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Stage #1: With trifluoroacetic acid In dichloromethane at 20℃; for 3 h; Stage #2: at 65℃; for 20 h;
terf-Butyl 3-ethynylbenzoate (117) (1.50 g, 9.37 mmoi) was dissolved in dry DCM (70 mL) and TFA (35.9 mL, 488 mmoi) was added carefully. The reaction was stirred at room temperature for 3 hours, concentrated in vacuo and toluene was added and then removed in vacuo to give a pale yellow solid. This material was dissolved in methanol (50 mL) and cone. H2S04 (-1 mL) was added and the resulting solution was stirred at 85 °C for 20 hours. Upon cooling to room temperature, the volatiies were removed in vacuo and the residue was diluted with EtOAc (200 mL) and sat. aq. NaHCO3 (100 mL) was added slowly. The layers were separated and the aqueous layer was extracted with EtOAc (200 mL), the organic layers were combined and washed with water (100 mL), brine (100 mL), dried ( gS04), filtered and concentrated in vacuo to give the title compound (131) (1.136 g, 96percent yield over 2 steps) as a pale yellow solid; 1H NMR (400 MHz, CDCI3) δ 8.17 (t, J = 1.5 Hz, 1 H), 8.03 - 8.00 (m, 1 H), 7.66 (dt, J = 7.7, 1.4 Hz, 1 H), 7.41 (td, J = 7.8, 0.4 Hz, 1 H), 3.93 (s, 3H), 3.12 (s, 1 H). LCMS Method C: rt 5.84 min.
bis(triphenylphosphine)palladium(II) dichloride[ No CAS ]
[ 10602-06-9 ]
2-bromo-6[2-(3-methoxycarbonylphenyl)-ethinyl]-pyridine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
copper(I) iodide; In water; triethylamine;
A. A solution of 15.1 g of 2,6-dibromopyridine in 500 ml of triethylamine is mixed under ice cooling with 10.2 g of 3-ethinylbenzoic acid methyl ester, 1.1 g of bis-(triphenylphosphine)-palladium(II) chloride ad 150 mg of copper(I) iodide and the mixture is stirred for 1 hour. Then, the ice bath is removed and it is stirred for 48 hours at room temperature. The precipitate is filtered off, the filtrate is evaporated to dryness, mixed with water and shaken out with ethyl acetate. The organic phase is dried on sodium sulfate, concentrated by evaporation and the residue is chromatographed on silica gel with hexane/0-12% ethyl acetate. 4.8 g of 2-bromo-6[2-(3-methoxycarbonylphenyl)-ethinyl]-pyridine of melting point 124-126 C. is obtained. IR (CHCl3): 2980, 2210, 1715, 1570, 1430, 1280, 1260, 1165, 1103 cm-1.
A. Under the conditions of example 5 A, 1 g of 3-{6-iodo-3-[6-(4-methoxyphenyl)-(5E)-5-hexenyloxy]-2-pyridyl}-propionic acid methyl ester is reacted with 320 mg of 3-ethinylbenzoic acid methyl ester, worked up, and the crude product is chromatographed on silica gel with hexane/0-15% ethyl acetate. 835 mg of 3-{6-[2-(3-methoxycarbonylphenyl)-ethinyl]-3-[6-(4-methoxyphenyl)-(5E)-5-hexenyloxy]-2-pyridyl}-propionic acid methyl ester is obtained as oil. IR(CHCl3): 2943, 1718, 1604, 1571, 1505, 1448, 1285, 1170, 1102, 1028, 962 cm-1.
3-{3-hydroxy-6-[2-(3-methoxycarbonylphenyl)-ethinyl]-2-pyridyl}-propionic acid methyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
A. Under the conditions of example 5A, 9.2 g of 3-(3-hydroxy-6-iodo-2-pyridyl)-propionic acid methyl ester is reacted with 4.8 g of 3-ethinylbenzoic acid methyl ester, worked up, and the crude product is chromatographed on silica gel with hexane/0-20% ethyl acetate. 4.7 g of 3-{3-hydroxy-6-[2-(3-methoxycarbonylphenyl)-ethinyl]-2-pyridyl}-propionic acid methyl ester of melting point 125-127 C. is obtained. IR(CHCl3): 3250 (broad), 2950, 1718, 1453, 1435, 1258, 1098, 1010 cm-1.
