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Structure of 102-50-1 * Storage: {[proInfo.prStorage]}
* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
A solution of sodium nitrite (3.38 g, 49.0 mmol) in water (8.1 ml) was added to a solution of 4-methoxy-2-methylaniline (6.69 g, 48.8 mmol) in acetic acid (350 ml) in an ice-water bath while maintaining the temperature at 25°C or lower, and stirred overnight at room temperature. Then, the reaction solution was poured into water and extracted with chloroform. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and then distilled under reduced pressure to remove the solvent, and the resulting residue was purified by a silica gel column chromatography (eluent: chloroform/methanol = 9/1) to obtain 5-methoxy-1H-indazole (1.30 g, 18percent).1H-NMR (DMSO-d6) δ; 3.76 (3H, s), 6.98 (1H, dd, J=8.8, 1.8Hz), 7.15 (1H, d, J=1.8Hz), 7.42 (1H, d, J=8.8Hz), 7.93 (1H, s), 12.89 (1H, brs).
Reference：
[1] Patent: EP1403255, 2004, A1, . Location in patent: Page 44
[2] Bulletin of the Chemical Society of Japan, 1985, vol. 58, # 1, p. 309 - 315
[3] Bioorganic and Medicinal Chemistry Letters, 2005, vol. 15, # 23, p. 5293 - 5297
[4] Bioorganic and Medicinal Chemistry Letters, 2001, vol. 11, # 9, p. 1153 - 1156
[5] Bioorganic and Medicinal Chemistry Letters, 2011, vol. 21, # 8, p. 2410 - 2414
3
[ 5367-32-8 ]
[ 102-50-1 ]
Yield
Reaction Conditions
Operation in experiment
80%
at 80℃; for 8 h;
General procedure: Nitro aromatic (1.0 mmol), B2(OH)4 (5.0 equiv, 5.0 mmol), and H2O (3.0 mL) were added in a10 mL tube. The reaction mixture was stirred at 80 °C for 8 h. When the reaction was completemonitored by TLC, the mixture was cooled to room temperature, extracted with ethyl acetate (3 ×20 mL). The combined organic phase was dried over anhydrous Na2SO4, filtered, andconcentrated under reduced pressure. The residue was purified by silica gel columnchromatography.
75%
With tetrahydroxydiboron; 5%-palladium/activated carbon; water In acetonitrile at 50℃; for 24 h;
General procedure: Nitrobenzene (0.6mmol), 5wtpercent Pd/C (0.5mmol percent, 0.003mmol), H2O (10 equiv, 6.0mmol), B2(OH)4 (3.3 equiv, 2.0mmol), and CH3CN (1.0mL) were added in a 10mL tube. The reaction mixture was stirred at 50°C for 24h. When the reaction was complete monitored by TLC, the mixture was cooled to room temperature. Water (5mL) was added, and extracted with EtOAc (3×5mL). The combined organic phase was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give aniline 2a (55mg, 99percent).
16.5 g
With palladium on activated charcoal; hydrogen In methanol for 0.25 h;
EXAMPLE 1396-((l-(2-(3-Fluoro-6-methoxy-8-methylquinolin-4-yl)ethyl)-2- oxabicyclo[2.2.2]octan-4-ylamino)methyl)-2H-pyrido[3,2-b][l,4]oxazin-3(4H)-oneStep 14-Methoxy-2-methylanilineA solution of 4-methoxy-2-methyl-l -nitrobenzene (20.0 g) in methanol (150 mL) was added Pd/C (1.0 g), then stirred under H2 for about 15 hours until the starting material disappeared on TLC. Filtered and the filtrate was concentrated under reduced pressure to give the title compound (16.5 g), which was used for the next step directly.
Reference：
[1] Analytical Chemistry, 1992, vol. 64, # 8, p. 837 - 842
[2] ChemCatChem, 2017, vol. 9, # 16, p. 3236 - 3244
[3] Synlett, 2018, vol. 29, # 13, p. 1765 - 1768
[4] Tetrahedron, 2017, vol. 73, # 27-28, p. 3898 - 3904
[5] Helvetica Chimica Acta, 1924, vol. 7, p. 698
[6] Journal of the Chemical Society, 1923, vol. 123, p. 2989[7] Journal of the Chemical Society, 1924, vol. 125, p. 1305
[8] Journal of Organic Chemistry, 1951, vol. 16, p. 586,606
[9] Roczniki Chemii, vol. 6, p. 883[10] Chem. Zentralbl., 1927, vol. 98, # I, p. 3006
[11] Tetrahedron, 1978, vol. 34, p. 3611 - 3615
[12] Patent: WO2013/3383, 2013, A1, . Location in patent: Page/Page column 279
4
[ 27060-75-9 ]
[ 102-50-1 ]
Reference：
[1] Organic Letters, 2014, vol. 16, # 17, p. 4388 - 4391
[2] Journal of Organic Chemistry, 2009, vol. 74, # 12, p. 4542 - 4546
5
[ 13334-71-9 ]
[ 102-50-1 ]
Reference：
[1] Organic Letters, 2015, vol. 17, # 23, p. 5934 - 5937
[2] Angewandte Chemie - International Edition, 2010, vol. 49, # 24, p. 4071 - 4074
6
[ 208399-66-0 ]
[ 102-50-1 ]
Reference：
[1] Journal of Organic Chemistry, 2015, vol. 80, # 5, p. 2545 - 2553
7
[ 154876-10-5 ]
[ 102-50-1 ]
Reference：
[1] Journal of Organic Chemistry, 1994, vol. 59, # 3, p. 682 - 687
8
[ 2581-34-2 ]
[ 102-50-1 ]
Reference：
[1] Journal of the Chemical Society, 1923, vol. 123, p. 2989[2] Journal of the Chemical Society, 1924, vol. 125, p. 1305
[3] Roczniki Chemii, vol. 6, p. 883[4] Chem. Zentralbl., 1927, vol. 98, # I, p. 3006
[5] Helvetica Chimica Acta, 1924, vol. 7, p. 698
[6] Tetrahedron, 1978, vol. 34, p. 3611 - 3615
9
[ 57197-11-2 ]
[ 102-50-1 ]
Reference：
[1] Organic and Biomolecular Chemistry, 2016, vol. 14, # 24, p. 5520 - 5524
10
[ 31601-41-9 ]
[ 102-50-1 ]
Reference：
