angewandte Chemie - International Edition, 2017, vol. 56, # 8, p. 2059 - 2063[5] Angew. Chem., 2017, vol. 129, # 8, p. 2091 - 2095,5
[6] Chemistry - A European Journal, 2017, vol. 23, # 52, p. 12758 - 12762
[7] European Journal of Medicinal Chemistry, 2017, vol. 126, p. 369 - 383
[8] Patent: WO2016/38552, 2016, A1, . Location in patent: Page/Page column 53
[9] Patent: WO2016/37578, 2016, A1, . Location in patent: Page/Page column 109
[10] Bulletin de la Societe Chimique de France, 1962, p. 915 - 919
[11] Journal of Organic Chemistry, 1994, vol. 59, # 12, p. 3259 - 3261
[12] Patent: US5373024, 1994, A,
Reference：
[1] Journal of Fluorine Chemistry, 1992, vol. 57, p. 307 - 321
7
[ 454-92-2 ]
[ 328-68-7 ]
Reference：
[1] Chemistry - A European Journal, 2017, vol. 23, # 52, p. 12758 - 12762
[2] Journal of the American Chemical Society, 2017, vol. 139, # 43, p. 15308 - 15311
8
[ 454-92-2 ]
[ 22227-63-0 ]
Reference：
[1] European Journal of Medicinal Chemistry, 2017, vol. 126, p. 369 - 383
9
[ 454-92-2 ]
[ 22235-25-2 ]
Reference：
[1] Chemistry - A European Journal, 2017, vol. 23, # 52, p. 12758 - 12762
10
[ 454-92-2 ]
[ 83265-53-6 ]
Reference：
[1] Patent: WO2016/23826, 2016, A1,
11
[ 454-92-2 ]
[ 79427-88-6 ]
Yield
Reaction Conditions
Operation in experiment
93%
With oxygen; potassium acetate; p-benzoquinone In ISOPROPYLAMIDE at 115℃; for 15 h;
III. General procedure for Pd (II) -catalyzedorfcho-hydroxylation with 5 atm 02 :A 50 mL high pressure reactor equipped with a magnetic stir bar was charged with Pd(OAc)2 (11.2 mg, 0.05 mmol), followed by the benzoic acidsubstrate (0.5 mmol), benzoquinone (54.0 mg, 0.5 mmol), KOAc (98.0 mg, 1 mmol) andN, N-dimethylacetamide (1.5 mL) . The reactor was filled with 02 (20 atm) , and then evacuated and backed-filled with 02 (5 atm, 2 times) . After the reaction mixture was stirred at 115 °C for 15 hours, it was permitted to cool to ambient temperature. The reaction was worked up and the crude product was purified following the procedure described above for hydroxylation with 1 atm O2.
Reference：
[1] Journal of the American Chemical Society, 2009, vol. 131, # 41, p. 14654 - 14655
[2] Patent: WO2011/37929, 2011, A2, . Location in patent: Page/Page column 14; 19-20
[3] Synlett, 2016, vol. 27, # 2, p. 277 - 281
12
[ 454-92-2 ]
[ 328-67-6 ]
Yield
Reaction Conditions
Operation in experiment
90%
With N-Bromosuccinimide; sulfuric acid In trifluoroacetic acid at 18 - 22℃; for 0.5 h;
a) Compound 1.2; 36 N H2SO4 (1.5 mL) and NBS (2.75 g, 15.0 mmol) were added to a solution of acid 1.1 (1.90 g, 10.0 mmol) in TFA (5 mL) at room temperature. After stirring for 30 min the reaction mixture was poured into water (200 mL) with vigorous stirring. The suspension was filtered and the resulting solid was rinsed with water and dried to give compound 1.2 (2.45 g, 90percent yield).
With sulfuric acid; nitric acid at 0 - 35℃; for 4h;
95.1
Reference Example 95 tert-butyl (3R*,4R*)-4-[[3-chloro-5-(trifluoromethyl)benzyl](methyl)amino]carbonyl}-3-(4-fluoro-2-methylphenyl)piperidine-1-carboxylate(Step 1)To a solution of 3-trifluoromethylbenzoic acid (203.4 g) in concentrated sulfuric acid (880 mL) was added 90% fuming nitric acid (210 mL) at 0° C. over 1 hr. The mixture was stirred at 35° C. for 3 hr, and slowly poured onto ice (about 1 kg). The precipitate was filtrated with water (500 mL), and dissolved in ethyl acetate (500 mL). The ethyl acetate solution was washed with water and dried, and the solvent was evaporated under reduced pressure to give 3-nitro-5-(trifluoromethyl)benzoic acid (232.5 g, 92%) as a white powder. 1H-NMR (300 MHz, CDCl3):δ 8.69 (1H, s), 8.74 (1H, s), 9.1 (1H, s)
91%
With sulfuric acid; nitric acid at 0 - 40℃; for 4h;
91%
With sulfuric acid; nitric acid at 0 - 35℃; for 3h;
91%
With sulfuric acid; nitric acid at 35℃; for 3h;
87%
With sulfuric acid; nitric acid at 20℃; for 3h;
4.16. 3-Nitro-5-(trifluoromethyl)benzoic acid (32a) [21]
Fuming nitric acid (5.5 mL) was added dropwise into a mixtureof 3-trifluoromethylbenzoic acid (5 g, 0.026 mol) and concentratedsulfuric acid (23 mL) under vigorous stirring. The reaction mixturewas stirred for 3 h at rt and then poured on ice. The crude productwas filtered, dissolved in EtOAc (30 mL) and washed with water(2 x 25 mL) and brine (1 x 25 mL). The organic layer was dried overanhydrous Na2SO4 and evaporated under reduced pressure. Yield:87% as a light yellow solid; mp 128-130 °C. 1H NMR (500 MHz,acetone) δ 9.00 (t, J = 1.8 Hz, 1H), 8.78 (t, J = 1.9 Hz, 1H), 8.66 (t,J = 1.7 Hz, 1H). 13C NMR (126 MHz, acetone) δ 164.52,149.77,134.72,132.76 (q, J = 34.2 Hz), 132.37 (q, J = 3.6 Hz), 128.46, 125.20 (q,J = 3.9 Hz), 123.72 (q, J =272.4 Hz).
80%
With sulfuric acid; nitric acid In water at 0 - 90℃; for 75h;
1.1 Step 1 : 3-Nitro-5-(trifluoromethyl)benzoic acid
Step 1 : 3-Nitro-5-(trifluoromethyl)benzoic acid To a mixture of 3-(trifluoromethyl)benzoic acid (5 g, 26.3 mmol) in H2SO4 (50 mL, 938 mmol) was added nitric acid (3.53 mL, 79 mmol). The mixture was stirred at 0 °C for 15 min and warmed to 90 °C over 1 h. Then the mixture was added to ice water dropwise. The mixture was filtered to give a white solid of 3-nitro-5-(trifluoromethyl)benzoic acid (5.2 g, 21.01 mmol, 80.0%): lH NMR (400 MHz, CD3OD) δ 8.99 (s, IH), 8.72 (s, IH), 8.61 (s, IH).
77%
With sulfuric acid; nitric acid at 0 - 90℃; for 1.08333h;
1 Step 1 3-Nitro-5- (trifluoromethyl) benzoic acid
To a mixture of 3- (trifluoromethyl) benzoic acid (5 g 26.3 mmol) in sulfuric acid (50 ml 938 mmol) was added nitric acid (3.53 ml 79 mmol) . The mixture was stirred at 0 for 15min and warmed to 90 over 1 hour. Then the mixture was added to ice water dropwise. The mixture was then filtered to give a white solid of 3-nitro-5- (trifluoromethyl) benzoic acid (5 g 20.20 mmol 77yield) 1HNMR(400 MHz METHANOL-d4) δ 8.99 (s 1H) 8.72 (s 1H) 8.61 (s 1H)
With sulfuric acid; nitric acid
With sulfuric acid; nitric acid
With nitronium tetrafluoborate In sulfolane
15 EXAMPLE 15 STR18
EXAMPLE 15 STR18 3-Sulfamoyl-5-trifluoromethylbenzoylguanidine hydrochloride, colorless crystals, melting point 235°-238° C. is obtained by reaction of 3-trifluoromethylbenzoic acid by nitration (100% strength HNO3 in 20% strength oleum, 3 hours at room temperature) to give 5-nitro-3-trifluoromethylbenzoic acid (melting point 126°-129 ° C.).
With diphenyl diselenide; dihydrogen peroxide In water at 20℃; for 6h; Green chemistry;
3.2. General Procedure for the Synthesis of Carboxylic Acids 2
General procedure: Diphenyl diselenide (3, 0.006 g; 0.02 mmol) was treated with H2O2 (30%·w/w, 0.1 mL, 1 mmol) andwater (0.2 mL) and stirred at room temperature at 800 rpm until the discoloration of the reaction mixture;then, the aldehyde 1 (1 mmol) was added. After 6 h, the aqueous mixture was extracted three times withEtOAc (3 × 20 mL). The collected organic layers were dried over Na2SO4 and the solvent evaporatedunder reduced pressure.
