* 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.
With N,N'-N,N'-[1-(benzo[d]thiazol-2-yl)ethanone O-4-[1-(benzo[d]thiazol-2-yl)ethylideneaminooxy]butyl oxime]bis[dichloropalladium(II)] trihydrate; tetrabutylammomium bromide; potassium hydroxide In water at 160℃; for 0.166667 h; Microwave irradiation; Green chemistry
General procedure: A mixture of the appropriate aryl bromides 4–8 (1 mmol), boronic acid 9a, 9b (1.2 mmol), 194 mg TBAB (0.6 mmol), palladium complex 3 (0.15 molpercent), 112 mg KOH (2 mmol), and 3 cm3 distilled water was mixed in a process glass vial. The vial was capped properly, and there after the mixture was heated under microwave irradiating conditions at 160 C and 250 W for the appropriate reaction time as listed in Table 1. After the reaction was almost complete (monitored by TLC), the reaction mixture was extracted with EtOAc (3 9 20 cm3). The combined organic extracts were dried over anhydrous MgSO4 then filtered and the solvent was evaporated under reduced pressure. The products were purified with flash column chromatography to give the corresponding pure crosscoupled products 10–14 (from aryl bromides and chloride,Table 1).
76%
With potassium carbonate In water at 70℃; for 9 h; Inert atmosphere
General procedure: In a typical run, h-BN(at)Fur(at)Pd(OAc)2 (0.05 mmol) was added to a mixture of arylboronic acid 1 (1.0 mmol), aryl bromide 2 (1.5 mmol) and K2CO3 (1.5 mmol) in water (1 mL). The resulting mixture was stirred at 70 °C under Ar protection, and the progress of the reaction was monitored by TLC. After completion of the reaction, ethyl acetate was added to the reaction mixture and the catalyst was separated. The organic phase was washed with water, dried over anhydrous Na2SO4 and the solvent was evaporated under reduced pressure. Finally, the residue was isolated by chromatography on a column of silica gel to afford the corresponding product 3.
70%
With potassium phosphate; tetrakis(triphenylphosphine) palladium(0) In water; ethylene glycol at 80℃; for 16 h; Inert atmosphere
General procedure: To a solution of 2a, 2c or 2h (3 mmol, 0.5 g) in ethylene glycol (5 mL) was added successively the boronic acid (4.5 or 9.0 mmol, 1.5 or 3 equiv), Pd(PPh3)4 (1molpercent), and a solution of K3PO4 (6 mmol, 2 equiv) inwater (2 mL). The reaction mixture was heated at 80°C for 16 h and was then hydrolyzed with a 1 M solution of sodium hydroxide (20 mL). The aqueous phase was extracted with ethylacetate (3 x 30 mL) and the combined organic layers were washed with brine (50 mL), dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel with petroleum ether/EtOAc (60/40) as eluent.
61%
With tetrakis(triphenylphosphine) palladium(0); sodium carbonate In water; acetonitrile at 90℃; for 16 h;
To a stirred solution of 5-bromopyridin-2-amine (1) (5.0 g, 28.9 mmol) in acetonitrile (75 mL) at room temperature was added phenylboronic acid (4.93 g, 40.5 mmol), Na2C03 (4.59 g, 43.4 mmol), H20 (25 mL) and Pd(PPh3)4 (3.30 g, 2.89 mmol). The resulting mixture was heated at 90°C for 16 h. After cooling to room temperature the reaction mixture was filtered through a pad of celite, and the filtrate was partitioned and extracted with EtOAc (5x100 mL). The combined organic layers were dried over anhydrous Na2S04 and concentrated under reduced pressure. The residue obtained was purified by column chromatography (silica gel, 0 to 20percent EtOAc/hexanes) to afford 5-phenylpyridin-2-amine (2) (3.0 g, 61 percent) as an off-white solid: MS (Multi-mode, ESI/APCI) m/z 172 [M + H]+.
1.8 g
With tetrakis(triphenylphosphine) palladium(0); sodium carbonate In 1,4-dioxane; water at 80℃; for 16 h; Inert atmosphere
To a stirred solution of 5-bromopyridin-2-amine (2.0 g, 11.55 mmol) in Dioxane: H2O (20:4 mL) was added phenylboronic acid (1.26 g, 10.40 mmol) and Na2CO3 (2.45 g, 23.14 mmol) at 25° C. The reaction mixture was degassed with Argon for 30 minutes. Tetrakis (668.5 mg, 0.578 mmol) was added. The reaction mixture was heated at 80° C. for 16 h. Then the reaction mixture was cooled, diluted with water (50 mL) and extracted in EtOAc (150 mL*2) The organic layer was washed with brine (20 mL), dried over anhydrous sodium sulfate and distilled off to give crude product which was purified by Flash chromatography to give pure 5-phenylpyridin-2-amine (1.8 g). 1H NMR: (400 MHz, DMSO) (31196) δ: 6.07 (s, 2H), 6.51-6.53 (m, 2H), 7.24-7.28 (m, 2H), 7.38-7.42 (m, 2H), 7.55-7.57 (m, 2H), 7.62-7.71 (m, 1H), 8.24-8.25 (d, J=2.0 Hz, 1H).
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2009, vol. 19, # 21, p. 6122 - 6126
[2] European Journal of Organic Chemistry, 2014, vol. 2014, # 27, p. 5901 - 5905
[3] Monatshefte fur Chemie, 2003, vol. 134, # 4, p. 573 - 583
[4] New Journal of Chemistry, 2016, vol. 40, # 8, p. 6568 - 6572
[5] Monatshefte fur Chemie, 2016, vol. 147, # 7, p. 1197 - 1205
[6] Synthesis, 2010, # 18, p. 3163 - 3173
[7] ACS Catalysis, 2013, vol. 3, # 12, p. 2776 - 2789
[8] Patent: WO2014/174397, 2014, A2, . Location in patent: Paragraph 0046; 0051; 0052
[9] Journal of Organometallic Chemistry, 2003, vol. 687, # 2, p. 327 - 336
[10] European Journal of Organic Chemistry, 2010, # 29, p. 5548 - 5551
[11] Heterocycles, 1987, vol. 26, # 10, p. 2711 - 2716
[12] Applied Organometallic Chemistry, 2017, vol. 31, # 12,
[13] Tetrahedron, 2016, vol. 72, # 52, p. 8557 - 8564
[14] Advanced Synthesis and Catalysis, 2017, vol. 359, # 3, p. 454 - 466
[15] Bioorganic and Medicinal Chemistry Letters, 2016, vol. 26, # 1, p. 114 - 120
[16] Patent: WO2014/187922, 2014, A1, . Location in patent: Page/Page column 157
[17] Journal of Medicinal Chemistry, 2008, vol. 51, # 15, p. 4724 - 4729
[18] Patent: EP1582516, 2005, A1, . Location in patent: Page/Page column 87
[19] Bioorganic and Medicinal Chemistry Letters, 2015, vol. 25, # 15, p. 3057 - 3061
[20] Patent: US2016/96835, 2016, A1, . Location in patent: Paragraph 0159
[21] Organic Process Research and Development, 2016, vol. 20, # 8, p. 1489 - 1499
[22] New Journal of Chemistry, 2017, vol. 41, # 24, p. 15420 - 15432
2
[ 20511-12-0 ]
[ 98-80-6 ]
[ 33421-40-8 ]
Yield
Reaction Conditions
Operation in experiment
28%
With sodium carbonate In water; toluene for 3 h; Inert atmosphere; Reflux
Synthesis of 5-phenyl-pyridin-2-ylamine A mixture of toluene (15 mL) and water (5 mL) was degassed with argon gas for 5 minutes. Sodium carbonate (481 mg, 4.5 mmol) was added and the resulting mixture was again degassed with argon gas for 5 minutes. Phenyl boronic acid (353 mg, 2.7 mmol) and 5-iodo-pyridin-2-ylamine (500 mg, 2.27 mmol) were added and the mixture was again degassed with argon gas for 5 minutes. Tetrakis palladium triphenyl phosphine (525 mg, 4.5 mmol) was then added and the mixture was again degassed with argon gas for 5 minutes. The resulting mixture was heated to reflux for 3 hours. The mixture was then diluted with ethyl acetate and washed with water followed by brine solution. The ethyl acetate layer was collected, dried over sodium sulphate and concentrated under reduced pressure. The resulting residue was purified by column chromatography using silica gel 60-120 mesh (35percent ethyl acetate in hexane) to afford 10 mg (28percent) of 5-phenyl-pyridin-2-ylamine. LCMS: 171.09 (M+1)+, 60.5percent.
