* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Reference：
[1] Journal of Organic Chemistry, 2009, vol. 74, # 6, p. 2598 - 2600
2
[ 5438-70-0 ]
[ 587-88-2 ]
Reference：
[1] Angewandte Chemie - International Edition, 2018, vol. 57, # 31, p. 9896 - 9900[2] Angew. Chem., 2018, vol. 130, p. 10044 - 10048,5
3
[ 5438-70-0 ]
[ 30132-15-1 ]
Reference：
[1] Indian Journal of Chemistry, Section B: Organic Chemistry Including Medicinal Chemistry, 1978, vol. 16, p. 605 - 609
4
[ 5438-70-0 ]
[ 63610-08-2 ]
Reference：
[1] Patent: KR101778331, 2017, B1,
5
[ 5438-70-0 ]
[ 1197-55-3 ]
Reference：
[1] Chemische Berichte, 1939, vol. 72, p. 839,847
6
[ 5438-70-0 ]
[ 17138-28-2 ]
Reference：
[1] Chemical and Pharmaceutical Bulletin, 1983, vol. 31, # 10, p. 3424 - 3445
7
[ 5445-26-1 ]
[ 5438-70-0 ]
Yield
Reaction Conditions
Operation in experiment
100%
With palladium 10% on activated carbon; hydrogen In methanol for 4 h;
A solution of ethyl 2-(4-nitrophenyl)acetate (3j) (1.05 g, 3.40 mmol) inMeOH (25 mL) was hydrogenated over 10percent Pd/C (catalytic amount) for 4h. The catalyst was filtered off and the resultingsolution was concentrated to afford ethyl 2-(4-aminophenyl)acetate (4j). 1H-NMR 200 MHz (CDCl3) δ: 1.29 (t, 3H, J=7.2Hz ), 3.72 (s, 2H), 4.13 (q, 2H, J=7.2 Hz), 6.51 (d, 2H, J= 7.2 Hz), 6.98 (d, 2H, J= 7.2 Hz). Quantitative yield
97%
With palladium on activated charcoal; hydrogen In methanol at 20℃; for 1.5 h;
Step 1: Ethyl 2- (4-aminophenyl) acetate[1974]To a solution of ethyl 4-nitrophenylacetate (500 mg, 2.39 mmol) in methanol (10 mL) was added Pd/C (64 mg) . The mixture was stirred at rt for 1.5 hours under hydrogen atomosphere. The mixture was filtered and the filtrate was concentrated to give ethyl 2- (4-aminophenyl) acetate as reddish liquid (420 mg, 97) .[1975]1H NMR (400 MHz, CD3OD) : δ ppm 7.03 (d, J 8.4 Hz, 2H) , 6.71 (d, J 8.4 Hz, 2H) , 4.13 (q, J 7.1 Hz, 1H) , 3.49 (s, 2H) , 1.24 (t, J 7.1 Hz, 3H) and MS-ESI: m/z 180.2 [M+H]+.
Reference：
[1] Patent: EP3381898, 2018, A1, . Location in patent: Paragraph 0200; 0272
[2] Patent: WO2015/161830, 2015, A1, . Location in patent: Paragraph 00698
[3] Journal of the American Chemical Society, 2011, vol. 133, # 32, p. 12875 - 12879
[4] Chemical Communications, 2013, vol. 49, # 80, p. 9089 - 9091
[5] ChemCatChem, 2016, vol. 8, # 14, p. 2351 - 2355
[6] Farmaco, 1993, vol. 48, # 4, p. 487 - 501
[7] Bioorganic and Medicinal Chemistry, 2010, vol. 18, # 22, p. 8092 - 8105
[8] Journal of the Chemical Society, 1917, vol. 111, p. 170
[9] Chem. Penicillin, <Princeton 1949>, S. 106, 139,
[10] Chemische Berichte, 1939, vol. 72, p. 839,847
[11] Chemische Berichte, 1934, vol. 67, p. 245
[12] Patent: US6150373, 2000, A,
[13] Patent: US5070087, 1991, A,
[14] Journal of Medicinal Chemistry, 2013, vol. 56, # 22, p. 9199 - 9221
[15] ChemMedChem, 2018, vol. 13, # 1, p. 30 - 36
8
[ 64-17-5 ]
[ 1197-55-3 ]
[ 5438-70-0 ]
Reference：
[1] Synthesis, 2001, # 14, p. 2143 - 2155
[2] Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1984, p. 2801 - 2807
[3] European Journal of Pharmaceutical Sciences, 2006, vol. 27, # 2-3, p. 188 - 193
[4] European Journal of Medicinal Chemistry, 2015, vol. 94, p. 284 - 297
[5] Steroids, 2017, vol. 123, p. 73 - 83
9
[ 1197-55-3 ]
[ 5438-70-0 ]
Reference：
[1] Journal of the American Chemical Society, 1991, vol. 113, # 1, p. 291 - 297
[2] Patent: US4670421, 1987, A,
[3] Patent: US4720506, 1988, A,
[4] Patent: US4205085, 1980, A,
10
[ 88975-34-2 ]
[ 5438-70-0 ]
Reference：
[1] Journal of the American Chemical Society, 1991, vol. 113, # 1, p. 291 - 297
11
[ 13475-17-7 ]
[ 5438-70-0 ]
Reference：
[1] European Journal of Organic Chemistry, 2018, vol. 2018, # 23, p. 2995 - 3000
12
[ 113180-63-5 ]
[ 5438-70-0 ]
Reference：
[1] Journal of the American Chemical Society, 1991, vol. 113, # 1, p. 291 - 297
13
[ 105113-62-0 ]
[ 5438-70-0 ]
Reference：
[1] Journal of the American Chemical Society, 1991, vol. 113, # 1, p. 291 - 297
14
[ 123-30-8 ]
[ 5438-70-0 ]
Reference：
[1] Patent: US4439448, 1984, A,
15
[ 104-03-0 ]
[ 5438-70-0 ]
Reference：
[1] Journal of Medicinal Chemistry, 2013, vol. 56, # 22, p. 9199 - 9221
[2] European Journal of Medicinal Chemistry, 2015, vol. 94, p. 284 - 297
[3] ChemMedChem, 2018, vol. 13, # 1, p. 30 - 36
16
[ 5044-24-6 ]
[ 5438-70-0 ]
Reference：
[1] Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1984, p. 2801 - 2807
17
[ 26165-63-9 ]
[ 5438-70-0 ]
Reference：
[1] Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1984, p. 2801 - 2807
18
[ 95337-70-5 ]
[ 5438-70-0 ]
Reference：
[1] Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1984, p. 2801 - 2807
19
[ 83756-25-6 ]
[ 5438-70-0 ]
Reference：
[1] Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1984, p. 2801 - 2807
20
[ 555-21-5 ]
[ 5438-70-0 ]
Reference：
[1] Chemische Berichte, 1939, vol. 72, p. 839,847
[2] European Journal of Medicinal Chemistry, 2015, vol. 94, p. 284 - 297
21
[ 140-29-4 ]
[ 5438-70-0 ]
Reference：
[1] European Journal of Medicinal Chemistry, 2015, vol. 94, p. 284 - 297
With palladium 10% on activated carbon; hydrogen; In methanol; for 4h;
A solution of ethyl 2-(4-nitrophenyl)acetate (3j) (1.05 g, 3.40 mmol) inMeOH (25 mL) was hydrogenated over 10% Pd/C (catalytic amount) for 4h. The catalyst was filtered off and the resultingsolution was concentrated to afford ethyl 2-(4-aminophenyl)acetate (4j). 1H-NMR 200 MHz (CDCl3) delta: 1.29 (t, 3H, J=7.2Hz ), 3.72 (s, 2H), 4.13 (q, 2H, J=7.2 Hz), 6.51 (d, 2H, J= 7.2 Hz), 6.98 (d, 2H, J= 7.2 Hz). Quantitative yield
97%
With palladium on activated charcoal; hydrogen; In methanol; at 20℃; for 1.5h;
Step 1: Ethyl 2- (4-aminophenyl) acetate[1974]To a solution of ethyl 4-nitrophenylacetate (500 mg, 2.39 mmol) in methanol (10 mL) was added Pd/C (64 mg) . The mixture was stirred at rt for 1.5 hours under hydrogen atomosphere. The mixture was filtered and the filtrate was concentrated to give ethyl 2- (4-aminophenyl) acetate as reddish liquid (420 mg, 97) .[1975]1H NMR (400 MHz, CD3OD) : delta ppm 7.03 (d, J 8.4 Hz, 2H) , 6.71 (d, J 8.4 Hz, 2H) , 4.13 (q, J 7.1 Hz, 1H) , 3.49 (s, 2H) , 1.24 (t, J 7.1 Hz, 3H) and MS-ESI: m/z 180.2 [M+H]+.
830 mg (97%)
palladium; In methanol;
A solution of 1 g (4.78 mmol) of ethyl-4-nitrophenylacetate in 10 ml of dry methanol was treated with 100 mg of 10% palladium-on-carbon and then hydrogenated at room temperature and at atmospheric pressure for 4 hours. The catalyst was removed by filtration and the filtrate was evaporated to give 830 mg (97%) of ethyl 4-aminophenylacetate as a mobile yellow oil.
In ethanol;
EXAMPLE 19 4[[3-[4-[Bis(4-fluorophenyl)hydroxymethyl]-1-piperidinyl]propyl]amino]benzeneacetic acid ethyl ester A solution of 4.18 g (0.02 mole) of ethyl p-nitrophenylacetate in 200 mL of ethanol is subjected to catalytic hydrogenation. The mixture is filtered to remove the catalyst and the filtrate is concentrated to obtain quantitative yield of ethyl 4-aminophenylacetate.
4-(ethoxycarbonylmethyl)phenyl hydrazine hydrochloride[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
88%
A solution of sodium nitrite (NaN02, 4.04g, 58.6 mmol) in H20 (20 mL) was added to a cooled (-5C, ice-salt) solution of ethyl 4-aminophenylacetate (10 g, 55.8 mmol) in conc. HCI (55 mL), at a rate such that the temperature did not exceed 0C. The mixture was stirred at 0C for 10 min and then added portion-wise to a cooled (-5C, ice-salt) and rapidly-stirred solution of tin(II) chloride (SnC12, 39.67g, 209.2 mmol) in conc. HCI (30 mL), at a rate such that the temperature did not exceed 0C. The resulting cream-colored suspension was warmed to 25C and stirred at room temperature for 2-3hrs and then was filtered under vacuum. The collected solid was washed with water and ether and then air dried to afford the desired product as a pale solid (HCI salt). Precipitate that formed in the filtrates upon standing for 16 h was collected by filtration, washed with water and ether, and air-dried. The combined solids were obtained in 88% yield (11.28 g). (at)H-NMR (DMSO-d6) No. 8.85 (broad, 2H), 7.73 (broad, 1 H), 7.10 (d, J = 8.4 Hz, 2H), 6.82 (d, J = 8.4 Hz, 2H), 4.03 (q, J = 7.0 Hz, 2H), 3.53 (s, 2H), 1.16 (t, J = 7.1 Hz, 3H) ; MS LC-MS [M+H]+ = 195.0, RT = 1.11 min.
Ethyl 2-(4-aminophenyl)acetate (895 mg, 5 mmol), water (8 mL) and concentrated sulfuric acid (1.2 mL) were added in a 50 mL single-neck flask, and the mixture was cooled to 0?, then a solution of sodium nitrite (414 mg, 6 mmol) in water (2 mL) was added slowly. The reaction mixture was kept at 0? for 0.5 hours, then a cooled solution of potassium iodide (1.66 g, 10 mmol) in water (6 mL) was added, and the reaction was continued at 0? for 2.5 hours. The reaction mixture was extracted with ethyl acetate (3?50 mL), and the organic layers were combined, washed with 5% aqueous HCl (2?20 mL) and then with saturated sodium bisulfite (2?50 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated in vacuo to remove the solvent, and the residue was separated by a silica gel column (petroleum ether: ethyl acetate =10:1-1:1) to give a product (white solid, 942 mg), with a yield of 65%, which was used for the next step directly.