With 2,4,6-trimethyl-pyridine; copper(l) chloride; In N,N-dimethyl acetamide; at 30℃; for 24h;Inert atmosphere;
General procedure: CuCl (0.04 mmol), 2,4,6-trimethylpyridine (0.4 mmol), trifluoromethylating reagent 2a (0.24 mmol) and terminal alkynes (0.2 mmol) were added to a Schlenk tube which was equipped with a stirring bar. DMAc (1 mL) was added under argon atmosphere to this tube. After the addition of all materials, the reaction mixture was kept for 24 h at 30 C. After the reaction, ethyl acetate was added. The organic layer was separated, and washed with water. The combined organic extracts were washed with brine, and dried over MgSO4. After evaporation of the solvent, the crude product was purified by chromatography on silica gel to give the product.
With triethylamine;copper(l) iodide; trans-bis(triphenylphosphine)palladium dichloride; triphenylphosphine; In N,N-dimethyl-formamide; at 120℃; for 0.333333h;microwave irradiation;
To a nitrogen de-gassed solution of <strong>[10602-06-9]methyl 3-ethynylbenzoate</strong> (131) (0.105 g, 0.655 mmol) in dry DMF (6 mL) were added triethylamine (0.308 mL, 2. 8 mmol) followed by fert-butyl 4-(4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)piperazine- 1-carboxylate {13) (0.250 g, 0 546 mmol), triphenylphosphine (0.021 g, 0.082 mmol), frans-dichlorobis(triphenylphosphine) palladium(ll) (0.038 g, 0.055 mmol) and Cu(l)l (0.016 g, 0.082 mmol). The reaction mixture was heated under microwave irradiation at 120 C for 20 minutes, concentrated to dryness in vacuo and purified by silica gel chromatography (Biotage Isolera, 40 g Si cartridge, 0-50% EtOAc in petroleum benzine 40-60 C) to give the title compound (132) (0.182 g, 57% yield) as an orange solid; 1H NMR (400 MHz, dg-DMSO) delta 10.28 (br s, 1 H), 8.78 (s, 1 H), 8.16 - 8.03 (m, 2H), 7.90 (d, J = 7.8 Hz, 1 H), 7.69 (t, J = 7.9 Hz, 1 H), 7.55 (d, J = 9.0 Hz, 2H), 6.96 (d, J = 9.0 Hz, 2H), 3.90 (s, 3H), 3.50 - 3.41 (m, 4H), 3.11 - 2.99 (m, 4H), 1.42 (s, 9H). LCMS Method C: rt 6.82 min; m/z 582.2 [M+H]+
57%
With copper(l) iodide; trans-bis(triphenylphosphine)palladium dichloride; triethylamine; triphenylphosphine; In N,N-dimethyl-formamide; at 120℃; for 0.333333h;Inert atmosphere; Microwave irradiation;
To a nitrogen de-gassed solution of <strong>[10602-06-9]methyl 3-ethynylbenzoate</strong> (131) (0.105 g, 0.655 mmoi) in dry DMF (6 mL) were added triethylamine (0.308 mL, 2.18 mmoi) followed by ferf-butyl 4-(4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)piperazine- 1-carboxylate (13) (0.250 g, 0.546 mmoi), triphenyiphosphine (0.021 g, 0.082 mmoi), frans-dichlorobis(triphenyiphosphine) palladium(ll) (0.038 g, 0.055 mmoi) and Cu(l)l (0.016 g, 0.082 mmoi). The reaction mixture was heated under microwave irradiation at 120 C for 20 minutes, concentrated to dryness in vacuo and purified by silica gel chromatography (Biotage Isoiera, 40 g Si cartridge, 0-50% EtOAc in petroleum benzine 40-60 C) to give the title compound (132) (0.182 g, 57% yield) as an orange solid; 1H NMR (400 MHz, d^DMSO) delta 10.28 (br s, 1 H), 8.78 (s, 1 H), 8.16 - 8.03 (m, 2H), 7.90 (d, J = 7.8 Hz, 1 H), 7.69 (t, J = 7.9 Hz, 1 H), 7.55 (d, J = 9.0 Hz, 2H), 6.96 (d, J = 9.0 Hz, 2H), 3.90 (s, 3H), 3.50 - 3.41 (m, 4H), 3.11 - 2.99 (m, 4H), 1.42 (s, 9H). LCMS Method C: rt 6.82 min; m/z 582.2 [M+H]+.