94%
With tris[2-(4,6-difluorophenyl)pyridinato-C2,N]-iridium(III); oxygen In acetonitrile at 20℃; Irradiation; Sealed tube; Green chemistry; chemoselective reaction;
Synthesis of carboxylic acids
General procedure: An oven-dried resealable test tube equipped with a magnetic stir bar was charged withaldehyde (1.0 mmol), Ir(dFppy)3 (0.005-0.01 mmol), and MeCN (4.0 mL, 0.25 M). Oxygen wasthen bubbled through the reaction mixture and sealed with a silicone septa screw-cap. A balloonfilled with oxygen was attached to the tube, and the test tube was placed under blue LEDs atroom temperature. The reaction was allowed to proceed for 3-12 h, and reaction progress waschecked by TLC. The solvent was removed under vacuum, and the corresponding carboxylic acidwas purified by flash silica gel chromatography.
91%
With oxygen; Langlois reagent In acetonitrile at 25℃; for 12h; Irradiation; Green chemistry;
65%
With [2,2]bipyridinyl; water; oxygen; sodium hydroxide at 50℃; for 10h; Sealed tube;
3.4. General Procedure for the Oxidation of Aldehyde 1
General procedure: Aldehyde 1 (0.2 mmol), Ag/C3N4 (10 mol%), NaOH (1 equiv), H2O (1 mL) were added into a 10 mL sealed tube under O2 (1 atm). The mixture was stirred at 50o C for 10 h. Then the reaction was stopped and 1M dilute hydrochloric acid was added to adjust the pH value to 3. The mixture was extracted with ethyl acetate (3 × 3 mL). The combined organic phase was dried with Na2SO4 and concentrated under reduced pressure. The residue was purified by flash column chromatography (5:1 hexanes and ethyl acetate).
With oxygen
With perchloric acid; mercury(II) diacetate; N-bromoacetamide In acetic acid at 24.9℃; other temperatures, ΔG(excit.), ΔH(excit.), ΔS(excit.);
With perchloric acid; bis(2,2'-bipyridyl) copper(II) permanganate In water; acetic acid at 14.9℃; other temperatures; ΔH, ΔS, ΔG; kinetics and mechanism of the oxidation of monosubstituted benzaldehydes by bis(2,2'-bipyridyl)copper(II) permanganate (BBCP); formation and decomposition of benzaldehyde-BBCP complexes;
With ((2,2'-(ethane-1,2-diylbis[(nitrilo-κN)methylidyne])bis(phenolato-κO))(2-))oxomanganese(1+) hexafluorophosphate In acetonitrile at 14.85℃;
With HABR In water; acetic acid at 14.85 - 44.85℃;
With pyridinium hydrobromide perbromide In water; acetic acid at 44.85℃;
With benzyltrimethylammonium tribromide; potassium bromide In water; acetic acid at 44.85℃; for 10h;
With benzyltrimethylammonium chlorobromate In water; acetic acid at 24.84℃;
With tetra-N-butylammonium tribromide; acetic acid at 14.84℃;
With 2,2'-bipyridinium chlorochromate In dimethyl sulfoxide at 24.84℃;
With morpholinium chlorochromate In dimethyl sulfoxide at 44.84℃;
With tetraethylammonium chlorochromate(VI) In dimethyl sulfoxide at 24.84℃;
Stage #1: 3-Trifluoromethylbenzaldehyde With bis(pyridine)silver(I) permanganate; acetic acid In water at 24.84℃; for 10h; Darkness;
Stage #2: With hydrogenchloride
With acidic cation resin catalyst; In cyclohexane;Reflux; Green chemistry;
The specific synthesis method is: 38.8 g (0.2 mol) of m-trifluoromethylbenzoic acid was added to the reactor, and 170 g of cyclohexane was used. After the alkane was dissolved, 15 g of methanol was added, and 4 g of a cationic acid resin catalyst was added thereto to stir, and the temperature was raised to reflux reaction, and the water produced by the system was taken out in time. After the reaction is completed, the catalyst is cooled and filtered, and the organic solvent is distilled off under negative pressure. After the solvent is evaporated, the methyl trifluoromethylbenzoate is colorless and transparent, and the content is 99.6%, and the yield is 95.8%.
86%
With thionyl chloride; at 75℃; for 2h;
Intermediate l g: methyl S-ftrifluoromethyDbenzoate. To a solution of 3- (trifluoromethyl)benzoic acid (5 g, 26.30 mmol, 1.00 equiv) in methanol (25 mL) was added dropwise thionyl chloride (9.39 g, 78.93 mmol, 3.00 equiv) and the resulting solution was stirred for 2 h at 75C in an oil bath. The mixture was concentrated under vacuum, diluted with 100 mL of ethyl acetate and then washed with 2x30 mL of sodium carbonate and 2x30 mL of brine. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum to yield 4.6 g (86%) of methyl 3- (trifluoromethyl)benzoate as yellow oil
76%
With sulfuric acid; for 6h;Reflux;
General procedure: A catalytic amount of concentrated H2SO4 wasadded to a solution of carboxylic acids 16(a-j) (1.0 mmol)in 50 mL of methanol, and the mixture was refluxed for 6 h. It was allowed to cool. The saturated solution ofNaHCO3 was added to the reaction mixture, and it wasextracted with EtOAc (2 X 50 mL). The combined organiclayer was dried Na2SO4 and concentrated to obtain puremethyl esters 17(a-j).
With thionyl chloride; at 40℃; for 1h;
General procedure: To a solution of 5.0 mmol of dierent substituted benzoic acids (1a~1p, 1s, and 1t), nicotinic acid(1q) or 2-phenylacetic acid (1r) in MeOH (15 mL) was added sulfurous dichloride (2 mL), then the mixture was allowed to reach 40 C and stirred for 1 h. The resulting solution was concentrated andpartitioned between sodium bicarbonate solution (PH 7~8) and ethyl acetate (3). The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated to yield the correspondingesters (2a~2t) in 89%-96% yields, which were taken up for the next step without any purification.
To lithium aluminum hydride (37.9 g, 1.2 mol, 1.2 equiv.) in THF (500 mL) at 0 C. was added 3-(trifluoromethyl)benzoic acid (200 g, 1.0 mol) in THF (1000 mL) dropwise at 0-10 C. The mixture was stirred overnight followed by dropwise addition of 10% sulfuric acid (500 ml) and water (1000 mL). The solution was filtrated and the filtrate was extracted with ethyl acetate (3×500 mL). The combined organic solution was washed with water (500 mL), dried over anhydrous sodium sulfate and concentrated in vacuo to give the title compound as an orange oil (180 g, 97%).
REFERENCE EXAMPLE 69 Methyl m-trifluoromethylbenzoate (69) STR88 An excess solution of diazomethane in ether was added to an ice-cooled and stirred solution of m-trifluoromethylbenzoic acid (8.0 g, 42.1 mmol) in 50 ml of ether. After concentration, the residue was distilled under reduced pressure to give a colorless transparent oil of methyl m-trifluoromethylbenzoate (8.4 g, 41.2 mmol, yield 97.8%, b.p. 76-78 C./12 mmHg), which was assigned the structure by the following data: IR(Liquid film method): 2990, 2950, 2840, 1725, 1610, 1590, 1430, 1330, 1300, 1260, 1165, 1130, 1085, 1070, 970, 915, 840, 810, 770, 750, 690, 660 cm-1. NMR(90 MHz, CDCl3, delta): 3.96(3H, s), 7.45-7.9(2H, m), 8.15-8.4(2H, m).
With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃; for 66h;
Example 46 Synthesis of N-(4-hydroxy-3-methylphenyl)-3- (trifluoromethyl) benzamide; To 3- (trifluoromethyl)benzoic (380 mg, 2.00 mmol), 4- amino-2-methylphenol (271 mg, 2.20 mmol) and EDC (767 mg, 4.00 mmol) was added CH2Cl2 (80 mL). The resulting mixture was stirred for 66 hours at RT, concentrated, dissolved in EtOAc and washed with water. The organics were dried over sodium sulfate, filtered and concentrated. The crude material was purified by silica gel chromatography (0-50percent EtOAc/hexanes) to yield N-(4-hydroxy-3-methylphenyl)-3- (trifluoromethyl) benzamide as a white solid. MS m/z = 296 [M+1]+. Calc'd for C15H12F3N02: 295.26.
With N-Bromosuccinimide; sulfuric acid; In trifluoroacetic acid; at 18 - 22℃; for 0.5h;
a) Compound 1.2; 36 N H2SO4 (1.5 mL) and NBS (2.75 g, 15.0 mmol) were added to a solution of acid 1.1 (1.90 g, 10.0 mmol) in TFA (5 mL) at room temperature. After stirring for 30 min the reaction mixture was poured into water (200 mL) with vigorous stirring. The suspension was filtered and the resulting solid was rinsed with water and dried to give compound 1.2 (2.45 g, 90% yield).
With 4-methyl-morpholine; In N,N-dimethyl-formamide;
(d) cis-4-(5-fluoro-2-(3-trifluoromethyl-benzoylamino)-benzoimidazol-1-yl)-cyclohexanecarboxylic acid ethyl ester 305 mg cis-4-(2-amino-5-fluoro-benzoimidazol-1-yl)-cyclohexanecarboxylic acid ethyl ester (1.0 mmol, 1.0 equiv) was combined in a flask with 569 mg O-benzotriazol-1-yl-N,N,N',N'-tetramethyluronium hexafluorophosphate (FIBTU, 1.5 mmol, 1.5 equiv), 285 mg 3-trifluoromethylbenzoic acid (1.5 mmol, 1.5 equiv) and 203 mg 1-hydroxybenzotriazole hydrate (HOBT, 1.5 mmol, 1.5 equiv), followed by the addition of 12 mL DMF and 165 muL N-methylmorpholine (NMM, 1.5 mmol, 1.5 equiv). The solution was allowed to stir for 24 h and then diluted with sat. NaHCO3. The solution was extracted (2*EtOAc), washed (1*brine), dried (Na2SO4) and concentrated under reduced pressure. Purification by flash chromatography (SiO2, 20% EtOAc/hexane) gave 0.39 g of the product as a tan solid (0.82 mmol).