Step A: ethyl 2-(4-(methylsulfonamido)phenyl)acetate The solution of ethyl 2-(4-aminophenyl)acetate (500 mg, 2.79 mmol) and triethylamine (0.58 mL, 4.18 mmol) in dichloromethane (30 mL) was added methanesulfonyl chloride (0.24 mL, 3.07 mmol) dropwise at room temperature and stirred overnight. The mixture was washed with brine, dried over sodium sulfate and evaporated under reduced pressure. The residue was purified by a standard method to give desired compound. LC-MS: m/z (M+H)=258.3
With triethylamine; In dichloromethane; at 20℃;
Step A: ethyl 2-(4-(methylsulfonamido)phenyl)acetate The solution of ethyl 2-(4-aminophenyl)acetate (500 mg, 2.79 mmol) and triethylamine (0.58 mL, 4.18 mmol) in dichloromethane (30 mL) was added methanesulfonyl chloride (0.24 mL, 3.07 mmol) dropwise at room temperature and stirred overnight. The mixture was washed with brine, dried over sodium sulfate and evaporated under reduced pressure. The residue was purified by a standard method to give desired compound. LC-MS : m/z (M+H) = 258.3
With triethylamine; In dichloromethane; at 20℃;
Step A: ethyl 2-(4-(methylsulfonamido)phenyl)acetate The solution of ethyl 2-(4-aminophenyl)acetate (500 mg, 2.79 mmol) and triethylamine (0.58 mL, 4.18 mmol) in dichloromethane (30 mL) was added methanesulfonyl chloride (0.24 mL, 3.07 mmol) dropwise at room temperature and stirred overnight. The mixture was washed with brine, dried over sodium sulfate and evaporated under reduced pressure. The residue was purified by a standard method to give desired compound. LC-MS : m/z (M+H) = 258.3
With iodine; sodium hydrogencarbonate; In water; acetonitrile; at 0 - 20℃; for 15h;
<strong>[5438-70-0]Ethyl 4-aminophenylacetate</strong> (21.2 g, 0.12 mol) was dissolved in acetonitrile (100 ml) followed by the addition of sodium hydrogen carbonate (2Og, 0.24 mol) and water (200 ml). The mixture was cooled to 0 0C and iodine (31 g, 0.12 mol) was added in 5 portions over 30 seconds whilst stirring vigorously. The black reaction mixture was strirred for an additional 15 hours whilst warming up to room temperature. Water was added and the mixture was extracted using diethyl ether (5xl00ml). The combined organic extracts were washed with water, saturated sodium thiosulfate solution and brine and dried over sodium sulphate, filtered and adsorbed onto silica gel. Purification by flash chromatography on silica gel using 5- 10% ethyl acetate in isohexane as eluant yielded the title compound as a red oil (21.5 g, 59%).
58%
With iodine; sodium hydrogencarbonate; In water; acetonitrile; at 0 - 20℃;
Ethyl 2-(4-aminophenyl)acetate (5.3g, 29.6mmol) was dissolved in 20 mL of acetonitrile, followed by the addition of NaHCO3(5 g, 59.2 mmol) and 50 mL of water. The reaction mixture was cooled to 0oC, iodine (7.8 g, 29.6 mmol) was added slowly. The black reaction mixture was stirred at room temperature overnight. TLC showed the reaction was completed and water was added. The reaction mixture was extracted with ethyl acetate. The organic layer was washed with saturated sodium thiosulfate solution and brine, dried over anhydrous Na2SO4, filtered, concentrated and purified by silica gel column chromatography (eluted with petroleum) to give ethyl 2-(4-amino-3-iodophenyl)acetate as a solid (5.3g, yield: 58%), 305.9(M+H)+.
58%
With iodine; sodium hydrogencarbonate; In water; acetonitrile; at 0 - 20℃;
[00194] Ethyl 2-(4-aminophenyl)acetate (5.3g, 29.6mmol) was dissolved in 20 mL of acetonitrile, followed by the addition of NaHCO3 (5 g, 59.2 mmol) and 50 mL of water. The reaction mixture was cooled to 0 oC, iodine (7.8 g, 29.6 mmol) was added slowly. The black reaction mixture was stirred at room temperature overnight. TLC showed the reaction was completed and water was added. The reaction mixture was extracted with ethyl acetate. The organic layer was washed with saturated sodium thiosulfate solution and brine, dried over anhydrous Na2SO4, filtered, concentrated and purified by silica gel column chromatography (eluted with petroleum) to give ethyl 2-(4-amino-3-iodophenyl)acetate as a solid (5.3g, yield: 58%), 305.9(M+H)+.
46%
With Iodine monochloride; triethylamine; In hexane; dichloromethane; ethyl acetate;
1. (4-Amino-3-iodo-phenyl) acetic acid ethyl ester To a cooled solution (5 C.) of (4-aminophenyl)acetic acid ethyl ester (25 g, 0.39 mol) in CH2Cl2 (150 mL) is added triethylamine (14.1 g, 0.139 mmol) followed by a solution of iodine monochloride (21.5 g, 0.132 mol) in CH2Cl2 (100 mL). Cooling is removed and the reaction mixture is stirred for 4 hours at room temperature. The solution is concentrated in vacuo and chromatographed with a gradient of hexane/ethyl acetate (5%-30%) within 1 hour to give the desired product (19.5 g, 46%). MS: 305.9 (M+1)+.
26%
With Iodine monochloride; sodium carbonate; In diethyl ether; water; at 20℃; for 4h;Darkness;
ethyl 2-(4-amino-3-iodophenyl)acetate - In a reactor protected from light, at rt, were added Et20 (93 mL), sat. Na2C03 (15 mL) and ethyl 2-(4-aminophenyl)acetate (2.50 g, 13.9 mmol). After few minutes of stirring, iodine monochloride (1 .14 mL, 22.7 mmol) was added to the solution. The Ex.8 reaction mixture was stirred at rt for 4h. The mixture was poured into water and the aqueous layer was extracted with EtOAc. The combined organic phase was dried over MgS04, filtered and the solution was concentrated under reduced pressure. The crude material was purified by column chromatography on silica gel (cyclohexane/EtOAc, 8:2) - Yield: 26% ; Appearance : yellowish oil ; 1 H NMR, d (ppm) (DMSO-d6): 1 .17 (t, 3H, J=7.1 Hz); 3.44 (s, 2H); 4.05 (q, 2H, J=7.1 Hz); 5.18 (s, 2H); 6.70 (d, 1 H, J=8.2Hz); 6.97 (dd, 1 H, J=8.3Hz, J=1 .9Hz); 7.45 (d, 1 H, J=1 .9Hz)
With nitric acid; In acetic acid; at 100℃; for 4h;
To a solution of 4- (aminophenyl) acetic acid ethyl ester (538 mg, 3.0 mmole) in acetic acid (20 mL) was added nitric acid (90%, 420 mg, 6 mmole). The reaction mixture was stirred at 100 C for 4 h. The reaction was cooled to rt. Acetic acid was partially removed under vacuum. The residue was diluted with EtOAc. The pH of the solution was adjusted to 8-9 with 10% NaOH. It was washed with water and brine, dried over Na2S04, filtered and evaporated. The crude product was isolated by silica gel chromatography to give 128 mg (20% yield) of a bright yellow solid. It was taken into the next step without further purification.
With trifluoroacetic acid; In toluene; at 60℃; for 24h;
A mixture of ethyl-2- (4-aminophenyl) acetate (0.161 mol), KOCN (0.322 mol) and TFA (0.225 mol) in toluene [(250ML)] was stirred at [60C] for 24 hours, then brought to room temperature and filtered. The precipitate was washed with H20, then with diethyl ether and dried under a vacuo. Yielding: intermediate 31 (100%).
ethyl [4-({(2E)-3-[5-(4-fluorophenyl)-1-methyl-1H-pyrazol-4-yl]prop-2-enoyl}amino)phenyl]acetate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
89%
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In DMF (N,N-dimethyl-formamide); at 20℃; for 15h;
A mixture of ethyl (4-aminophenyl) acetate (0. 88 g), (2E)- 3- [5- (4-FLUOROPHENYL)-1-METHYL-LH-PYRAZOL-4-YL] ACRYLIC acid (1.0 g), 1-HYDROXY-LH-1, 2,3-benzotriazole hydrate (0.81 g), 1-ETHYL- 3- (3-dimethylaminopropyl) carbodiimide hydrochloride (1.02 g) and N, N-dimethylformamide (30 ML) was stirred at room temperature for 15 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with IN hydrochloric acid, saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate, and concentrated to give ethyl [4- ({(2E)-3-[5-(4-fluorophenyl)-1-methyl-1H-pyrazol-4-yl]prop-2- enoyl} amino) phenyl] acetate as colorless crystals (1.49 g, yield 89%). Recrystallization thereof from ethyl acetate-hexane gave colorless prism crystals. melting point: 177-178C.
Step d : Ethyl [4- (2-heptyloxy-4-iodobenzylamino)- phenyl] acetate; A solution of ethyl (4-aminophenyl) acetate (1.76 g, 9.84 mmol) and acetic acid (0.71 ml) in DMF (71 ml) is added to a solution of 2-heptyloxy- 4-iodobenzaldehyde of Step c (3.1 g, 8.94 mmol), acetic acid (0.71 ml) in DMF (71 ml). The mixture is stirred for 12 hours and then 1.12 g of sodium cyanoborohydride (17.89 mmol) is added. The mixture is heated at 60C for 4 hours. The desired product is extracted by addition of ethyl ether. The organic phase is washed with brine and then with water, dried with magnesium sulphate and concentrated using a rotary evaporator. The product is purified by chromatography on a silica column, eluted with a heptane/ethyl acetate 9: 1 mixture. After evaporation of the solvents, 4.11 g (96%) of the expected compound are recovered in the form of a yellow oil. 1H NMR/CDC13 : 0.9 (t, 3H); 1.2 to 1.4 (m, 7H); 1.5 (m, 2H); 1.8 (m, 2H); 3.5 (s, 2H); 4 (t, 2H); 4.1 (q, 2H); 4.3 (s, 2H); 6.6 (d, 2H); 7 (d, 1H) ; 7.1 (dd, 2H); 7.2 (d, 1H) ; 7.25 (d, 1H) ; 7.3 (s, 1H).
4-[(4S)-fluoro-1-[4-[N'-(2-trifluoromethylphenyl)ureido]phenylacetyl]-(2S)-pyrrolidinylmethoxy]benzoic Acid[ No CAS ]
[ 317356-44-8 ]
Yield
Reaction Conditions
Operation in experiment
84%
With triethylamine; In tetrahydrofuran;
Example 69 4-[(4S)-fluoro-1-[4-[N'-(2-trifluoromethylphenyl)ureido]phenylacetyl]-(2S)-pyrrolidinylmethoxy]benzoic Acid To a stirred solution of ethyl 4-aminophenylacetate (1.13 g, 6.31 mmol) and Et3N (965 ml, 6.92 mmol) in THF (10 ml) was added 2-trifluoromethylphenyl isocyanate (953 ml, 6.31 mmol) and the reaction mixture was stirred at room temperature for 2 days. Resulting precipitate was collected under a reduced pressure and the filtrate was washed with n-hexane to give ethyl 4-[N'-(2-trifluoromethylphenyl)ureido]phenylacetate (1.93 g, 84%) as white needles. mp 137-1390C; 1H-NMR (CDCl3) delta 1.25-1.29 (m, 3H), 3.59 (s, 2H), 4.15-4.20 (m, 2H), 7.05 (br s, 1H), 7.13-7.23 (m, 6H), 7.47-7.51 (m, 1H), 7.54-7.56 (m, 1H), 8.01-8.03 (m, 1H).
(34-1) 2-Amino-6-ethoxycarbonylmethylbenzothiazole <strong>[5438-70-0]Ethyl 4-aminophenylacetate</strong> (18 g) was dissolved in acetic acid (120 ml) and ethyl thiocyanate (29.3 g) was added thereto. Under ice cooling, bromine (6.2 ml) was added dropwise thereinto over 45 minutes while maintaining the reaction temperature at about 10 C. After the completion of the addition, the resultant mixture was stirred at room temperature for 1.5 hr and then at 80 C. for about 2 hr until the reaction was completed. Then the reaction solution was poured into ice water, basified with an 8 N aqueous solution of sodium hydroxide, extracted with chloroform, washed with water, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure to give the title compound (22.23 g) as orange crystals (yield: 93.66%). 1H-NMR (400 MHz, CDCl3): delta(ppm) 1.26(3H, t, J=7.2Hz), 3.65(2H, s), 4.16(2H, q, J=7.2Hz), 5.31(2H, br-s), 7.22(1H, dd, J=2.0, 8.4Hz), 7.48(1H, d, J=8.4Hz), 7.53(1H, d, J=2.0Hz).
