* 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.
Step B / Intermediate B9: 3,4,5-trimethoxyani.ineTo a solution of 1 ,2,3-trimethoxy-5-nifrobenzene (6.64 g, 31.2 mrnol ) in ethanol (250 mL) was added palladium on carbon (10 percent, 300 mg) and hydrazine hydrate (85 percent, 5.7 mL). After emission of gas has ceased, the reaction mixture was heated at refluxed for 1 hour, cooling to room temperature, filtered and evaporated to afford the product 3,4,5-trimethoxyaniline as a white solid (5.5 g, yield 96.4 percent). H NMR (400 MHz, DMSO-d6) δ ppm 5.86 (s, 2H), 4.82 (br, 2H), 3.64 (s, 6H), 3.50 (s, 3H).
Reference：
[1] Patent: WO2012/92880, 2012, A1, . Location in patent: Page/Page column 60
[2] Bioorganic and Medicinal Chemistry, 2009, vol. 17, # 9, p. 3414 - 3425
[3] Chemische Berichte, 1888, vol. 21, p. 615
[4] Australian Journal of Scientific Research, Series A: Physical Sciences, 1950, vol. 3, p. 467,500
[5] Journal of Pharmacy and Pharmacology, 1958, vol. 10, p. 47,59
[6] Chemische Berichte, 1959, vol. 92, p. 862,866
[7] Acta Chemica Scandinavica (1947-1973), 1963, vol. 17, p. 1151 - 1156
[8] Journal of the Chemical Society, 1963, p. 922 - 927
[9] Journal of Pharmaceutical Sciences, 1973, vol. 62, # 8, p. 1392 - 1394
[10] Australian Journal of Chemistry, 1981, vol. 34, # 4, p. 799 - 817
[11] PLoS ONE, 2015, vol. 10, # 6,
[12] Journal of the American Chemical Society, 2015, vol. 137, # 21, p. 6920 - 6931
3
[ 115483-29-9 ]
[ 24313-88-0 ]
Reference：
[1] Tetrahedron, 2006, vol. 62, # 51, p. 11925 - 11932
[2] Synlett, 1999, # 9, p. 1413 - 1414
[3] Advanced Synthesis and Catalysis, 2008, vol. 350, # 3, p. 406 - 410
4
[ 2675-79-8 ]
[ 24313-88-0 ]
Yield
Reaction Conditions
Operation in experiment
60%
With ammonium hydroxide; ethylenediaminediacetic acid; copper(II) oxide; potassium hydroxide In water at 130℃; for 12 h; Sealed tube
261mg (1mmol) of 3,4,5-trimethoxybromobenzene, 0.35mL aqueous ammonia (25-28percent, 4.655mmol), 8mg (0.1mmol) CuO, 70mg (0.4mmol) ethylenediamine-N,N'-diacetic acid, 112mg (2mmol) KOH, 1mL H2O was added 10mL reaction tube, sealed, under the reaction conditions of 130°C for 12h. After the reaction was stopped, extraction with ethyl acetate, washed with brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated under reduced pressure, purified by silica gel column chromatography purification, 3,4,5-trimethoxy aniline 110 mg of, yield 60percent.
Reference：
[1] Organic Preparations and Procedures International, 2013, vol. 45, # 4, p. 321 - 324
[2] Chemistry of Heterocyclic Compounds (New York, NY, United States), 1983, p. 40 - 42[3] Khimiya Geterotsiklicheskikh Soedinenii, 1983, vol. 19, # 1, p. 46 - 48
[4] Justus Liebigs Annalen der Chemie, 1905, vol. 340, p. 230
[5] Chemische Berichte, 1959, vol. 92, p. 862,866
[6] Chimica Therapeutica, 1972, vol. 7, p. 466 - 469
6
[ 25245-29-8 ]
[ 24313-88-0 ]
Yield
Reaction Conditions
Operation in experiment
87%
With ammonium hydroxide; caesium carbonate In water for 7 h; Reflux
General procedure: A mixture of aryl halide (1 mmol), NH4OH(2 mmol),Cs2CO3(1 mmol) and CuO/ZnO/Al2O3 nanocatalyst(0.1 g), in water was stirred at reflux condition. After reactioncompletion, (monitored by TLC), the mixture reactionwas cooled to room temperature and catalyst filtered. Thenthe residue was evaporated to dryness, the residue waspoured into a saturated NaCl solution, extracted with ethylacetate and dried over anhydrous MgSO4.Evaporation of the solvent followed by column chromatography on silicagel gave the pure products in high yields.
Reference：
[1] Chinese Journal of Chemistry, 2014, vol. 32, # 5, p. 396 - 398
[2] Catalysis Letters, 2018, vol. 148, # 12, p. 3750 - 3756
7
[ 4521-61-3 ]
[ 24313-88-0 ]
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2006, vol. 16, # 22, p. 5864 - 5869
[2] Synthesis, 1983, # 1, p. 38 - 40
[3] Chemistry of Heterocyclic Compounds (New York, NY, United States), 1983, p. 40 - 42[4] Khimiya Geterotsiklicheskikh Soedinenii, 1983, vol. 19, # 1, p. 46 - 48
[5] Chimica Therapeutica, 1972, vol. 7, p. 466 - 469
[6] Chimica Therapeutica, 1972, vol. 7, p. 466 - 469
[7] Organic Preparations and Procedures International, 2013, vol. 45, # 4, p. 321 - 324
8
[ 182163-96-8 ]
[ 24313-88-0 ]
Reference：
[1] Journal of Organic Chemistry, 2015, vol. 80, # 5, p. 2545 - 2553
9
[ 118-41-2 ]
[ 24313-88-0 ]
Reference：
[1] Angewandte Chemie, 1932, vol. 45, p. 536
[2] Bioorganic and Medicinal Chemistry Letters, 2006, vol. 16, # 22, p. 5864 - 5869
[3] Chemistry of Heterocyclic Compounds (New York, NY, United States), 1983, p. 40 - 42[4] Khimiya Geterotsiklicheskikh Soedinenii, 1983, vol. 19, # 1, p. 46 - 48
[5] Justus Liebigs Annalen der Chemie, 1905, vol. 340, p. 230
[6] Chemische Berichte, 1959, vol. 92, p. 862,866
[7] Journal of Pharmaceutical Sciences, 1973, vol. 62, # 8, p. 1392 - 1394
[8] Organic Preparations and Procedures International, 2013, vol. 45, # 4, p. 321 - 324
[9] PLoS ONE, 2015, vol. 10, # 6,
[10] Patent: WO2012/92880, 2012, A1,
10
[ 42543-45-3 ]
[ 24313-88-0 ]
Reference：