[1] Journal of the American Chemical Society, 1919, vol. 41, p. 1457
11
[ 39495-15-3 ]
[ 102-50-1 ]
Reference：
[1] Journal of the American Chemical Society, 1919, vol. 41, p. 1457
12
[ 100-84-5 ]
[ 102-50-1 ]
Reference：
[1] Journal of Organic Chemistry, 1994, vol. 59, # 3, p. 682 - 687
13
[ 95-48-7 ]
[ 102-50-1 ]
Reference：
[1] Organic and Biomolecular Chemistry, 2016, vol. 14, # 24, p. 5520 - 5524
[2] Organic and Biomolecular Chemistry, 2016, vol. 14, # 24, p. 5520 - 5524
14
[ 5307-05-1 ]
[ 102-50-1 ]
Reference：
[1] Organic and Biomolecular Chemistry, 2016, vol. 14, # 24, p. 5520 - 5524
Reference：
[1] Journal of Medicinal Chemistry, 1984, vol. 27, # 5, p. 577 - 585
20
[ 102-50-1 ]
[ 861084-04-0 ]
Reference：
[1] Organic Process Research and Development, 2014, vol. 18, # 4, p. 501 - 510
21
[ 102-50-1 ]
[ 54413-93-3 ]
Reference：
[1] Journal of Organic Chemistry, 1949, vol. 14, p. 670,678
22
[ 102-50-1 ]
[ 105728-90-3 ]
Reference：
[1] Journal of the American Chemical Society, 1987, vol. 109, # 2, p. 341 - 348
23
[ 102-50-1 ]
[ 885519-30-2 ]
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2005, vol. 15, # 23, p. 5293 - 5297
24
[ 102-50-1 ]
[ 478834-25-2 ]
Reference：
[1] Patent: EP1403255, 2004, A1,
25
[ 102-50-1 ]
[ 78299-75-9 ]
Reference：
[1] Patent: EP1403255, 2004, A1,
26
[ 102-50-1 ]
[ 1206800-17-0 ]
Reference：
[1] Organic Process Research and Development, 2014, vol. 18, # 4, p. 501 - 510
27
[ 102-50-1 ]
[ 1206800-18-1 ]
Reference：
[1] Organic Process Research and Development, 2014, vol. 18, # 4, p. 501 - 510
28
[ 102-50-1 ]
[ 1206800-24-9 ]
Reference：
[1] Organic Process Research and Development, 2014, vol. 18, # 4, p. 501 - 510
[2] Organic Process Research and Development, 2014, vol. 18, # 4, p. 501 - 510
General procedure: Nitro aromatic (1.0 mmol), B2(OH)4 (5.0 equiv, 5.0 mmol), and H2O (3.0 mL) were added in a10 mL tube. The reaction mixture was stirred at 80 C for 8 h. When the reaction was completemonitored by TLC, the mixture was cooled to room temperature, extracted with ethyl acetate (3 ×20 mL). The combined organic phase was dried over anhydrous Na2SO4, filtered, andconcentrated under reduced pressure. The residue was purified by silica gel columnchromatography.
75%
With tetrahydroxydiboron; 5%-palladium/activated carbon; water; In acetonitrile; at 50℃; for 24h;
General procedure: Nitrobenzene (0.6mmol), 5wt% Pd/C (0.5mmol %, 0.003mmol), H2O (10 equiv, 6.0mmol), B2(OH)4 (3.3 equiv, 2.0mmol), and CH3CN (1.0mL) were added in a 10mL tube. The reaction mixture was stirred at 50C for 24h. When the reaction was complete monitored by TLC, the mixture was cooled to room temperature. Water (5mL) was added, and extracted with EtOAc (3×5mL). The combined organic phase was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give aniline 2a (55mg, 99%).
16.5 g
With palladium on activated charcoal; hydrogen; In methanol; for 0.25h;
EXAMPLE 1396-((l-(2-(3-Fluoro-6-methoxy-8-methylquinolin-4-yl)ethyl)-2- oxabicyclo[2.2.2]octan-4-ylamino)methyl)-2H-pyrido[3,2-b][l,4]oxazin-3(4H)-oneStep 14-Methoxy-2-methylanilineA solution of 4-methoxy-2-methyl-l -nitrobenzene (20.0 g) in methanol (150 mL) was added Pd/C (1.0 g), then stirred under H2 for about 15 hours until the starting material disappeared on TLC. Filtered and the filtrate was concentrated under reduced pressure to give the title compound (16.5 g), which was used for the next step directly.
3.A Preparation of 2-Ethyl-5-methoxy-1-(phenylmethyl)-1H-indole-3-acetic acid hydrazide.
A. N-tert-Butoxycarbonyl-4-methoxy-2-methylaniline. By the procedure in Example 1, Part C, 13.7 g (0.1 mole) of 4-methoxy-2-methylaniline was reacted with 25 g (0.1145 mol) of di-tert-butyl dicarbonate to give 17. 25 g (73% yield) of N-tert-butoxycarbonyl-4-methoxy-2-methylaniline melting at 80°-82° C., after crystallizing from hexane. Analyses: Calc'd for C13 H19 NO3: C, 65.80; H, 8.07; N, 5.90. Found: C, 65.86; H, 8.15; N, 5.61.
73%
15.A Example 15
Part A. Preparation of N-tert-Butoxycarbonyl-4-methoxy-2-methylaniline. By the procedure in Example 1, Part A, 13.7 g (0.1 mole) of 4-methoxy-2-methylaniline was reacted with 25 g (0.1145 mol) of di-tert-butyl dicarbonate to give 17.25 g (73% yield) of N-tert-butoxycarbonyl-4-methoxy-2-methylaniline melting at 80°-82° C., after crystallizing from hexane. Analyses for C13 H19 NO3: Calculated: C, 65.80; H, 8.07; N, 5.90 Found: C, 65.86; H, 8.15; N, 5.61.
73%
9.A Preparation of 2-Ethyl-5-methoxy-1-(phenylmethyl)-1H-indole-3-acetamide
A. N-tert-Butoxycarbonyl-4-methoxy-2-methylaniline. By the procedure in Example 1, Part A, 13.7 g (0.1 mole) of 4-methoxy-2-methylaniline was reacted with 25 g (0.1145 mol) of di-tert-butyl dicarbonate to give 17.25 g (73% yield) of N-tert-butoxycarbonyl-4-methoxy-2-methylaniline melting at 80°-82° C., after crystallizing from hexane. Analyses: Calc'd for C13 H19 NO3: C, 65.80; H, 8.07; N, 5.90. Found: C, 65.86; H, 8.15; N, 5.61.