Reference：
[1] Journal of the American Chemical Society, [2] Journal of the American Chemical Society, 2009, vol. 131, p. 3621 - 3630
[3] Journal of Organic Chemistry, 2009, vol. 74, # 15, p. 5228 - 5236
[4] RSC Advances, 2018, vol. 8, # 37, p. 21030 - 21039
[5] Patent: US2009/239848, 2009, A1, . Location in patent: Page/Page column 19; 20
3
[ 1072-98-6 ]
[ 98-80-6 ]
[ 33421-40-8 ]
Yield
Reaction Conditions
Operation in experiment
52.1%
With tris-(dibenzylideneacetone)dipalladium(0); tricyclohexylphosphine In water; N,N-dimethyl-formamide at 130℃; for 0.5 h; Inert atmosphere; Microwave irradiation; Sealed tube
5-Chloropyridin-2-amine (500 mg, 3.89 mmol), phenyl boronic acid (711 mg, 5.83 mmol), and Na2CO3 (11.67 mmol) were added to a mixture of 4:1 DMF/Water (10 mL). The resulting solution was stirred and degassed with argon for 5 min. P(Cy)3 (49.0 mg,0.175 mmol) and Pd2(dba)3 (53.4 mg, 0.58 mmol) were then added and the reaction was heated under microwave irradiation for 30 min at 130 °C. The crude reaction was adsorbed onto silica and purified using flash chromatography utilizing a DCM/MeOH gradient to yield compound 5-phenylpyridin-2-amine (345 mg, 52.1percent). 1H NMR (400 MHz, DMSO-d6) δ 8.23 (dd, J = 2.5, 0.6 Hz, 1H), 7.77 (dd, J = 8.0, 1.5 Hz, 1H), 7.69 (dd, J = 8.6, 2.6 Hz, 2H), 7.53 (d, J = 7.2 Hz, 2H), 7.38 (d, J = 7.2 Hz, 2H), 6.53 (d, J = 9.3 Hz, 1H), 6.10 (s, 2H). ESIMS m/z [M+H] 171.
Reference：
[1] Tetrahedron Letters, 2005, vol. 46, # 20, p. 3573 - 3577
[2] Tetrahedron, 2008, vol. 64, # 17, p. 3813 - 3825
[3] Organic and Biomolecular Chemistry, 2012, vol. 10, # 47, p. 9410 - 9417
[4] European Journal of Medicinal Chemistry, 2014, vol. 86, p. 714 - 723
[5] ACS Catalysis, 2015, vol. 5, # 5, p. 3120 - 3123
[6] New Journal of Chemistry, 2017, vol. 41, # 24, p. 15420 - 15432
With sodium hydroxide; ammonium chloride; sodium In iron(II) nitrate hexahydrate; diethyl ether; ammonia
Preparation A3 2-Amino-5-phenylpyridine A solution of 2-chloro-5-phenylpyridine (4.0 g., 0.021 mole) in dry diethyl ether (160 ml.) was added dropwise to a solution of sodium (3.39 g., 0.15 g-atom) in liquid ammonia (160 ml.) containing ferrous nitrate hexahydrate (0.095 g.). The resulting suspension was allowed to reflux for 4 hours. Ammonium chloride was added and the ammonia allowed to evaporate. The residue was treated with 5percent aqueous sodium hydroxide (5 ml.). The mixture was filtered. The aqueous layer was extracted with ether (2 * 100 ml.). The combined ethereal layers were washed with brine and dried over sodium sulfate. The solution was concentrated and the residue recrystallized from methylcyclohexane. The product was triturated with chloroform (100 ml.). The mixture was filtered and the filtrate evaporated to give 2-amino-5-phenylpyridine (1.3 g., 36percent), m.p. 133°-135° (lit. m.p. 133° in Chem. Ber., 91, 247 (1958).
With (+/-)-7-(2,3-diacetoxypropyl)theophylline; palladium diacetate; lithium carbonate In water at 120℃; for 0.166667 h; Microwave irradiation; Green chemistry
General procedure: Suzuki–Miyaura couplings were performed in glass tubes suitable for microwave. Halopyridines (0.44 mmol), phenyl boronic acid (65.17 mg, 0.53 mmol), Li2CO3 (63.7 mg, 0.89 mmol), 1 mol percent of Pd(OAc)2 (1 mg, 4.45 ϰ 10-3 mol), and 2 mol percent of the corresponding ligand in 3 mL of distilled water. The mixtures were stirred and heated at 120 °C under microwave radiation during 10 min with a ramp of 1 min in a CEM Discover reactor coupled to a CEM Explorer robotic system. The resulting reaction mixture was cooled to room temperature and the mixture extracted with CH2Cl2 (3 ϰ 2 mL), the organic phase was treated with anhydrous Na2SO4 after filter over celite and analyzed by Gas Chromatography (GC–MS) on an Agilent 6890N GC with a 30.0 m DB-1MS capillary column coupled to an Agilent 5973 Inert Mass Selective detector. Additional experiments of catalysis were carried out under the same reaction conditions using different bases Na2CO3, K2CO3, Li2CO3, Cs2CO3, Rb2CO3, NaOH, KOH, Et3N, and DIPEA.