[1] Monatshefte fuer Chemie, 1967, vol. 98, p. 1962 - 1972
[2] Chimica Therapeutica, 1972, vol. 7, p. 466 - 469
[3] Bioorganic and Medicinal Chemistry Letters, 2006, vol. 16, # 22, p. 5864 - 5869
[4] Synthesis, 1983, # 1, p. 38 - 40
11
[ 15494-44-7 ]
[ 616-38-6 ]
[ 24313-88-0 ]
Reference：
[1] Advanced Synthesis and Catalysis, 2013, vol. 355, # 1, p. 81 - 86
12
[ 1336-21-6 ]
[ 2675-79-8 ]
[ 24313-88-0 ]
Reference：
[1] European Journal of Organic Chemistry, 2012, # 26, p. 4897 - 4901
13
[ 85657-95-0 ]
[ 24313-88-0 ]
Reference：
[1] Synthesis, 1983, # 1, p. 38 - 40
14
[ 1916-07-0 ]
[ 24313-88-0 ]
Reference：
[1] Advanced Synthesis and Catalysis, 2013, vol. 355, # 1, p. 81 - 86
15
[ 1016-19-9 ]
[ 24313-88-0 ]
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2006, vol. 16, # 22, p. 5864 - 5869
16
[ 634-36-6 ]
[ 24313-88-0 ]
Reference：
[1] Chemische Berichte, 1888, vol. 21, p. 615
[2] Journal of the American Chemical Society, 2015, vol. 137, # 21, p. 6920 - 6931
17
[ 372-19-0 ]
[ 24313-88-0 ]
Reference：
[1] Journal of the Chemical Society, Perkin Transactions 2: Physical Organic Chemistry (1972-1999), 1980, p. 832 - 834
18
[ 24313-88-0 ]
[ 25245-29-8 ]
Reference：
[1] Chemical Communications, 2015, vol. 51, # 21, p. 4477 - 4480
[2] European Journal of Medicinal Chemistry, 2009, vol. 44, # 6, p. 2685 - 2688
[3] Journal of the American Chemical Society, 2008, vol. 130, # 8, p. 2535 - 2545
[4] Chemical Communications, 2017, vol. 53, # 80, p. 11008 - 11011
[5] RSC Advances, 2017, vol. 7, # 86, p. 54881 - 54891
[6] ChemMedChem, 2010, vol. 5, # 12, p. 2016 - 2025
[7] Bioorganic and Medicinal Chemistry, 2006, vol. 14, # 13, p. 4627 - 4638
[8] Acta Chemica Scandinavica (1947-1973), 1963, vol. 17, p. 1151 - 1156
[9] Journal of Medicinal Chemistry, 1998, vol. 41, # 6, p. 913 - 918
[10] Organic Letters, 2013, vol. 15, # 11, p. 2742 - 2745
19
[ 24313-88-0 ]
[ 487-11-6 ]
Reference：
[1] Organic and Biomolecular Chemistry, 2005, vol. 3, # 15, p. 2868 - 2871
20
[ 24313-88-0 ]
[ 2675-79-8 ]
Reference：
[1] Chemistry - A European Journal, 2007, vol. 13, # 10, p. 2805 - 2811
[2] European Journal of Organic Chemistry, 2003, # 15, p. 2829 - 2839
[3] Journal of Organic Chemistry, 2000, vol. 65, # 25, p. 8811 - 8815
[4] Australian Journal of Chemistry, 1991, vol. 44, # 5, p. 705 - 728
[5] Australian Journal of Chemistry, 1992, vol. 45, # 12, p. 1967 - 1982
21
[ 24313-88-0 ]
[ 182163-96-8 ]
Reference：
[1] European Journal of Organic Chemistry, 2003, # 15, p. 2829 - 2839
[2] Organic Letters, 2013, vol. 15, # 11, p. 2742 - 2745
22
[ 575484-83-2 ]
[ 24313-88-0 ]
[ 841290-80-0 ]
Yield
Reaction Conditions
Operation in experiment
91%
at 120℃; for 10 h; Inert atmosphere; Large scale
Step B: Preparation of 6-[[5-Fluoro-2-(3,4,5-trimethoxyanilino)pyrimidin-4-yl]amino]-2,2-dimethyl-4H-pyrido[3,2-b][1,4]oxazin-3-one 6-[(2-chloro-5-fluoro-pyrimidin-4-yl)amino]-2,2-dimethyl-4H-pyrido[3,2-b][1,4]oxazin-3-one (Step A) (568 kg, 1.00 mol eq) is mixed with 3,4,5-trimethoxyaniline (402 kg, 1.25 mol eq) in N-methylpyrrolidin-2-one (2835 kg) with stirring under a nitrogen atmosphere. To this is added water (11 kg) and the mixture heated to about 120° C. and stirred for about 10 hours. This is then cooled to about 65° C. and the pH adjusted to pH 8.5 with 4percent w/w aqueous sodium hydroxide solution. The resulting slurry is further cooled to about 20° C., stirred for at least 6 hours and then filtered. The filtered solid is washed twice with water (2*1440 kg) then twice with acetone (2*1140 kg) and finally dried under vacuum at about 40° C. to give the title compound (754 kg, 91percent) as a colored solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.42 (s, 6H) 3.59 (s, 3H) 3.66 (s, 6H) 7.04 (s, 2H) 7.32 (d, J=8.5 Hz, 1H) 7.68 (d, J=8.5 Hz, 1H) 8.13 (d, J=3.4 Hz, 1H) 9.10 (br. s, 1H) 9.14 (br. s, 1H) 11.06 (br. s, 1H). m/z 471 [MH]+.
With hydrogenchloride; CuCl2; sulfur dioxide; sodium nitrite; In water; acetic acid;
EXAMPLE 21A 3,4,5-trimethoxybenzenesulfonyl chloride The procedure in J. Het. Chem. 23, 1253 (1986) was followed. A solution of 3,4,5-trimethoxyaniline (5.0 g) in acetic acid (26 mL) and 12M HCl (47 mL) at -10-5 C. was treated slowly with a solution of NaNO2 (2 g) in water (7 mL), stirred at -5 C. for another 30 minutes, added in portions to a cold (-5 C.) solution of CuCl2 and SO2 in acetic acid (35 mL) and water (6 mL), stirred at -5-0 C. for 3 hours, warmed to room temperature overnight, poured over ice, filtered, and dried to provide the desired product.
3,4,5-trimethoxybenzenesulfonyl chloride The procedure in J. Het. Chem. 23,1253 (1986) was followed.. A solution of 3,4,5-trimethoxyaniline (5.0 g) in acetic acid (26 ML) and 12M HCl (47 ML) at -10-5 C was treated slowly with a solution of NaNO2 (2 g) in water (7 ML), stirred at -5 C for another 30 minutes, added in portions to a cold (-5 C) solution of CuCl2 and SO2 in acetic acid (35 ML) and water (6 ML), stirred at -5-0 C for 3 hours, warmed to room temperature overnight, poured over ice, filtered, and dried to provide the desired product.