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In tetrahydrofuran; at 20℃;
B) W-(3-lodo-4-methylphenyl)-3-(trifluoromethyl)benzamide; A solution of <strong>[35944-64-0]3-iodo-4-methylaniline</strong> (1.22 g, 5.25 mmol), 3-(trifluoromethyl)benzoic acid (0.95 g, 5 mmol), HOBt (0.68 g, 5 mmol), and EDCI (1.05 g, 5.5 mmol) in THF (20 mL) was stirred overnight at rt. Water was added and the aqueous layer was extracted with dichloromethane. The combined organic layers were dried over sodium sulfate, concentrated on a rotavap, and then subjected to silica gel column chromatography (3:1 hexane/ethyl acetate) yielding the desired product.
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In N,N-dimethyl-formamide; at 20℃; for 48.0h;
A solution of <strong>[45865-42-7]2-amino-5-t-butyl-4-methylthiazole</strong> (1.0 g), 3-(trifluoromethyl)benzoic acid (1.2 g), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide monohydrochloride (1.2 g) and 1-hydroxybenzotriazole monohydrate (1.0 g) in N,N,-dimethyl formamide (10 ml) was stirred at room temperature for 48 hours. To the reaction solution, ethyl acetate was added and the reaction solution was washed sequentially with 2M hydrochloric acid, an aqueous 2M sodium hydroxide solution, and saturated brine, dried over anhydrous sodium sulfate and filtrated. Thereafter, the filtrate was concentrated under vacuum to obtain a yellow amorphous substance of 5-t-butyl-4-methyl-2-(3-trifluoromethylbenzoyl)aminothiazole (1.7 g). 1H-NMR (200 MHz, CHLOROFORM-D) d ppm; 1.42(s, 9H), 2.20(s, 3H), 7.55 (t, J=7.5 Hz, 1H), 7.78 (d, J=7.5 Hz, 1H), 8.05 (d, J=7.5 Hz, 1H), 8.16 (s, 1H), MS(ESI) (Positive)m/z, 343(M+H)
Stage #1: 3-(trifluoromethyl)benzoic acid With lithium aluminium deuteride In tetrahydrofuran at 0℃; Heating / reflux;
Stage #2: With deuteriated sodium hydroxide; water-d2 In tetrahydrofuran at 0℃;
4
To a mixture of LiAlD4 (16.8 g, 0.40 mol) in THF (1.5 L) was added 3-trifluoromethylbenzoic acid 34 (76 g, 0.40 mol) in portions at 0° C. The resulting mixture was heated at reflux for 8 hr then cooled to room temperature and stirred overnight. The reaction was quenched by the addition of D2O (16.5 mL), 15% NaOD solution in D2O (16.5 mL) and D2O (50 mL) under the cooling of an ice-bath. The solid was filtered, and the filtrate was concentrated in vacuo to give compound 35 (69.4 g, 97% yield) as a pale-yellow oil.
2.L.1
1. 3-(trifluoromethyl)cyclohexanecarboxylic acidDissolve 3-(trifluoromethyl)-benzoic acid (2 g) in acetic acid (100 mL) and add platinum oxide (400 mg). Hydrogenate the mixture under 50 psi of hydrogen at 600C for 16 h. Filter the mixture through celite and concentrate under reduced pressure. Add toluene to the residue and concentrate again, repeating this procedure three additional times, to afford the title acid.
With hydrogen In acetic acid at 60℃; for 16h;
1.I.1
1. 3-(trifluoromethyl)cyclohexanecarboxylic acidDissolve 3-(trifluoromethyl)-benzoic acid (2 g) in acetic acid (100 mL) and add platinum oxide (400 mg). Hydrogenate the mixture under 50 psi of hydrogen at 6O0C for16 h. Filter the mixture through celite and concentrate under reduced pressure. Add toluene to the residue and concentrate again, repeating this procedure three additional times, to afford the title acid.
With oxygen; potassium acetate; palladium diacetate; p-benzoquinone In N,N-dimethyl acetamide at 115℃; for 15h;
93%
With oxygen; potassium acetate; p-benzoquinone In ISOPROPYLAMIDE at 115℃; for 15h;
III
III. General procedure for Pd (II) -catalyzedorfcho-hydroxylation with 5 atm 02 :A 50 mL high pressure reactor equipped with a magnetic stir bar was charged with Pd(OAc)2 (11.2 mg, 0.05 mmol), followed by the benzoic acidsubstrate (0.5 mmol), benzoquinone (54.0 mg, 0.5 mmol), KOAc (98.0 mg, 1 mmol) andN, N-dimethylacetamide (1.5 mL) . The reactor was filled with 02 (20 atm) , and then evacuated and backed-filled with 02 (5 atm, 2 times) . After the reaction mixture was stirred at 115 °C for 15 hours, it was permitted to cool to ambient temperature. The reaction was worked up and the crude product was purified following the procedure described above for hydroxylation with 1 atm O2.
With oxygen; potassium acetate; palladium diacetate; p-benzoquinone In N,N-dimethyl acetamide at 115℃; for 15h; Schlenk technique; regioselective reaction;
(21) Synthesis of para-Hydroxylated Arenes
General procedure: A 50 mL Schlenk-type tube (with a Teflon high-pressure valveand side arm) was charged with m-toluic acid (68.0 mg, 0.50mmol), benzoquinone (54.0 mg, 0.50 mmol), KOAc (98.0 mg,1.00 mmol), Pd(OAc)2 (11.2 mg, 0.050 mmol), and N,N-dimethylacetamide(1.5 mL). The reaction tube was evacuated and backfilledwith O2 (3×, ballon). After the reaction mixture wasstirred at 115 °C for 15 h, it was allowed to cool down to r.t. Thereaction mixture was diluted with EtOAc (10 mL) and then filteredthrough a pad of Celite. The filtrate was concentrated invacuo to yield crude 2-hydroxylbenzoic acid. A mixture of thecrude product, Cu2O (3.6 mg, 0.025 mmol), and 1,10-phenanthroline(9.0 mg, 0.050 mmol) in a solution of NMP (1.5 mL) andquinoline (0.5 mL) was heated under an atmosphere of N2 at220 °C for 12 h. The reaction mixture was quenched by additionof 0.2 M aq HCl (10 mL), diluted with EtOAc (10 mL), and thenfiltered through a pad of Celite. The filtrate was washed withbrine (10 mL), dried over Na2SO4, and concentrated in vacuo.The residue was purified by silica gel preparative TLC to give pcresol.
Step 1: synthesis of N-(4-methyl-3-nitrophenyl)-3-(trifluoromethyl)benzamide (66)A solution of 3-(trifluoromethyl)benzoic acid (8 g, 42.1 mmol), HATU (19.20 g, 50.5 mmol) and DIPEA (13.91 mL, 84 mmol) in DMF (350 mL) was stirred for 15 min at rt. 4-methyl-3-nitroaniline (6.40 g, 42.1 mmol) was added and stirred overnight at 60C. After cooling to room temperature the reaction was quenched with H20. After stirring for 10 minutes the resulting precipitate was collected and washed with water to give compound N-(4-methyl-3-nitrophenyl)-3-(trifluoromethyl)benzamide 66 (12 g, 88%). (m/z) = 325 (M+H)+.
88%
Step 1: synthesis of N-(4-methyl-3-nitrophenyl)-3-(trifluoromethyl)benzamide (66) A solution of 3-(trifluoromethyl)benzoic acid (8 g, 42.1 mmol), HATU (19.20 g, 50.5 mmol) and DIPEA (13.91 mL, 84 mmol) in DMF (350 mL) was stirred for 15 min at rt. 4-methyl-3-nitroaniline (6.40 g, 42.1 mmol) was added and stirred overnight at 60 C. After cooling to room temperature the reaction was quenched with H2O. After stirring for 10 minutes the resulting precipitate was collected and washed with water to give compound N-(4-methyl-3-nitrophenyl)-3-(trifluoromethyl)benzamide 66 (12 g, 88%). (m/z)=325 (M+H)+.
82.6%
General procedure: A mixture of 4-substituted-3-nitrobenzoic acid 10a-d, 14a-g (5 mmol), EDCI (6 mmol) and HOBt in anhydrous DMF (20 mL) was stirred at room temperature for about 0.5-2 h. Then the appropriate aniline 11a-j, 7a-b (4 mmol) was added with triethylamine (5 mmol) and stirred at room temperature for 4-24 h. Then the reaction mixture was diluted to 100 mL with water and extracted with EtOAc (3×30 mL). The combined organic layers were washed with saturated solution of NaCl, then dried over MgSO4 and concentrated under reduced pressure. The residue was chromatographed over silica gel column using acetic ether and petroleum ether (1:10-1:8, v:v) as eluent to obtain compounds 12a-o, 15a-h as white solid.
Stage #1: 1,3-bis(trifluoromethyl)benzene With trifluorormethanesulfonic acid In chloroform for 4h; Inert atmosphere;
Stage #2: With water In chloroform Inert atmosphere;
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In N,N-dimethyl-formamide; at 80℃; for 8h;
General procedure: A mixture ofcompound 10 (0.15 g, 0.772 mmol), HOBt (0.23 g,1.70 mmol), EDCI (0.37 g, 1.93 mmol), benzoic acid(0.19 g, 1.54 mmol), and TEA (0.32 mL, 2.32 mmol) indry DMF (20 mL) was stirred at 80 C for 8 h. The mixturewas quenched with water (40 mL), then extracted withethyl acetate (3 x 40 mL). The combined organic layerextracts were washed with brine, dried over anhydrousMgSO4, filtered, and concentrated under reduced pressure.The residue was purified by flash column chromatography.The desired product was obtained as white solid (0.13 g,56.4 %).