In N,N-dimethyl acetamide; at 160℃; for 0.5h;Microwave irradiation; Sealed tube;
Example 1. Preparation 1 - Preparation of Forumula III Ethyl 4-aminophenyl acetate (3.67 g, 20.45 mmol) was added to a 20 mL microwave vial along with 4-bromo-l-fluoro-2-nitrobenzene (3.00 g, 13.64 mmol) and DMA (10 mL). The reaction mixture was sealed and placed under microwave irradiation for 30 minutes at 160 C. Water was added to the crude reaction mixture and the product was extracted with EtOAc. The organic extract was washed with brine lx, acidified water (pH ~4) 2x, and brine 2x. The organic layer was collected then dried with MgS04. The concentrated crude was purified using flash chromatography with hexanes/EtOAc to afford ethyl 2-(4-((4-bromo-2-nitrophenyl)amino)phenyl)acetate 3 as a blood-red oil (4.2 g, 81 ). ESMS m/z 379 (M+H)+.
In 1-methyl-pyrrolidin-2-one; at 110℃; for 48h;
Step 25.5: r4-(4-Bromo-2-nitro-phenylamino)-phenvn-acetic acid ethyl ester; A mixture of 1-bromo-4-fluoro-3-nitrobenzene (MATRIX SCIENTIFIC) (10.7 g, 48.7 mmol) and 4-aminophenylacetic acid ethyl ester (8.7 g, 48.7 mmol) in NMP (50 ml_) is stirred for 48 h at 110 0C. The reaction mixture is allowed to cool at rt, diluted with EtOAc and H2O. The layers are separated and the aqueous phase is extracted with EtOAc. The combined organic phase is washed brine, dried (Na2SO4), filtered and concentrated. Silica gel column chromatography purification (Hexane/EtOAc, 4:1) of the crude product affords the title compound as an orange oil: ES-MS: 380.9 [M+2]+; single peak at In= 5.75 min (System 1); Rf = 0.27 (Hexane/EtOAc, 4:1).
With hydrogenchloride; potassium hydroxide; sodium hydrogencarbonate; triethylamine In N,N,N,N,N,N-hexamethylphosphoric triamide; ethanol; dichloromethane; water
109 Preparation of p-[2-(cyclopentyl)ethylamino]phenylacetic acid
EXAMPLE 109 Preparation of p-[2-(cyclopentyl)ethylamino]phenylacetic acid To a solution of cyclopentylethan-2-ol(15.0 g.) and triethylamine (14 ml.) in dry methylene chloride (320 ml.) at -8° C. is added methanesulfonylchloride (5.73 ml.), dropwise. The reaction mixture is stirred at -10° C. for 30 minutes and then diluted with methylene chloride, extracted with ice-water (250 ml.), followed by cold 10% hydrochloric acid (200 ml.); cold saturated sodium bicarbonate (200 ml.) and cold brine (200 ml.). The organic phase is dried over magnesium sulfate and the solvent removed in vacuo to provide crude mesylate. A solution of 18.1 g. of the above mesylate and 19.8 g. of ethyl p-aminophenylacetate in hexamethylphosphoramide is heated at 120° C. for 20 hours. After cooling, the reaction mixture is diluted with 30 ml. of ethanol:water (1:1) (30 ml.) and chilled. More ethanol is added and the solid material is collected. This solid is recrystallized twice from ethanol to provide the ester. A mixture of the ester, 22.0 g. of potassium hydroxide and 200 ml. of ethanol-water (8:1) is stirred under reflux for 6 hours. Concentrated hydrochloric acid (about 80 ml.) is added to the warm mixture and cooling and dilution with water affords a white solid which is collected by filtration and recrystallized from ethanol to yield the product as a white solid.
With sodium hydroxide; sodium chloride; In hexane; water; benzene;
PREPARATION 6 Ethyl 4-(isobutyrylamino)phenylacetate: Compound 6 10 g of ethyl 4-aminophenylacetate was dissolved in 100 ml of benzene and to this was added 25 ml of water. To the solution were added dropwise a solution of 6 g of isobutyryl chloride in 20 ml of benzene and a solution of 2.4 g of 93% NaOH in 25 ml of water simultaneously under stirring over 15 minutes. After completion of the dropwise addition, the reaction mixture was stirred for 3 hours and allowed to stand at room temperature overnight. After separating the benzene layer, washing it with 1N-HCl solution and further washing with a saturated solution of sodium chloride, the benzene layer was dried over anhydrous sodium sulfate. After separating sodium sulfate by filteration, the solvent was distilled off under reduced pressure and the residue was dissolved in 30 ml of benzene and crystallized from 90 ml of n-hexane. The formed crystals were separated by filteration and were dried at a temperature below 60 C. under reduced pressure to give 12.3 g of ethyl 4-(isobutyrylamino)phenylacetate (Yield: 88.3%). M.P. 92.5-93.5 C.
With sodium chloride; acetic anhydride; sodium hydrogencarbonate; In ethyl acetate;
PREPARATION 4 Ethyl 4-acetylaminophenylacetate: Compound 4 To 179.2 g (1 mole) of ethyl p-aminophenylacetate was added 800 ml of ethyl acetate and it was made to a homogeneous solution with stirring at room temperature. To the solution was added a mixed solution of 103.4 ml (1.05 mole) of acetic anhydride (96%) and 100 ml of ethyl acetate and the solution was stirred for 3 hours. After completion of the reaction, the reaction mixture was washed with a saturated solution of sodium bicarbonate and also with a saturated solution of sodium chloride. After drying the ethyl acetate layer over anhydrous magnesium sulfate, ethyl acetate was distilled off. The residue was recrystallized from ethyl acetate-n-hexane to give 206.6 g of ethyl 4-acetyl-aminophenylacetate (Yield: 93.4%). M.P. 77-78 C.
N-benzyloxycarbonyl-L-glutamic acid α-benzyl ester[ No CAS ]
[ 5438-70-0 ]
[ 543-27-1 ]
[ 83397-25-5 ]
Yield
Reaction Conditions
Operation in experiment
93%
With triethylamine;palladium; In tetrahydrofuran; ethanol; water; ethyl acetate; N,N-dimethyl-formamide;
(a) To a mixture of 250 ml of tetrahydrofuran and 250 ml of N,N-dimethylformamide were added 74.28 g (0.2 mole) of N-carbobenzoxy-L-glutamic acid alpha-benzyl ester and 28 ml (0.2 mole) of triethylamine. Under stirring with ice cooling, 26.4 ml (0.2 mole) of isobutyl chlorocarbonate was then added dropwise and stirred for 15 minutes. Thereafter, a solution of 35.84 g (0.2 mole) of ethyl p-aminophenylacetate in 50 ml of tetrahydrofuran and 50 ml of N,N-dimethylformamide was added and the mixture was stirred for 30 minutes under ice cooling and then for 8 hours at room temperature. The reaction solvent was distilled off in vacuo and to the residue were added 1,200 ml of ethyl acetate and 200 ml of water. The water layer was removed. The ethyl acetate layer was washed successively with 2 N hydrochloric acid, saturated sodium bicarbonate solution and saturated sodium chloride solution and dried over anhydrous magnesium sulfate. After the ethyl acetate was distilled off in vacuo, the residue was recrystallized from ethyl acetate-n-hexane to give an intermediate. Yield: 96.16 g (90.7%). To 53.26 g (0.1 mole) of the intermediate obtained above were added 1,600 ml of ethanol and 600 ml of water and heated until a solution was formed. Thereafter 0.5 g of palladium black was added and the mixture was subjected to hydrogenation at atmospheric pressure to eliminate the protective group. Palladium was filtered off while hot and the filtrate was treated with activated charcoal and concentrated. The precipitated crystals were then collected by filtration, washed with ice water and dried to give 28.57 g (93% yield) of N-(4-ethoxycarbonylmethylphenyl)-L-glutamine, m.p. 179.8-180.5 C. [alpha]D25 =+29.5 (c=1, 2 N HCl)
With dmap; triethylamine; In N,N-dimethyl-formamide; at 20℃; for 15h;
Example 306; 5-[(4-Aminophenylacetyl)amino]-3-(4-fluorophenyl)-4-(4-pyrimidinyl)isoxazole; a: Synthesis of ethyl- 4-tert-butoxycarbonylaminophenylacetate; To 23 mL of a DMF solution containing 1.94 g of ethyl-4-aminophenyl acetate, 0.15 g of DMAP, 4.6 mL of triethylamine and 3 g of di-t-butyl dicarbonate were added, followed by 15 hours' stirring at room temperature. After addition of water, the reaction liquid was extracted with ether. The ether extract was dried over anhydrous magnesium sulfate and from which the solvent was distilled off under reduced pressure. Thus obtained residue was purified on 200 g silica gel chromatography (eluent, ethyl acetate: hexane = 1:5) to provide 0.70 g (yield: 17%) of the title compound as an oily substance. 1H-NMR(CDCl3)delta: 7.29(d, J=8.4Hz, 2H), 7.19(d, J=8.4Hz, 2H), 6.44(bs, 1H), 4.12(q, J=7.3Hz, 2H), 3.53(s, 2H), 1.50(s, 9H), 1.22(t, J=7.3Hz, 3H). Mass;m/e: 279(M+), 57(base).
In toluene; at 85℃; for 4h;
Step A: ethyl 2-(4-((tert-butoxycarbonyl)amino)phenyl)acetate A solution of di-tert-butyl dicarbonate (387 mg, 1.77 mmol) in toluene (5 ml) was added a vessel containing ethyl 2-(4-aminophenyl)acetate (288 mg, 1.61 mmol), the reaction mixture was heated at 85 C. for 4 h. LCMS showed that the desired product was detected, the mixture was concentrated to give the residue, the residue was purified by a standard method to give the desired product. LC-MS: m/z (M+H)=280.3
In toluene; at 85℃; for 4h;
A solution of di-tert-butyl dicarbonate (387 mg, 1.77 mmol) in toluene (5 ml) was added a vessel containing ethyl 2-(4-aminophenyl)acetate (288 mg,1.61mmol)> the reaction mixture was heated at 85 C for 4h. LCMS showed that the desired product was detected, the mixture was concentrated to give the residue, the residue was purified by a standard method to give the desired product. LC-MS : m/z (M+H)=280.3
In toluene; at 85℃; for 4h;
Step A: ethyl 2-(4-((tert-butoxycarbonyl)amino)phenyl)acetate A solution of di-tert-butyl dicarbonate (387 mg, 1.77 mmol) in toluene (5 ml) was added a vessel containing ethyl 2-(4-aminophenyl)acetate (288 mg, 1.61 mmol) , the reaction mixture was heated at 85 C for 4h. LCMS showed that the desired product was detected, the mixture was concentrated to give the residue, which was purified by a standard method to give the desired product. LC-MS : m/z (M+H)=280.3
With N-chloro-succinimide; In chloroform; at 20℃; for 0.25h;
Description 3;Ethyl (4-amino-3-chlorophenyl)acetate;Ethyl-4-aminophenylacetate (2Og, 112mmol) was dissolved in chloroform (300ml) and treated with N-chlorosuccinimde (14.92g, 112mmol) and stirred for 15 minutes at room temperature under argon. Reaction mixture was washed with water, brine and dried over magnesium sulphate. Evaporated to a brown oil which was purified by chromatography on silica gel eluting with ethyl acetate (0- 45%) in hexane to give the title compound as a orange oil (10.12g, 47.4mmol). LC/MS: Rt=2.59, [MH]+ 214.
With N-chloro-succinimide; In chloroform; at 20℃; for 0.25h;
Description 2Ethyl (4-amino-3-chlorophenyl)acetateEthyl-4-aminophenylacetate (2Og, 112mmol) was dissolved in chloroform (300ml) and treated with N-chlorosuccinimde (14.92g, 112mmol) and stirred for 15 minutes at room temperature under argon. Reaction mixture was washed with water, brine and dried over magnesium sulphate. Evaporated to a brown oil which was purified by chromatography on silica gel eluting with ethyl acetate (0- 45%) in hexane to give the title compound as a orange oil (10.12g, 47.4mmol). LC/MS: Rt=2.59, [MH]+ 214.
With N-chloro-succinimide; In chloroform; at 20℃; for 0.25h;
Description 3; Ethyl (4-amino-3-chlorophenyl)acetate; Ethyl-4-aminophenylacetate (2Og, 112mmol) was dissolved in chloroform (300ml) ? and treated with N-chlorosuccinimde (14.92g, 112mmol) and stirred for 15 minutes at room temperature under argon. Reaction mixture was washed with water, brine and dried over magnesium sulphate. Evaporated to a brown oil which was purified by chromatography on silica gel eluting with ethyl acetate (0- 45%) in hexane to give the title compound as a orange oil (10.12g, 47.4mmol). LC/MS: Rt=2.59, [MH]+ 214.