In tetrahydrofuran Heating;
In tetrahydrofuran for 2h; Reflux;
Preparation of S-methoxy^-cyclopropyl-indole-S-carbaldehyde; A solution of 4-methoxy-2-methylaniline (10 g, 72.9 mmol, 1 eq.) and ferf-butyl dicarbonate (18.3 g, 84.8 mmol, 1.2 eq.) in THF (90 ml_) was refluxed for 2 hours. After cooling, the reaction mixture was evaporated under reduced pressure and the residue was dissolved in EtOAc. The organic layer was washed with a saturated NH4CI and brine, dried on Na2SO4, and evaporated to give crude N-(ferf-butoxycarbonyl)-4-methoxy-2-methylaniline that was used without further purification. Yield: quant. MS (m/z): 238.9 (MH+).Et3N (3.3 mL) was added to a solution of MeNH(OMe)-HCI (1.2 g, 12.4 mmol, 1 eq.) in methylene chloride (35 mL). The solution was stirred at room temperature for 30 minutes, then the reaction was cooled to 00C and cyclopropanecarbonylchloride (1 g, 12.4 mmol, 1 eq.) was added. After 5 hours, the reaction mixture was diluted with methylene chloride, washed with 1 N HCI and saturated NaHCO3. The organic layer was dried on Na2SO4 and evaporated to give crude N-methoxy-N-methylcyclopropanecarboxamide, which was utilized in the next step without further purification. Yield: 94%.A solution of N-(ferf-Butoxycarbonyl)-4-methoxy-2-methylaniline (2.7 g, 1 1.6 mmol) in THF (34 mL) was cooled to -78°C under N2 and sec-BuLi (1.3 M in cyclohexane, 17.9 mL, 23.2 mmol) was added slowly keeping the temperature below -400C. After 15 minutes, a solution of N-methoxy-N-methylcyclopropanecarboxamide (1.5 g, 1 1.6 mmol) in THF (34 mL), was added by drops. The reaction mixture was stirred for 1 hour, then the cooling bath was removed and the mixture was stirred for additional 1 hour. The reaction was poured into a mixture of Et2O and 1 N HCI. The organic layer was separated, washed with water, dried on Na2SO4, and evaporated under reduced pressure to give crude f-butyl-2-(2-cyclopropyl-2-oxoethyl)-4- methoxyphenyl carbamate. The desired compound was purified by flash chromatography. Yield: 61 %. MS (m/z): 306.3 (MH+).A solution of f-butyl-2-(cyclopropyl-2-oxopropyl)-4-methoxyphenylcarbamate (1.5 g, 4.9 mmol) and trifluoroacetic acid (5 mL) in methylene chloride (25 mL) was stirred for 4 hours. Water was added and the organic layer separated, dried on Na2SO4 and evaporated to give 5- methoxy-2-cyclopropyl-indole. Yield: 69%. For the formylation step, the same procedure described for 5-methoxy-indole-3- carbaldehyde and S-methoxy^-methyl-indole-S-carbaldehyde was used. Yield: 95%. MS (m/z): 216.2 (MH+).
With acetic acid; sodium nitrite; In water; at 20℃;
A solution of sodium nitrite (3.38 g, 49.0 mmol) in water (8.1 ml) was added to a solution of 4-methoxy-2-methylaniline (6.69 g, 48.8 mmol) in acetic acid (350 ml) in an ice-water bath while maintaining the temperature at 25C or lower, and stirred overnight at room temperature. Then, the reaction solution was poured into water and extracted with chloroform. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and then distilled under reduced pressure to remove the solvent, and the resulting residue was purified by a silica gel column chromatography (eluent: chloroform/methanol = 9/1) to obtain 5-methoxy-1H-indazole (1.30 g, 18%).1H-NMR (DMSO-d6) delta; 3.76 (3H, s), 6.98 (1H, dd, J=8.8, 1.8Hz), 7.15 (1H, d, J=1.8Hz), 7.42 (1H, d, J=8.8Hz), 7.93 (1H, s), 12.89 (1H, brs).
With potassium phosphate; copper(l) iodide; C18H15N3O2; at 25℃; for 24h;Sealed tube;
1.37 g (10 mmol) of 2-methyl-4-methoxyaniline, 1.88 g (12 mmol) of bromobenzene, 152 mg L-CHO (0.5 mmol), 95 mg (0.5 mmol) cuprous iodide, 4.24 g (20 mmol) potassium phosphate, 20 mL of 1,3-propanediol was added to a 50 mL sealed tube, capped, and reacted at 25 C for 24 h. After completion of the reaction, the reaction solution was added to 100 mL of water and extracted three times with ethyl acetate, 30 mL each time. The combined ethyl acetate was dried over anhydrous sodium sulfate, filtered and evaporated Using 100 to 200 mesh silica gel column chromatography, 1.97 g of off-white 2-methyl-4-methoxydiphenylamine was obtained in a yield of 93%
93%
With potassium phosphate; copper(l) iodide; In diethylene glycol; at 70℃; for 14h;Sealed tube;
Run 0: A 30 mL vial was charged with CuI (95 mg, 0.5 mmol), PSAP(300 mg, 0.5 mmol, > 100 mesh), K 3 PO 4 (4.24 g, 20 mmol), 4-me-thoxy-2-methylaniline (10 mmol), bromobenzene (15 mmol), DEG(20 mL), and a magnetic stir bar. The vessel was sealed with a septumand placed into a preheated oil bath at 70 C. The reaction mixturewas held at this temperature for 14 hours. After reaction, the reactionmixture was filtered, washed sequentially with water and methanol,and the residue was dried in vacuo to afford the recovered PSAP. Thefiltrate was poured into water (500 mL), the precipitates were collect-ed and dissolved in methanol. After removal of insoluble material, thefiltrate was dropped into water to afford the crude product as precip-itates. The crude product was dissolved in MeOH and precipitatedwith water once again, filtered and washed with water, dried in vacuoto afford 2-methyl-4-methoxydiphenylamine as off-white solids(1.98 g, 93%). All reuse runs were performed in the same manner andproduced off-white solids.Run 1: Yield: 1.89 g (89%).Run 2: Yield: 1.81 g (85%).Run 3: Yield: 1.77 g (83%).Run 4: Yield: 1.79 g (84%).Run 5: Yield: 1.70 g (80%).1 H NMR (400 MHz, CDCl 3 ): delta = 7.22 (t, J = 7.5 Hz, 3 H, ArH), 6.92-6.69(m, 5 H, ArH), 3.83 (s, 3 H, OCH 3 ), 2.25 (s, 3 H, CH 3 ).13 C NMR (100 MHz, CDCl 3 ): delta = 156.4, 146.3, 134.1, 133.5, 129.3,125.1, 118.8, 116.4, 114.8, 111.9, 55.5, 18.3.MS (ESI + ): m/z = 214 [M + H] + .Anal. Calcd for C 14 H 15 NO·0.05H 2 O: C, 78.51; H, 7.11; N, 6.54; Found: C,78.11, H, 7.07; N, 6.51.