Reference：
[1] Tetrahedron Letters, 2014, vol. 55, # 42, p. 5841 - 5845
[2] Russian Journal of General Chemistry, 1996, vol. 66, # 12, p. 1925 - 1938
8
[ 827614-64-2 ]
[ 108-86-1 ]
[ 33421-40-8 ]
Reference：
[1] European Journal of Organic Chemistry, 2012, # 3, p. 595 - 603
9
[ 1072-97-5 ]
[ 24388-23-6 ]
[ 33421-40-8 ]
Reference：
[1] European Journal of Organic Chemistry, 2012, # 3, p. 595 - 603
10
[ 1008-88-4 ]
[ 112-80-1 ]
[ 33421-40-8 ]
[ 87109-10-2 ]
Reference：
[1] Patent: US4386209, 1983, A,
11
[ 1008-88-4 ]
[ 33421-40-8 ]
Reference：
[1] Heterocycles, 1986, vol. 24, # 7, p. 1815 - 1819
[2] Journal of Heterocyclic Chemistry, 2008, vol. 45, # 6, p. 1641 - 1649
12
[ 910791-85-4 ]
[ 33421-40-8 ]
Reference：
[1] Journal of Organic Chemistry, 2008, vol. 73, # 22, p. 8800 - 8807
13
[ 1072-97-5 ]
[ 108-90-7 ]
[ 33421-40-8 ]
Reference：
[1] Advanced Synthesis and Catalysis, 2017, vol. 359, # 4, p. 616 - 622
14
[ 1072-97-5 ]
[ 33421-40-8 ]
Reference：
[1] European Journal of Organic Chemistry, 2012, # 3, p. 595 - 603
15
[ 108-86-1 ]
[ 33421-40-8 ]
Reference：
[1] European Journal of Organic Chemistry, 2012, # 3, p. 595 - 603
16
[ 504-29-0 ]
[ 33421-40-8 ]
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2016, vol. 26, # 1, p. 114 - 120
With N,N'-N,N'-[1-(benzo[d]thiazol-2-yl)ethanone O-4-[1-(benzo[d]thiazol-2-yl)ethylideneaminooxy]butyl oxime]bis[dichloropalladium(II)] trihydrate; tetrabutylammomium bromide; potassium hydroxide; In water; at 160℃; for 0.166667h;Microwave irradiation; Green chemistry;
General procedure: A mixture of the appropriate aryl bromides 4-8 (1 mmol), boronic acid 9a, 9b (1.2 mmol), 194 mg TBAB (0.6 mmol), palladium complex 3 (0.15 mol%), 112 mg KOH (2 mmol), and 3 cm3 distilled water was mixed in a process glass vial. The vial was capped properly, and there after the mixture was heated under microwave irradiating conditions at 160 C and 250 W for the appropriate reaction time as listed in Table 1. After the reaction was almost complete (monitored by TLC), the reaction mixture was extracted with EtOAc (3 9 20 cm3). The combined organic extracts were dried over anhydrous MgSO4 then filtered and the solvent was evaporated under reduced pressure. The products were purified with flash column chromatography to give the corresponding pure crosscoupled products 10-14 (from aryl bromides and chloride,Table 1).
76%
With potassium carbonate; In water; at 70℃; for 9h;Inert atmosphere;
General procedure: In a typical run, h-BN(at)Fur(at)Pd(OAc)2 (0.05 mmol) was added to a mixture of arylboronic acid 1 (1.0 mmol), aryl bromide 2 (1.5 mmol) and K2CO3 (1.5 mmol) in water (1 mL). The resulting mixture was stirred at 70 C under Ar protection, and the progress of the reaction was monitored by TLC. After completion of the reaction, ethyl acetate was added to the reaction mixture and the catalyst was separated. The organic phase was washed with water, dried over anhydrous Na2SO4 and the solvent was evaporated under reduced pressure. Finally, the residue was isolated by chromatography on a column of silica gel to afford the corresponding product 3.
70%
With potassium phosphate; tetrakis(triphenylphosphine) palladium(0); In water; ethylene glycol; at 80℃; for 16h;Inert atmosphere;
General procedure: To a solution of 2a, 2c or 2h (3 mmol, 0.5 g) in ethylene glycol (5 mL) was added successively the boronic acid (4.5 or 9.0 mmol, 1.5 or 3 equiv), Pd(PPh3)4 (1mol%), and a solution of K3PO4 (6 mmol, 2 equiv) inwater (2 mL). The reaction mixture was heated at 80C for 16 h and was then hydrolyzed with a 1 M solution of sodium hydroxide (20 mL). The aqueous phase was extracted with ethylacetate (3 x 30 mL) and the combined organic layers were washed with brine (50 mL), dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel with petroleum ether/EtOAc (60/40) as eluent.
61%
With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In water; acetonitrile; at 90℃; for 16h;
To a stirred solution of 5-bromopyridin-2-amine (1) (5.0 g, 28.9 mmol) in acetonitrile (75 mL) at room temperature was added phenylboronic acid (4.93 g, 40.5 mmol), Na2C03 (4.59 g, 43.4 mmol), H20 (25 mL) and Pd(PPh3)4 (3.30 g, 2.89 mmol). The resulting mixture was heated at 90C for 16 h. After cooling to room temperature the reaction mixture was filtered through a pad of celite, and the filtrate was partitioned and extracted with EtOAc (5x100 mL). The combined organic layers were dried over anhydrous Na2S04 and concentrated under reduced pressure. The residue obtained was purified by column chromatography (silica gel, 0 to 20% EtOAc/hexanes) to afford 5-phenylpyridin-2-amine (2) (3.0 g, 61 %) as an off-white solid: MS (Multi-mode, ESI/APCI) m/z 172 [M + H]+.
With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,2-dimethoxyethane; water; for 6h;Heating / reflux;
Dissolving 5.0 g (29 mmol) of 2-amino-5-bromopyridine, 3.6 g (30 mmol) of phenylboronic acid and 0.67 g of tetrakis (triphenylphosphine) palladium into 90 milliliter of 1,2-dimethoxyethane, adding 45 milliliter of 2.0M sodium carbonate aqueous solution, the resultant suspension was refluxed under heating for 6 hours. After completion of the reaction, the resultant solution was further dissolved into ethyl acetate, filtering the solution, washing with water, dried with the use of sodium sulfate. Removing the solvent by distillation, 4.0 g of crude 5-phenyl-2-amino-pyridine was obtained.
With bis-triphenylphosphine-palladium(II) chloride; sodium carbonate; In 1,4-dioxane; water;Inert atmosphere; Reflux;
General procedure: To 0.329 g (1.5 mmol) 4-iodoaniline, 1.8 mmol ArB(OH)2, 0.318 g (3 mmol) Na2CO3 and 75 mg (0.075 mmol) PdCl2(PPh3)2, 15 mL of a blended solution of dioxane and water (v/v = 3/1) was added under N2 atmosphere. Then the reaction was heated to reflux and monitored by TLC. Upon cooling, the reaction mixture was dilute with sat. NH4Cl solution, then extracted with EA (3×20 mL), and the organic layer was washed with saturated NaCl aqueous solution, dried over anhydrous Na2SO4 and purified by flash chromatography to afford different 4-aminobiphenyl derivatives. According to the reductive amination procedure, the 4-aminobiphenyl derivative was further treated with salicylaldehyde and to afford the corresponding compound 5&6.