With caesium carbonate;palladium diacetate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane; at 150℃; for 0.333333h;Microwave irradiation;
EXAMPLE 94; A mixture of 2-chloro-5-cyano-6-amino pyrimdine (0,1 g), 3,4,5-trimethoxy aniline (0.71 mmol), palladium(II) acetate (1 mol%), 9.9-dimethyI-4,5- bis(diphenylphosphino)xanthene (1.5 mol%) and cesium carbonate (L29 mmol) in dioxane (2 mL) was heated in a microwave at 1500C for 20 minutes, cooled, filtered through diatomaceous earth (Celite) and concentrated.. The concentrate was purified by HPLC on a C18 column with acetonitrile/water/0.1% trifluoroacetic acid, 1H NMR (DMSOd6) delta 9 35 (br s, IH), 8.15 (s, IH), 6.45 (s, 2H), 5,5 (s, 2H), 3.73 (s, 6H), 3.70 (s, 3H).
In isopropyl alcohol; at 100 - 110℃; for 1h;Heating / reflux;
A mixture of 3,4,5-trimethoxyaniline (1.83 g, 10 mmol) and diphenyl-cyanocarbon-imidate (2.62 g, 11 mmol) in iso-propanol (30 mL) was stirred at 100-1l0oC for 1h. The reaction was cooled and filtered, washing with ether to provide the title compound (2.79 g, 85percent yield) as a white solid. 1H-NMR (500 MHz, DMSO-d6) 10.8 (s, 1H), 7.45 (t, 2H), 7.31 (m, 3H), 6.83 (s, 2H), 3.76 (s, 6H), 3.65 (s, 3H) ppm; MS (FIA) 328.1 (M+H); HPLC (method A) 3.211 min.
With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃; for 16h;
To a solution of 7-methoxycoumarin-4-acetic acid (0.10 g, 0.4 mmol) in 2 mL of CH2Cl2 was added EDCI (0.11 g, 0.6 mmol) and 3,4,5-trimethoxyaniline (0.078 g, 0.4 mmol). The mixture was stirred at room temperature for 16 h. The reaction mixture was partitioned between CH2Cl2 and brine. The aqueous layer was extracted with EPO <DP n="142"/>CH2Cl2 and the combined organic extracts were washed with brine and dried overMgSO4.The crude product was purified by silica chromatography (1-10% MeOH/ CH2Cl2) to afford the desired product. Calc'd for C21H21NO7: 399.4, [M+H]+ = 400.
EXAMPLE 33 N-cyclohexyl-N-(1-methylethyl)-4-(3,4,5-trimethoxyphenylamino)benzamide STR45 A slurry of cuprous oxide (300 mg, 2.1 mmol) in a solution of 3,4,5-trimethoxyaniline (733 mg, 4.0 mmol) and p-bromobenzoic acid N-isopropyl-N-cyclohexyl amide (1.290 g, 3.98 mmol) in 2,4,6-collidine (20 ml) is refluxed with stirring under a nitrogen atmosphere for 18 hr. The reaction is cooled, poured onto dilute aqueous HCl and extracted three times with ethyl acetate. The combined organic layers are washed twice with saturated aqueous NaCl solution, twice with 5% NaOH solution, twice with saturated NaCl solution and dried (Na2 SC4). The drying agent is filtered and the filtrate concentrated in vacuo to give the crude product. This material is chromatographed on silica gel using mixtures of methanol, methylene chloride and ammonium hydroxide as the eluents to give the title compound.
1-Methyl-4-[N-(3,4,5-trimethoxyphenyl)-carbamoyl]piperazine (hydrochloride)[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
44%
In diethyl ether; ethanol; dichloromethane;
EXAMPLE 2 1-Methyl-4-[N-(3,4,5-trimethoxyphenyl)-carbamoyl]piperazine (hydrochloride) A solution of 10 g (0.061 mole) 1-methyl-4-chloroformyl-piperazine in 100 ml dry methylene chloride is added to a solution of 11.2 g (0.061 mole) 3,4,5-trimethoxy-aniline in a 100 ml methylenechloride. After stirring at ambient temperature for 24 hours, the solvent is evaporated off in vacuo; the residue is dissolved in the minimum of ethanol and then the crude hydrochloride precipated by the addition of diethyl ether, and dried. Purification by recrystallisation from an acetone 3-ethanol 1 mixture gives the pure product (9.4 g; 44% yield) which melts at 184-86 C.
4-(3,4,5-trimethoxyphenyl)piperazine monohydrobromide[ No CAS ]
[ 38869-07-7 ]
Yield
Reaction Conditions
Operation in experiment
With sodium carbonate; In methanol;
REFERENCE EXAMPLE 20 18.3 Grams of 3,4,5-trimethoxyaniline and 31.2 g of bis(beta-bromoethyl)amine monohydrobromide are mixed with 170 ml of methanol and refluxed by heating under a nitrogen gas stream for 10 hours. After cooling the reaction mixture, 5.3 g of anhydrous sodium carbonate are added to the mixture and refluxed by heating for and additional 10 hours. Under reduced pressure, about 70 ml of methanol are removed off by distillation, and the mixture is allowed to stand to cool at room temperature. The crystals thus precipitated are collected by filtration and washed with a small amount of ethanol. Recrystallization from ethanol obtains 38 g of 4-(3,4,5-trimethoxyphenyl)piperazine monohydrobromide in the form of colorless plate-like crystals with a melting point of 227-228 C. Then this compound is dissolved in 20% sodium hydroxide aqueous solution and extracted with chloroform. The chloroform layer is washed with a saturated sodium chloride aqueous solution three times, then dried, and chloroform is removed by distillation. A free form of 4-(3,4,5-trimethoxyphenyl)piperazine is obtained as a single substance in the form of a colorless viscous oily material.
With triethylamine; In water; ethyl acetate; benzene;
EXAMPLE 6 4-[N-(3,4,5-trimethoxyphenyl)-sulphamoyl]-morpholine. (C13 H20 N2 O6 S=332.38) To a solution of 4.8 g (0.026 mole) 3,4,5-trimethoxyaniline and 2.6 g (0.026 mole) triethylamine in 200 ml dry benzene are added 5.7 g (0.031 mole) N-chlorosulphonyl morpholine. The mixture obtained is heated at the reflux of the solvent, with stirring, for 14 hours. After evaporation of the solvent under vacuum, the oily residue is taken up in a mixture of water and ethyl acetate. The two phases are decanted, the organic phase washed with a 2 N-hydrochloric acid solution, dried and concentrated to dryness; the residual solid is triturated in ether and the insoluble material dried to give 4.1 g of a slightly coloured solid (47% yield). Purification is by recrystallisation from water. Melting point=148 C.
N-[5-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-acetoxybenzoyl]-3,4,5-trimethoxyaniline[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With triethylamine; In dichloromethane;
Example 106 N-[5-(5,6-Dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-acetoxybenzoyl]-3,4,5-trimethoxyaniline 3,4,5-Trimethoxyaniline (0.216 g, 1.18 mmol), triethylamine (0.119 g, 1.18 mmol) and <strong>[37091-73-9]2-chloro-1,3-dimethylimidazolinium chloride</strong> (0.199 g, 1.18 mmol) were added to a methylene chloride solution (20 ml) of 5-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-acetoxybenzoic acid (0.200 g, 0.535 mmol) and the resulting solution was stirred at room temperature for 12 hours. The reaction solution was poured into ice water and then extracted with methylene chloride. The extract was washed with water and then dried, and the solvent was removed by distillation. The obtained residue was purified by preparative thin-layer chromatography (chloroform: methanol = 10:1) to obtain the titled compound (0.109 g, 0.202 mmol, 38percent).