methyl 3-(1-(4-hydroxy-3-((3-(trifluoromethyl)phenyl)carbamoyl)phenyl)-1H-1,2,3-triazol-4-yl)benzoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
86%
With copper(II) sulfate; sodium L-ascorbate; In water; tert-butyl alcohol; at 20 - 80℃; for 46h;Inert atmosphere;
General procedure: Azide 13 (300 mumol), alkyne (750 mumol), CuSO4 (9.6 mg, 60 mumol) and sodium ascorbate (60.0 mg, 300 mumol) were dissolved in 1:1 t-BuOH/H2O (3 mL). The mixture was stirred for 2 h at rt. After the completion of the reaction, the mixture was filtered and washed with H2O (70 mL) (solid A). The filtrate was extracted with EtOAc (3 * 70 mL). The combined organic extracts were dried over anhyd MgSO4, filtered, and concentrated by rotary evaporation (residue B). The solid A and residue B were combined and purified by column chromatography to afford 8 or 9.
86%
With copper(II) sulfate; sodium L-ascorbate; In water; tert-butyl alcohol; at 80℃; for 46h;
Formula 7 of the azide compound (300 mumol), alkynyl (750 mumol), CuSO4 (9.6 mg, 60 mumol) and Na. An ascorbate (60.0 mg, 300 mumol) 1: was dissolved in 1 t-BuOH / H2O (3 mL). The mixture was stirred at room temperature for 2 hours. After the reaction was completed, the mixture was filtered of and washed using H2O (70 mL) (solid A). The filtrate was extracted with EtOAc (3 × 70 mL). The combined organic extracts were then dried using anhydrous MgSO4, filtered and concentrated by rotaryevaporation (residue B). It was combined and the solid residue A and B, was purified by column chromatography to give the compound of formula 2 and 3. Formula 3 for the general production method in accordance with, 1:1 t-BuOH/H2O (4 mL) to compound 7h (112 mg, 350 mumol), 3 - ethynyl-benzoic acid methyl ester (62.0 mg, 380 mumol), CuSO4 ( 22.3 mg, 140 mumol) andNa. ascorbate (69.0 mg, 350Was dissolved mumol). The mixture was at room temperature for 2 hours, and was stirred at 80 oC for 44 hours. Column chromatography (4: 1 hexane / EtOAc ? 30: 1 CH2Cl2 / MeOH) Compound 3n was obtained using as a brown solid (145 mg, 86%).