1.8 g
With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In 1,4-dioxane; water; at 80℃; for 16h;Inert atmosphere;
To a stirred solution of 5-bromopyridin-2-amine (2.0 g, 11.55 mmol) in Dioxane: H2O (20:4 mL) was added phenylboronic acid (1.26 g, 10.40 mmol) and Na2CO3 (2.45 g, 23.14 mmol) at 25 C. The reaction mixture was degassed with Argon for 30 minutes. Tetrakis (668.5 mg, 0.578 mmol) was added. The reaction mixture was heated at 80 C. for 16 h. Then the reaction mixture was cooled, diluted with water (50 mL) and extracted in EtOAc (150 mL*2) The organic layer was washed with brine (20 mL), dried over anhydrous sodium sulfate and distilled off to give crude product which was purified by Flash chromatography to give pure 5-phenylpyridin-2-amine (1.8 g). 1H NMR: (400 MHz, DMSO) (31196) delta: 6.07 (s, 2H), 6.51-6.53 (m, 2H), 7.24-7.28 (m, 2H), 7.38-7.42 (m, 2H), 7.55-7.57 (m, 2H), 7.62-7.71 (m, 1H), 8.24-8.25 (d, J=2.0 Hz, 1H).
EXAMPLE 10 Amination of 3-Phenylpyridine A mixture of 33.2 g (0.85 mole) of sodamide, 450 cc of toluene containing 0.1 cc of oleic acid, and 126.9 g (0.82 mole) of 3-phenylpyridine was placed in a liter Magne Drive, equipped as described in Example 2. The autoclave was closed and purged of air with ammonia, pressurized to 45 psi with ammonia and then to 215 psi with nitrogen. Cooling water was turned on the reflux condenser. The autoclave was heated with stirring to 150 C. and maintained between 150 and 160 C. for about 3 hours, during which time hydrogen evolved and passed through the pressure relief valve. The autoclave was cooled to room temperature and vented to atmospheric pressure. The reaction mixture was carefully hydrolyzed with 100 cc of water. The toluene phase was separated and the aqueous phase was extracted twice with 25 cc of toluene. The toluene extracts were combined and distilled to give 46.9 g of a mixture of 2-amino-5-phenylpyridine and 2-amino-3-phenylpyridine boiling 201-227 C. at 24 mm Hg. A GLC analysis showed that the ratio of 2,5-isomer:2,3-isomer was 38.1:1. The 2-amino-5-phenylpyridine, crystallized from pyridine, had a melting point of 136-137 C.
With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In water; toluene; for 3h;Inert atmosphere; Reflux;
Synthesis of 5-phenyl-pyridin-2-ylamine A mixture of toluene (15 mL) and water (5 mL) was degassed with argon gas for 5 minutes. Sodium carbonate (481 mg, 4.5 mmol) was added and the resulting mixture was again degassed with argon gas for 5 minutes. Phenyl boronic acid (353 mg, 2.7 mmol) and 5-iodo-pyridin-2-ylamine (500 mg, 2.27 mmol) were added and the mixture was again degassed with argon gas for 5 minutes. Tetrakis palladium triphenyl phosphine (525 mg, 4.5 mmol) was then added and the mixture was again degassed with argon gas for 5 minutes. The resulting mixture was heated to reflux for 3 hours. The mixture was then diluted with ethyl acetate and washed with water followed by brine solution. The ethyl acetate layer was collected, dried over sodium sulphate and concentrated under reduced pressure. The resulting residue was purified by column chromatography using silica gel 60-120 mesh (35% ethyl acetate in hexane) to afford 10 mg (28%) of 5-phenyl-pyridin-2-ylamine. LCMS: 171.09 (M+1)+, 60.5%.
With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 20℃; for 2h;
To a solution of 2-<strong>[1798-06-7](4-iodophenyl)acetic acid</strong> 53-1 (816 mg, 3.14 mmol), 5- phenylpyridin-2-amine 53-2 (534mg, 3.14 mmol) and HATU (1.19 g, 3.14 mmol) in DMF (1 mL) was added DIEA (1.57 mL, 9.42 mmol) at room temperature. The mixture was stirred at room temperature for 2 hours. The mixture was diluted with ethyl acetate (50 mL), washed with saturated NaHCO3 aqueous solution, water and brine, dried over Na2SO4, and concentrated by rotary evaporation. The crude product was purified by silica gel flash chromatography, eluted with 40% ethyl acetate in hexane to give 2-(4-Iodophenyl)-N-(5-phenylpyridin-2-yl)acetamide 53-3 as pale yellow solid. MS m/z 415.2 (M + 1)
With N-ethyl-N,N-diisopropylamine; HATU In N,N-dimethyl-formamide at 20℃; for 2h;
5.6
To a mixture of 2-(4-bromo-3-(trifluoromethyl)phenyl)acetic acid 46-6 (71 mg, 0.25 mmol), 5-phenylpyridin-2-amine (64 mg, 0.38 mmol) and HATU (148 mg, 0.38 mmol) in DMF (1 mL) was added DIEA (125 μL, 0.75 mmol) at room temperature. The mixture was stirred at room temperature for 2 hours. The mixture was diluted with ethyl acetate (50 mL), washed with saturated NaHCO3 aqueous solution, water and brine, dried over Na2SO4, and concentrated by rotary evaporation. The crude product was purified by silica gel flash chromatography, eluted with 40% ethyl acetate in hexane to give 2-(4-bromo-3- (trifluoromethyl)phenyl)-N-(5-phenylpyridin-2-yl)acetamide 46-7 as pale yellow solid. MS m/z 435.2 (M + 1)
To a solution of 3-(4-bromophenyl)propanoic acid (200 mg, 0.8?73 mmol) in DMF (2 mL) was added HATU (498 mg, 1.310 mmol) and N-methyl morpholine (384 jil, 3.492 mmol). The reaction mixture was stirred at room temperature under inert atmosphere for 30 mm, followed by the addition of 5-pheny1pyridin-2arnine (163 mg, 0.960 mmol). The reaction mixture was left to stir for 16 h, then it was diluted with H20 (20 mL) and extracted with EtOAc (3x20 mL). The combined organic layer was dried oyer Na2SO4 and was concentrated under reduced pressure. The erude residue was washed with methanol and dried in yacuum oyen at 50C oyernight to afford a white solid (158 mg, 48%). ?H NMR (400 MHz, DMSO-d) 10.58 (s, 1H), 8.62 (d, .1=2.0 Hz, 1H), 8.17-8.15 (m, 1H), 8.09-8.06 (m, 1H), 7.71-7.68 (m, 2H), 7.49-7.46 (m, 4H), 7.40-7.36 (m, IH), 7.24-7.22 (m, 2H), 2.89 (t, J7.6 Hz, 2H), 2.72 (t, .J7.6 Hz, 2H).
General procedure: General CoulinQ Procedure I Methanesulfonyl chloride (1 .5 eq.) was added to a stirred solution of N-methylimidazole (1 .0 eq.) in dichloromethane (25 mL), cooled to 0 °C and the reaction mixture was stirred for 10 to 15 mi Carboxylic acid A (1 .0 eq.) was added at 0 °C and again the reaction mixture was stirred for 20 mm at 10 °C to 15 °C. Amine B (1 .2 eq.) was added to the reaction mixture, whichwas subsequently heated in a sealed glass tube at 55 °C to 60 °C for 16 h. After completion of the reaction, volatiles were removed under reduced pressure. The residual material was triturated with dichloromethane (50 mL), filtered and the wet cake was washed with dichloromethane (100 mL)then dried under reduced pressure to obtain pure product. Additional purificationby flash chromatography over silica was performed when necessary.