N-[5-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-(pyridin-3-ylmethyloxy)benzoyl]-3,4,5-trimethoxyaniline[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With triethylamine; In dichloromethane;
Example 128 N-[5-(5,6-Dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-(3-pyridylmethyloxy)benzoyl]-3,4,5-trimethoxyaniline 3,4,5-Trimethoxyaniline (0.260 g, 1.42 mmol), triethylamine (0.144 g, 1.42 mmol) and <strong>[37091-73-9]2-chloro-1,3-dimethylimidazolinium chloride</strong> (0.240 g, 1.42 mmol) were added to a methylene chloride solution (20 ml) of 5-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-(3-pyridylmethyloxy)benzoic acid (0.200 g, 0.473 mmol) and the resulting solution was stirred at room temperature for 12 hours. The reaction solution was poured into ice water and then extracted with methylene chloride. The extract was washed with water and then dried, and the solvent was removed by distillation. The obtained residue was purified by preparative thin-layer chromatography (chloroform: methanol = 10:1) and then recrystallized from ether to obtain the titled compound (0.050 g, 0.085 mmol, 18percent).
With sulfur dioxide; In hydrogenchloride; acetic acid; aniline;
Example J 3,4,5-Trimethoxybenzenesulfonyl Chloride 3,4,5-Trimethoxybenzenesulfonyl chloride was synthesised from 3,4,5-trimethoxyaniline according to the procedure described in G. Pifferi and R. Monguzzi, Journal of Pharmaceutical Sciences, 1973, 62, 1393. In this procedure the aniline was dissolved in concentrated hydrochloric acid and to the resulting mixture was added a solution of aqueous sodium nitrite at 0 C., the resulting mixture containing the desired diazonium salt was added at 5 C. to a saturated solution of sulfur dioxide in glacial acetic acid containing substoichiometric amount of cuprous chloride. The mixture was stirred at ambient temperature for 3 h, poured into cold water, and the product extracted with dichloromethane. The solvent was evaporated and the solid residue was recrystallized from hexanes.
In diethylene glycol dimethyl ether; at 165℃; for 18h;Inert atmosphere;
3,4,5-Trimethoxyaniline (6.82 g) and 2-(methylthio)pyrimidin-4(3H)-one (5.26 g) were suspended in diglyme (50 ml) and heated at 165° C. for 18 hours under nitrogen to give a red solution. The reaction was cooled to room temperature then poured into 500 ml diethyl ether with stirring to give an oily precipitate that was filtered and re-dissolved in water (250 ml). A solid precipitate formed which was stirred for 30 minutes then filtered to give the title compound as a cream solid (3.80 g, 37percent); NMR Spectrum (300 MHz, DMSO) 3.63 (s, 3H), 3.76 (s, 6H), 5.80 (d, 1H), 6.95 (s, 2H), 7.76 (d, 1H); Mass Spectrum MH+ 278.5.
General procedure: A solution of 3,4,5-trimethoxyaniline (1.83 g, 10 mmol) and acid anhydride (10 mmol) in glacial acetic acid (15 mL) was heated under reflux for 12 h. After the evaporation of the reaction mixture to dryness under reduced pressure, the residue was neutralized by a solution of sodium bicarbonate (4%) until effervescence ceased. The precipitate obtained was washed with water, dried (P2O5) and recrystallized from an appropriate solvent.
General procedure: A solution of 3,4,5-trimethoxyaniline (1.83 g, 10 mmol) and acid anhydride (10 mmol) in glacial acetic acid (15 mL) was heated under reflux for 12 h. After the evaporation of the reaction mixture to dryness under reduced pressure, the residue was neutralized by a solution of sodium bicarbonate (4%) until effervescence ceased. The precipitate obtained was washed with water, dried (P2O5) and recrystallized from an appropriate solvent.
General procedure: A solution of 3,4,5-trimethoxyaniline (1.83 g, 10 mmol) and acid anhydride (10 mmol) in glacial acetic acid (15 mL) was heated under reflux for 12 h. After the evaporation of the reaction mixture to dryness under reduced pressure, the residue was neutralized by a solution of sodium bicarbonate (4%) until effervescence ceased. The precipitate obtained was washed with water, dried (P2O5) and recrystallized from an appropriate solvent.
With potassium carbonate;tris-(dibenzylideneacetone)dipalladium(0); In iso-butanol; at 80.0℃; for 2.5h;Inert atmosphere;
7-Bromo-2-chlorothieno[3,2-d]pyrimidine (200 mg, 0.81 mmol) was dissolved in 2-butanol (4 mL) and then potassium carbonate (223 mg, 1.61 mmol) and 3,4,5-trimethoxybenzenamine (110 mg, 0.81 mmol) were added. After blowing nitrogen to the reaction mixture for 10 minutes, Pd2(dba)3 (50 mg, 0.048 mmol) and Xphos (35 mg, 0.073 mmol) were added. The reaction mixture was stirred at 80 C for 2.5 hours and then filtered with celite. The filtrate was diluted with ethyl acetate and washed with brine. The organic layer was dried with magnesium sulfate, filtered with celite, and then concentrated. Purification by chromatography (15% ethyl acetate/hexane) yielded the target compound (120 mg, 43% yield). [0504] 1H NMR (300 MHz, DMSO-d 6) delta 9.42 (s, 1H), 8.33 (s, 1H), 7.85 (s, 1H), 6.65 (s, 2H), 3.76 (s, 6H), 3.60 (s, 3H), MS m/z: 352.45 [M+1].
43%
With potassium carbonate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene;tris-(dibenzylideneacetone)dipalladium(0); In iso-butanol; at 80.0℃; for 2.5h;Buchwald amination;
Step 1: 2-chloro-N-(3,4,5-trimethoxyphenyl)thieno[3,2-d]pyrimidin-7-amine 7-Bromo-2-chlorothieno[3,2-d]pyrimidine (200 mg, 0.81 mmol) was dissolved in 2-butanol (4 mL) and then potassium carbonate (223 mg, 1.61 mmol) and 3,4,5-trimethoxybenzenamine (110 mg, 0.81 mmol) were added. After blowing nitrogen to the reaction mixture for 10 minutes, Pd2(dba)3 (50 mg, 0.048 mmol) and Xphos (35 mg, 0.073 mmol) were added. The reaction mixture was stirred at 80 C. for 2.5 hours and then filtered with celite. The filtrate was diluted with ethyl acetate and washed with brine. The organic layer was dried with magnesium sulfate, filtered with celite, and then concentrated. Purification by chromatography (15% ethyl acetate/hexane) yielded the target compound (120 mg, 43% yield). 1H NMR (300 MHz, DMSO-d6) delta 9.42 (s, 1H), 8.33 (s, 1H), 7.85 (s, 1H), 6.65 (s, 2H), 3.76 (s, 6H), 3.60 (s, 3H), MS m/z: 352.45 [M+1].