Multi-step reaction with 2 steps
1.1: N-ethyl-N,N-diisopropylamine; HATU / N,N-dimethyl-formamide / 0.25 h / 20 °C
1.2: 60 °C
2.1: hydrogen / palladium on activated charcoal / methanol / 4 h
Multi-step reaction with 2 steps
1.1: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; benzotriazol-1-ol / N,N-dimethyl-formamide / 20 °C
1.2: 20 °C
2.1: 5%-palladium/activated carbon; hydrogen / methanol; tetrahydrofuran / 20 °C
Multi-step reaction with 2 steps
1.1: N-ethyl-N,N-diisopropylamine; HATU / N,N-dimethyl-formamide / 0.25 h / 20 °C
1.2: 60 °C
2.1: palladium on activated charcoal; hydrogen / methanol / 4 h
To a solution of <strong>[2557-13-3]methyl 3-(trifluoromethyl)benzoate</strong> (2.8 g) in methanol (10 mL) was added NaOH (17.14 mL). The mixture was stirred at RT overnight. After removal of methanol in vacuo, HC1 (2 M) was added to adjust the above mixture to pH 2. The resulting white solid was filtered, washed with water and dried in vacuo to afford 3-(trifluoromethyl)benzoic acid (2.8 g) as a white solid. MS(ES+) m/z 191 (MH+).
With caesium carbonate; catacxium A In N,N-dimethyl-formamide at 145℃; for 24h; Molecular sieve; Inert atmosphere;
8
Outside the glovebox, a 100 mL Schlenk flask equipped with a magnetic stir bar was charged with commercially available 3-(trifluoromethyl)benzoic acid (BFA) (3.09 g, 16.2 mmol) and bromoanisole BrMIP (3.60 g, 14.6 mmol). The flask was transferred to glovebox (%O2 ≤0.005) and Pd(OAc)2 (157 mg, 5 mol %), n-butyl-di-1-adamantylphosphine (530 mg, 10 mol %), Cs2CO3 (11.92 g, 36.6 mmol) and powdered dry molecular sieves 3 Å (1.0 g) were added. The flask was closed with the rubber septum and taken out of the glovebox. Anhydrous DMF degassed with nitrogen was added through the septum and the obtained mixture was first stirred at room temperature for 1 h under the positive pressure of nitrogen, and then placed in a preheated oil bath (145 °C) for 24 h. The reaction mixture was cooled to room temperature and quenched with 2M HCl (100 mL). Ethylacetate (50 mL) was added and the resulting suspension was stirred for 15 min, filtered through a pad of celite and the layers were cut. The water layer was extracted with ethyl acetate (50 mL) and all organic phases were combined, washed with brine (50 mL) and evaporated under reduced pressure to obtain a yellow oil. The crude product was purified by column chromatography to give 4'-fluoro-5'-Isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl-2-carboxylic acid as a colorless oil (3.11g, 60%). 1H NMR (DMSO-d6) δ 0.95 (d, J = 8.0, 6H), 3.36 (s, 1H), 626 (d, J =12.0, 1H), 6.83 (d, J = 8.0, 1H), 7.03 (d, J = 8.0, 1H), 7.25 (m, 1H), 7.74 (s, 1H).
60%
With caesium carbonate In N,N-dimethyl-formamide at 145℃; for 24h; Inert atmosphere; Molecular sieve;
8
Example 8: Preparation of biaryl of Formula XII' (R6=COOH); Outside the glovebox, a 100 mL Schlenk flask equipped with a magnetic stir bar was charged with commercially available 3-(trifluoromethyl)benzoic acid (BFA) (3.09 g, 16.2 mmol) and bromoanisole BrMIP (3.60 g, 14.6 mmol). The flask was transferred to glovebox (%02 <0.005) and Pd(OAc)2 (157 mg, 5 mol %), n-butyl-di-1 - adamantylphosphine (530 mg, 10 mol %), Cs2C03 (1 1.92 g, 36.6 mmol) and powdered dry molecular sieves 3 A (1 .0 g) were added. The flask was closed with the rubber septum and taken out of the glovebox. Anhydrous DMF degassed with nitrogen was added through the septum and the obtained mixture was first stirred at room temperature for 1 h under the positive pressure of nitrogen, and then placed in a preheated oil bath (145 °C) for 24 h. The reaction mixture was cooled to room temperature and quenched with 2M HCI (100 mL) . Ethylacetate (50 mL) was added and the resulting suspension was stirred for 15 min, filtered through a pad of celite and the layers were cut. The water layer was extracted with ethyl acetate (50 mL) and all organic phases were combined, washed with brine (50 mL) and evaporated under reduced pressure to obtain a yellow oil. The crude product was purified by column chromatography to give 4'-fluoro-5'-isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl-2- carboxylic acid as a colorless oil (3.1 1 g, 60%). H NMR (DMSO-d6) δ 0.95 (d, J = 8.0, 6H), 3.36 (s, 1 H), 6.26 (d, J = 12.0, 1 H), 6.83 (d, J = 8.0, 1 H), 7.03 (d, J = 8.0, 1 H), 7.25 (m, 1 H), 7.74 (s, 1 H).
With tert.-butylhydroperoxide; copper(II) oxide In water at 85℃; for 15h;
78%
With di-tert-butyl peroxide; copper(II) bis(trifluoromethanesulfonate) In 1,2-dichloro-ethane at 130℃; for 12h; Sealed tube;
General procedure for the amidation of benzoic acids:
General procedure: A 50 mL sealed tube (with a Teflon high pressure valve) equipped with a magnetic stir bar was charged with Cu(OTf)2 (0.05 mmol), followed by carboxylic acid (0.5 mmol), formamide (2.0 mmol), tert-butyl peroxide (DTBP, 1 mmol), and DCE (1 mL). After the reaction mixture was stirred at 130 °C for 12 h, it was allowed to cool to ambient temperature. The reaction mixture was diluted with ethyl acetate, and then filtered through a small pad of Celite. The filtrate was washed with saturated aqueous NaHCO3 (5 mL) and brine (5 mL, twice). The organic phase was dried (Na2SO4) and concentrated in vacuo. The residue was purified by silica gel preparative TLC to give the corresponding product.
3-(Trifluoromethyl)benzoic acid 6 (0.500 g, 2.63 mmol) was placed in 5mL SOCl2.The reaction solution was heated to reflux for 1 hour with stirring.It was then naturally cooled to room temperature, diluted with 15 mL of dry toluene and concentrated in vacuo to give an oily residue.After the residue was dissolved in 20 mL of dichloromethane, 7 (0.478 g, 3.16 mmol) was added with stirring.Then 0.2 mL of triethylamine was added. The reaction mixture was stirred at room temperature overnight, then concentrated.The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate.The organic phase was concentrated under reduced pressure and then purified by column chromatography (hexane: ethyl acetate = 1:1)Compound 8 (0.70 g, yield: 82%) was obtained as a white solid.
80%
Step 4: 3-(trifluoromethyl)benzoic acid (0.500 g, 2.63 mmol) was dispersed in 5 mL thionyl chloride. The reaction system was heated to 80 C. and maintained under stirring and refluxing for 1 hour, then cooled to room temperature. 10 mL toluene was added to the reaction liquid with slow stirring, and then the reaction solution was concentrated by rotary evaporation under reduced pressure to yield light yellow oil. The concentrated substance was dissolved in 15 ml methylene chloride, and then <strong>[2840-04-2]5-amino-2-methyl-benzoic acid</strong> (0.478 g, 3.16 mmol) and diisopropylethylamine (0.1 mL) were added to this solution. The reaction system was stirred overnight at room temperature to precipitate a large amount of white solid. The reaction solution was concentrated under reduced pressure and dispersed in ethyl acetate, washed with saturated ammonium chloride solution and then with saturated brine. The final organic phase was dried with anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography to give Product 5 (0.68 g, yield: 80%) as a white solid.
1-[3-(trifluoromethyl)benzoyl]piperazine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
50%
5.1.5 1-[3-(Trifluoromethyl)benzoyl]piperazine (8a) A solution of 3-(trifluoromethyl)benzoic acid (9.5 g, 0.05 mol) and CDI (8.90 g, 0.055 mol) was stirred in 30 ml anhydrous THF at room temperature for 30 min. In a separate round bottom flask added piperazine (10.76 g, 0.125 mol) and <strong>[142-64-3]piperazine dihydrochloride</strong> (20 g, 0.125 mol) in 60 ml of water. The reaction mixture was stirred for 5 min and added 14 g NaCl. Then add the brine solution to the round bottom flask containing acyl imidazole and stir the reaction mixture for 5 h. The mixture was filtered and the filtrate distilled by rotary evaporation to remove THF. The aqueous layer was washed with ethyl acetate (3 * 10 ml) to remove diacylated product. The pH of the aqueous layer was adjusted to about 9 using saturated solution of NaOH and washed with ethyl acetate (4 * 30 ml). The organic layer was washed with water (4 * 25 ml), dried over anhydrous Na2SO4 for overnight, concentrated by rotary evaporation and purified by flash chromatography to afford 1-[3-(trifluoromethyl) benzoyl]piperazine as colorless solid (6.5 g, 50%). The intermediate compounds 1-(3-fluorobenzoyl)piperazine (8b), 1-(3-methoxybenzoyl)piperazine (8c), 1-(4-tert-butylbenzoyl)piperazine (8d), N,N-dimethyl-3-(piperazin-1-ylcarbonyl)aniline (8e), 1-(4-bromobenzoyl) piperazine (8f) and 1-(2,4-dichlorobenzoyl) piperazine (8g) were prepared by commercially available materials 3-fluorobenzoic acid, 3-methoxybenzoic acid, 4-tert-butylbenzoic acid, 3-(dimethylamino) benzoic acid, 4-bromobenzoic acid and 2,4-dichlorobenzoic acid respectively using the similar procedure of 1-[3-(trifluoromethyl)benzoyl]piperazine (8a) described above.