2-methyl-N-(5-phenylpyridin-2-yl)pyrimidine-5-carboxamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
16%
General procedure: General CouIinQ Procedure 2 HATU (1 .5 eq.) was added to a stirred solution of Carboxylic acid A (1 .0 eq.) and Amine B (1.2 eq.) in DMF (25 mL) at 0 C and, after 30 mm. ofadditional stirring, DIPEA (4.0 eq.) was added in dropwise fashion and the total reaction mixture was stirred at RT for 16 h. After completion of the reaction, ice water was added to the reaction mixture and the precipitated solid was filtered and washed with ethyl acetate (100 ml) and diethyl ether (100 ml) before drying under reduced pressure to obtain pure product.Additional purification by flash chromatography over silica was performed when necessary.
Preparation of Compound 77-6Compound chloroacetate (Chloroacetic acid) 8.88 g (93.9 mmol), dissolved in 17mL H2O and then triethylamine (Triethylamine) 17mL was added slowly and then the 2-amino-5-phenyl pyridine (2-Amino-5-phenylpyridine) 20 g ( put 117 mmol)Was 5 hours at 90 . After cooling to room temperature, ethyl alcohol (Ethyl alcohol) into a 20mL 2 hours of reaction at 0 , filtered (Filter) to the desired compound 77-6 to give a 20 g (75%).
With silver trifluoromethane sulfate; In chlorobenzene; at 120℃; for 24h;
General procedure: A mixture of 2-aminopyridine (0.1mmol), alkynoate (0.1mmol) and AgSO3CF3 (30mol%) in chlorobenzene (0.8mL) was stirred at 120C for 24h. After the reaction was finished, water (5mL) was added and the solution was extracted with ethyl acetate (3×5mL), the combined extract was dried with anhydrous MgSO4. Solvent was removed, and the residue was separated by column chromatography to give the pure sample.
2-amino-1-(2-ethoxy-2-oxoethyl)-5-phenyl-pyridin-1-ium bromide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
90%
In tetrahydrofuran; at 0 - 20℃; for 8h;Inert atmosphere;
General procedure: An oven dried round bottom (RB) flask was charged with 2-aminopyridine (1.0 g, 10.63 mmol) and tetrahydrofuran (15 mL). The RB flask was capped with rubber septum and after purging N2 gas, ethyl bromoacetate (1.33 g, 7.96 mmol) was added in portion using syringe and stirred the reaction mixture under N2 gas atmosphere at 0 C. The temperature of the reaction mixture was slowly raised to room temperature and stirred for 8 h to obtain pink colored precipitate. After complete consumption of 2-aminopyridine as monitored by thin layer chromatography, reaction mixture was filtered and residue was washed with diethyl ether to provide pure solid compound.
phenyl(6-phenylimidazo[1,2-a]pyridin-3-yl)methanone[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
72%
With iron(III) chloride; In toluene; at 60℃; for 18h;
General procedure: A mixture of 2-aminopyridine (0.2 mmol), 3-phenylpropiolaldehyde (0.2 mmol) and ferric chloride (5 mol%) in toluene (1 mL) was placed in a test tube (10 mL) equipped with a magnetic stirring bar. The mixture was stirred at 60 C for 18 h. After the reaction was finished, water (5 mL) was added and the solution was extracted with ethyl acetate (3×5 mL), the combined extract was dried with anhydrous MgSO4. Solvent was removed, and the residue was separated by column chromatography to give the pure sample.
[1,1'-biphenyl]-4-yl(6-phenylimidazo[1,2-a]pyridin-3-yl)methanone[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
72%
With iron(III) chloride; In toluene; at 60℃; for 18h;
General procedure: A mixture of 2-aminopyridine (0.2 mmol), 3-phenylpropiolaldehyde (0.2 mmol) and ferric chloride (5 mol%) in toluene (1 mL) was placed in a test tube (10 mL) equipped with a magnetic stirring bar. The mixture was stirred at 60 C for 18 h. After the reaction was finished, water (5 mL) was added and the solution was extracted with ethyl acetate (3×5 mL), the combined extract was dried with anhydrous MgSO4. Solvent was removed, and the residue was separated by column chromatography to give the pure sample.
4-(1,3-dioxoisoindolin-2-yl)-N-(5-phenylpyridin-2-yl)butanamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
Stage #1: 4-phthalimidobutyric acid With triethylamine; HATU In dichloromethane at 20℃; for 0.166667h;
Stage #2: 5-phenyl-pyridin-2-ylamine In dichloromethane at 20℃; for 24h;
1. General synthetic procedure of compounds 1-19
General procedure: The intermediate compound (1.93 mmol) and HATU (960 mg, 2.52 mmol) were dissolved in anhydrous dichloromethane (10 ml), and then triethylamine (394 μL, 2.92 mmol) was added dropwise. The mixture was stirred at room temperature for 10 min. 2-Aminophenylpyridine (330 mg, 1.94 mmol) was added afterwards and allowed to react at room temperature for 24 h. After removal of inorganic salt residue by filtration, the filtrate was mixed with 60-100 mesh silica gel, and purified by silica gel column (mobile phase: petroleum ether / ethyl acetate = 20:1 - 10:1 gradient elution) to give a white solid as the product.
4-(5-fluoro-1,3-dioxoisoindolin-2-yl)-N-(5-phenylpyridin-2-yl)butanamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
40.3%
Intermediate compound (370 mg, 1.47 mmol) and HATU (730 mg, 1.92 mmol)Dissolve in anhydrous dichloromethane (10ml), add triethylamine (300muL, 2.22mmol) dropwise, stir at room temperature for 10min, then add 2-aminophenylpyridine(251 mg, 1.47 mmol), reacted at room temperature for 24 h. Filter to remove inorganic salt residue,The filtrate was mixed with 60-100 mesh silica gel and separated by silica gel column.(mobile phase: petroleum ether / ethyl acetate = 20:1 - 10:1 gradient elution),A white solid of 240 mg was obtained in a yield of 40.3%.
General procedure: The intermediate compound (1.93 mmol) and HATU (960 mg, 2.52 mmol) were dissolved in anhydrous dichloromethane (10 ml), and then triethylamine (394 muL, 2.92 mmol) was added dropwise. The mixture was stirred at room temperature for 10 min. 2-Aminophenylpyridine (330 mg, 1.94 mmol) was added afterwards and allowed to react at room temperature for 24 h. After removal of inorganic salt residue by filtration, the filtrate was mixed with 60-100 mesh silica gel, and purified by silica gel column (mobile phase: petroleum ether / ethyl acetate = 20:1 - 10:1 gradient elution) to give a white solid as the product.