3-[2-(1,3-thiazol-4-yl)ethynyl]benzoic acid trifluoroacetate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
22%
Example 75: Synthesis of 3-[2-(l,3-thiazol-4-yl)ethynyl]benzoic acid: 3-[2-(l,3-thiazol-4-yl)ethynyl]benzoic acid. A mixture of 3-ethynyl-l-yl- benzoic acid methyl ester (40 mg, 0.25 mmol), 4-bromo-thiazole (82 mg, 0.5 mmol), palladium tetrakis-triphenylphosphine (29 mg, 0.025 mmol) and copper iodide (9.5 mg, 0.05 mmol), potassium carbonate (69 mg, 0.5 mmol) in 1,2- dimethoxyethane/water (1 mL/0.3 mL) was degassed with N2 for 5 minutes and then heated at 60 °C for 4 hours. After cooling to ambient temperature, the crude mixture was filtered through celite and washed with dichloromethane. The filtrate was concentrated and purified by preparative thin layered chromatography eluting with ethyl acetate/hexane (30percent) to give the ester intermediate. To this intermediate in tetrahydrofuran/methanol (1 mL/0.2 mL) was added sodium hydroxide solution (2 N in water, 0.2 mL, 0.4 mmol) and the solution was stirred at room temperature for 18 hours. 1 N hydrochloric acid aqueous solution was added dropwise until pH = 1 and the reaction mixture was purified through preparative HPLC to give 18 mg (22percent for 2 steps) of the pure product as a white solid. FontWeight="Bold" FontSize="10" H NMR (300MHz, DMSO) delta = 13.2 (br. s., 1H), 9.18 (d, J=2.1 Hz, 1H), 8.19 (d, J=1.8 Hz, 1H), 8.05 (t, J=1.5 Hz, 1H), 7.98 (td, J=1.4, 7.8 Hz, 1H), 7.81 (td, J=1.4, 7.8 Hz, 1H), 7.57 (t, J=7.8 Hz, 1H). LCMS (ESI) mlz 230.0 (M+l)+.
3-[2-(1H-indol-5-yl)ethynyl]benzoic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
Example 75: Synthesis of 3-[2-(l,3-thiazol-4-yl)ethynyl]benzoic acid: 3-[2-(l,3-thiazol-4-yl)ethynyl]benzoic acid. A mixture of 3-ethynyl-l-yl- benzoic acid methyl ester (40 mg, 0.25 mmol), 4-bromo-thiazole (82 mg, 0.5 mmol), palladium tetrakis-triphenylphosphine (29 mg, 0.025 mmol) and copper iodide (9.5 mg, 0.05 mmol), potassium carbonate (69 mg, 0.5 mmol) in 1,2- dimethoxyethane/water (1 mL/0.3 mL) was degassed with N2 for 5 minutes and then heated at 60 C for 4 hours. After cooling to ambient temperature, the crude mixture was filtered through celite and washed with dichloromethane. The filtrate was concentrated and purified by preparative thin layered chromatography eluting with ethyl acetate/hexane (30%) to give the ester intermediate. To this intermediate in tetrahydrofuran/methanol (1 mL/0.2 mL) was added sodium hydroxide solution (2 N in water, 0.2 mL, 0.4 mmol) and the solution was stirred at room temperature for 18 hours. 1 N hydrochloric acid aqueous solution was added dropwise until pH = 1 and the reaction mixture was purified through preparative HPLC to give 18 mg (22% for 2 steps) of the pure product as a white solid. FontWeight="Bold" FontSize="10" H NMR (300MHz, DMSO) delta = 13.2 (br. s., 1H), 9.18 (d, J=2.1 Hz, 1H), 8.19 (d, J=1.8 Hz, 1H), 8.05 (t, J=1.5 Hz, 1H), 7.98 (td, J=1.4, 7.8 Hz, 1H), 7.81 (td, J=1.4, 7.8 Hz, 1H), 7.57 (t, J=7.8 Hz, 1H). LCMS (ESI) mlz 230.0 (M+l)+. Example 77: Synthesis of 3-[2-(lH-indol-5-yl)ethynyl]benzoic acid: 3-[2-(lH-indol-5-yl)ethynyl]benzoic acid was prepared by the same procedure as example 75. NMR (300MHz, CDC13) delta = 9.30 (br. s., 1H), 8.23 (t, J=1.8 Hz, 1H), 7.98 (td, J=1.5, 7.9 Hz, 1H), 7.87 (d, J=0.9 Hz, 1H), 7.72 (td, J=1.3, 7.9 Hz, 1H), 7.47 - 7.23 (m, 4H), 6.59 - 6.50 (m, 1H). LCMS (ESI) mlz 262.0 (M+l)+.