General procedure: 5.1.5 Preparation of 1-(2-fluorobenzoyl)piperazine (5) A solution of 2-fluorobenzoic acid (7.00 g, 0.05 mol) and CDI (8.90 g, 0.055 mol) was stirred in dry THF (30 mL) at room temperature for 30 min. In a separate round bottom flask add piperazine (10.76 g, 125 mmol) and <strong>[142-64-3]piperazine dihydrochloride</strong> (20.0 g, 125 mmol) in 60 mL of water. Stir the reaction mixture for 5 min and add 14.0 g of NaCl. Add this brine solution to the round bottom flask containing acyl imidazole. Stir the reaction mixture for 5 hour. The mixture was filtered and the filtrate distilled by rotary evaporation to remove THF. The aqueous layer was washed with ethyl acetate (3 * 10 mL) to remove diacylated product. The PH of the aqueous layer was adjusted to about 9 using saturated solution of NaOH and washed with ethyl acetate (4 * 30 mL). The aqueous layer was discarded. The organic layer was washed with water (4 * 25 mL), dried over anhydrous Na2SO4 and concentrated by rotary evaporation and purified by flash chromatography to afford 1-(2-fluorobenzoyl)piperazine as colourless solid (4.90 g, 48%). The other intermediates 1-(2-chlorobenzoyl)piperazine (6) and 1-[3-(trifluoromethyl)benzoyl]piperazine (7) were prepared by using the general procedure described above.
N-(5-bromo-6-methylpyridin-3-yl)-3-(trifluoromethyl)benzamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
at 20℃;Inert atmosphere;
General procedure: 1.2.2.1. General method Bl To a stirred solution of Intermediate Gen-1 (1 to 1.2 eq.), and amine derivative (1 eq.) in DCM or DMF are added TBTU or HATU (1 to 1.2 eq.) followed by TEA or NMM (2 to 3 eq.) at room temperature under argon, the reaction mixture is stirred at room temperature until completion. Then the reaction is quenched with water, the layers are separated. The organic layer is dried over Na2SO i, filtered and evaporated to dryness. Alternatively, the reaction is concentrated in vacuo, the residue is partionned between EtOAc or a mixture of EtOAc/nBuOH and a saturated aqueous NH4C1 solution or water. The layers are separated, the organic layer is dried over Na2S04, filtered and evaporated to dryness. Then the residue is purified by chromatography on silica gel to afford the expected Intermediate.
at 20℃;Inert atmosphere;
General procedure: To a stirred solution of Intermediate Gen-i (ito 1.2 eq.), and amine derivative (1 eq.) in DCM or DMF are added TI3TU or HATU (ito 1.2 eq.) followed by TEA or NMM (2 to 3 eq.) at room temperature under argon, the reaction mix- tare is stirred at room temperature until completion. Then the reaction is quenched with water, the layers are separated. The organic layer is dried over Na2SO4, filtered and evaporated to dryness. Alternatively, the reaction is concentrated in vacuo, the residue is partionned between EtOAc or a mixture of EtOAc/nl3uOH and a saturated aqueous NH4C1 solution or water. The layers are separated, the organic layer is dried over Na2SO4, filtered and evaporated to dryness. Then the residue is purified by chromatography on silica gel to afford theexpected Intermediate.
2,3-dihydrobenzofuran-3-yl 3-(trifluoromethyl)benzoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
86%
With tert.-butylhydroperoxide; tetra-(n-butyl)ammonium iodide In 1,2-dichloro-ethane at 60℃; for 6h;
14
The reaction flask was charged with Bu4NI (0.2 mmol, 74 mg)Compound 1a (2.8 mmol, 336 mg),Compound 2n (2 mmol, 380 mg), t-BuOOH (824 [mu] L),1,2-dichloroethane (4.0 mL).The system was then heated in air at 60 ° C for about 6 hours, quenched with saturated sodium sulfite solution, extracted with ethyl acetate (40 mL x 3)The solvent was removed by rotary evaporator, adsorbed on silica gel, and the product 3n was obtained by simple column chromatography.The yield was 86%.
85%
With tert.-butylhydroperoxide; tetra-(n-butyl)ammonium iodide In water; 1,2-dichloro-ethane at 60℃; for 6h;
N-(3-trifluoromethylbenzoyl)-3-methylanthranilic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With pDRf1-(4-coumaroyl:CoA ligase 5 from Arabidopsis thaliana)-(hydroxycinnamoyl/benzoyl-CoA:anthranilate N-hydroxycinnamoyl/benzoyltransferase 1 from Dianthus caryophyllus) recombinant yeast In dimethyl sulfoxide at 30℃; for 24h;
Production of cinnamoyl, dihydrocinnamoyl, and benzoyl anthranilates
General procedure: An overnight culture from a single colony of the pDRf1-4CL5-HCBT1 recombinant yeast grown on 2X YNB medium without amino acids, supplemented with 6% glucose and 2X CSM-Ura, was used to inoculated 4 mL of fresh minimal medium at an OD600 = 0.15 and shaken at 200 rpm at 30°C. All precursors were prepared in DMSO and added 5 hours post inoculation at the concentrations indicated in S1, S2 and S3 Tables. The anthranilate acceptors were added to the medium at a final concentration of 300 μM (for anthranilate, 3-hydroxyanthranilate, 3-methylanthranilate, and 5-nitroanthranilate) or 50 μM (for 3-chloroanthranilate, 5-methylanthranilate, 3-methoxyanthranilate, 5-fluoroanthranilate, 5-iodoanthranilate, and 5-chloroanthranilate). These concentrations were selected to limit toxicity and growth inhibition due to either the supplied precursors or the metabolites produced. The cultures were shaken at 200 rpm at 30°C for 24 h in the presence of the precursors for the production of cinnamoyl, dihydrocinnamoyl, and benzoyl anthranilates. Yeast colonies harboring the pDRf1-HCBT1 or pDRf1-4CL5 control vectors were grown under similar conditions. For the detection of metabolites, an aliquot of the culture medium was collected and cleared by centrifugation (21,000xg for 5 min at 4°C), mixed with an equal volume of cold methanol:water (1:1, v/v), and filtered using Amicon Ultra centrifugal filters (3,000 Da MW cutoff regenerated cellulose membrane; Millipore, Billerica, MA) prior to LC-TOF MS analysis. The separation and identification of the metabolites were performed using high-performance liquid chromatography (HPLC), electrospray ionization (ESI), and time-of-flight (TOF) mass spectrometry (MS) as previously described [35]. For each compound, the measured masses agreed with the expected theoretical masses within less than 5 ppm mass error. Standard solutions of DHavnD and dianthramide B were prepared in methanol:water (1:1, v/v). Values obtained for the production of DHavnD and dianthramide B are the average of four replicates (n = 4). ESI-MS spectra of other cinnamoyl, dihydrocinnamoyl, and benzoyl anthranilates were obtained from single feeding experiments for each combination of precursors.
With tert.-butylhydroperoxide; sodium acetate; tetra-(n-butyl)ammonium iodide In tetrahydrofuran; water at 80℃; for 12h;
27 example 27
TBAI in the reaction bottle (0.3mmol, 111 mg), compound1l (2mmol, 380 mg), compound2 (4mmol, 341 mg), NaOAc (4mmol, 164 mg), TBHP (0.60 ml), water (4.0 ml), tetrahydrofuran (4.0 ml). Then the system in the air 80 °C heating under the conditions of about 12 hours, quenched with saturated sodium sulfite solution, extraction with ethyl acetate (40 ml × 3), silica gel adsorption, through the simple column chromatography can get product 3l,the yield is 90%. The prepared test data mainly of the product are as follows, can be known through the analysis, the actual synthetic product is consistent with the theoretical analysis.
85%
With tert.-butylhydroperoxide; sodium acetate; tetra-(n-butyl)ammonium iodide In tetrahydrofuran; water at 80℃; for 12h;
N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)-3-(trifluoromethyl)benzamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
14%
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃;
N-(4- (4,4,5, 5-tetramethyl-l,3,2-dioxaborolan-2-yl)naphthalen-l-yl)-3-(trifluoromethyl)benzamide (compound 4). 4-Aminonaphthalene-l-boronic acid pinacol ester (75.0 mg, 0.267 mmol), 3- (Trifluoromethyl)benzoic acid (67.5 mg, 0.348 mmol), HOBt (55.1 mg, 0.348 mmol), EDCI (68.0 mg, 0.348 mmol) and DIPEA (141 mu, 0.803 mmol) were dissolved in DMF (790 mu) and stirred overnight at room temperature. The crude mixture was diluted in ethyl acetate and washed with NH4C1 and Na2C03. The organic layer was dried over Na2S04 and concentrated in vacuo. The crude organic product was purified by column chromatography (20% ethyl acetate in hexanes) to afford 16.6 mg of compound 4 (14% yield). TLC (hexanes:EtOAc, 80:20 v/v): Rf = 0.4; 1H NMR (300 MHz, MeOD) delta 8.87-8.84 (m, 1H), 8.41-8.36 (m, 2H), 8.13-8.04 (m, 2H), 8.01-7.96 (m, 1H), 7.85-7.78 (m, 1H), 7.68 (d, J = 6.0 Hz, 1H), 7.58-7.55 (m, 2H), 1.47 (s, 12H); ESI-MS (m/z): [M]+ calcd. for C24H23BF3N03, 441.17; [M+l]+ found, 442.2.