46. 1-(4-Methoxy-2-methylphenyl)-3-quinolin-4-ylurea hydrochloride 4-Methoxy-2-methyl aniline in tetrahydrofuran (10 ml) was added to a stirred suspension of carbonyl diimidazole (0.26 g) in tetrahydrofuran (10 ml). After stirring for 1 h, solvent was removed at reduced pressure, the residue dissolved in dimethylformamide (8 ml) and <strong>[578-68-7]4-aminoquinoline</strong> (0.23 g) added. The mixture was heated at 95 C. for 30 min, cooled and poured into water and extracted with dichloromethane (2*20 ml). The combined organic phase was washed with water, dried (Na2SO4) and solvent removed at reduced pressure. The residue was column chromatographed (silica gel ethyl acetate/hexane mixture) to give, after conversion to the hydrochloride salt the title compound (0.02 g). 1H NMR delta: 2.33 (3H, s), 3.75 (3H, s), 6.80 (1H, dd, J 2.54+11 Hz), 6.85 (1H, m), 7.50 (1H, d, J 8.7 Hz), 7.89-7.95 (1H, m), 8.08-8.18 (2H, m), 8.71 (1H, d, J 6.8 Hz), 8.97 (1H, d, J 6.8 Hz), 9.13 (1H, d, J 8.7 Hz), 9.92 (1H, bs), 11.23 (1H, bs). m/z (API+): 308 (MH+).
6,7-dimethoxy-4-(4-methoxy-2-methyl-phenylamino)-quinoline-3-carbonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
250.2 mg (71.7%)
With pyridine hydrochloride; In 2-ethoxy-ethanol;
6,7-Dimethoxy-4-(4-methoxy-2-methyl-phenylamino)-quinoline-3-carbonitrile A reaction mixture of 248.7 mg (1 mmol) of <strong>[214470-55-0]4-chloro-6,7-dimethoxy-3-quinolinecarbonitrile</strong>, 164.6 mg (1.2 mmol) of 4-methoxy-2-methyl-aniline and 115.6 mg (1 mmol) of pyridine hydrochloride in 10 mL of 2-ethoxyethanol was refluxed under N2 for 3 hr. After removal of the solvent, the residue was diluted with water and neutralized to pH 7-8 with diluted sodium carbonate solution. The precipitate was filtered and washed with water and ether. After drying in vacuo. this yielded 250.2 mg (71.7%) of the product as a off red solid, m.p.>131 C. (dec.), mass (electrospray, m/e): M+H 349.9.
250.2 mg (71.7%)
With pyridine hydrochloride; In 2-ethoxy-ethanol;
6,7-Dimethoxy-4-(4-methoxy -2-methyl-phenylamino)-quinoline-3-carbonitrile A reaction mixture of 248.7 mg (1 mmol) of <strong>[214470-55-0]4-chloro-6,7-dimethoxy-3-quinolinecarbonitrile</strong>, 164.6 mg (1.2 mmol) of 4-methoxy-2-methyl-aniline and 115.6 mg (1 mmol) of pyridine hydrochloride in 10 mL of 2-ethoxyethanol was refluxed under N2 for 3 hr. After removal of the solvent, the residue was diluted with water and neutralized to pH 7-8 with diluted sodium carbonate solution. The precipitate was filtered and washed with water and ether. After drying in vacuo, this yielded 250.2 mg (71.7%) of the product as a off red solid, m.p.>131 C(dec.), mass (electrospray, m/e): M+H 349.9.
250.2 mg (71.7%)
With pyridine hydrochloride; In 2-ethoxy-ethanol;
Example 367 6,7-Dimethoxy-4-(4-methoxy-2-methyl-phenylamino)-quinoline-3-carbonitrile A reaction mixture of 248.7 mg (1 mmol) of <strong>[214470-55-0]4-chloro-6,7-dimethoxy-3-quinolinecarbonitrile</strong>, 164.6 mg (1.2 mmol) of 4-methoxy-2-methyl-aniline and 115.6 mg (1 mmol) of pyridine hydrochloride in 10 mL of 2-ethoxyethanol was refluxed under N2 for 3 hr. After removal of the solvent, the residue was diluted with water and neutralized to pH 7-8 with diluted sodium carbonate solution. The precipitate was filtered and washed with water and ether. After drying in vacuo. this yielded 250.2 mg (71.7 %) of the product as a off red solid, m.p. >131 C(dec.), mass (electrospray, m/e): M+H 349.9.
EXAMPLE 6 The experiment was carried out as in Example 1 but using 2-methyl-4-methoxyaniline instead of 2-methylaniline. At a conversion of 98.0%, 2-methyl-4-methoxy-diphenylamine was formed at a selectivity of 98.0%. The filtrate resulting after separation of the catalyst was concentrated to separate and recover a phenol fraction, after which the concentrated liquid was distilled under reduced pressure to give 39.3 g (yield 94.0%) of a fraction boiling a 192 to 198 C.
Part C To a solution of monoacid 4 (1.86 g. 10 mmol) in DMF (10 mL) and HOBt (2.7 g, 20 mmol), EDC (2.0 mg, 10.5 mmol) was added. After the reaction mixture was stirred at room temperature for 10 min, 4-[1,2,4]triazol-1-yl-phenylamine (2.7 g, 20 mmol) was added. The resulting mixture was stirred at room temperature overnight and was poured into ice-water mixture (100 mL). The formed precipitate was then collected by filtration and was washed with saturated NaHCO3, H2O, 1 N HCl and H2O. The resulted solid was dried under vacuum overnight to give the product 5 (2.7 g, 89%). 1H NMR (400 MHz, DMSO-d6): 10.04 (s, 1H), 7.95 (d, 1H), 7.83 (d, 1H), 7.16 (d, 1H), 6.84 (d, 1H), 6.76 (dd, 1H), 3.84 (s, 3H), 3.73 (s, 3H), 2.18 (s, 3H).