2) 200 mg (0.8 mmol) of the product from step 1) is mixed with 120 mg (0.9 mmol) HOBT and 0.06 ml (0.6 mmol) DIC in dry DMF under ice-water bath condition. The mixture is stirred for 30 min. under N2 protection, then 160 mg (0.9 mmol) 3,4,5-trimethoxyaniline is subsequently added, the mixture is let to naturally resume room temperature and stirred overnight. The resulted reactant is evaporated to dryness under reduced pressure, the residue is dissolved in ethyl acetate and subsequently filtered, the filtrate is evaporated to dryness, separated using preparatory thin layer silica plate to obtain 180 mg product, yield: 55.6%.
With N-ethyl-N,N-diisopropylamine; In dimethyl sulfoxide; at 20℃; for 16.0h;
Step 1 5-Chloro-N-(3,4,5-trimethoxyphenyl)thiazolo[5,4-d]pyrimidin-7-amine Procedure: To a stirred solution of <strong>[13479-88-4]5,7-dichlorothiazolo[5,4-d]pyrimidine</strong> (200 mg, 0.97 mmol) and 3,4,5-trimethoxybenzenamine (230 mg, 1.25 mmol) in 7 mL of DMSO was added DIEA (188 mg, 1.45 mmol) in one portion at room temperature. Then the reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was poured into 40 mL of water, and the solid obtained was filtered, washed with water (10 mL) to give a crude product. It was purified by silica gel chromatography (silica gel 200-300 mesh, eluting with ethyl acetate) to give 5-chloro-N-(3,4,5-trimethoxyphenyl)thiazolo[5,4-d]pyrimidin-7-amine (337 mg, 98.6%) as a yellow solid. LC-MS: 353.0 [M+H]+, 726.9 [2M+H]+, tR=1.56 min.
2-methoxy-5-(((3,4,5-trimethoxyphenyl)imino)methyl)phenyl acetate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
64%
In ethanol; for 3h;Reflux;
General procedure: The appropriate amine (10 mmol) was refluxed with the appropriate aldehyde (10 mmol) in ethanol (50 mL) for 3 h. The reaction mixture was reduced in vacuo, and the resulting solution was allowed to stand until solid product crystallised from solution. The resulting imine was recrystallised from ethanol.
With palladium diacetate; caesium carbonate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane; at 100℃; for 1h;Sealed tube; Inert atmosphere;
General procedure: In a sealed tube and under an argon atmosphere were added successively, Pd(OAc)2 (11 mg; 5 mol%), Xantphos (29 mg; 5 mol%),1-bromo-4-methoxybenzene (187 mg; 1 mmol), 3,4,5-trimethoxyaniline (275 mg; 1.5 mmol), Cs2CO3 (652 mg; 2 mmol)in dioxane (2 mL). After heating at 100 C for 12 h, the resulting suspension was cooled to room temperature and filtered through a pad of Celite eluting with ethyl acetate, and the inorganic salts were removed. The filtrate was concentrated and a rapid purification by silica gel column chromatography of the residue to eliminate the excess of 3,4,5-trimethoxyaniline gave the desired product 1a which was immediately engaged in the alkylation step. 1a: (75 mg, 26%);
General procedure: To a solution of the acid derivative (1mmol) in CH2Cl2 were added triethylamine (2mmol) and ethyl chloroformate (1mmol), followed by stirring at 0C for 30min. After addition of the appropriate amine derivative (1.2mmol), the mixture was stirred for an additional 1h at 0C. Then, the reaction mixture was warmed to room temperature and stirred overnight. After the solvent was evaporated under reduced pressure, acetone was added, filtered, and evaporated. The residue was dissolved in CH2Cl2, and the organic phase was washed with a 1% NaHCO3 solution and brine, dried over Na2SO4, and evaporated under vacuum. The final residue was purified by flash column chromatography (Combiflash Rf) using CH2Cl2-MeOH (0-5%) as eluents. 4.3.5 (E)-3-(1H-Indol-3-yl)-N-(3,4,5-trimethoxyphenyl)acrylamide 3e Yield 53%, mp 246-248 C; IR (FTIR/FTNIR-ATR): 1733 cm-1 (C=O), 3304 cm-1 (N-H). 1H NMR (DMSO-d6) delta: 11.68 (1H, s), 9.96 (1H, s), 7.95 (1H, m), 7.83 (1H, s), 7.74 (1H, d, J = 15.6 Hz), 7.48 (1H, m), 7.23 (2H, m), 7.10 (2H, s), 6.79 (1H, d, J = 15.6 Hz), 3.77 (6H, s), 3.63 (3H, s). 13C NMR (DMSO-d6) delta: 165.5, 153.4, 138.1, 136.6, 135.2, 133.7, 131.8, 125.5, 123.0, 121.1, 120.6, 116.7, 113.1, 112.8, 97.1, 60.8, 56.3; HRMS C20H21N2O4 [M+H]+ Calcd 353.1501, Found m/z 353.1503.
General procedure: To a solution of 3-aminobenzo[b]thiophene-2-carboxylate 7 (0.9 mmol) in glacial acetic acid (5ml) water solution of NaNO2( 1.8 mmol) was added dropwise. The mixture was left under stirring for 2h at rt. Then ammonium acetate (32.4 mmol) and an appropriate primary amine 9a-e (10 mmol) were added. The precipitate was filtered off, and the crude was recrystallized from ethanol.
5-Bromo-2-methyl-3-((3,4,5-trimethoxyphenyl)selenyl)-1H-indole[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
41%
General procedure: Similar to the reported method [19], a mixture of the appropriate indole (0.6 mmol), 1,2-bis-(3,4,5-trimethoxyphenyl)diselenide(0.35 mmol, 0.45 g mixture of 1,2-bis-(3,4,5-trimethoxyphenyl)diselenide with 1,10-selenobis(3,4,5-trimethoxybenzene)), FeCl3 (20 molpercent) and I2 (1 molpercent, 0.0001 g/mL in CH3CN) was placed into the microwave cavity (closed vessel mode). Microwave irradiation at 150 W was used, the temperature being ramped from 25 °C to 80 °C. Once 80 °C was reached, takingabout 1 min, the reaction mixture was held at this temperature for 30 min while stirring, until complete consumption of the starting material, as monitored by TLC. After the evaporation of the solvent,the residual crude product was purified by column chromatography on silica gel (200-300 mesh) with petroleumether/AcOEt (v/v 5:1) or pure CH2Cl2.