4-(4-fluoro-1,3-dioxoisoindolin-2-yl)-N-(5-phenylpyridin-2-yl)butanamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
40.5%
Intermediate compound (370 mg, 1.47 mmol) and HATU (730 mg, 1.92 mmol)Dissolved in anhydrous dichloromethane (10 ml), triethylamine (300 muL, 2.22 mmol) was added dropwise.After stirring at room temperature for 10 min, 2-aminophenylpyridine (251 mg, 1.47 mmol) was added.The reaction was carried out at room temperature for 24 h. Filtration, removal of inorganic salt residue, the filtrate was mixed with 60-100 mesh silica gel,Separation and purification on a silica gel column (mobile phase: petroleum ether / ethyl acetate = 20:1 - 10:1 gradient elution)245 mg of a white solid were obtained in a yield of 40.5%.
General procedure: The intermediate compound (1.93 mmol) and HATU (960 mg, 2.52 mmol) were dissolved in anhydrous dichloromethane (10 ml), and then triethylamine (394 muL, 2.92 mmol) was added dropwise. The mixture was stirred at room temperature for 10 min. 2-Aminophenylpyridine (330 mg, 1.94 mmol) was added afterwards and allowed to react at room temperature for 24 h. After removal of inorganic salt residue by filtration, the filtrate was mixed with 60-100 mesh silica gel, and purified by silica gel column (mobile phase: petroleum ether / ethyl acetate = 20:1 - 10:1 gradient elution) to give a white solid as the product.
4-(4,5-difluoro-1,3-dioxoisoindolin-2-yl)-N-(5-phenylpyridin-2-yl)butanamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
40.1%
the intermediate compound (365 mg, 1.45 mmol) and HATU (720 mg, 1.89 mmol)Dissolve in anhydrous dichloromethane (10 ml), add triethylamine (300 muL, 2.18 mmol) dropwise, stir at room temperature for 10 min, then add 2-aminophenylpyridine (250 mg, 1.45 mmol).The reaction was carried out at room temperature for 24 h. Filter to remove inorganic salt residue,The filtrate was mixed with 60-100 mesh silica gel, and purified by silica gel column (mobile phase: petroleum ether / ethyl acetate = 20:1 - 10:1 gradient elution) to give 232 mg of white solid.The yield was 40.1%.
General procedure: The intermediate compound (1.93 mmol) and HATU (960 mg, 2.52 mmol) were dissolved in anhydrous dichloromethane (10 ml), and then triethylamine (394 muL, 2.92 mmol) was added dropwise. The mixture was stirred at room temperature for 10 min. 2-Aminophenylpyridine (330 mg, 1.94 mmol) was added afterwards and allowed to react at room temperature for 24 h. After removal of inorganic salt residue by filtration, the filtrate was mixed with 60-100 mesh silica gel, and purified by silica gel column (mobile phase: petroleum ether / ethyl acetate = 20:1 - 10:1 gradient elution) to give a white solid as the product.
4-(4,7-difluoro-1,3-dioxoisoindolin-2-yl)-N-(5-phenylpyridin-2-yl)butanamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
40.1%
he intermediate compound (365 mg, 1.45 mmol) and HATU (720 mg, 1.89 mmol)Dissolve in anhydrous dichloromethane (10 ml), add triethylamine (300 muL, 2.18 mmol) dropwise, stir at room temperature for 10 min, then add 2-aminophenylpyridine (250 mg, 1.45 mmol).The reaction was carried out at room temperature for 24 h. Filtration, removal of inorganic salt residue, the filtrate was mixed with 60-100 mesh silica gel,Separation and purification on a silica gel column (mobile phase: petroleum ether / ethyl acetate = 20:1 - 10:1 gradient elution)A white solid 232 mg was obtained in a yield of 40.1%.
General procedure: The intermediate compound (1.93 mmol) and HATU (960 mg, 2.52 mmol) were dissolved in anhydrous dichloromethane (10 ml), and then triethylamine (394 muL, 2.92 mmol) was added dropwise. The mixture was stirred at room temperature for 10 min. 2-Aminophenylpyridine (330 mg, 1.94 mmol) was added afterwards and allowed to react at room temperature for 24 h. After removal of inorganic salt residue by filtration, the filtrate was mixed with 60-100 mesh silica gel, and purified by silica gel column (mobile phase: petroleum ether / ethyl acetate = 20:1 - 10:1 gradient elution) to give a white solid as the product.
4-(5-chloro-1,3-dioxoisoindolin-2-yl)-N-(5-phenylpyridin-2-yl)butanamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
55.1%
4-Chlorophthalic anhydride (362 mg, 2.0 mmol) and 4-aminobutyric acid (206 mg, 2.0 mmol) were added to glacial acetic acid (10 mL), and the mixture was heated to 100 C for 3 h.The reaction was quenched with water (10 mL), NaOH solution (0.1 mol/L)The pH of the solution was adjusted to 6-8. Dichloromethane extraction (10mL × 3),Wash with saturated NaHCO3 solution, wash with water, and combine with organicAfter drying, it was 460 mg of a yellow solid.LC-MS and 1 H-NMR confirmed the expected intermediate compound in a yield of 86.4%.The intermediate compound (460 mg, 1.72 mmol) and HATU (854 mg, 2.25 mmol) were dissolved in anhydrous dichloromethane (10 ml), triethylamine (360 muL, 2.58 mmol) was added dropwise, and stirred at room temperature for 10 min. 2-Aminophenylpyridine (293 mg, 1.72 mmol) was reacted at room temperature for 24 h. Filter to remove inorganic salt residue,The filtrate was spun dry to give a brown oil.Obtained as a white solid; the filtrate was again dried, ethyl acetate was dissolved hot, and cooled at low temperature for 2 hAfter suction filtration, a pale yellow solid was obtained, and the dry weight was about 400 mg, and the yield was 55.1%.
General procedure: The intermediate compound (1.93 mmol) and HATU (960 mg, 2.52 mmol) were dissolved in anhydrous dichloromethane (10 ml), and then triethylamine (394 muL, 2.92 mmol) was added dropwise. The mixture was stirred at room temperature for 10 min. 2-Aminophenylpyridine (330 mg, 1.94 mmol) was added afterwards and allowed to react at room temperature for 24 h. After removal of inorganic salt residue by filtration, the filtrate was mixed with 60-100 mesh silica gel, and purified by silica gel column (mobile phase: petroleum ether / ethyl acetate = 20:1 - 10:1 gradient elution) to give a white solid as the product.
4-(4-chloro-1,3-dioxoisoindolin-2-yl)-N-(5-phenylpyridin-2-yl)butanamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
52.3%
Intermediate compound (444 mg, 1.92 mmol) and HATU (950 mg, 2.5 mmol)Dissolved in anhydrous dichloromethane(10 ml), triethylamine (390 muL, 2.88 mmol) was added dropwise.After stirring for 10 min at room temperature, 2-aminophenylpyridine was added.(330 mg, 1.92 mmol), reacted at room temperature for 24 h. filter,The inorganic salt residue is removed, the filtrate is spun dry, and the ethyl acetate is thermally dissolved.Filtration under low temperature for 2 h gave a pale yellow solid.The dry weight was about 412 mg, and the yield was 52.3%.
General procedure: The intermediate compound (1.93 mmol) and HATU (960 mg, 2.52 mmol) were dissolved in anhydrous dichloromethane (10 ml), and then triethylamine (394 muL, 2.92 mmol) was added dropwise. The mixture was stirred at room temperature for 10 min. 2-Aminophenylpyridine (330 mg, 1.94 mmol) was added afterwards and allowed to react at room temperature for 24 h. After removal of inorganic salt residue by filtration, the filtrate was mixed with 60-100 mesh silica gel, and purified by silica gel column (mobile phase: petroleum ether / ethyl acetate = 20:1 - 10:1 gradient elution) to give a white solid as the product.