Example 7 Part A To a solution of 1 (80 mg, 0.5 mmol) in DMF (5 mL) at 0 C., HOBt (135 mg, 1.0 mmol) was added, followed by EDCI (191 mg, 1.0 mmol). After stirring at 0 C. for 0.5 h, 4-[1,2,4]triazol-1-yl-phenylamine (80 mg, 0.5 mmol) was added. 4-Methoxy-2-methyl-phenylamine (70 mg, 0.5 mmol) was added 10 min later. The reaction was then warmed up to RT and was stirred at this temperature for overnight. Water was added and the formed precipitated was collected by filtration, which was purified using prep-HPLC to give the desired product (30 mg). LC-MS m/z 418.2 (M+H).
General procedure: To a stirred mixture of 4-hydroxy-2-quinolones 2 (4.0 mmol) and sodium acetate (3.8 g) in water (20 mL), a solution of aryl diazonium chloride [prepared from aniline (637 mg), conc.HCl (2 mL and sodium nitrite (345 mg) in water (2 mL)] was added dropwise at 0-5 C. After completion of addition, the reaction mass was stirred for 1h at the same temperature. The reaction mass was allowed to warm at ambient temperature and stirred for 30 min. The products were isolated by filtration and washed with cold isopropanol. Finally, it was purified by recrystallization in 95% ethanol, to afford pure products. The representative procedure was followed for the syntheses of compounds 4-82.
With acetic acid; at 20℃; for 6.0h;Inert atmosphere;
2,2,3-Tribromopropanal (50.0 g, 0.18 mol) was slowly added to asuspension of 4-methoxy-2-methylaniline (5, 25.0 g, 0.18 mol) in300 ml of glacial acetic acid. The reaction mixture was stirred for6 hatroomtemperature, then diluted with ethyl acetate andwashedwith water, brine and 2 N sodium hydroxide solution, subsequentlydried over magnesium sulfate and evaporated under reduced pressure.The residuewas purified by chromatography on silica gel, usingethyl acetate and heptane as eluents to yield 3-bromo-6-methoxy-8-methylquinoline (6, 20.5 g, 81 mmol, 45%). 1H NMR (CDCl3):d = 2.73 (s, 3H), 3.90 (s, 3H), 6.82 (d, 1H, J = 2.0 Hz), 7.21 (d, 1H,J = 2.1 Hz), 8.17 (d, 1H, J = 1.9 Hz), 8.76 (d, 1H, J = 2.0 Hz). LC-MS:Rt = 1.99 min; MS: m/z = 254 [M]+, 255 [M+1]+.
45%
With acetic acid; at 20℃; for 6.0h;
2,2,3-Tribromopropanal (2) (50.0 g, 0.18 mol) was added slowly to a suspension of 4-methoxy-2-methylaniline (25.0g, 0.18 mol) in glacial AcOH (300 mL). The mixture was stirred for 6 h at r.t., then diluted with EtOAc (300 mL) and washed with H2O (2 × 100 mL), brine (100 mL) and 2 MNaOH solution (100 mL). The organic layer was dried over MgSO4 and evaporated under reduced pressure. The residue was purified by chromatography on silica gel, using EtOAc and heptane as eluents to yield 3-bromo-6-methoxy-8-methylquinoline (4) (20.5 g, 81 mmol, 45%).
With hydrogenchloride; In water; isopropyl alcohol; for 6h;Reflux;
General procedure: The synthesis of target compound 3 (Scheme 1C), started with the synthesis of a reported method for compound i.?3 2-Bromo-i,i-diethoxyethane (compound 10) was reacted with ethyl2-cyanoacetate to obtain compound 1 lwhich was cyclized to compound 12 using acetamidine hydrochloride under basic conditions. Chlorination of compound 12 using POC13 provided compound 13 in 80% yield. Displacement of the chloride of compound 13 with 4-methoxy-N- methyl aniline (compound 14) and catalytic amounts of HC1 in isopropanol, provided compound1. Methylation of compound 1 with Mel under basic conditions afforded compound 3 in 85% yield. The synthesis of target compound 5 (Scheme 1C), involved N-formylation of 4-methoxy- 2-methylanline (compound 15) to afford compound 16 in 70% yield. LAH reduction of compound 16 provided substituted aniline compound 17. Displacement of the chloride of compound 13 with anilines (compounds 15 and 17) and catalytic amounts of HC1 in isopropanol provided compounds 4 and 5 (75% and 70% respectively).
With cobalt(II) phthalocyanine; copper(l) chloride; In dichloromethane; at 10℃;
Reaction flask was added 2-methyl-4-methoxyaniline 0.137 g (1 mmol),phenylhydrazine 0.140 g (1.3 mmol), CoPc 0.057 g (0.1 mmol), CuCl0.01 g (0.1 mmol) and10 ml of methylene chloride, 10 C reaction; TLC until complete reaction was followedover; crude product was purified by column chromatography obtained after the reaction(petroleum ether: ethyl acetate = 100: 1) to give the desired product (yield 86%) .