In 1-methyl-pyrrolidin-2-one; water; at 120℃; for 10.0h;Inert atmosphere; Large scale;
Step B: Preparation of 6-[[5-Fluoro-2-(3,4,5-trimethoxyanilino)pyrimidin-4-yl]amino]-2,2-dimethyl-4H-pyrido[3,2-b][1,4]oxazin-3-one 6-[(2-chloro-5-fluoro-pyrimidin-4-yl)amino]-2,2-dimethyl-4H-pyrido[3,2-b][1,4]oxazin-3-one (Step A) (568 kg, 1.00 mol eq) is mixed with 3,4,5-trimethoxyaniline (402 kg, 1.25 mol eq) in N-methylpyrrolidin-2-one (2835 kg) with stirring under a nitrogen atmosphere. To this is added water (11 kg) and the mixture heated to about 120 C. and stirred for about 10 hours. This is then cooled to about 65 C. and the pH adjusted to pH 8.5 with 4% w/w aqueous sodium hydroxide solution. The resulting slurry is further cooled to about 20 C., stirred for at least 6 hours and then filtered. The filtered solid is washed twice with water (2*1440 kg) then twice with acetone (2*1140 kg) and finally dried under vacuum at about 40 C. to give the title compound (754 kg, 91%) as a colored solid. 1H NMR (400 MHz, DMSO-d6) delta ppm 1.42 (s, 6H) 3.59 (s, 3H) 3.66 (s, 6H) 7.04 (s, 2H) 7.32 (d, J=8.5 Hz, 1H) 7.68 (d, J=8.5 Hz, 1H) 8.13 (d, J=3.4 Hz, 1H) 9.10 (br. s, 1H) 9.14 (br. s, 1H) 11.06 (br. s, 1H). m/z 471 [MH]+.
6-bromo-N-(3,4,5-trimethoxyphenyl)imidazo[1,2-a]pyridine-3-carboxamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
1.1 g
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; acetonitrile; at 20℃; for 18h;Inert atmosphere;
[1294j 46-Bromo-N-(3 ,4,5 -trimethoxyphenyl)imidazo [1 ,2-a]pyridine-3 -carboxamide can beprepared as shown in Scheme 41: A stirring solution of <strong>[944896-42-8]6-bromoimidazo[1,2-a]pyridine-3-carboxylic acid</strong> (0.91 g, 3.7 mmol), EDCI (1.08 g, 5.6 mmol), HOBt (0.76 g, 5.6 mmol) and 3,4,5-trimethoxyaniline (0.76 g, 4.1 mmol) in acetonitrile/DMF (8/3 mL) under argon was added i-Pr2NEt (2.00 g, 2.6 ml), 15.4 mmol) drop wise for 5 mm at room temperature. The resulting off-brown homogeneous reaction mixture was continued to stir at room temperature for 1 8h. Subsequently, the heterogeneous reaction mixture was diluted with water and the solid was collected by filtration. The solid was suction dried on funnel to obtain 6-bromo-N-(3 ,4,5 -trimethoxyphenyl)imidazo [1 ,2-a]pyridine-3 - carboxamide (1.1 g) as a white solid. ?H NMR (300 MHz, DMSO-d6) oe 10.17 (s, 1H), 9.64 (s, 1H), 8.56 (d, J= 1.1 Hz, 1H), 7.75 (d, J= 9.7 Hz, 1H), 7.64 (dd, J= 9.5, 1.9 Hz, 1H), 7.15 (s, 2H), 3.78 (s, 6H), 3.63 (s, 3H).
6,8-dichloro-3-(3,4,5-trimethoxyphenyl)quinazolin-4(3H)-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
44%
With bismuth (III) nitrate pentahydrate; In neat (no solvent); at 80℃; for 12h;
General procedure: An oven-dried round-bottom flask was charged with 2-aminobenzoic acid (0.5 mmol), aniline (0.6 mmol), Bi(NO3)3 (0.05 mmol), and CH(OEt)3 (2 mL), and the mixture was stirred in apreheated oil bath at 80 C for 12 h. After cooling to room temperature,the reaction mixture was admixed with hot CH2Cl2. The prude products were collected by filtration and then re-crystallized from ethanol to afford pure 3-substituted quinazolinones (3a-3t).
2-chloro-5,6-dimethyl-N-(3,4,5-trimethoxyphenyl)pyrimidin-4-amine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
36%
With N-ethyl-N,N-diisopropylamine; In isopropyl alcohol; at 85℃; for 84h;Micellar solution; Sealed tube;
2-Chloro-5,6-dimethyl-iV-(3,4,5-trimethoxyphenyl)pyrimidin-4-amine (RJ1-037): A mixture of RJl-008 (0.354 g, 2.0 mmol), 3,4,5-trimethoxyaniline (0.385 g, 2.1 mmol), DIPEA (0.42 mL, 2.4 mmol) and iPrOH (2 mL) was added to a 5 mL microwave vial which was then sealed and placed in a hot oil bath at 85 C with stirring for 3.5 days. At this point, a large amount of yellow- white precipitate was observed in the vial so the reaction mixture was filtered and the solid washed with MeOH (2 x 10 mL) and water (10 mL) before being left to dry in vacuo to give RJ1-037 as an off-white solid (0.232 g, 36%). m.p. = 214-217 C. NMR (400 MHz, DMSO-) delta 8.61 (s, 1H), 7.04 (s, 2H), 3.74 (s, 6H), 3.63 (s, 3H), 2.30 (s, 3H), 2.12 (s, 3H). LRMS (ESI+) m/z 324.2 (M35C1+H)+, 326.2 (M37C1+H)+; HRMS (ESI+) m/z calculated for C15H18CIN3O3 (M+H)+ 324.11095, found 324.11200.
36%
With N-ethyl-N,N-diisopropylamine; In isopropyl alcohol; at 85℃; for 84h;Sealed tube;
A mixture of RJl-008 (0.354 g, 2.0 mmol), 3,4,5-trimethoxyaniline (0.385 g, 2.1 mmol), DIPEA (0.42 mL, 2.4 mmol) and iPrOH (2 mL) was added to a 5 mL microwave vial which was then sealed and placed in a hot oil bath at 85 C with stirring for 3.5 days. At this point, a large amount of yellow-white precipitate was observed in the vial so the reaction mixture was filtered and the solid washed with MeOH (2 x 10 mL) and water (10 mL) before being left to dry in vacuo to give RJ1-037 as an off-white solid (0.232 g, 36%). m.p. = 214-217 C. lH NMR (400 MHz, DMSO-ifc) delta 8.61 (s, 1H), 7.04 (s, 2H), 3.74 (s, 6H), 3.63 (s, 3H), 2.30 (s, 3H), 2.12 (s, 3H). LRMS (ESI+) m/z 324.2 (M35C1+H)+, 326.2 (M37C1+H)+; HRMS (ESI+) m/z calculated for C15H18CIN3O3 (M+H)+ 324.11095, found 324.11200.(M+H)+ 298.05084, found 298.04992.