With N-chloro-succinimide; In chloroform; at 20℃; for 0.25h;
Intermediate 3: Ethyl (4-amino-3-chlorophenyl)acetate; N-chlorosuccinimide (1 eq, 7.45g, 55.8mmol) was added to a solution of ethyl A- aminophenylacetate (1 Og, 55.8mmol) in chloroform (20OmIs). The reaction mixture was stirred at room temperature, under argon, for 15 minutes.The reaction mixture was washed with water (25OmIs) and the organic layer collected using a hydrophobic frit. This was evaporated to dryness to give a dark brown oil, 9.8g. This was purified in 2 batches using the Biotage Horizon, reverse phase 100gC18 cartridge. The product was eluted using a 5-100% gradient of acetonitrile in water. Approx. 120OmIs solvent was used for each batch.Clean fractions from the first batch were combined and evaporated to dryness to yield the title compound as a dark red/brown oil, 2.28g. MS (ES+) m/z 214 [M+H]+ (CiOH1235CINO2). 1H-NMR (400MHz, CDCI3) delta 1.25 (3H, t, J 11.2), 3.47(2H, s), 4.00 (2H, bs), 4.14 (2H, t, J 12), 6.71 (1 H, d, J 13.2), 6.98 (1 H, dd, J13.3, J 3.2), 7.19 (1 H, d, J 3.2).
With N-chloro-succinimide; In acetonitrile; at 50℃; for 1h;Inert atmosphere;
21.1 (4-Amino-3-chloro-phenyl)-acetic acid ethyl ester; N-Chlorosuccinimide (391 mg, 2.93 mmol) was added to a solution of (4-amino-phenyl)-acetic acid ethyl ester (500 mg, 2.79 mmol; [5438-70-0]) in acetonitrile (10 ml) under an argon atmosphere. The reaction mixture was heated to 50 C. for 1 h. The solvent was removed under reduced pressure and the residue taken up in iPrOAc/brine 1/1. The layers were separated and the aqueous layer was extracted with iPrOAc. The combined organic layers were dried over Na2SO4. The solvent was removed under reduced pressure and the residue was purified by column chromatography (silica gel, iPrOAc/heptane) to give the title compound (481 mg, 2.25 mmol; 81%) as brown oil. MS: m/e=214.1 [M+H+].
With N-chloro-succinimide; In chloroform; at 20℃; for 0.25h;
Ethyl-4-aminophenylacetate (2Og, 112mmol) was dissolved in chloroform (300ml) and treated with N-chlorosuccinimde (14.92g, 112mmol) and stirred for 15 minutes at room temperature under argon. Reaction mixture was washed with water, brine and dried over magnesium sulphate. Evaporated to a brown oil which was purified by chromatography on silica gel eluting with ethyl acetate (0- 45%) in hexane to give the title compound as a orange oil (10.12g, 47.4mmol). LC/MS: Rt=2.59, [MH]+ 214.
With N-chloro-succinimide; In chloroform; at 20℃; for 0.25h;Inert atmosphere;
N-chlorosuccinimide (1 eq, 7.45g, 55.8mmol) was added to a solution of ethyl A- aminophenylacetate (10g, 55.8mmol) in chloroform (20OmIs). The reaction mixture was stirred at room temperature, under argon, for 15 minutes.The reaction mixture was washed with water (25OmIs) and the organic layer collected using a hydrophobic frit. This was evaporated to dryness to give a dark brown oil,9.8g.This was purified in 2 batches using the Biotage Horizon, reverse phase 100g C18 cartridge. The product was eluted using a 5-100% gradient of acetonitrile in water. Approx. 120OmIs solvent was used for each batch.Clean fractions from the first batch were combined and evaporated to dryness to yield the title compound as a dark red/brown oil, 2.28g. MS (ES+) m/z 214 [M+H]+ (C1OH1235CINO2). 1H-NMR (400MHz, CDCI3) delta 1.25 (3H, t, J 1 1.2), 3.47 (2H, s), 4.00 (2H, bs), 4.14 (2H, t, J 12), 6.71 (1 H, d, J 13.2), 6.98 (1 H, dd, J 13.3, J 3.2), 7.19 (1 H, d, J 3.2).
In 1-methyl-pyrrolidin-2-one; at 150℃; for 0.5h;Molecular sieve; Microwave irradiation;
Description 24Ethyl {4-[4,9-bis(ethyloxy)-6-methyl-1 ,3-dioxo-1 ,3-dihydro-2H-benzo[f)isoindol-2- yl]phenyl}acetatei ^-BisCethyloxyJ-delta-methyl^.S-naphthalenedicarboxylic acid (0.1g, 0.3mmol), ethyl (4-aminophenyl)acetate (130mg, 0.63mmol) and 4A powdered molecular sieves (120mg) were suspended in N-methylpyrrolidine (1ml) in a microwave vial, sealed and heated in a microwave at 15O0C for 30 minutes. Cooled, diluted with EtOAc and washed with water. The aqueous was extracted with further EtOAc. The combined organics were washed with 2M HCI, brine, dried (MgSO4), and concentrated in vacuo. Chromatography purification was carried out (1Og Sitheta2, elution with 5-30%EtOAc in hexanes) to yield the title compound as an off white solid (105mg, 75%). LC/MS: Rt=3.88, [MH]+ 462.
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃;
To a solution of (S)-2-(tert- butoxycarbonylamino)-3-phenylpropanoic acid (1.5 g, 5.65 mmol) in DMF (15 mL) was added EDC (2.168 g, 11.31 mmol), etaOBT (1.732 g, 11.31 mmol) and DIEA(3.95 mL, 22.62 mmol) and stirred at rt for 15 min. To this mixture was added ethyl 2-(4-aminophenyl)acetate (1.013 g, 5.65 mmol) and stirred overnight under argon. The reaction mixture was diluted with ethylacetate, washed with 10% LiCl solution. The organic layers were pooled, dried over MgSO4 and subjected to flash column chromatography using DCM/MeOeta to give IA. (2.3 g, 95 %). LCMS: m/z 427.3 (M+eta)+. 1H NMR (CD3OD, 400 MHz) delta: 7.35 (d, J= 8.25 Hz, 2 H) 7.18 (d, J= 3.85 Hz, 4 H) 7.12 (d, J= 7.70 Hz, 3 H) 4.34 (t, J= 7.15 Hz, 1 H) 4.04 (q, J= 7.15 <n="104"/>Hz, 2 H) 3.50 (s, 2 H) 3.23 (m, 2H) 3.03 (dd, J= 13.47, 6.32 Hz, 1 H) 2.85 (dd, J= 13.47, 8.52 Hz, I H) 1.30 (s, 9 H) 1.15 (t, J= 6.87 Hz, 3 H) ppm.
Description 12: ethyl (4-[5-acetyl-3-ethyl-4-methyl-1,3-thiazol-2(3H)- ylidene]amino}phenyl)acetate; A mixture of ethyl-4-aminophenylacetate (1.79g, lOmmol), ethyl isothiocycanate (1.04g, 12mmol, 1.05ml) and triethylamine (2ml) in ethanol (50ml) was stirred at reflux for 2 hours.The solvent was then removed by rotary evaporation, the resulting material was then suspended in toluene (50ml) and treated with 3-chloro-2,4-pentanedione (1.34g, l Ommol,1.19ml) and the whole mix stirred at 9O0C (oil bath temperature) for 3 hours. The reaction mix was allowed to cool and diluted with ethyl acetate (50ml). The mix was washed with saturated aqueous sodium bicarbonate solution (80ml), and then brine solution (50ml).The organic layer was dried over sodium sulphate and the solvent removed by rotary evaporation to give a brown oil (2.57g), which was dissolved in dichloromethane and added to a 2Og pre-packed isolute silica column and eluted from 0-50% ethyl acetate in petroleum ether to give the title compound as a yellow oil (2.06g, 60%).LC/MS (ES): Found 347 (ES+), retention time 2.84mins. C18H22N2O3S requires 346.1H NMR (400MHz, CDCI3): delta 1.26 (3H, m), 1.35 (3H, t, J=7Hz), 2.25 (3H, s), 2.62 (3H, s),3.59 (2H, s), 4.04 (2H, q, J=7Hz), 4.15 (2H, m), 7.01 (2H, m), 7.27 (2H, m).
With dmap; In N,N-dimethyl-formamide; at 110℃; for 18h;
A mixture of 6-chloro-2H-3,1-benzoxazine-2,4(1 H)-dione (998mg, 5.05mmol), ethyl (4-aminophenyl)acetate (996mg, 5.56mmol) and 4-dimethylaminopyridine (31 mg, 0.252mmol) in dimethylformamide (20ml) was heated at 1 100C for 18 hrs. After cooling the solvent was evaporated and the residue partitioned between saturated aqueous sodium bicarbonate and ethyl acetate. The organic layer was separated, dried (Na2SO4) and the solvent evaporated to afford a brown oil. This was purified by flash chromatography (Biotage SP4, 40+M, 0 - > 50% ethyl acetate / hexane) to afford the title compound as a yellow solid (670mg, 40%). MS (ES+) m/z 333 [M+H+] (Ci7H1735CIN2O3).1H-NMR (250MHz, CDCI3) delta 1.26 (3H, t, J 7.25), 3.60 (2H, s), 4.15 (2H, q, J 7.25), 5.30 (2H, broad s), 6.65 (1 H, d, J 8.75), 7.19 (1 H, dd, J 8.75, 2.5), 2.28 (2H, m), 7.42 (1 H, d, J 2.25), 7.51 (2H, m), 7.67 (1 H, broad s).
<strong>[3260-89-7]2-chloro-6-(methyloxy)benzoic acid</strong> (460mg, 2.47mmol) in thionyl chloride (5ml) was stirred at 600C for 3hrs. The excess thionyl chloride was evaporated to afford a yellow oil. This was dissolved in chloroform (5ml) and ethyl (4-aminophenyl)acetate (443mg, 2.47mmol) added and the reaction was heated at 600C for 1 hour. After cooling the solution was poured into saturated sodium bicarbonate and the phases separated. The organic layer was dried (Na2SO4), solvent evaporated and the residue purified by flash chromatography (SP4, 25+M, 0 ? 50% ethyl acetate / hexane) to afford the title as a light brown solid (682mg, 76%). MS (ES+) m/z 348 [M+H+] (Ci8H1835CINO4).1H-NMR (250MHz, CDCI3) 51.26 (3H, t, J 7), 3.60 (2H, s), 3.85 (3H, s), 4.14 (2H1 q, J 7.25), 6.85 (2H, d, J 8.5) 7.02 (2H, d, J 7.75), 7.30 (3H, m), 7.41 (1 H, broad s), 7.60 (2H, d, J 8.5).
With caesium carbonate;palladium diacetate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; In 1,4-dioxane; at 90℃; for 2h;
To a solution of N-[4-(2-chloropyrimidin-4-yl)phenyl]-2-methyl- propanamide (0.525 g, 1.75 mmol) in /?-dioxane (30 mL), 4-aminophenyl acetic acid ethyl ester (0.313 g, 1.75 mmol), Cs2C03 ( 1.14 g, 3.5 mmol), BINAP (0.201 g, 0.324 mmol), and Pd(OAc)2 (0.067 g, 0.298 mmol) were added. The resulting mixture was stirred for 2 h at 90 C. The mixture was allowed to cool, diluted with EtOAc, and concentrated onto silica. The residue was purified by column chromatography (Si02, EtOAc/Hexanes, 0-100%) to afford the title compound (0.48 g, 62%).
With N-ethyl-N,N-diisopropylamine; In butan-1-ol; at 115℃; for 192h;Inert atmosphere;
To a vial with stirbar were added 5,6-dichloro-pyrimidin-4-ylamine (1 .4 g, 8.537 mmol, 1 .0 eq), (4-amino-phenyl)-acetic acid ethyl ester (4.3 g, 23.993 mmol, 2.8 eq), Lambda/JV-diisopropylethylamine (4.5 ml, 25.61 1 mmol, 3.0 eq), dissolved in n-butanol (100 ml). The reaction suspension was flushed with nitrogen and heated to 1 15C for 8 days. The mixture was concentrated in vacuo, dissolved in EtOAc, washed with water (2x) and brine (1 x), dried over sodium sulfate, and concentrated in vacuo. The crude mixture was purified using Biotage column chromatography eluting from 30-70 % EtOAc/hexanes. Fractions containing the desired product were combined and concentrated under reduced pressure to afford (4-(6-amino-5-chloro-pyrimidin-4- ylamino)-phenyl)-acetic acid ethyl ester (1 .71 g, 49 % yield) as white crystals. MS: m/z = 307 [M+H]+. 1 H-NMR (DMSO-d6) delta 8.41 (s, 1 H), 7.93 (s, 1 H), 7.55 (d, 2H), 7.19 (d, 2H), 6.76 (bs, 2H), 4.1 1 (q, 2H), 1 .21 (t, 3H).