4-(5,6-dichloro-1,3-dioxoisoindolin-2-yl)-N-(5-phenylpyridin-2-yl)butanamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
68.2%
Intermediate compound (576 mg, 1.92 mmol) and HATU (950 mg, 2.50 mmol)Dissolved in anhydrous dichloromethane (10 ml), triethylamine (400 muL, 2.89 mmol) was added dropwise.After stirring for 10 min at room temperature, 2-aminophenylpyridine was added.(324 mg, 1.92 mmol), reacted at room temperature for 24 h. Filter to remove inorganic salt residue,The filtrate was spun dry to give a brown oil.The filtrate was again dried and the ethyl acetate was dissolved in hot water, cooled at low temperature for 2 h, and filtered.Light yellow solid,The dry weight was about 594 mg, and the yield was 68.2%.
General procedure: The intermediate compound (1.93 mmol) and HATU (960 mg, 2.52 mmol) were dissolved in anhydrous dichloromethane (10 ml), and then triethylamine (394 muL, 2.92 mmol) was added dropwise. The mixture was stirred at room temperature for 10 min. 2-Aminophenylpyridine (330 mg, 1.94 mmol) was added afterwards and allowed to react at room temperature for 24 h. After removal of inorganic salt residue by filtration, the filtrate was mixed with 60-100 mesh silica gel, and purified by silica gel column (mobile phase: petroleum ether / ethyl acetate = 20:1 - 10:1 gradient elution) to give a white solid as the product.
N-(5-phenylpyridin-2-yl)-4-(4,5,6,7-tetrachloro-1,3-dioxoisoindolin-2-yl)butanamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
69%
The intermediate compound (726 mg, 1.97 mmol) and HATU (975 mg, 2.57 mmol)Dissolved in anhydrous dichloromethane (10 ml), triethylamine (400 muL, 2.96 mmol) was added dropwise, and stirred at room temperature for 10 min, then 2-aminophenylpyridine (335 mg, 1.97 mmol) was added and allowed to react at room temperature for 24 h. Filtration, removal of inorganic salt filter residue, the filtrate was spun dry to obtain a brown oil; a small amount of dichloromethane was dissolved and filtered; the filtrate was again dried, ethyl acetate was dissolved, and then cooled at low temperature for 2 h.After suction filtration, a pale yellow solid was obtained, which was dried and weighed about 718 mg, yield 69.0%.
General procedure: The intermediate compound (1.93 mmol) and HATU (960 mg, 2.52 mmol) were dissolved in anhydrous dichloromethane (10 ml), and then triethylamine (394 muL, 2.92 mmol) was added dropwise. The mixture was stirred at room temperature for 10 min. 2-Aminophenylpyridine (330 mg, 1.94 mmol) was added afterwards and allowed to react at room temperature for 24 h. After removal of inorganic salt residue by filtration, the filtrate was mixed with 60-100 mesh silica gel, and purified by silica gel column (mobile phase: petroleum ether / ethyl acetate = 20:1 - 10:1 gradient elution) to give a white solid as the product.
4-(5-bromo-1,3-dioxoisoindolin-2-yl)-N-(5-phenylpyridin-2-yl)butanamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
55.1%
The intermediate compound (600 mg, 1.93 mmol) and HATU (954 mg, 2.51 mmol) were dissolved in anhydrous dichloromethane(10 ml), triethylamine (405 muL, 2.90 mmol) was added dropwise, and stirred at room temperature for 10 min, then 2-aminophenylpyridine was added.(328 mg, 1.93 mmol), reacted at room temperature for 24 h. Filtration, removal of inorganic salt residue, the filtrate is spun dry to obtain a brown oil;Dichloromethane was dissolved and filtered; the filtrate was again dried, ethyl acetate was dissolved in vacuo, and then cooled at low temperature for 2 h and filtered to give a pale yellow solid.Dry weighing about 495mg, yield 55.1%
General procedure: The intermediate compound (1.93 mmol) and HATU (960 mg, 2.52 mmol) were dissolved in anhydrous dichloromethane (10 ml), and then triethylamine (394 muL, 2.92 mmol) was added dropwise. The mixture was stirred at room temperature for 10 min. 2-Aminophenylpyridine (330 mg, 1.94 mmol) was added afterwards and allowed to react at room temperature for 24 h. After removal of inorganic salt residue by filtration, the filtrate was mixed with 60-100 mesh silica gel, and purified by silica gel column (mobile phase: petroleum ether / ethyl acetate = 20:1 - 10:1 gradient elution) to give a white solid as the product.
4-(5-nitro-1,3-dioxoisoindolin-2-yl)-N-(5-phenylpyridin-2-yl)butanamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
58.4%
The intermediate compound (572 mg, 1.93 mmol) and HATU (954 mg, 2.51 mmol) were dissolved in anhydrous dichloromethane (10 ml), and triethylamine (405 muL, 2.90 mmol) was added dropwise.After stirring at room temperature for 10 min, 2-aminophenylpyridine (328 mg, 1.93 mmol) was added and allowed to react at room temperature for 24 h. Filtration, removal of inorganic salt residue, the filtrate is spun dry to obtain a brown oil;Dichloromethane was dissolved and filtered; the filtrate was again dried, ethyl acetate was dissolved in vacuo, and then cooled to dryness for 2 h and filtered to give a pale-yellow solid, dry weight about 500 mg, yield 58.4%.
General procedure: The intermediate compound (1.93 mmol) and HATU (960 mg, 2.52 mmol) were dissolved in anhydrous dichloromethane (10 ml), and then triethylamine (394 muL, 2.92 mmol) was added dropwise. The mixture was stirred at room temperature for 10 min. 2-Aminophenylpyridine (330 mg, 1.94 mmol) was added afterwards and allowed to react at room temperature for 24 h. After removal of inorganic salt residue by filtration, the filtrate was mixed with 60-100 mesh silica gel, and purified by silica gel column (mobile phase: petroleum ether / ethyl acetate = 20:1 - 10:1 gradient elution) to give a white solid as the product.
4-(4-nitro-1,3-dioxoisoindolin-2-yl)-N-(5-phenylpyridin-2-yl)butanamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
57.5%
The intermediate compound (570 mg, 1.93 mmol) and HATU (954 mg, 2.51 mmol) were dissolved in anhydrous dichloromethane(10 ml), triethylamine (405 muL, 2.90 mmol) was added dropwise, and stirred at room temperature for 10 min, then 2-aminophenylpyridine was added.(328 mg, 1.93 mmol), reacted at room temperature for 24 h. Filtration, removal of inorganic salt residue, the filtrate is spun dry to obtain a brown oil;Dichloromethane was dissolved and filtered; the filtrate was again dried, ethyl acetate was dissolved in vacuo, and then cooled at low temperature for 2 h and filtered to give a pale yellow solid.The dry weight was about 490 mg, and the yield was 57.5%.