ethyl {2-cyano-2-[2-(4-methoxy-2-methylphenyl)hydrazinylidene]acetyl}carbamate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
Example 1A Ethyl {2-cyano-2-[2-(4-methoxy-2-methylphenyl)hydrazinylidene]acetyl}carbamate A solution of 5.00 g (36.45 mmol) of 4-methoxy-2-methylaniline in 50 ml of 6N aqueous hydrochloric acid was cooled to 0 C. A solution of 2.51 g (36.45 mmol) of sodium nitrite in 15 ml of water was added dropwise such that the reaction temperature did not exceed 5 C. The mixture was then stirred at 0 C. for a further 30 min In another flask, 6.09 g (39.0 mmol) of ethyl (cyanoacetyl)carbamate were dissolved in 150 ml of water, 30 ml of pyridine were added and the mixture was cooled to 0 C. The solution prepared beforehand of the diazonium salt of 4-methoxy-2-methylaniline was slowly added dropwise with stirring, and the reaction mixture was then stirred at RT for 30 min. The solid formed was filtered off with suction, washed with water and dried under HV. This gave 7.42 g (purity 64%) of the title compound. LC-MS (Method 2): Rt=2.05 min., m/z=305 (M+H)+
2-chloro-4-(4-methoxy-2-methylanilino)pyridine-3-carbonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
63%
With potassium phosphate; palladium diacetate; bis[2-(diphenylphosphino)phenyl] ether; In 1,4-dioxane; at 120℃;Inert atmosphere;
A mixture of 2-chloro- 4-iodopyridine-3-carbonitrile (1.7 g, 6.4 mmol), 4-methoxy-2-methylaniline (880 mg, 6.4 mmol), DPEPhos [bis(2-diphenylphosphinophenyl)ether] 690 mg, 1.3 mmol), palladium(II) acetate (145 mg, 0.646 mmol), and K3PO4 (3.7 mg, 0.017 mmol) in dioxane (20 mL) was degassed under vacuum and heated at 120 C overnight. The mixture was cooled to rt, concentrated to dryness, and purified by flash column chromatography to yield the title Compound (1.1 g, 63% yield) as a brown solid.
63%
With potassium phosphate; palladium diacetate; bis[2-(diphenylphosphino)phenyl] ether; In 1,4-dioxane; at 120℃;
To a round bottom flask were added <strong>[1171919-75-7]2-chloro-4-iodopyridine-3-carbonitrile</strong> (1.7 g, 6.4 mmol), 4-methoxy-2- methylaniline (880 mg, 6.4 mmol), DPEPhos [bis(2-diphenylphosphinophenyl)ether] (690 mg, 1.3 mmol), palladium(II) acetate (145 mg, 0.646 mmol), K3PO4 (3.7 g, 0.017 mmol), and dioxane (15 mL). The reaction mixture was degassed and heated at 120 C overnight. The mixture was cooled to rt, concentrated to dryness, and purified by flash column chromatography to yield the title compound (1.1 g, 63% yield) as a brown solid. MS (ESI): mass calcd. for ci4H12ciN3O, 273.1 ; m/z found, 274 [M+H]+.
63%
With potassium phosphate; palladium diacetate; bis[2-(diphenylphosphino)phenyl] ether; In 1,4-dioxane; at 120℃;
A mixture of 2-chloro- 4-iodopyridine-3-carbonitrile (1.7 g, 6.4 mmol), 4-methoxy-2-methylaniline (880 mg, 6.4 mmol),DPEPhos [bis(2-diphenylphosphinophenyl)ether] 690 mg, 1.3 mmol), palladium(II) acetate (145 mg, 0.646 mmol), and K3P04 (3.7 mg, 0.0 17 mmol) in dioxane (20 mL) was degassed under vacuum and heated at 120 C overnight. The mixture was cooled to rt, concentrated to dryness, and purified by flash column chromatography to yield the title compound (1.1 g, 63% yield) as a brown solid.
63%
With potassium phosphate; palladium diacetate; bis[2-(diphenylphosphino)phenyl] ether; In 1,4-dioxane; at 120℃;
To a round bottom flask were added <strong>[1171919-75-7]2-chloro-4-iodopyridine-3-carbonitrile</strong> (1.7 g, 6.4 mmol), 4-methoxy-2-methylaniline (880 mg, 6.4 mmol), DPEPhos [bis (2-diphenylphosphinophenyl) ether] (690 mg, 1.3 mmol), palladium (II) acetate (145 mg, 0.646 mmol), K 3PO 4 (3.7 g, 0.017 mmol), and dioxane (15 mL). The reaction mixture was degassed and heated at 120 overnight. The mixture was cooled to rt, concentrated to dryness, and purified by flash column chromatography to yield the title compound (1.1 g, 63% yield) as a brown solid. MS (ESI) : mass calcd. for C 14H 12ClN 3O, 273.1 m/z found, 274 [M+H] +.
N-(4-methoxy-2-methylphenyl)-2-m-tolylquinoline-4-carboxamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
Stage #1: 2-m-tolyl-Cinchoninic acid; 2-methyl-4-methoxyaniline With benzotriazol-1-ol In N,N-dimethyl-formamide for 0.25h;
Stage #2: With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In N,N-dimethyl-formamide at 20℃; for 4h;
30 5.4. General procedure for the synthesis of the carboxamide derivatives (5-9)
General procedure: Method 1: To a 25 mL round-bottom flask, 2-phenyl-4-quinolinecarboxylic acid 4a-n (1.5 mmol) and substituted aniline(1.5 mmol) were added, dissolved in appropriate DMF and followed by the addition of HOBT (1.5 mmol) with stirring. After 15 min, EDCI (1.5 mmol) and TEA (1.5 mmol) were added and the reaction mixture was stirred for 4 h at room temperature. The reaction solution was poured into water and the product was extracted with EtOAc three times. The combined organic phases were washed with HCl (1 N), NaHCO3 (1 N), dried over anhydrous Na2SO4 and concentrated under reduced pressure to give crude product. The crude compound was then purified by recrystallization to afford compounds 5-9.
Stage #1: 2-(o-methylphenyl)quinoline-4-carboxylic acid; 2-methyl-4-methoxyaniline With benzotriazol-1-ol In N,N-dimethyl-formamide for 0.25h;
Stage #2: With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In N,N-dimethyl-formamide at 20℃; for 4h;
30 5.4. General procedure for the synthesis of the carboxamide derivatives (5-9)
General procedure: Method 1: To a 25 mL round-bottom flask, 2-phenyl-4-quinolinecarboxylic acid 4a-n (1.5 mmol) and substituted aniline(1.5 mmol) were added, dissolved in appropriate DMF and followed by the addition of HOBT (1.5 mmol) with stirring. After 15 min, EDCI (1.5 mmol) and TEA (1.5 mmol) were added and the reaction mixture was stirred for 4 h at room temperature. The reaction solution was poured into water and the product was extracted with EtOAc three times. The combined organic phases were washed with HCl (1 N), NaHCO3 (1 N), dried over anhydrous Na2SO4 and concentrated under reduced pressure to give crude product. The crude compound was then purified by recrystallization to afford compounds 5-9.