To a solution of 50 (50.0 mg, 0.134 mmol) in DMF (1.0 mL) was added ethyl 2-(4-aminophenyl)acetate (48.1 mg, 0.268 mmol) and the reaction mixture was stirred at 65 C for 15 h. After cooling, sat. NaHCO3 aqueous solution (1.0 mL) and H2O (3.0 mL) were added to the reaction mixture and the mixture was extracted with EtOAc. The combined organic layer was washed with brine, dried over Na2SO4, and concentrated in vacuo. The residue was chromatographed (EtOAc/hexane = 0% to 30%) to give ethyl 2-[4-[(2-phenyl-6,7,8,9-tetrahydro-5H-cyclohepta[d]pyrimidin-4-yl)amino]phenyl]acetate (51) (52.9 mg, 0.132 mmol, 98%) as a colorless amorphous solid. 1H NMR (CDCl 3) delta: 1.27 (3H, t, J = 7.3 Hz), 1.70-1.79 (4H, m), 1.90-1.95 (2H, m), 2.69-2.72 (2H, m), 3.01-3.04 (2H, m), 3.62 (2H, s), 4.17 (2H, q, J = 7.3 Hz), 6.59 (1H, s), 7.31 (2H, d, J = 8.6 Hz), 7.40-7.46 (3H, m), 7.65 (2H, d, J = 8.6 Hz), 8.37-8.39 (2H, m).To a solution of 51 (52.0 mg, 0.130 mmol) in THF (2.0 mL) and H2O (1.0 mL) was added 1 N NaOH aqueous solution (0.390 mL) and the mixture was stirred for 15 h. After 1 N HCl aqueous solution (0.390 mL) was added, the solvent was evaporated. H2O was added to the residue and the mixture was triturated. The resulting precipitate was collected by filtration to give the title compound (47.1 mg, 0.126 mmol, 97%) as a colorless solid. 1H NMR (DMSO-d6) delta: 1.61-1.67 (4H, m), 1.84-1.89 (2H, m), 2.86-2.88 (2H, m), 2.94-2.97 (2H, m), 3.55 (2H, s), 7.24 (2H, d, J = 8.6 Hz), 7.43-7.48 (3H, m), 7.68 (2H, d, J = 8.6 Hz), 8.25-8.28 (2H, m), 8.66 (1H, s), 12.27 (1H, s). MS (ESI) m/z: 374 (M+H)+.
To a solution of 54 (49.8 mg, 0.144 mmol) in DMF (1.0 mL) was added ethyl 2-(4-aminophenyl)acetate (51.5 mg, 0.287 mmol) and the reaction mixture was stirred at 65 C for 15 h. After cooling, sat. NaHCO3 aqueous solution (1.0 mL) and H2O (3.0 mL) were added to the reaction mixture and the mixture was extracted with EtOAc. The combined organic layer was washed with brine, dried over Na2SO4, and concentrated in vacuo. The residue was chromatographed (EtOAc/hexane = 0% to 50%) to give ethyl 2-[4-[(2-phenyl-5,7-dihydrofuro[3,4-d]pyrimidin-4-yl)amino]phenyl]acetate (55) (52.5 mg, 0.140 mmol, 97%) as a pale yellow amorphous solid. 1H NMR (CDCl 3) delta: 1.27 (3H, t, J = 7.4 Hz), 3.64 (2H, s), 4.18 (2H, q, J = 7.4 Hz), 4.83 (2H, t, J = 2.3 Hz), 5.02 (2H, t, J = 2.3 Hz), 6.44 (1H, s), 7.33 (2H, d, J = 8.6 Hz), 7.46-7.50 (5H, m), 8.37-8.40 (2H, m). MS (ESI) m/z: 376 (M+H)+.To a solution of 55 (52.0 mg, 0.139 mmol) in THF (2.0 mL) and H2O (0.5 mL) was added 1 N NaOH aqueous solution (0.277 mL) and the mixture was stirred for 15 h. After 1 N HCl aqueous solution (0.277 mL) was added, the solvent was evaporated. H2O was added to the residue and the mixture was triturated. The resulting precipitate was collected by filtration to give the title compound (47.5 mg, 0.136 mmol, 98%) as a colorless solid. 1H NMR (DMSO-d6) delta: 3.57 (2H, s), 4.94 (2H, s), 5.06 (2H, s), 7.29 (2H, d, J = 8.6 Hz), 7.48-7.51 (3H, m), 7.75 (2H, d, J = 8.6 Hz), 8.32-8.34 (2H, m), 9.20 (1H, s), 12.31 (1H, s). MS (ESI) m/z: 348 (M+H)+.
With potassium carbonate; In acetonitrile; at 85℃; for 2h;
To a solution of 56 (161 mg, 0.670 mmol) in MeCN (3.0 mL) were added ethyl 2-(4-aminophenyl)acetate (100 mg, 0.558 mmol) and K2CO3 (154 mg, 1.12 mmol). The reaction mixture was stirred at 85 C for 2 h. After cooling, the reaction mixture was filtered and the filtrate was concentrated in vacuo. The residue was chromatographed (EtOAc/hexane = 0% to 30%) to give ethyl 2-[4-[(2-phenylquinazolin-4-yl)amino]phenyl]acetate (57) (144 mg, 0.376 mmol, 67%) as a colorless amorphous solid. 1H NMR (CDCl 3) delta: 1.30 (3H, t, J = 7.2 Hz), 3.68 (2H, s), 4.21 (2H, q, J = 7.2 Hz), 7.41 (2H, d, J = 8.0 Hz), 7.48-7.57 (5H, m), 7.81-7.84 (1H, m), 7.88-7.91 (3H, m), 8.02 (1H, d, J = 8.6 Hz), 8.56 (2H, dd, J = 8.0, 1.7 Hz). MS (ESI) m/z: 384 (M+H)+.To a solution of 57 (140 mg, 0.365 mmol) in THF (5 mL), EtOH (3 mL), and H2O (2 mL) was added 1 N NaOH aqueous solution (1.10 mL) and the mixture was stirred for 13 h. After 1 N HCl aqueous solution (1.10 mL) was added, the solvent was evaporated. H2O was added to the residue and the mixture was triturated. The resulting precipitate was collected by filtration to give the title compound (64.0 mg, 0.180 mmol, 49%) as a pale yellow solid. 1H NMR (DMSO-d6) delta: 3.60 (2H, s), 7.35 (2H, d, J = 8.0 Hz), 7.49-7.54 (3H, m), 7.60-7.63 (1H, m), 7.87 (2H, d, J = 3.4 Hz), 7.92 (2H, d, J = 8.0 Hz), 8.43 (2H, dd, J = 7.2, 2.0 Hz), 8.58 (1H, d, J = 8.0 Hz), 9.90 (1H, s), 12.32 (1H, s). MS (ESI) m/z: 356 (M+H)+.
To a solution of 1H-thieno[2,3-d]pyrimidine-2,4-dione (62) (92.8 mg, 0.552 mmol) in toluene (1 mL) were added N,N-dimethylaniline (0.140 mL, 1.10 mmol) and phosphoryl chloride (0.280 mL, 3.00 mmol). The reaction mixture was warmed to 100 °C and stirred for 3 h. After cooling to room temperature, H2O was added to the reaction mixture and the mixture was extracted with CHCl3. The combined organic layer was washed with brine, dried over Na2SO4, and concentrated in vacuo to give <strong>[18740-39-1]2,4-dichlorothieno[2,3-d]pyrimidine</strong> (63). This compound was used for the next reaction without further purification.To a solution of 63 in DMF (4 mL) was added ethyl 2-(4-aminophenyl)acetate (95.2 mg, 0.531 mmol) and the reaction mixture was stirred at 65 °C for 2.5 h. After cooling, H2O was added to the reaction mixture and the mixture was extracted with EtOAc. The combined organic layer was washed with brine, dried over Na2SO4, and concentrated in vacuo. The residue was chromatographed (EtOAc/hexane = 0percent to 100percent) to give the title compound (85.9 mg, 0.247 mmol, 45percent) as a colorless solid. 1H NMR (CDCl 3) delta: 1.28 (3H, t, J = 7.4 Hz), 3.64 (2H, s), 4.18 (2H, q, J = 7.4 Hz), 7.03 (1H, d, J = 5.7 Hz), 7.21 (1H, s), 7.29 (1H, d, J = 5.7 Hz), 7.32 (2H, d, J = 8.6 Hz), 7.56 (2H, d, J = 8.6 Hz).
ethyl 2-[4-[(2-phenyl-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino]phenyl]acetate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
98%
In N,N-dimethyl-formamide; at 65℃; for 23h;
To a solution of 28a (198 mg, 0.526 mmol) in DMF (3.0 mL) was added ethyl 2-(4-aminophenyl)acetate (194 mg, 1.08 mmol) and the reaction mixture was stirred at 65 C for 23 h. After cooling, H2O was added to the reaction mixture and the mixture was extracted with EtOAc. The combined organic layer was washed with brine, dried over Na2SO4, and concentrated in vacuo. The residue was chromatographed (EtOAc/hexane = 0% to 50%) to give ethyl 2-[4-[(2-phenyl-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino]phenyl]acetate (66) (209 mg, 0.515 mmol, 98%) as a pale yellow oil. 1H NMR (CDCl 3) delta: 1.26 (3H, t, J = 7.2 Hz), 2.24-2.29 (2H, m), 2.95 (2H, t, J = 6.3 Hz), 3.11 (2H, t, J = 5.7 Hz), 3.61 (2H, s), 4.16 (2H, q, J = 7.2 Hz), 6.59 (1H, s), 7.31 (2H, d, J = 8.6 Hz), 7.39-7.45 (3H, m), 7.68 (2H, d, J = 8.6 Hz), 8.33-8.36 (2H, m). MS (ESI) m/z: 406 (M+H)+.To a solution of 66 (209 mg, 0.515 mmol) in THF (2.0 mL) and MeOH (2.0 mL) was added 1 N NaOH aqueous solution (1.0 mL) and the mixture was stirred for 2 h. After 1 N HCl aqueous solution (1.0 mL) was added, the solvent was evaporated. H2O was added to the residue and the mixture was triturated. The resulting precipitate was collected by filtration to give the title compound (120 mg, 0.318 mmol, 62%) as a colorless solid. 1H NMR (DMSO-d6) delta: 2.17-2.21 (2H, m), 2.90 (2H, t, J = 6.3 Hz), 3.18 (2H, dd, J = 6.6, 4.9 Hz), 3.56 (2H, s), 7.25 (2H, d, J = 8.6 Hz), 7.43-7.47 (3H, m), 7.66 (2H, d, J = 8.6 Hz), 8.17 (1H, s), 8.21-8.23 (2H, m), 12.30 (1H, s). MS (ESI) m/z: 378 (M+H)+.
To a solution of 29 (34.8 mg, 0.0852 mmol) in DMF (1.1 mL) was added ethyl 2-(4-aminophenyl)acetate (31.8 mg, 0.177 mmol) and the reaction mixture was stirred at 65 C for 23 h. After cooling, H2O was added to the reaction mixture and the mixture was extracted with EtOAc. The combined organic layer was washed with brine, dried over Na2SO4, and concentrated in vacuo. The residue was chromatographed (EtOAc/hexane = 0% to 50%) to give ethyl 2-[4-[(5,5-dioxo-2-phenyl-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino]phenyl]acetate (30) (33.2 mg, 0.0759 mmol, 89%) as a colorless oil. 1H NMR (CDCl 3) delta: 1.27 (3H, t, J = 7.2 Hz), 2.54-2.61 (2H, m), 3.11 (2H, t, J = 6.6 Hz), 3.46-3.48 (2H, m), 3.64 (2H, s), 4.18 (2H, q, J = 7.2 Hz), 7.34 (2H, d, J = 8.6 Hz), 7.42-7.52 (3H, m), 7.66 (2H, d, J = 8.6 Hz), 8.35 (2H, dd, J = 8.6, 1.7 Hz), 8.62 (1H, s). MS (ESI) m/z: 438 (M+H)+.To a solution of 30 (33.2 mg, 0.0759 mmol) in THF (0.5 mL) and MeOH (0.5 mL) was added 1 N NaOH aqueous solution (0.3 mL) and the mixture was stirred for 14 h. After 1 N HCl aqueous solution (0.3 mL) was added, the solvent was evaporated. H2O was added to the residue and the mixture was triturated. The resulting precipitate was collected by filtration to give the title compound (18.8 mg, 0.0459 mmol, 60%) as a colorless solid. 1H NMR (DMSO-d6) delta: 2.36-2.42 (2H, m), 3.08 (2H, t, J = 6.6 Hz), 3.61 (2H, s), 3.73-3.76 (2H, m), 7.34 (2H, d, J = 8.6 Hz), 7.50-7.58 (3H, m), 7.63 (2H, d, J = 8.6 Hz), 8.26-8.28 (2H, m), 8.77 (1H, s), 12.35 (1H, s). MS (ESI) m/z: 410 (M+H)+.