With potassium hexamethylsilazane; In 1,4-dioxane; at 100℃; for 1h;
Compound bromo-5-iodopyridine (5) (20 g, 70.4 mmol)dissolved in 40 mL of dioxane in an oven-dried flask wasadded in KN(Si(CH3)3)2 (56.1 g, 281.6 mmol), and 3,4,5-trimethoxyaniline (4) (12.9 g, 70.4 mmol). The reaction mixturewas heated at 100 C for 1 hour. After cooling, the dioxanesolution was filtered and evaporated in vacuo. Theresidue was retaken in 30 mL of ethylacetate, washed (2 × 30mL brine), and evaporated to give crude product. This waspurified through column chromatography with ethyl acetate/hexane (2:1) to afford pure compound 6, with 21.6 g in 91%yield. 1H NMR (300 MHz, DMSO-d6) delta: 3.64 (s, 3H), 3.78(s, 6H), 6.43 (s, 2H), 7.52 (t, 1H), 8.04 (d, 1H, J = 1.9 Hz),8.14 (d, 1H, J=2.3 Hz), 8.48 (s, 1H); MS (ESI): 340 [M+H]+.
4-chloro-6-morpholino-N-(3,4,5-trimethoxyphenyl)-1,3,5-triazin-2-amine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
88.4%
With N-ethyl-N,N-diisopropylamine; In 1,4-dioxane; at 20℃; for 6h;
To a stirred solution of 4-(4,6-dichloro-1,3,5-triazin-2-yl)morpholine (2) (5g, 21.36 mmol) in 1,4-dioxane (50ml) 3,4,5-trimethoxy aniline (3.91g, 21.36 mmol) and DIPEA (5.5 mL, 32.04 mmol) were added and stirred at RT for 6h. After completion of the reaction, as indicated by TLC, the reaction mixture was extracted with ethyl acetate. Combined organic layers were collected, dried over dry sodium sulfate and concentrated in vacuo to yield the product 3 as pale yellow solid; yield: 88.4%, 7.2g, m.p. 223-225 C. 1H NMR (400 MHz, CDCl3) delta 7.16 (bs, 1H), 6.89 (s, 2H), 3.86-3.83 (m, 13H), 3.78-3.73 (m, 4H). ESI-MS (m/z): calcd. for C16H20ClN5O4 381.12, found 382.17 [M + H]+.
N-benzyl-N-(2,2-dimethoxyethyl)-3,4,5-trimethoxyaniline[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
85%
General procedure: NaBH(OAc)3 (3.3 g, 15 mmol) was added to a stirring solutionof benzaldehyde (1.0 mL, 10 mmol) and aniline (1.1 mL,12 mmol) in CHCl3 (60 mL) and the mixture was stirred atroom temperature (rt) for one hour (h). 2,2-Dimethoxyacetaldehyde (30 mmol) was then introduced into the reaction mixturefollowed by NaBH(OAc)3 (3.3 g, 15.0 mmol) and the resultantmixture was stirred at rt for further 8 h. The mixture was thenquenched with saturated aqueous solution of K2CO3 (60 mL)and the aqueous (aq) layer was extracted with CHCl3(2 × 30 mL). The combined organic layers were dried withMgSO4, filtered and evaporated to give the crude compound 9aas a pale yellow oil (3.87 g).
(E)-2-(allyloxy)-4-((3,4,5-trimethoxyphenyl)diazenyl)phenol[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
51%
General procedure: 3,4,5-trimethoxyaniline (0.183 g, 1 mmol) was dissolved either in ethanol or water (5 mL) and cooled inice bath to -10 C. Then concentrated (37%) HCl (1 mL) was added dropwise and keep stirrer thesolution for 5 minutes. An ice-cold aqueous solution (5 mL) of NaNO2 (0.139 g, 2 mmol) was preparedand cooled at below -10 C in ice bath, concentrated (37%) HCl (1 mL) was added and then this solutionwas added dropwise to the aniline solution. The reacction mixture stirred in ice bath for one hour toprepare diazonium salt. Another basic solution of required phenolic compound (0.9 mmol) was preparedin aqueous solution of NaOH (0.800 g, 5 mL) and cooled in an ice bath to below -10 C. This cold basicphenolic solution was added dropwise into chilled diazonium salt solution. Then additional NaOH wasadded to neutralize the pH and then ice bath was removed. Further, reaction mixture was stirred foranother 2h at room temperature (r.t.). Afterwards the reaction mixture was acidifed by addition aqueousHCl (1N) and the product was extracted from aqueous solution using ethylacetate (50 mL x 3). Organiclayers were combined and washed with water (20 mL x 2), brine (20 mL x 2), dried over anhydrousNaSO4 and solvent was removed under vacuum. The product was purified through flash silica gel columnchromatography using ethylacetate/hexane mixture.
(E)-8-((3,4,5-trimethoxyphenyl)diazenyl)-2,3-dihydrobenzo[b][1,4]dioxin-5-ol[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
20%
General procedure: 3,4,5-trimethoxyaniline (0.183 g, 1 mmol) was dissolved either in ethanol or water (5 mL) and cooled inice bath to -10 C. Then concentrated (37%) HCl (1 mL) was added dropwise and keep stirrer thesolution for 5 minutes. An ice-cold aqueous solution (5 mL) of NaNO2 (0.139 g, 2 mmol) was preparedand cooled at below -10 C in ice bath, concentrated (37%) HCl (1 mL) was added and then this solutionwas added dropwise to the aniline solution. The reacction mixture stirred in ice bath for one hour toprepare diazonium salt. Another basic solution of required phenolic compound (0.9 mmol) was preparedin aqueous solution of NaOH (0.800 g, 5 mL) and cooled in an ice bath to below -10 C. This cold basicphenolic solution was added dropwise into chilled diazonium salt solution. Then additional NaOH wasadded to neutralize the pH and then ice bath was removed. Further, reaction mixture was stirred foranother 2h at room temperature (r.t.). Afterwards the reaction mixture was acidifed by addition aqueousHCl (1N) and the product was extracted from aqueous solution using ethylacetate (50 mL x 3). Organiclayers were combined and washed with water (20 mL x 2), brine (20 mL x 2), dried over anhydrousNaSO4 and solvent was removed under vacuum. The product was purified through flash silica gel columnchromatography using ethylacetate/hexane mixture.
4-morpholino-N-(3,4,5-trimethoxyphenyl)thieno[3,2-d]pyrimidin-2-amine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
75.9%
With trifluoroacetic acid; In 2,2,2-trifluoroethanol; at 140℃; for 1.5h;Microwave irradiation;
General procedure: To a stirred suspension of 50 mg 2-cholro analogues 1, 4, 6 or9 (1 equiv) and aromatic amine (2 equiv) in 2mL of 2,2,2-trifluoroethanol (TFE) was added TFA (40 ml) dropwise. The reagents were placed in a sealed microwave vial and the reactions were performed under microwave irradiation (140 C for 90 min). The solventwas removed in vacuo and the residue was re-dissolved in dichloromethane (CH2Cl2) (10 mL). The solution was washed with saturated sodium bicarbonate solution (3 x 10 mL), and the aqueous extracts were combined and washed with CH2Cl2 (10 mL). The combined organic layers were dried with sodium sulfate anhydrous (Na2SO4). The solvent was removed under reduced pressure and the crude material was purified by column chromatographyon silica gel.