N-(4-methoxy-2-methylphenyl)-6-methyl-2-p-tolylquinoline-4-carboxamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
Stage #1: 6-methyl-2-<i>p</i>-tolyl-quinoline-4-carboxylic acid; 2-methyl-4-methoxyaniline With benzotriazol-1-ol In N,N-dimethyl-formamide for 0.25h;
Stage #2: With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In N,N-dimethyl-formamide at 20℃; for 4h;
30 5.4. General procedure for the synthesis of the carboxamide derivatives (5-9)
General procedure: Method 1: To a 25 mL round-bottom flask, 2-phenyl-4-quinolinecarboxylic acid 4a-n (1.5 mmol) and substituted aniline(1.5 mmol) were added, dissolved in appropriate DMF and followed by the addition of HOBT (1.5 mmol) with stirring. After 15 min, EDCI (1.5 mmol) and TEA (1.5 mmol) were added and the reaction mixture was stirred for 4 h at room temperature. The reaction solution was poured into water and the product was extracted with EtOAc three times. The combined organic phases were washed with HCl (1 N), NaHCO3 (1 N), dried over anhydrous Na2SO4 and concentrated under reduced pressure to give crude product. The crude compound was then purified by recrystallization to afford compounds 5-9.
N-(4-methoxy-2-methylphenyl)-2-p-tolylquinoline-4-carboxamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
In tetrahydrofuran at 20℃; for 4h; Cooling;
5.4. General procedure for the synthesis of the carboxamide derivatives (5-9)
General procedure: Method 2: To a 25 mL round-bottom flask, 2-phenyl-4-quinoline carboxylic acid (5.0mmol) was added, dissolved in appropriate THF and a few drops of DMF were added. Then the mixture was cooled in an ice bath and sulfoxide chloride was slowly dropped into it with stirring for 30 min. The resulting solution was warmed slowly to 45 °C, stirred at this temperature for 6h and the solvent was evaporated off at low pressure to give a crude residue. Methyl 3-aminothiophene-2-carboxylate (0.31 g, 2.0mmol) and trimethylamine (0.10 g, 1.0mmol) were added to a 25 mL round-bottom flask, dissolved in appropriate THF, and the solution of the above crude residue in THF was added dropwise with stirring in an ice bath. The reaction mixture was stirred at room temperature for 4h. The solvent was evaporated under reduced pressure and the crude product purified by flash column chromatography on silica gel and eluted with a mixture of EtOAc/petroleum ether (1:8, v/v) to afford 5-9.
Stage #1: 2-methyl-4-methoxyaniline With ammonium thiocyanate In acetonitrile at 20℃; for 0.166667h;
Stage #2: With mono(N,N,N-trimethylbenzenaminium) tribromide In acetonitrile at 20℃;
Intermediate I-3A: 6-methoxy-4-methylbenzo [djthiazol-2-amine
To 4-methoxy-2-methylaniline (209 mg, 1.524 mmol) in acetonitrile (8 mL) wasadded ammonium thiocyanate (174 mg, 2.285 mmol). The mixture was stirred at roomtemperature for 10 mm. Then it was cooled with tap water, and benzyltrimethylammoniumtribromide (594 mg, 1.524 mmol) in acetonitrile (3.0 mL) was added dropwise. The mixture was then stirred at room temperature overnight. HPLC andLCMS indicated a clean reaction. The mixture was diluted with EtOAc/saturated sodium bicarbonate. The organic layer was collected, washed with brine, dried over sodium sulfate. After evaporation of solvent, the cmde product was dissolved in a small amount of chloroformlMeOH, and charged to a 24 g silica gel cartridge which was eluted with5% EtOAc in hexanes for 3 mm., then a 12 mm gradient from 5% to 50% EtOAc in hexanes. The desired fractions were combined and concentrated to give Intermediate I-3A (240 mg, 1.235 mmol, 81 % yield) as a pale solid. ‘H NMR (500MHz, methanol-d4) 7.03 (d, J=2.5 Hz, 1H), 6.71 (d, J1.9 Hz, 1H), 3.79 (s, 3H), 2.46 (s, 3H); LC-MS:method A, RT = 1.22 mm, MS (ESI) m/z: 195.0 (M+H)
2-bromo-N-(4-methoxy-2-methylphenyl)thiophene-3-carboxamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
7.5 g
With triethylamine; 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 80℃;
<strong>[24287-95-4]2-bromo-3-thiophenecarboxylic acid</strong> (5.0 g),HATU (10.11g),2-methyl-4-methoxyaniline (3.64 g) and triethylamine (7.30 g)The reaction was stirred at 80 C overnight by adding N,N-dimethylformamide (100 mL).After cooling to room temperature, the reaction solution was poured into water (1000 mL)The extract is washed with water, dried, and concentrated.The desired product was isolated by silica gel column chromatography ( petroleum ether: ethyl acetate, 15:1 to 4:1)(Brown solid, 7.5 g).
With triethylamine; In dichloromethane; at 20℃; for 2h;
General procedure: 1 drop of DMF was added to a suspension of 2-bromobenzoic acid (2g, 9.95mmol) in 5ml SOCl2, the mixture was heated under reflux for 2h, then concentrated and diluted with DCM 20ml, concentrated again and re-diluted with DCM 20ml and concentrated. The residue was dissolved in 20ml DCM, added dropwise to a solution of 4-methoxy-2-methylaniline (1.4g, 9.95mmol) and triethylamine (3.43ml, 24.9mmol) in 10ml DCM, and then stirred for 2h. The mixture was concentrated to give brown solid, which was treated with EtOH/H2O (10ml/20ml) to give off-white solid 2.5g, yield: 78.4%.
4-methoxy-2-methyl-N-(2,2,2-trifluoroethyl)aniline[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
93%
2 mmol of trifluoroethylamine hydrochloride, 1 mL of water, 34 uL of acetic acid, and 1 mL of dichloromethane were placed in a reaction tube, and a rubber stopper was placed and fixed on a stirrer. Take 42 mg of sodium nitrite in a 1.5 mL sample tube, add 1 mL of water to the sample tube, and shake the sample tube.Dissolve sodium nitrite.Dissolving the dissolved sodium nitrite solution into the reaction tube with a syringe,Stir for half an hour at room temperature.Dissolve the iron porphyrin of formula 3 with 1 mL of dichloromethane (R1 = COOH, R2 = R3 = Cl, L = OAc) (catalytic amount, primary amineA molar amount of 9/1000), 0.24 mmol of 4-methoxy-2-methylaniline was taken in the sample tube. After half an hour, the mixed solution in the sample tube was dropped into the reaction tube, and stirred while stirring for 12 hours. The reaction solution was cooled to room temperature and filtered to remove a portion.The impurities are concentrated and purified by column chromatography to obtain the target product. The column chromatography eluate is a mixture of petroleum ether and acetone.Solvent. The structure of 4-methoxy-2-methyl-N-(2,2,2-trifluoroethyl)aniline is as follows:The compound was a pale yellow liquid with a yield of 93%
methyl 3-((4-methoxy-2-methylphenyl)carbamoyl)benzoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
90%
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 dichloromethane at 0 - 20℃; for 16h; Inert atmosphere;