4-(2-methyl-5-aminophenoxy)piperidine-1-carboxylic acid tert-butyl ester[ No CAS ]
tert-butyl 4-(2-methyl-5-(3-(trifluoromethyl)benzoylamino)phenoxy)piperidine-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
82%
With N-ethyl-N,N-diisopropylamine; HATU In N,N-dimethyl-formamide at 20℃; for 2h;
1 Synthesis of tert-butyl 4-(2-methyl-5-(3-(trifluoromethyl)benzoylamino)phenoxy)piperidine-1-car boxylate compound c
5 mmol of tert-butyl 4-(2-methyl-5-aminophenoxy) piperidine-1-carboxylate b, 5 mmol of 3-trifluoromethylbenzoicacid, 10 mmol of N,N-diisopropylethylamine (DIPEA) and 15 ml of anhydrous N,N-dimethylformamide (DMF) weresuccessively added to a 50 ml round bottom flask, and 6 mmol of 2-(7-azobenzotriazole)-N,N,N’,N’-tetramethylureahexafluorophosphate (HATU) was added under stirring. The reaction system was reacted under stirring at room temperature for 2 hours. The reaction system was extracted with ethyl acetate and dried over anhydrous sodium sulfate.The solvent was removed by a rotary evaporator, and the crude product was separated on silica gel column to obtain a product of tert-butyl 4-(2-methyl-5-(3-(trifluoromethyl)benzoylamino)phenoxy)piperidine-1-car boxylate compound c(yield: 82%). Exact Mass (calculated): 478.20; MS (ESI) m/z (M+H)+: 479.20.
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℃; for 2h;
With 2,2'-dipyridyldisulphide; triphenylphosphine In dichloromethane at 25℃; for 1h;
N-Acylbenzotriazoles
General procedure: 2,2′-Dipyridyl disulfide (0.43 g 1.63 mmol, 1.2 equiv) and PPh3 (0.51g, 1.96 mmol, 1.2 equiv) were dissolved in anhyd CH2Cl2 (5 mL) and the solution was stirred in a round-bottomed flask for 5 min. Then, acid 1q (0.2 g, 1.63 mmol, 1.0 equiv) was added to the solution, followed by the addition of 1H-benzotriazole (0.39 g, 3.27 mmol, 2.0equiv). The resultant mixture was stirred for 1 h at r.t. After completionof reaction (monitored by TLC), the reaction mass was concentrated under reduced pressure to complete dryness. Purification ofthe residue by flash column chromatography (silica gel) using gradient mixtures of EtOAc and n-hexane afforded the product 2q in pureform; white crystalline solid; yield: 0.296 g (81%);
61%
Stage #1: 3-(trifluoromethyl)benzoic acid With trichloroisocyanuric acid; triphenylphosphine In dichloromethane at 20℃; for 0.5h;
Stage #2: 1,2,3-Benzotriazole In dichloromethane at 20℃;
(1H-1,2,3-Benzo[d][1,2,3]triazol-1-yl)(phenyl)methanone (2a); Typical Procedure
General procedure: Trichloroisocyanuric acid (0.640 g, 2.76 mmol, 0.35 equiv) and PPh3 (0.640 g, 2.76 mmol, 1.2 equiv) were taken in anhyd DCM in a round-bottomed flask. After stirring for 10 min, benzoic acid (1a; 0.962 g, 7.89 mmol, 1.0 equiv) was added and the reaction mixture was stirred for an additional 30 min. Then, benzoic acid (0.939 g, 7.89 mmol, 1.0 equiv) was added and the resulting mixture was allowed to stir for 4-5 h. After completion of the reaction (monitored by TLC), the reaction mass was concentrated under reduced pressure until dry. Purification using flash column chromatography (SiO2) using gradient mixtures of EtOAc and n-hexane gave 2a in pure form; white solid; yield: 1.62 g (92%, 7.29 mmol) mp 111-114 °C; Rf = 0.6 (5% EtOAc/n-hexane).
58%
With trichloroisocyanuric acid In dichloromethane at 20℃;
53%
Stage #1: 3-(trifluoromethyl)benzoic acid With thionyl chloride In dichloromethane at 0 - 5℃; for 0.25h;
Stage #2: 1,2,3-Benzotriazole In dichloromethane at 35℃;
Complex 2 (8.3 mg, 10 mmol), CsOHH2O (0.84 g, 5 mmol),alcohol (5 mmol) was added to a 25 mL schlenk tube and the solutionwas heated at 150 C (oil bath) for 24 h in an open systemunder argon. After cooling to room temperature, the degassedwater (5 mL)was added and the mixturewas extracted with diethylether (3 10 mL). A sample of ether phasewas subjected to the GCMSanalysis and the residual solution was evaporated, then subjected to the NMR analysis. The aqueous phase was acidifiedwith 6 M HCl and extracted with ethyl acetate (5 20 mL). Thecombined organic phasewaswashed with brine (25 mL), dried overanhydrous Na2SO4, and evaporated under reduced pressure, thepure carboxylic acid was collected and weighed for calculating theyield, which was further characterized by its 1H NMR which isconsist with the standard sample.
3-(2-amino-5-iodo-1H-benzo[d]imidazol-1-yl)propyl acetate[ No CAS ]
(E)-3-(5-iodo-2-((3-(trifluoromethyl)benzoyl)imino)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)propyl acetate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
77%
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℃; for 14h;
5 (E)-3-(5-iodo-2-((3-(trifluoromethyl)benzoyl)imino)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)propyl acetate
In a glass RBF equipped with a Teflon-coated magnetic stirrer was dissolved 3 -(2-amino-5-iodo- 1H-benzo [djimidazol- 1 -yl)propyl acetate (1 eq.) from the previous step, 3 -trifluoromethyl-benzoic acid (1 eq.) and HATU (1.2 eq.) in DMF (0.1 M). To this was then added ethyl-diisopropyl-amine (2.5 eq.) and the resulting yellow solution was allowed to stir at RT for 14 h. The crude reaction mixture was diluted with EtOAc and washed sequentially with water, 10% aq. HC1, water and brine. The organic extract was then dried over MgSO4, filtered and the filtrate concentrated in vacuo. Further purification by way of column chromatography (Si02, gradient elution, 9:1 (v/v) Hex: EtOAc - EtOAc) furnished the desired product as an off-white solid (77% yield).
77%
With N-ethyl-N,N-diisopropylamine; HATU In N,N-dimethyl-formamide at 20℃; for 14h;
5 Step 5: (E)-3-(5-iodo-2-((3-(trifluoromethyl)benzoyl)imino)-2,3-dihydro-lH- benzol d]imidazol-l-yl)propyl acetate:
In a glass RBF equipped with a Teflon-coated magnetic stirrer was dissolved 3-(2-amino-5-iodo-lH-benzo[d]imidazol-l-yl)propyl acetate (1 eq.) from the previous step, 3-trifluoromethyl-benzoic acid (1 eq.) and HATU (1.2 eq.) in DMF (0.1 M). To this was then added ethyl-diisopropyl-amine (2.5 eq.) and the resulting yellow solution was allowed to stir at RT for 14 h. The crude reaction mixture was diluted with EtOAc and washed sequentially with water, 10% aq. HC1, water and brine. The organic extract was then dried over MgS04, filtered and the filtrate concentrated in vacuo. Further purification by way of column chromatography (S1O2, gradient elution, 9: 1 (v/v) Hex: EtOAc -> EtOAc) furnished the desired product as an off-white solid (77% yield).
With trichloroisocyanuric acid; bromine In Carbon tetrachloride at -10 - 100℃; for 18h; Photolysis;
10 Exploring the scope of chlorodecarboxylation reaction of arenecarboxylic acids
General procedure: Round bottom flask equipped with Dimroth condenser (chilled to -10 °C) was charged with arenecarboxylic acid (1.8 mmol), chloroisocyanurate, brominating agent and solvent (8 mL). The mixture was magnetically stirred and heated in an oil bath under 3 W LED warm-white lamp irradiation (LL) or under fluorescent room light irradiation (FL). The cooled reaction mixture was filtered through a short silica gel pad, washed with 1 M aq Na2SO3, dried over Na2SO4, filtered and the solvent was removed by distillation. In case of volatile product the yield was determined by gas chromatography (GC) with internal standard. The results are presented in Table 7
81 %Spectr.