(E)-3-benzylidene-N-(tert-butyl)-2-(3,5-dimethylphenyl)-4-oxo-1-(3,4,5-trimethoxyphenyl) azetidine-2-carboxamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
81%
General procedure: To an equimolar mixture of amine 1 (1 equiv), aldehyde 2 (1 equiv), phenylpropiolic acid 3 (1 equiv) in acetonitrile (3ml), was added isocyanide 4 (1 equiv) and the reaction mixture was stirred at RT for 8-12h. After completion of the reaction (as observed by TLC analysis), sodium hydride (2 equiv) was added to the solution. A clear formation of product 5 was observed by TLC analysis. Solvent was evaporated and the crude was diluted with ethyl acetate followed by washing with water and brine. The organic layer was concentrated in vacuo and crude was purified by the silica gel column chromatography.
(E)-4-benzylidene-1-(tert-butyl)-3-(4-chloro-3-fluorophenyl)-3-((3,4,5-trimethoxyphenyl)amino)pyrrolidine-2,5-dione[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
72%
General procedure: To an equimolar mixture of amine 1 (1 equiv), aldehyde 2 (1equiv), phenylpropiolic acid 3 (1 equiv) in methanol (3mL), was added isocyanide 4 (1 equiv) and the reaction mixture was stirred at RT for 8-12h. After completion of the reaction (as observed by TLC analysis), potassium carbonate (3 equiv) was added to the solution. A clear formation of product 6 was observed by TLC analysis. Solvent was evaporated and the crude was diluted with ethyl acetate followed by washing with water and brine. The organic layer was concentrated in vacuo and crude was purified by the silica gel column chromatography.
With N-ethyl-N,N-diisopropylamine; In dimethyl sulfoxide; at 60℃;
General procedure: A solution of <strong>[848398-41-4]2,4-dichloro-5,7-dihydrofuro[3,4-d]pyrimidine</strong> (4, 1.89g, 10mmol) in DMSO (10mL) was added commercially available 3,4-dimethoxyaniline (1.53g, 10mmol) and DIPEA (2.58g, 20mmol). The solution was heated to 60C and stirred overnight. Then the solution was poured into water and extracted with EtOAc, the organic layer was washed by brine, dried with anhydrous Na2SO4, and filtered and concentrated under reduced pressure. The crude product was further purified by flash chromatography on silica gel (EtOAc/hexane=1:1) to afford 8 compound 5 (2.00g, yield 65%) as an off-white solid. 1H NMR (400MHz, CDCl3) delta: 6.90-6.81 (m, 3H), 4.88 (s, 2H), 4.42 (s, 2H), 3.92 (s, 3H), 3.89 (s, 3H).
With N-ethyl-N,N-diisopropylamine; In ethanol; for 18.0h;Reflux;
General procedure: 4-chloroquin(az)olinederivative (1.0 eq.), aniline derivative (1.1 eq.), and iPr2NEt (2.5 eq.) were suspended inethanol (10 mL) and refluxed for 18 h. The crude mixture was purified by flash chromatographyusing EtOAc:hexane followed by 1-5 % methanol in EtOAc; After solventremoval under reduced pressure, the product was obtained as a free following solid orrecrystallized from ethanol/water.
2-fluoro-4-methyl-N-(3,4,5-trimethoxyphenyl)benzamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
97%
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 20℃; for 2h;
General procedure: To a solution of 2-fluorobenzoic acid (4a) (80mg, 0.57mmol) in DMF (4mL) were added Et3N (0.12mL, 0.86mmol), 3,4,5-trimethoxyaniline (115mg, 0.63mmol) and HATU (239mg, 0.63mmol). The mixture was stirred for 2h at room temperature and water (40mL) was added. The resulting precipitate was filtered and dried to give 170mg of 5a (98%) as a white solid.
96%
With triethylamine; HATU; In N,N-dimethyl-formamide; for 2h;
(1) Dissolving <strong>[7697-23-6]2-fluoro-4-methylbenzoic</strong> acid (50 mg) in N, N-dimethylformamide (4 mL),Add triethylamine (70 muL), 3,4,5-trimethoxyaniline (66 mg),O-(7-Azabenzotriazol-1-yl)-N,N,N?,N?-tetramethyluronium hexafluorophosphate (137mg), reaction for 2h,Water was added, extracted with ethyl acetate, and column chromatography was performed to obtain 2-fluoro-4-methyl-N- (3,4,5-trimethoxyphenyl) benzamide (100 mg),The yield was 96%.
2-fluoro-4-methoxy-N-(3,4,5-trimethoxyphenyl)benzamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
99.6%
With triethylamine; HATU; In N,N-dimethyl-formamide; for 2h;
(1) Dissolving <strong>[394-42-3]2-fluoro-4-methoxybenzoic acid</strong> (80 mg) in N, N-dimethylformamide (4 mL),Add triethylamine (100 muL), 3,4,5-trimethoxyaniline (95 mg),O-(7-Azabenzotriazol-1-yl)-N,N,N?,N?-tetramethyluronium hexafluorophosphate (196mg), reaction for 2h,Water was added, extracted with ethyl acetate, column chromatography, to give 2-fluoro-4-methoxy -N- (3,4,5- trimethoxyphenyl) benzamide (157 mg of),The yield was 99.6%.
99%
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 20℃; for 2h;
General procedure: To a solution of 2-fluorobenzoic acid (4a) (80mg, 0.57mmol) in DMF (4mL) were added Et3N (0.12mL, 0.86mmol), 3,4,5-trimethoxyaniline (115mg, 0.63mmol) and HATU (239mg, 0.63mmol). The mixture was stirred for 2h at room temperature and water (40mL) was added. The resulting precipitate was filtered and dried to give 170mg of 5a (98%) as a white solid.
2-fluoro-3-methyl-N-(3,4,5-trimethoxyphenyl)benzamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
95%
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 20℃; for 2h;
General procedure: To a solution of 2-fluorobenzoic acid (4a) (80mg, 0.57mmol) in DMF (4mL) were added Et3N (0.12mL, 0.86mmol), 3,4,5-trimethoxyaniline (115mg, 0.63mmol) and HATU (239mg, 0.63mmol). The mixture was stirred for 2h at room temperature and water (40mL) was added. The resulting precipitate was filtered and dried to give 170mg of 5a (98%) as a white solid.
2-fluoro-6-methyl-N-(3,4,5-trimethoxyphenyl)benzamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
98%
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 20℃; for 2h;
General procedure: To a solution of 2-fluorobenzoic acid (4a) (80mg, 0.57mmol) in DMF (4mL) were added Et3N (0.12mL, 0.86mmol), 3,4,5-trimethoxyaniline (115mg, 0.63mmol) and HATU (239mg, 0.63mmol). The mixture was stirred for 2h at room temperature and water (40mL) was added. The resulting precipitate was filtered and dried to give 170mg of 5a (98%) as a white solid.
Chemistry
Pharmaceutical Intermediates
Inhibitors/Agonists
Material Science
For Research Only
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