To a solution of 75 (50.0 mg, 0.122 mmol) in DMF (1.0 mL) was added ethyl 2-(4-aminophenyl)acetate (44.0 mg, 0.246 mmol) and the reaction mixture was stirred at 65 C for 15 h. After cooling, sat. NaHCO3 aqueous solution and H2O were added to the reaction mixture and the mixture was extracted with EtOAc. The combined organic layer was washed with brine, dried over Na2SO4, and concentrated in vacuo. The residue was chromatographed (EtOAc/hexane = 0% to 30%) to give ethyl 2-[4-[(6,6-dioxo-2-phenyl-7,8-dihydro-5H-thiopyrano[4,3-d]pyrimidin-4-yl)amino]phenyl]acetate (76) (51.1 mg, 0.117 mmol, 96%) as a colorless amorphous solid. 1H NMR (DMSO-d6) delta: 1.20 (3H, t, J = 7.3 Hz), 3.35 (2H, t, J = 6.4 Hz), 3.62 (2H, t, J = 6.4 Hz), 3.67 (2H, s), 4.10 (2H, q, J = 7.3 Hz), 4.46 (2H, s), 7.30 (2H, d, J = 8.7 Hz), 7.47-7.50 (3H, m), 7.69 (2H, d, J = 8.7 Hz), 8.27 (2H, dd, J = 6.4, 3.2 Hz), 8.66 (1H, s). MS (ESI) m/z: 438 (M+H)+.To a solution of 76 (50.2 mg, 0.115 mmol) in THF (2.0 mL) were added H2O (0.5 mL) and 1 N NaOH aqueous solution (0.345 mL), and the mixture was stirred for 2 h. After 1 N HCl aqueous solution (0.345 mL) was added, the solvent was evaporated. H2O was added to the residue and the mixture was triturated. The resulting precipitate was collected by filtration to give the title compound (44.3 mg, 0.108 mmol, 94%) as a colorless solid. 1H NMR (DMSO-d6) delta: 3.35 (2H, t, J = 6.6 Hz), 3.58 (2H, s), 3.62 (2H, t, J = 6.6 Hz), 4.47 (2H, s), 7.29 (2H, d, J = 8.6 Hz), 7.47-7.50 (3H, m), 7.69 (2H, d, J = 8.6 Hz), 8.26-8.29 (2H, m), 8.65 (1H, s), 12.30 (1H, s). MS (ESI) m/z: 410 (M+H)+.
ethyl 2-[4-[(5-cyano-6-methylsulfanyl-2-phenyl-pyrimidin-4-yl)amino]phenyl]acetate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
83%
In N,N-dimethyl-formamide at 80℃; for 1.5h;
30 ethyl 2-[4-[(5-cyano-6-methylsulfanyl-2-phenylpyrimidin-4-yl)amino]phenyl]acetate (23)
5.1.30 Ethyl 2-[4-[(5-cyano-6-methylsulfanyl-2-phenyl-pyrimidin-4-yl)amino]phenyl]acetate (23) To a solution of 22 (480 mg, 1.83 mmol) in DMF (6 mL) was added ethyl 2-(4-aminophenyl)acetate (658 mg, 3.67 mmol) and the reaction mixture was stirred at 80 °C for 1.5 h. After cooling, H2O was added and the reaction mixture was extracted twice with EtOAc. The combined extract was washed with brine, dried over Na2SO4, and concentrated in vacuo. The resulting residue was chromatographed (EtOAc/CH2Cl2 = 0-10%) to give the title compound (620 mg, 1.53 mmol, 83%) as a colorless solid. 1H NMR (CDCl3) δ: 1.28 (3H, t, J = 7.2 Hz), 2.77 (3H, s), 3.65 (2H, s), 4.19 (2H, q, J = 7.2 Hz), 7.12 (1H, s), 7.36 (2H, d, J = 8.6 Hz), 7.47-7.55 (3H, m), 7.64 (2H, d, J = 8.6 Hz), 8.41-8.44 (2H, m); MS (ESI) m/z: 405 (M+H)+.
4-chloro-2-phenyl-pyrimidine-5-carboxamide[ No CAS ]
[ 5438-70-0 ]
ethyl 2-[4-[(5-carbamoyl-2-phenyl-pyrimidin-4-yl)amino]phenyl]acetate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
99%
In N,N-dimethyl-formamide; at 80℃; for 4h;
5.1.9 Ethyl 2-[4-[(5-carbamoyl-2-phenyl-pyrimidin-4-yl)amino]phenyl]acetate (8a) To a solution of 7a (600 mg, 2.57 mmol) in DMF (5 mL) was added ethyl 2-(4-aminophenyl)acetate (690 mg, 3.85 mmol) and the reaction mixture was stirred at 80 C for 4 h. After cooling, the reaction mixture was poured into 0.2 N HCl aqueous solution (20 mL). The resulting precipitate was collected by filtration to give the title compound (961 mg, 2.55 mmol, 99%) as a pale yellow solid. 1H NMR (CDCl3) delta: 1.20 (3H, t, J = 6.9 Hz), 3.68 (2H, s), 4.10 (2H, q, J = 6.9 Hz), 7.34 (2H, d, J = 8.6 Hz), 7.53-7.60 (3H, m), 7.74 (2H, d, J = 8.6 Hz), 7.89 (1H, s), 8.35-8.37 (2H, m), 8.46 (1H, s), 9.01 (1H, s), 11.49 (1H, s); MS (ESI) m/z: 377 (M+H)+.
With N-ethyl-N,N-diisopropylamine; In ethanol; for 65h;Reflux;
To a solution of 10 (2.17 g, 9.81 mmol) in EtOH (20 mL) were added ethyl 2-(4-aminophenyl)acetate (2.10 g, 11.7 mmol) and N,N-diisopropylethylamine (2.55 mL, 14.6 mmol) and the reaction mixture was refluxed for 65 h. After cooling, the solvent was evaporated under reduced pressure and the residue was dissolved in EtOAc. The resultant solution was washed with 1 N HCl aqueous solution, sat. NaHCO3 aqueous solution, and brine. The organic layer was dried over Na2SO4 and concentrated in vacuo. The residue was chromatographed (EtOAc/hexane = 5% to 50%) to give the title compound (3.33 g, 9.15 mmol, 93%) as a solid. 1H NMR (CDCl3) delta: 1.26 (3H, t, J = 6.9 Hz), 2.25-2.28 (2H, m), 2.88 (2H, t, J = 6.6 Hz), 3.11-3.13 (2H, m), 3.59 (2H, s), 4.15 (2H, q, J = 6.9 Hz), 6.63 (1H, s), 7.29 (2H, d, J = 6.6 Hz), 7.54 (2H, d, J = 6.6 Hz).
With palladium diacetate; caesium carbonate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; In 1,4-dioxane; at 120℃; for 2h;Inert atmosphere; Microwave irradiation;
A 10-mL microwave vial was charged with tert-butyl 2-(4-chloro-6,7-dihydro- 5H-cyclopenta[^]pyridin-2-yl)-lH-pyrrole-l-carboxylate (0.138 g, 0.43 mmol), 4- aminophenyl acetic acid ethyl ester (0.093 g, 0.52 mmol), palladium acetate (0.005 g, 0.021 mmol), rac-BINAP (0.020 g, 0.032 mmol) and cesium carbonate (0.353 g, 1.08 mmol) in dioxane (4 mL) under argon. The reaction mixture was heated to 120 C under microwave irradiation for 2 h. After this time, the reaction mixture was cooled, diluted with ethyl acetate (50 mL) then filtered through celite. The filtrate was washed with saturated sodium chloride (10 mL), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by chromatography on silica using dichloromethane/methanol (10:0 to 9: 1) to afford an -4: 1 mixture of tert-butyl 2-(4-((4-(2- ethoxy-2-oxoethyl)phenyl)amino)-6,7-dihydro-5H-cyclopenta[pyridin-2-yl)-lH-pyrrole-l- carboxylate as a brown oil (0.110 g, 55%). MW = 461.55 ]H NMR (CDC13, 500 MHz) delta 7.30-7.22 (m, 3H), 7.16-7.13 (m, 2H), 6.93 (s, 1H), 6.30 (dd, / = 3.0, 1.5Hz, 1H), 6.16 (t, / = 3.5 Hz, 1H), 5.67 (s, 1H), 4.15 (q, / = 7.5 Hz, 2H), 3.58 (s, 2H), 3.03 (t, / = 7.5 Hz, 2H), 2.82 (t, / = 7.5 Hz, 2H), 2.18 (quin, / = 7.5 Hz, 2H), 1.39 (s, 9H), 1.26 (t, / = 7.5 Hz, 3H); ESI MS m/z 462 [M+H]+, and ethyl 2-(4-((2-(lH-pyrrol-2-yl)-6,7-dihydro-5H- cyclopenta[^]pyridin-4-yl)amino)phenyl)acetate. MW = 361.44. ]H NMR (CDC13, 500 MHz) delta 9.60 (br s, 1H), 7.30-7.27 (m, 2H), 7.18-7.14 (m, 2H), 7.10 (s, 1H), 6.84-6.81 (m, 1H), 6.51-6.48 (m, 1H), 6.23-6.20 (m, 1H), 5.67 (s, 1H), 4.18 (q, / = 7.0 Hz, 2H), 3.61 (s, 2H), 2.98 (t, / = 7.5 Hz, 2H), 2.78 (t, / = 7.0 Hz, 2H), 2.17 (quin, / = 7.5 Hz, 2H), 1.28 (t, / = 7.0 Hz, 3H); ESI MS m/z 362 [M+H]+
With palladium diacetate; caesium carbonate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; In 1,4-dioxane; at 120℃; for 2h;Inert atmosphere; Microwave irradiation;
A 10-mL vial was charged with 3-(4-chloro-6,7-dihydro-5H- cyclopenta[^]pyridin-2-yl)cyclopent-2-enol (0.120 g, 0.51 mmol), 4-aminophenylacetic acid ethyl ester (0.096 g, 0.53 mmol), palladium acetate (0.006 g, 0.025 mmol), rac-BINAP (0.024 g, 0.038 mmol) and cesium carbonate (0.414 g, 1.27 mmol) in dioxane (6 mL) under argon. The reaction mixture was heated to 120 C under microwave irradiation for 2 h. The reaction mixture was cooled, and diluted with ethyl acetate (75 mL) and water (5 mL). The organic layer was washed with saturated sodium chloride (2 x 5 mL), dried over sodium sulfate, filtered, and the filtrate concentrated under reduced pressure. The residue was purified by chromatography on silica using 80:20: 1 dichloromethane/methanol/conc. NuEta4OmicronEta as the eluent to afford the title compound (0.109 g, 56%) as an oil. MW = 378.46. ]H NMR (CDCI3, 500 MHz) delta 7.28 (d, / = 8.0 Hz, 2H), 7.14 (d, / = 8.0 Hz, 2H), 6.93 (s, 1H), 6.50 (d, / = 1.5 Hz, 1H), 5.83 (s, 1H), 5.00-4.94 (m, 1H), 4.18 (q, / = 7.0 Hz, 2H), 3.61 (s, 2H), 3.03 (t, / = 7.5 Hz, 2H), 2.90-2.82 (m, 1H), 2.79 (t, / = 7.5 Hz, 2H), 2.66-2.58 (m, 1H), 2.46-2.37 (m, 1H), 2.20-2.11 (m, 3H), 1.87-1.80 (m, 1H), 1.28 (t, 7 = 7.0 Hz, 3H). ESI m/z 379 [M+H]+.