With copper(I) tetrakis(acetonitrile)tetrafluoroborate; N-fluoro-2,4,6-trimethylpyridinium tetrafluoroborate; anhydrous zinc chloride In acetonitrile at 30℃; for 12h; Inert atmosphere; Irradiation; Sealed tube;
methyl (S)-3-(3-hydroxyphenyl)-2-(3-(trifluoromethyl)benzamido)propanoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
General procedure: Thearyl acid (1 eq) was dissolved into DMF (1-3 mL/1 mmol) and cooled to 0°C. HATU(1.2 eq) and DIPEA (3.5 eq) were then added and reaction was stirred at 0°C for5-10 min. The amino acid methyl ester (1 eq) was then added and reaction wasallowed to warm and stir at room temperature overnight. Reaction was pouredinto water,and extracted with EtOAc. The organic layers were combined andwashed with a 1N HCl(aq) solution, sat. NaHCO3 (aq)solution, and brine, dried over MgSO4, and concentrated in vacuo.The crude material was purified by flash chromatography (0-100percent EtOAc:Hexanes gradient).9-99percent
ethyl (3-(trifluoromethyl)benzoyl)-L-leucinate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
General procedure: Thearyl acid (1 eq) was dissolved into DMF (1-3 mL/1 mmol) and cooled to 0C. HATU(1.2 eq) and DIPEA (3.5 eq) were then added and reaction was stirred at 0C for5-10 min. The amino acid methyl ester (1 eq) was then added and reaction wasallowed to warm and stir at room temperature overnight. Reaction was pouredinto water,and extracted with EtOAc. The organic layers were combined andwashed with a 1N HCl(aq) solution, sat. NaHCO3 (aq)solution, and brine, dried over MgSO4, and concentrated in vacuo.The crude material was purified by flash chromatography (0-100% EtOAc:Hexanes gradient).9-99%
With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 25℃; for 8h;
General procedure: 3-(trifluoromethyl) benzoic acid (511mg, 2.69mmol) was stirred in a solvent of 58 dimethyl formamide (10mL).The reaction solution was added with 59 HATU (1.12g, 2.96mmol), 72 DIPEA (890mul, 5.37mmol) and the appropriate substituted aromatic amine (500mg, 2.69mmol), followed by stirring for about 8h at room temperature. The reaction mixture was diluted with ethyl acetate and washed with a saturated aqueous sodium bicarbonate solution and saline. The organic layer thus obtained was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting mixture was concentrated to give the crude product, which was purified by silica gel column chromatography (eluting with 0-5% EtOAc in 82 petroleum ether) to afford the 110 product as a white solid (815mg, 84%). 1H NMR (400MHz, Methanol-d4) delta 8.27 (s, 1H), 8.21 (d, J=8.4Hz, 1H), 8.06 (d, J=1.8Hz, 1H), 7.91 (d, J=7.4Hz, 1H), 7.75 (t, J=8.0Hz, 1H), 7.59 (dd, J=8.3, 1.8Hz, 1H), 7.30 (d, J=8.4Hz, 1H), 2.40 (s, 3H). MS m/z: 358.12 ([M+H]+).
With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 25℃; for 8h;
General procedure: 3-(trifluoromethyl) benzoic acid (511mg, 2.69mmol) was stirred in a solvent of 58 dimethyl formamide (10mL).The reaction solution was added with 59 HATU (1.12g, 2.96mmol), 72 DIPEA (890mul, 5.37mmol) and the appropriate substituted aromatic amine (500mg, 2.69mmol), followed by stirring for about 8h at room temperature. The reaction mixture was diluted with ethyl acetate and washed with a saturated aqueous sodium bicarbonate solution and saline. The organic layer thus obtained was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting mixture was concentrated to give the crude product, which was purified by silica gel column chromatography (eluting with 0-5% EtOAc in 82 petroleum ether) to afford the 110 product as a white solid (815mg, 84%).
With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 25℃; for 8h;
General procedure: 3-(trifluoromethyl) benzoic acid (511mg, 2.69mmol) was stirred in a solvent of 58 dimethyl formamide (10mL).The reaction solution was added with 59 HATU (1.12g, 2.96mmol), 72 DIPEA (890mul, 5.37mmol) and the appropriate substituted aromatic amine (500mg, 2.69mmol), followed by stirring for about 8h at room temperature. The reaction mixture was diluted with ethyl acetate and washed with a saturated aqueous sodium bicarbonate solution and saline. The organic layer thus obtained was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting mixture was concentrated to give the crude product, which was purified by silica gel column chromatography (eluting with 0-5% EtOAc in 82 petroleum ether) to afford the 110 product as a white solid (815mg, 84%).
With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 25℃; for 8h;
General procedure: 3-(trifluoromethyl) benzoic acid (511mg, 2.69mmol) was stirred in a solvent of 58 dimethyl formamide (10mL).The reaction solution was added with 59 HATU (1.12g, 2.96mmol), 72 DIPEA (890mul, 5.37mmol) and the appropriate substituted aromatic amine (500mg, 2.69mmol), followed by stirring for about 8h at room temperature. The reaction mixture was diluted with ethyl acetate and washed with a saturated aqueous sodium bicarbonate solution and saline. The organic layer thus obtained was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting mixture was concentrated to give the crude product, which was purified by silica gel column chromatography (eluting with 0-5% EtOAc in 82 petroleum ether) to afford the 110 product as a white solid (815mg, 84%).
N-[2-(3-chlorophenyl)ethyl]-3-(trifluoromethyl)benzamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
93%
General procedure: A solution of 24 (1.0 equiv.), HOBt (1.1 equiv.) and EDC (1.5 equiv.) in DMF (1.3 mmol/mL) was stirred at rt for 15 minutes. The appropriate amine (2.0 equiv.) was added and the resulting solution was stirred at rt for 5 hours. Reaction media was diluted with water and aqueous phase was extracted 3 times with EtOAc. Combined organic layers were washed successively with a solution of HCl 1N, a saturated solution of NaHCO3 and brine, dried over Na2SO4 and concentrated. The resulting solid was then purified by column chromatography on silica gel using the appropriate heptanes:EtOAc mixture.
N-[(4-methoxyphenyl)methyl]-N-methyl-3-(trifluoromethyl)benzamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
68%
General procedure: A solution of 24 (1.0 equiv.), HOBt (1.1 equiv.) and EDC (1.5 equiv.) in DMF (1.3 mmol/mL) was stirred at rt for 15 minutes. The appropriate amine (2.0 equiv.) was added and the resulting solution was stirred at rt for 5 hours. Reaction media was diluted with water and aqueous phase was extracted 3 times with EtOAc. Combined organic layers were washed successively with a solution of HCl 1N, a saturated solution of NaHCO3 and brine, dried over Na2SO4 and concentrated. The resulting solid was then purified by column chromatography on silica gel using the appropriate heptanes:EtOAc mixture.
With potassium acetate; palladium diacetate; at 80℃; under 760.051 Torr; for 24h;
0.6 mmol of potassium acetate and 0.3 mmol of m-trifluoromethylbenzoic acid,Palladium acetate 0.03 mmol, peroxydi-tert-butyl ether 0.6 mmol,0.8 mL of hexafluoroisopropanol was added to a 15 mL reaction tube and placed in an oil bath at 80 C.Reacted in an air atmosphere at a pressure of 1 atmosphere for 24 hours; cooled to room temperature,The reaction solution was diluted with ethyl acetate, washed with water and dried over anhydrous Na2SO4 Filtered, concentrated,Purification by thin layer chromatography gave 33 mg of the desired product.White solid, yield 54%
With dipotassium hydrogenphosphate; bis[dichloro(pentamethylcyclopentadienyl)iridium(III)]; 1,1'-binaphthyl-2,2'-diyl hydrogenphosphate; silver(I) acetate; XPhos In 2,2,2-trifluoroethanol at 140℃; for 24h; Sealed tube;
75%
With dipotassium hydrogenphosphate; bis[dichloro(pentamethylcyclopentadienyl)iridium(III)]; silver(I) acetate In 2,2,2-trifluoroethanol at 140℃; for 24h;
6.1; 6.2; 6.3
(1) Add 0.0380 g (0.24 mmol) of 3-trifluoromethylbenzoic acid, 0.0040 g (0.005 mmol) of pentamethylcyclopentadiene dichloride dimer, and 0.0174 g (0.14 g of dipotassium hydrogen phosphate) in the reaction tube mmol), silver acetate 0.040 g (0.24 mmol), bromotrifluoroacetone 0.0382 g (0.2 mmol) and 1 mL trifluoroethanol, and react at 140°C for 24 hours; TLC follows the response until it is completely over;(3) The crude product obtained after the completion of the reaction was separated by column chromatography (petroleum ether: ethyl acetate = 30: 1) to obtain the target product (yield 75%).
1-methyl-2-[3-(trifluoromethyl)phenyl]-1H-benzo[d]imidazole[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
73.8%
With benzotriazol-1-ol; 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 100℃; for 16h; Sealed tube; Inert atmosphere;
Benzimidazoles 3a-3l (general procedure).
General procedure: 1-[Bis-(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]-pyridinium 3-oxide hexa uorophosphate (1.227 mmol), HOBT (1.227 mmol), and DIPEA (2.454 mmol) were added to a magnetically stirred solution of N-1-methylbenzene-1,2-diamine (1, 0.818 mmol) and arylcarboxylic acid 2 (0.818 mmol) in DMF (3 mL) in a Biotage reaction tube. The tube was sealed with an aluminum cap with a septum, and the reaction mixture was stirred at 100°C for 16 h. Progress of the reaction was monitored by TLC of samples of the reaction mixture, taken with a 1-mL syringe through the cap septum. Used the sealed tube which having aluminium cap with septa (purchased from Biotage) and sample took via 1 mL syringe. Upon completion of the reaction, the reaction mixture was cooled to room temperature and poured into water (15 mL) and treated with ethyl acetate (3 × 15 mL), and the combined organic extracts were dried over anhydrous sodium sulphate and ltered. The solvent was distilled off from the ltrate under reduced pressure to leave a crude product, which was puri ed by recrystallization or trituration with diethyl ether or pentane.