1 Step-1: Synthesis of Methyl 3-((4-methoxy-2-methylphenyl)carbamoyl)benzoate (3).
To a stirred solution of 3-(methoxycarbonyl)benzoic acid 2 (1 g, 5.55 mmol) in CH2CI2 (15 mL) were added 4-methoxy-2-methylanibne 1 (0.71 mL, 5.55 mmol), HATU (2.53 g, 6.66 mmol) and ethyldiisopropylamine (2.42 mL, 13.87 mmol) at 0 °C under inert atmosphere. The reaction mixture was gradually warmed to RT and stirred for 16 h. The progress of the reaction was monitored by TLC; after the completion, the reaction mixture was diluted with water (30 mL) and extracted with CH2CI2 (2 x 40 mL). The combined organic extracts were washed with brine (15 mL), dried over anhydrous Na2S04, filtered and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography (eluent: 40% EtOAcri? -hexanes) to afford compound 3 (1.5 g, 5.01 mmol, 90%) as an off white solid. NMR (500 MHz, CDCh): d 8.50 (br s, 1H), 8.21 (br d, J= 7.8 Hz, 1H), 8.13 (br d, J= 7.3 Hz, 1H), 7.66 (br s, 1H), 7.61-7.55 (m, 2H), 6.82-6.76 (m, 2H), 3.96 (s, 3H), 3.81 (s, 3H), 2.31 (s, 3H).
2-(4-methoxy-2-methylphenylamino)benzoic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
91.47%
Stage #1: sodium carbonate; chlorobenzene With copper In N,N-dimethyl-formamide; toluene for 0.25h; Reflux;
Stage #2: 2-methyl-4-methoxyaniline In N,N-dimethyl-formamide; toluene for 10.6h; Reflux;
1-3; 1-4 Example 3
15.6g (0.1mol) o-chlorobenzoic acid, 0.15g Cu catalyst, 16.5g (0.16mol) sodium carbonate as an acid binding agent,120g of toluene and 17g of DMF were sequentially added to a 500ml reaction flask, heated to reflux, stirred and mixed for 15min,Take 13.7g (0.1mol) of 2-methyl-4-methoxyaniline into a constant pressure dropping funnel and add it to the reaction flask. After 1.6h,The reaction was carried out under reflux for 9 hours. During the reaction, the water produced by the reaction was separated through an oil-water separator, and samples were taken and tested every 2 hours during the reaction.After the reaction, the excess lye was neutralized with dilute HCl, and the intermediate product was extracted with toluene.The organic phase was extracted, washed with toluene, evaporated, concentrated and dried under vacuum to obtain 23.6 g of off-white 2-methyl-4-methoxy-2'-carboxydiphenylamine, yield 91.47%, 2-methyl-4-methoxy The conversion rate of aniline was 99.85%.The obtained intermediate product was decarboxylated in a methanol system at elevated temperature to obtain 19.38 g of the target product, 2-methyl-4-methoxydiphenylamine, with a yield of 90.99%.
Stage #1: 2-methyl-4-methoxyaniline; ortho-chlorobenzoic acid With potassium phosphate tribasic trihydrate; sodium carbonate; copper dichloride In toluene at 110℃; for 5h;
Stage #2: With N-Methylformamide In toluene at 50 - 180℃; for 8h;
1-7
(1) Add toluene and cuprous chloride into the reaction kettle, add 2-methyl-4 methoxyaniline and o-chlorobenzoic acid with stirring, add acid binding agent after stirring, and heat to 110°C and reflux for 5 hours to obtain Condensation product. (2) After distilling the condensation product at 130°C to recover all toluene, add 3m3 of water and the condensation product to the reactor, add industrial hydrochloric acid to make the pH reach 2, while stirring, filter, wash with 5m3 of water to neutral, and dry After obtaining product 1; (3) Add N-methylformamide and product 1 to the reaction kettle, heat to 50°C to dissolve all the solid materials, heat to 180°C, and react for 8 hours to obtain the product after purification. The acid binding agent is sodium carbonate and tripotassium phosphate trihydrate with a weight ratio of 2.2:1; the weight ratio of toluene and 2-methyl-4 methoxyaniline is 8:1; and the 2-methyl group The molar ratio of 4-methoxyaniline, o-chlorobenzoic acid and acid binding agent is 1:1:0.7; the cuprous chloride accounts for 1wt% of 2-methyl-4methoxyaniline. The weight ratio of the N-methylformamide to product 1 is 6.2:1.
With N,N,N-trimethylbenzenemethanaminium dichloroiodate In water; dimethyl sulfoxide at 70℃; for 1h;
General Procedure
General procedure: (50 mg scale) To a stirred solution of aniline 1a-s (0.27-0.47 mmol), ammonium thiocyanate(1.1 equiv) in 9:1 DMSO:H2O (3.4-6.0 mL; 80 mM final concentration), was addedbenzyltrimethylammonium dichloroiodate (1.2 equiv). The reaction mixture was heated at 70°Cfor 1 hour, then allowed to cool to ambient temperature. H2O (25 mL) was added. The mixturewas diluted using ethyl acetate, and the organic layer was separated. The aqueous layer waspartitioned with EtOAc (2 x 20 mL) and the combined organic layers were washed with 10%aqueous sodium dithionite (2 x 20 mL), followed by saturated sodium bicarbonate solution (2 x20 mL) and then water (2 X 20 mL). The organic layer was dried over anhydrous magnesiumsulfate and the solvents were evaporated. The crude product was then purified using flashchromatography (EtOAc/Hexanes) to give pure 2a-s.(1.0 g scale) The above procedure was applied using 1.0 g of anilines 1a-s (5.4-9.4 mmol).Correspondingly-scaled quantities of solvent and reagents were used, with the same reactiontime (1 h) and temperature (70°C) giving products 2a-s in the yields indicated
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