ethyl 2-(4-(2-chloro-4-methyl-5H-pyrrolo[2,3-d]pyrimidin-7(6H)-yl)phenyl)acetate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
44%
With sodium hydrogencarbonate; sodium iodide; In N,N-dimethyl-formamide; at 130℃; for 1h;
NaHC03 (2.36 g, 28.12 mmol) and Nal (1.40 g, 9.37 mmol) were added to a suspension of 2,4-dichloro-5-·(2-chloroethyl)-6-methylpyrimidine (2.11 g, 9.37 mmol) and ethyl 2-(4-aminophenyl)acetate (1.68 g, 9.37 mmol) in dry DMF and the mixture was stirred for 1 h at 130C. The reaction mixture was cooled to RT and water (30 ml) was added. The yellow precipitate was filtered, washed with water (2 x 5 ml) and diethylether (2 x 5 ml), dried to give ethyl 2-(4-(2-chloro-4-methyi-5H-pyrrolo[2,3-d]pyrimidin-7(6H)- yl)phenyl)acetate (1.37 g, 44 %) as a slight yellow solid.LC-MS (Method 1): m/z: [M+Hf = 332.2, R1 = 3.7 min13C-NMR (101 MHz, COCI3, o ppm): 14.2, 20.6, 22.2, 40.7, 49.3, 60.8, 117.7, 118.5, 129.2, 129.8, 138.8,158.8, 159.1, 165.5, 171.5
2, 4-dichloro-5-(2-chloroethyl)-6-ethylpyrimidine[ No CAS ]
[ 5438-70-0 ]
ethyl 2-(4-(2-chloro-4-ethyl-5H-pyrrolo[2,3-d]pyrimidin-7(6H)-yl)phenyl)acetate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
56%
With sodium hydrogencarbonate; sodium iodide; In N,N-dimethyl-formamide; at 130℃; for 0.666667h;
NaHC03 (1.60 g, 19.05 mmol) and Nal (1.00 g, 6.67 mmol) were added to a suspension of 2,4-dichloro-5-(2-chloroethyl)-6-ethylpyrimidine (1.50g, 6.26 mmol) and ethyl 2-(4-aminophenyl)acetate (1.10 g, 6.13 mmol) in dry DMF (5 ml) and the mixture was stirred for 40 min at 130C. The reaction mixture wascooled to RT and water (50 ml) was added. The crude product was extracted with dichloromethane (4 x20 ml). The combined organic layers were dried over Na2 S04, filtered and the solvent was removed under reduced pressure. The residue was purified by flash chromatography to give ethyl 2-(4-(2-chloro-4-ethyl-5H-pyrrolo[2,3-d]pyrimidin-7(6H)-yl)phenyl)acetate (1.22 g, 56 %) as a white solid.13C-NMR (101 MHz, COCI3, o ppm): 11.5, 14.0, 21.3, 26.8, 49.3, 60.2, 118.2, 118.4, 129.1, 129.6, 138.6,157.5, 163.3, 165.2, 171.1
With N-ethyl-N,N-diisopropylamine; In acetonitrile; at 100℃; for 4h;
Synthesis of compound 1.6. To a solution of 1.5 (2.37 g, 0.01072 mol, 1.00 equiv), in acetonitrile (35 mL) was added diisopropylethylamine ( 3.81mL, 0.02144 mol, 2.0 equiv) and tert-butyl 2-(4-aminophenyl)acetate (2.0 g, .009648 mol, 0.9 equiv). The mixture was heated at 100 C for 4 hours. After completion, reaction mixture was concentrated under reduced pressure and triturated with water to obtain solids. The precipitate was collected and dried under reduced pressure to yield pure compound 1.6 (2.45g, 58.3%). MS (ES): m/z 392.14 [M+H]+.
(S)-5-(1-((tert-butoxycarbonyl)amino)ethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-1,3-oxazole-4-carboxylic acid[ No CAS ]
(S)-ethyl 2-(4-(5-(1-((tert-butoxycarbonyl)amino)ethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)oxazole-4-carboxamido)phenyl)acetate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
76%
With 1-hydroxy-7-aza-benzotriazole; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In dichloromethane; at 0 - 20℃; for 2.5h;
Step 2: (S) -Ethyl 2- (4- (5- (1- ( (tert-butoxycarbonyl) amino) ethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazole-4-carboxamido) phenyl) acetate[1977]To 15 mL of dichloromethane were added (S) -5- (1- ( (tert-butoxycarbonyl) amino) ethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazole-4-carboxylic acid (250 mg, 0.53 mmol) , ethyl 4-aminophenylacetate (115 mg, 0.64 mmol) , 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (154 mg, 0.80 mmol) and 1-hydroxy-7-azabenzotriazole (182 mg, 1.33 mmol) . To the mixture was added N, N-diisopropylethylamine (0.37 mL, 2.14 mmol) dropwise at 0 . The resulting mixture was stirred at rt for 2.5 hours. The reaction mixture was washed with water (10 mL × 2) and the organic layer was dried over anhydrous sodium sulfate. The organic solvent was removed and the residue was purified by silica gel column chromatography (PE/EtOAc (v/v) 5/1) to give a white solid (256 mg, 76) .[1978]1H NMR (400 MHz, CDCl3) : delta ppm 7.68 (d, J 8.4 Hz, 2H) , 7.63 (dd, J1 8.3 Hz, J2 1.9 Hz, 1H) , 7.59 (s, 1H) , 7.32 (d, J 8.4 Hz, 2H) , 7.27 (d, J 6.2 Hz, 1H) , 6.72 (t, JF-H 75.0 Hz, 1H) , 5.35 -5.30 (m, 1H) , 4.16 (q, J 7.1 Hz, 2H) , 4.01 (d, J 6.9 Hz, 2H) , 3.61 (s, 2H) , 1.57 (d, J 7.0 Hz, 3H) , 1.43 (s, 9H) , 1.37 -1.33 (m, 1H) , 1.26 (t, J 7.1 Hz, 3H) , 0.73 -0.68 (m, 2H) , 0.44 -0.41 (m, 2H) and MS-ESI: m/z 574.2 [M-55]+.
ethyl 2-(4-(4,6-dichloro-1,3,5-triazin-2-ylamino)phenyl)acetate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
85%
With potassium carbonate; In water; acetone; at 0℃;Green chemistry;
To a solution of ethyl-4-aminophenylacetate 2a (10mmol) and K2CO3 (10 mmol) in water (20 mL), cyanuricchloride 1 (10 mmol) in acetone (20 mL) was added portionwise at 0C. The reaction mixture was stirred at this temperature for 2 h and the progress of the reaction was followed by TLC (ethylacetate-hexane; 2:1). After completion of the reaction, the reaction mixture was concentrated under vacuum and the residue was extracted by dichloromethane(3x20 mL). The combined dichloromethane (DCM) washed with sat. NaCl (2x 10 mL), dried over MgSO4 anhydrous,filter and the solvent was removed under vacuum and then residue recrystallized from dichloromethane and hexane(2:1).The product 3a was obtained as off white solid, in 85.0% yield; mp: 154-5C; IR (KBr) cm-1: 3271(NH, amine), 1757(CO, ester), 1628 (C=N); 1H NMR (CDCl3) 1.23 (CH3, t,3H, J = 5.2), 3.60 (CH2-Ph, s, 2H), 4.16 (CH2, q, 2H, J =7.6),7.28 (ArH, d, 2H, J =8.8), 7.45 (ArH, d, 2H, J =8.2), 7.62(NH, s, 1H); 13C NMR (CDCl3) 14.2, 40.7, 61.1, 121.4,130.2, 131.7, 134.7, 164.0, 170.1, 171.4; Anal. Calcd forC13H12Cl2N4O2 (327.17): C, 47.72; H, 3.70; N, 17.12; found:C, 47.98; H, 3.94; N, 17.34; m/z: (M, M+2): 327.53, 329.51.
4-(2-(ethyl(m-tolyl)amino)-2-oxoethyl)-4H-thieno[3,2-b]pyrrole-5-carboxylic acid[ No CAS ]
ethyl 2-(4-(4-(2-(ethyl(m-tolyl)amino)-2-oxoethyl)-4H-thieno[3,2-b]pyrrole-5-carboxamido)phenyl)acetate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
38%
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 60℃; for 18h;
To a solution of 4-(2-(ethyl(m-tolyl)amino)-2-oxoethyl)-4H-thieno [3 ,2-bj pyrrole5-carboxylic acid (50mg, 0. lsmmol) in DMF (3mL), ethyl 2-(4-aminophenyl)acetate (3 1mg, 0.l8mmol), HATU (111mg, 0.29mmol) and diisopropylethylamine (56mg, 0.44mmol) was added. The reaction was heated to 60C for 18h. The reaction mixture cooled, diluted with ethyl acetate, and washed with water. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was then concentrated. The residue was purified by column chromatography (silica, heptane/ethyl acetate) to afford the desired product (28mg, 38%) as an orange solid. ?H NMR (300 MHz, DMSO-d6) oe 9.93 (s, 1H), 7.64 (d, J= 7.6, 2H), 7.50 - 7.11 (m, 9H), 4.99 (s, 2H), 4.06 (q,J= 6.4 Hz, 2H), 3.60 (s, 4H), 2.37 (s, 3H), 1.17 (t,J=7.2, 3H), 0.98 (t, J= 6.4, 3H); ESI MS m/z 476 [M + Hj HPLC 97.2 % (AUC), TR 7.61 mm; UV (EtOH) 2max 308 nm, E 34,350.
1-[(3,5-dichlorophenyl)methoxy]carbonyl}piperidine-4-carboxylic acid[ No CAS ]
(3,5-dichlorophenyl)methyl 4-[4-(2-ethoxy-2-oxoethyl)phenyl]carbamoyl}piperidine-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
77%
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In N,N-dimethyl-formamide; at 0 - 20℃; for 20h;
1-[(3,5-dichlorophenyl)methoxy]carbonyl}piperidine-4-carboxylic acid (0.20g, 0.60mmol), 79 ethyl 4-aminophenylacetate (0.10mg, 0.60mmol) and 62 1-hydroxybenzotriazole (HOBt, 0.10g, 0.72mmol) were dissolved in 51 DMF (4.00mL). The reaction mixture was cooled to 0C, and 63 triethylamine (0.17mL, 1.20mmol) and 75 (3-Dimethylaminopropyl)-N?-ethylcarbodiimide hydrochloride (EDC, 0.14g, 0.72mmol) were added. Reaction mixture was stirred at room temperature for 20h. After completion, the reaction mixture was diluted with water, and extracted with ethyl acetate. The organic layer was washed with water and brine, dried with anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was triturated with ether and n-hexane, washed with n-hexane to afford the 80 (3,5-dichlorophenyl)methyl 4-[4-(2-ethoxy-2-oxoethyl)phenyl]cabamoyl}piperidine-1-carboxylate as a white solid (0.23mg, 77%). This compound (0.23g, 0.47mmol) was dissolved in 82 THF/83 water mixed solvent (1:1, 10mL), and 84 lithium hydroxide monohydrate (0.20mg, 4.66mmol) was added. After stirring at room temperature for 15h, the reaction mixture was diluted with water, and washed with ethyl acetate. The aqueous layer was acidified with 1N HCl aqueous solution to pH=2.00, and extracted with ethyl acetate twice. The organic layer was washed with water, dried with anhydrous sodium sulfate, and concentrated under reduced pressure to afford the 85 title compound as a white solid (0.20g, 90%). (0028) 1H NMR (DMSO-d6, 600MHz), delta ppm: 9.88 (s, 1H, NH), 7.57 (br.s, 1H, CH), 7.52 (m, J=8.3, 2H, 2CH), 7.43 (m, 2H, 2CH), 7.16 (m, J=8.5, 2H, 2CH), 5.09 (m, 2H, CH2), 4.06 (d, J=13, 2H, CH2), 3.49 (s, 2H, CH2), 2.89 (m, 2H, CH2), 2.54 (m, 1H, CH), 1.8 (d, J=11.1, 2H, CH2), 1.53 (1, J=11x(3), 2H, CH2); 13C NMR (150MHz, DMSO-d6) delta 173.25, 171.40, 168.68, 161.18, 154.53, 147.22, 141.84, 138.44, 138.26, 134.53, 132.67, 130.15, 130.00, 127.88, 126.73, 124.64, 119.52, 65.15, 43.56, 42.81, 40.60, 40.53. HRESIMS (negative) m/z 463.0864 [M-H]- (calcd 463.0833).
ethyl 2-(4-(3-tert-butyl-2-methoxybenzamido)phenyl)acetate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
43%
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In chloroform; at 0 - 80℃;Inert atmosphere;
General procedure: Ethyl 2-(4-aminophenyl)acetate (33f, 1.3 eq) was dissolved inCHCl3 (abs., 25 mL/mmol) and cooled to 0 C. 4-(Dimethylamino)pyridine(0.10 eq), 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide(1.1 eq) and the respective benzoic acid (35a-i, 1.0 eq) were added. Themixture was warmed to room temperature and afterwards stirredovernight at 80 C under reflux. 5% aqueous hydrochloric acid (equal volume as CHCl3) was added, phases were separated, and the aqueouslayer was extracted three times with EtOAc (equal volume as CHCl3).The combined organic layers were dried over Na2SO4 and the solventswere removed in vacuum. Further purification was performed bycolumn chromatography or crystallization.