N-(4-methylthiazol-2-yl)-3-(trifluoromethyl)benzamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
80%
With HATU; potassium carbonate In N,N-dimethyl-formamide at 20℃; for 8h;
4.1.42. 4-((4-Methylpiperazin-1-yl)methyl)-N-(4-methylthiazol-2-yl)-3-(trifluoromethyl)benzamide (51a)
General procedure: To a solution of 50 (1 g, 2.3 mmol) in DMF (20 mL) were addedK2CO3 (3.2 g, 23 mmol), 4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)benzoic acid (0.84 g, 2.8 mmol) and HATU (1.1 g,3 mmol) in batches, and the reaction was allowed to be stirred at rtfor 8h. The mixture was extracted by DCM (100 mL 3) andwashed with water (100 mL 2) followed by brine (100 mL). Theorganic layers were dried over sodium sulfate, filtered, concentratedand purified by silica gel column chromatography (elutingwith 0e30% EtOAc in heptane) to afford 51a as a white solid (0.72 g,72%).
1-(3-bromo-4-methylphenyl)ethane-1-amine hydrochloride[ No CAS ]
N-(1-(3-bromo-4-methylphenyl)ethyl)-3-(trifluoromethyl)benzamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
86.5%
With N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate
4.2 Step 2:
Step 2: Synthesis of N-(1-(3-bromo-4-methylphenyl)ethyl)-3-(trifluoromethyl)benzamide The intermediate 1-(3-bromo-4-methylphenyl)ethane-1-amine hydrochloride (3 g, 11.97 mmol), HATU (5 g, 11.97 mmol) and DIPEA (4.64 g, 35.92 mmol) were weighed and placed in a round bottom flask. 50 ml of anhydrous N,N-dimethylformamide was added. After stirring for 30 min at room temperature, 3-trifluoromethylbenzoic acid (2.3 g, 11.97 mmol) was added dropwise to the reaction solution. The reaction solution was stirred at room temperature for 4 hours. After the reactants were reacted completely, saturated brine was added to the reaction solution and extracted with ethyl acetate 3 times. The organic layer was dried with anhydrous sodium sulfate and filtered and the solvent was evaporated to dryness. The crude product was purified by silica gel column chromatography to obtain a total of 4 g of yellow oily liquid. The yield was 86.5%. 1H NMR (400 MHz, Chloroform-d) δ 8.04 (s, 1H), 7.97 (d, J = 7.8 Hz, 1H), 7.77 (d, J = 7.8 Hz, 1H), 7.58 (d, J = 7.9 Hz, 1H), 7.57 - 7.55 (m, 1H), 7.28 (s, 1H), 7.24 (d, J = 1.6 Hz, 1H), 7.23 (s, 1H), 5.31 - 5.26 (m, 1H), 2.39 (s, 3H), 1.61 (d, J = 6.9 Hz, 3H).
86.5%
Stage #1: 1-(3-bromo-4-methylphenyl)ethane-1-amine hydrochloride With N-ethyl-N,N-diisopropylamine; O-(7-azabenzotriazol-1-yl)-n,n,n',n'-tetramethyluronium hexafluoro-phosphate In N,N-dimethyl-formamide at 20℃; for 0.5h;
Stage #2: 3-(trifluoromethyl)benzoic acid In N,N-dimethyl-formamide at 20℃; for 4h;
4.2 Step 2: Synthesis of N-(1-(3-bromo-4-methylphenyl)ethyl)-3-(trifluoromethyl)benzamide
The intermediate 1-(3-bromo-4-methylphenyl)ethane-1-amine hydrochloride (3 g, 11.97 mmol), HATU (5 g, 11.97 mmol) and DIPEA (4.64 g, 35.92 mmol) were weighed and placed in a round bottom flask. 50 ml of anhydrous N,N-dimethylformamide was added. After stirring for 30 min at room temperature, 3-trifluoromethylbenzoic acid (2.3 g, 11.97 mmol) was added dropwise to the reaction solution. The reaction solution was stirred at room temperature for 4 hours. After the reactants were reacted completely, saturated brine was added to the reaction solution and extracted with ethyl acetate 3 times. The organic layer was dried with anhydrous sodium sulfate and filtered and the solvent was evaporated to dryness. The crude product was purified by silica gel column chromatography to obtain a total of 4 g of yellow oily liquid. The yield was 86.5%. 1H NMR (400 MHz, Chloroform-d) δ 8.04 (s, 1H), 7.97 (d, J = 7.8 Hz, 1H), 7.77 (d, J = 7.8 Hz, 1H), 7.58 (d, J = 7.9 Hz, 1H), 7.57 - 7.55 (m, 1H), 7.28 (s, 1H), 7.24 (d, J = 1.6 Hz, 1H), 7.23 (s, 1H), 5.31 - 5.26 (m, 1H), 2.39 (s, 3H), 1.61 (d, J = 6.9 Hz, 3H).
86.5%
Stage #1: 1-(3-bromo-4-methylphenyl)ethane-1-amine hydrochloride With N-ethyl-N,N-diisopropylamine; O-(7-azabenzotriazol-1-yl)-n,n,n',n'-tetramethyluronium hexafluoro-phosphate In N,N-dimethyl-formamide at 20℃; for 0.5h;
Stage #2: 3-(trifluoromethyl)benzoic acid In N,N-dimethyl-formamide at 20℃; for 4h;
4.2 Step 2: Synthesis of N-(1-(3-bromo-4-methylphenyl)ethyl)-3-(trifluoromethyl)benzamide
The intermediate 1-(3-bromo-4-methylphenyl)ethane-1-amine hydrochloride (3 g, 11.97 mmol), HATU (5 g, 11.97 mmol) and DIPEA (4.64 g, 35.92 mmol) were weighed and placed in a round bottom flask. 50 ml of anhydrous N,N-dimethylformamide was added. After stirring for 30 min at room temperature, 3-trifluoromethylbenzoic acid (2.3 g, 11.97 mmol) was added dropwise to the reaction solution. The reaction solution was stirred at room temperature for 4 hours. After the reactants were reacted completely, saturated brine was added to the reaction solution and extracted with ethyl acetate 3 times. The organic layer was dried with anhydrous sodium sulfate and filtered and the solvent was evaporated to dryness. The crude product was purified by silica gel column chromatography to obtain a total of 4 g of yellow oily liquid. The yield was 86.5%. 1H NMR (400 MHz, Chloroform-d) δ 8.04 (s, 1H), 7.97 (d, J = 7.8 Hz, 1H), 7.77 (d, J = 7.8 Hz, 1H), 7.58 (d, J = 7.9 Hz, 1H), 7.57 - 7.55 (m, 1H), 7.28 (s, 1H), 7.24 (d, J = 1.6 Hz, 1H), 7.23 (s, 1H), 5.31 - 5.26 (m, 1H), 2.39 (s, 3H), 1.61 (d, J = 6.9 Hz, 3H).
N-(4-(7-(2-morpholinoethoxy)-6-methoxy-2-methylquinolin-3-yloxy)phenyl)-3-(trifluoromethyl)benzamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
60%
With benzotriazol-1-ol; N-[3-(N,N-dimethylamino)-propyl]-N'-ethyl-carbodiimide hydrochloride; triethylamine In N,N-dimethyl-formamide at 0 - 20℃; for 12h; Inert atmosphere;
4.9. Synthesis of the target diarylamide compounds 1m-p
General procedure: A mixture of compound 11a,b (0.18 mmol), appropriate benzoicacid derivative (0.36 mmol), HOBt (54 mg, 0.39 mmol), and EDCI (87mg, 0.45 mmol) in dry DMF (2 mL) was cooled to 0 C under nitrogenatmosphere. Triethylamine (0.06 mL, 0.45 mmol) was added thereto at0 C. The mixture was then stirred at room temperature for 12 h. Thereaction mixture was partitioned between water (10 mL) and ethyl acetate(10 mL), and the organic layer was separated. The aqueous layerwas then extracted with ethyl acetate (3 × 5 mL), and the combinedorganic extracts were washed with saline and dried with anhydrousNa2SO4. The organic solvent was evaporated, and the crude residue waspurified by normal phase column chromatography using hexane-ethylacetate to get the target product.
60%
With benzotriazol-1-ol; N-[3-(N,N-dimethylamino)-propyl]-N'-ethyl-carbodiimide hydrochloride; triethylamine In N,N-dimethyl-formamide at 0 - 20℃; for 12h; Inert atmosphere;
4.9. Synthesis of the target diarylamide compounds 1m-p
General procedure: A mixture of compound 11a,b (0.18 mmol), appropriate benzoicacid derivative (0.36 mmol), HOBt (54 mg, 0.39 mmol), and EDCI (87mg, 0.45 mmol) in dry DMF (2 mL) was cooled to 0 C under nitrogenatmosphere. Triethylamine (0.06 mL, 0.45 mmol) was added thereto at0 C. The mixture was then stirred at room temperature for 12 h. Thereaction mixture was partitioned between water (10 mL) and ethyl acetate(10 mL), and the organic layer was separated. The aqueous layerwas then extracted with ethyl acetate (3 × 5 mL), and the combinedorganic extracts were washed with saline and dried with anhydrousNa2SO4. The organic solvent was evaporated, and the crude residue waspurified by normal phase column chromatography using hexane-ethylacetate to get the target product.
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