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In chloroform; at 0 - 80℃;Inert atmosphere;
General procedure: Ethyl 2-(4-aminophenyl)acetate (33f, 1.3 eq) was dissolved inCHCl3 (abs., 25 mL/mmol) and cooled to 0 C. 4-(Dimethylamino)pyridine(0.10 eq), 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide(1.1 eq) and the respective benzoic acid (35a-i, 1.0 eq) were added. Themixture was warmed to room temperature and afterwards stirredovernight at 80 C under reflux. 5% aqueous hydrochloric acid (equal volume as CHCl3) was added, phases were separated, and the aqueouslayer was extracted three times with EtOAc (equal volume as CHCl3).The combined organic layers were dried over Na2SO4 and the solventswere removed in vacuum. Further purification was performed bycolumn chromatography or crystallization.
ethyl 2-(4-(4-tert-butyl-2-methoxybenzamido)phenyl)acetate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
67%
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In chloroform; at 0 - 80℃;Inert atmosphere;
General procedure: Ethyl 2-(4-aminophenyl)acetate (33f, 1.3 eq) was dissolved inCHCl3 (abs., 25 mL/mmol) and cooled to 0 C. 4-(Dimethylamino)pyridine(0.10 eq), 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide(1.1 eq) and the respective benzoic acid (35a-i, 1.0 eq) were added. Themixture was warmed to room temperature and afterwards stirredovernight at 80 C under reflux. 5% aqueous hydrochloric acid (equal volume as CHCl3) was added, phases were separated, and the aqueouslayer was extracted three times with EtOAc (equal volume as CHCl3).The combined organic layers were dried over Na2SO4 and the solventswere removed in vacuum. Further purification was performed bycolumn chromatography or crystallization.
ethyl 2-(4-(4-tert-butyl-3-methoxybenzamido)phenyl)acetate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
71%
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In chloroform; at 0 - 80℃;Inert atmosphere;
General procedure: Ethyl 2-(4-aminophenyl)acetate (33f, 1.3 eq) was dissolved inCHCl3 (abs., 25 mL/mmol) and cooled to 0 C. 4-(Dimethylamino)pyridine(0.10 eq), 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide(1.1 eq) and the respective benzoic acid (35a-i, 1.0 eq) were added. Themixture was warmed to room temperature and afterwards stirredovernight at 80 C under reflux. 5% aqueous hydrochloric acid (equal volume as CHCl3) was added, phases were separated, and the aqueouslayer was extracted three times with EtOAc (equal volume as CHCl3).The combined organic layers were dried over Na2SO4 and the solventswere removed in vacuum. Further purification was performed bycolumn chromatography or crystallization.
ethyl 2-(4-(3-tert-butylbenzamido)phenyl)acetate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
96%
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In chloroform; at 0 - 80℃;Inert atmosphere;
General procedure: Ethyl 2-(4-aminophenyl)acetate (33f, 1.3 eq) was dissolved inCHCl3 (abs., 25 mL/mmol) and cooled to 0 C. 4-(Dimethylamino)pyridine(0.10 eq), 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide(1.1 eq) and the respective benzoic acid (35a-i, 1.0 eq) were added. Themixture was warmed to room temperature and afterwards stirredovernight at 80 C under reflux. 5% aqueous hydrochloric acid (equal volume as CHCl3) was added, phases were separated, and the aqueouslayer was extracted three times with EtOAc (equal volume as CHCl3).The combined organic layers were dried over Na2SO4 and the solventswere removed in vacuum. Further purification was performed bycolumn chromatography or crystallization.
ethyl 2-(4-(5-tert-butyl-2-methoxybenzamido)phenyl)acetate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
87%
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In chloroform; at 0 - 80℃;Inert atmosphere;
General procedure: Ethyl 2-(4-aminophenyl)acetate (33f, 1.3 eq) was dissolved inCHCl3 (abs., 25 mL/mmol) and cooled to 0 C. 4-(Dimethylamino)pyridine(0.10 eq), 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide(1.1 eq) and the respective benzoic acid (35a-i, 1.0 eq) were added. Themixture was warmed to room temperature and afterwards stirredovernight at 80 C under reflux. 5% aqueous hydrochloric acid (equal volume as CHCl3) was added, phases were separated, and the aqueouslayer was extracted three times with EtOAc (equal volume as CHCl3).The combined organic layers were dried over Na2SO4 and the solventswere removed in vacuum. Further purification was performed bycolumn chromatography or crystallization.
ethyl 2-(4-(3-bromobenzamido)phenyl)acetate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
99%
With pyridine; In tetrahydrofuran; N,N-dimethyl-formamide; at 20℃; for 2h;Inert atmosphere;
General procedure: An aminobenzoic acid or a corresponding ester (33a-e,g-j, 38q,1.0 eq) was dissolved in THF (abs., 20 mL/mmol), and DMF (abs., 1 mL/mmol) and pyridine (3.0 eq) were added. The respective benzoylchloride (34a-c,e,f, 1.3 eq) was then added dropwise at room temperature.The mixture was stirred for two hours at room temperature.5% aqueous hydrochloric acid (equal volume as THF) and EtOAc (equalvolume as THF) were added, phases were separated, and the aqueouslayer was extracted twice with EtOAc (equal volume as THF). Thecombined organic layers were dried over Na2SO4 and the solvents wereremoved in vacuum. Further purification was performed by columnchromatography or crystallization.
ethyl 2-(4-(3-bromo-2-methoxybenzamido)phenyl)acetate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
98%
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In chloroform; at 0 - 80℃;Inert atmosphere;
General procedure: Ethyl 2-(4-aminophenyl)acetate (33f, 1.3 eq) was dissolved inCHCl3 (abs., 25 mL/mmol) and cooled to 0 C. 4-(Dimethylamino)pyridine(0.10 eq), 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide(1.1 eq) and the respective benzoic acid (35a-i, 1.0 eq) were added. Themixture was warmed to room temperature and afterwards stirredovernight at 80 C under reflux. 5% aqueous hydrochloric acid (equal volume as CHCl3) was added, phases were separated, and the aqueouslayer was extracted three times with EtOAc (equal volume as CHCl3).The combined organic layers were dried over Na2SO4 and the solventswere removed in vacuum. Further purification was performed bycolumn chromatography or crystallization.
ethyl 2-(4-(5-bromo-2-methoxybenzamido)phenyl)acetate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
98%
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In chloroform; at 0 - 80℃;Inert atmosphere;
General procedure: Ethyl 2-(4-aminophenyl)acetate (33f, 1.3 eq) was dissolved inCHCl3 (abs., 25 mL/mmol) and cooled to 0 C. 4-(Dimethylamino)pyridine(0.10 eq), 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide(1.1 eq) and the respective benzoic acid (35a-i, 1.0 eq) were added. Themixture was warmed to room temperature and afterwards stirredovernight at 80 C under reflux. 5% aqueous hydrochloric acid (equal volume as CHCl3) was added, phases were separated, and the aqueouslayer was extracted three times with EtOAc (equal volume as CHCl3).The combined organic layers were dried over Na2SO4 and the solventswere removed in vacuum. Further purification was performed bycolumn chromatography or crystallization.
ethyl 2-(4-(4-tert-butylbenzamido)phenyl)acetate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
96%
With pyridine; In tetrahydrofuran; N,N-dimethyl-formamide; at 20℃; for 2h;Inert atmosphere;
General procedure: An aminobenzoic acid or a corresponding ester (33a-e,g-j, 38q,1.0 eq) was dissolved in THF (abs., 20 mL/mmol), and DMF (abs., 1 mL/mmol) and pyridine (3.0 eq) were added. The respective benzoylchloride (34a-c,e,f, 1.3 eq) was then added dropwise at room temperature.The mixture was stirred for two hours at room temperature.5% aqueous hydrochloric acid (equal volume as THF) and EtOAc (equalvolume as THF) were added, phases were separated, and the aqueouslayer was extracted twice with EtOAc (equal volume as THF). Thecombined organic layers were dried over Na2SO4 and the solvents wereremoved in vacuum. Further purification was performed by columnchromatography or crystallization.
sodium sulfate (9.69 g, 139.50 mmol) was added to 2,2,2- trichloroacetaldehyde (9.05 g, 61.38 mmol) in water (56 mL). The mixture was stirred at rt for 15 mm. Ethyl 2-(4-aminophenyl)acetate (10 g, 55.80 mmol) dissolved in 1 N HCI (56 mL) was added dropwise to the previous solution followed by hydroxylamine hydrochloride (9.69 g, 139.50 mmol) dissolved inwater (56 mL). The reaction mixture was heated at 80C for 3h. After cooling tort, the solid formed was collected by filtration, washed with water and dried under vacuum until constant weight affording 2-{4-[2-(N- hydroxyimino)acetamido]phenyl}acetic acid (9.60 g, 77%) as pale brown solid.1H NMR (300 MHz, DMSO-d6, d in ppm): 3.51 (s, 2H), 7.19 (d, 2H, J=8.5Hz), 7.60 (d, 2H, J=8.6Hz), 7.64 (s, 1H), 10.14 (s, 1H), 12.14 (s, 1H), 12.26 (br(s),1 H).
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In dichloromethane; at 40℃; for 8h;
The condensation reaction of oleic acid with H2N-R0 or OH-R0 gives the target compound: oleic acid (0.564 g, at room temperature)2.0 mmol), ethyl 4-aminophenylacetate (0.432 g, 2.4 mmol) and triethylamine (0.303 g, 3.0 mmol, 0.4 mL)In a 25 mL round bottom flask, two drops of catalyst DMAP were added dropwise to the above mixture, and 10 mL of solvent CH 2 Cl 2 (water removal) was added to dissolve.The mixed solution was prepared; another condensing agent EDC·HCl (0.576 g, 3.0 mmol) was dissolved in 4 mL of solvent CH 2 Cl 2 to prepare a condensing agent.a solution, and a condensing agent solution is dropwise added to the above mixed solution, and refluxed at 40 C for 8 hours; after the reaction is completed, the reaction solution is used.Wash with 1M HCl to pH 3, extract with dichloromethane (3×15 mL), and then rinse the organic phase with saturated sodium hydrogen carbonateWash the mixture twice with saturated brine, dry the organic phase with anhydrous sodium sulfate, filter and concentrate to give the crude product;The n-hexane-ethyl acetate mixture with a ratio of 10:1 was purified on a silica gel column to obtain 0.727 g of a white solid, which was targeted.Compound, yield: 82%
Stage #1: 4,7-dichlorofuro[2,3-d]pyridazine; ethyl (4-amino-3,5-dibromophenyl)acetate
Stage #2: 2-Methoxyphenylboronic acid With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2 In 1,2-dimethoxyethane; water Further stages;
Stage #1: 4,7-dichlorofuro[2,3-d]pyridazine; ethyl (4-amino-3,5-dibromophenyl)acetate
Stage #2: 2-Methoxyphenylboronic acid With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2 In 1,2-dimethoxyethane; water
ethyl 2-(4-(thieno[3,2-d]pyrimidin-4-ylamino)phenyl)acetate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
91%
In isopropyl alcohol at 100℃; for 0.5h; Microwave irradiation;
General procedure B: Synthesis of compounds 2, 10, 13, and 18.
General procedure: Chloride 5, or 12 (0.2mmol), amine 8, 9, or 17 (0.2mmol) were suspended in isopropanol (4mL). The reaction mixture was irradiated under microwave at 100°C for 0.5h. The completion of the reaction was monitored by LC-MS analysis. The reaction mixture was filtered to get the titled compound.
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