General procedure: The intermediate compound (1.93 mmol) and HATU (960 mg, 2.52 mmol) were dissolved in anhydrous dichloromethane (10 ml), and then triethylamine (394 muL, 2.92 mmol) was added dropwise. The mixture was stirred at room temperature for 10 min. 2-Aminophenylpyridine (330 mg, 1.94 mmol) was added afterwards and allowed to react at room temperature for 24 h. After removal of inorganic salt residue by filtration, the filtrate was mixed with 60-100 mesh silica gel, and purified by silica gel column (mobile phase: petroleum ether / ethyl acetate = 20:1 - 10:1 gradient elution) to give a white solid as the product.
4-(5-methyl-1,3-dioxoisoindolin-2-yl)-N-(5-phenylpyridin-2-yl)butanamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
50.5%
4-Methyl phthalic anhydride (490 mg, 3.0 mmol) and 4-aminobutyric acid (320 mg, 3.1 mmol) were added to glacial acetic acid (10 mL) and heated to 100 C for 3 h.The reaction was quenched with water (10 mL) and the NaOH solution (0.1 mol/L) was adjusted to pH 6-8.Dichloromethane extraction (10mL × 3), washed with saturated NaHCO3 solution, washed with water,The organic phases were combined and dried over anhydrous sodium sulfate.After drying, it was obtained as a yellow solid 700 mg.LC-MS and 1 H-NMR confirmed the expected intermediate compound, yield 93.7%. Intermediate compound (700 mg, 2.81 mmol) and HATU (1.4 g, 3.65 mmol)Dissolved in anhydrous dichloromethane (10 ml), triethylamine (580 muL, 4.22 mmol) was added dropwise.After stirring at room temperature for 10 min, 2-aminophenylpyridine (484 mg, 2.81 mmol) was added.The reaction was carried out at room temperature for 24 h. Filtration, removal of inorganic salt residue, the filtrate was mixed with 60-100 mesh silica gel,Separation and purification on a silica gel column (mobile phase: petroleum ether / ethyl acetate = 20:1 - 10:1 gradient elution)573 mg of a white solid were obtained in a yield of 50.5%.
General procedure: The intermediate compound (1.93 mmol) and HATU (960 mg, 2.52 mmol) were dissolved in anhydrous dichloromethane (10 ml), and then triethylamine (394 muL, 2.92 mmol) was added dropwise. The mixture was stirred at room temperature for 10 min. 2-Aminophenylpyridine (330 mg, 1.94 mmol) was added afterwards and allowed to react at room temperature for 24 h. After removal of inorganic salt residue by filtration, the filtrate was mixed with 60-100 mesh silica gel, and purified by silica gel column (mobile phase: petroleum ether / ethyl acetate = 20:1 - 10:1 gradient elution) to give a white solid as the product.
4-(4-methyl-1,3-dioxoisoindolin-2-yl)-N-(5-phenylpyridin-2-yl)butanamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
50.5%
intermediate compound (686 mg, 2.75 mmol) and HATU (1.4 g, 3.65 mmol)Dissolved in anhydrous dichloromethane (10 ml), triethylamine (580 muL, 4.22 mmol) was added dropwise, and stirred at room temperature for 10 min, then 2-aminophenylpyridine (484 mg, 2.81 mmol) was added and allowed to react at room temperature for 24 h. Filtration, removal of inorganic salt filter residue, the filtrate is mixed with 60-100 mesh silica gel, silica gelColumn separation and purification (mobile phase: petroleum ether / ethyl acetate = 20:1-10:1 gradient elution),564 mg of a white solid were obtained in a yield of 50.5%.
General procedure: The intermediate compound (1.93 mmol) and HATU (960 mg, 2.52 mmol) were dissolved in anhydrous dichloromethane (10 ml), and then triethylamine (394 muL, 2.92 mmol) was added dropwise. The mixture was stirred at room temperature for 10 min. 2-Aminophenylpyridine (330 mg, 1.94 mmol) was added afterwards and allowed to react at room temperature for 24 h. After removal of inorganic salt residue by filtration, the filtrate was mixed with 60-100 mesh silica gel, and purified by silica gel column (mobile phase: petroleum ether / ethyl acetate = 20:1 - 10:1 gradient elution) to give a white solid as the product.
4-(5-(tert-butyl)-1,3-dioxoisoindolin-2-yl)-N-(5-phenylpyridin-2-yl)butanamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
50.5%
The intermediate compound (620 mg, 2.14 mmol) and HATU (1.178 g, 2.79 mmol)Dissolved in anhydrous dichloromethane (10 ml), triethylamine (470 muL, 3.21 mmol) was added dropwise, and stirred at room temperature for 10 min, then 2-aminophenylpyridine (370 mg, 2.15 mmol).The reaction was carried out at room temperature for 24 h. Filtration, removal of inorganic salt residue, the filtrate was mixed with 60-100 mesh silica gel,Separation and purification on a silica gel column (mobile phase: petroleum ether / ethyl acetate = 20:1 - 10:1 gradient elution)573 mg of a white solid were obtained in a yield of 50.5%.
General procedure: The intermediate compound (1.93 mmol) and HATU (960 mg, 2.52 mmol) were dissolved in anhydrous dichloromethane (10 ml), and then triethylamine (394 muL, 2.92 mmol) was added dropwise. The mixture was stirred at room temperature for 10 min. 2-Aminophenylpyridine (330 mg, 1.94 mmol) was added afterwards and allowed to react at room temperature for 24 h. After removal of inorganic salt residue by filtration, the filtrate was mixed with 60-100 mesh silica gel, and purified by silica gel column (mobile phase: petroleum ether / ethyl acetate = 20:1 - 10:1 gradient elution) to give a white solid as the product.
4-(1,3-dioxo-5-(phenylethynyl)isoindolin-2-yl)-N-(5-phenylpyridin-2-yl)butanamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
33.6%
The intermediate compound (608 mg, 1.82 mmol) and HATU (907 mg, 2.37 mmol)Dissolved in anhydrous dichloromethane (10 ml), triethylamine (373 muL, 2.73 mmol) was added dropwise, and stirred at room temperature for 10 min, then 2-aminophenylpyridine (313 mg, 1.82 mmol).The reaction was carried out for 48 h at room temperature. Filtration, removal of inorganic salt residue, the filtrate is dried,Obtained a brown oil; a small amount of dichloromethane dissolved, filtered;Ethyl acetate was dissolved in hot water, cooled at low temperature for 2 h, and suction filtered to give a pale yellow solid.The dry weight was about 304 mg, and the yield was 33.6%
General procedure: The intermediate compound (1.93 mmol) and HATU (960 mg, 2.52 mmol) were dissolved in anhydrous dichloromethane (10 ml), and then triethylamine (394 muL, 2.92 mmol) was added dropwise. The mixture was stirred at room temperature for 10 min. 2-Aminophenylpyridine (330 mg, 1.94 mmol) was added afterwards and allowed to react at room temperature for 24 h. After removal of inorganic salt residue by filtration, the filtrate was mixed with 60-100 mesh silica gel, and purified by silica gel column (mobile phase: petroleum ether / ethyl acetate = 20:1 - 10:1 gradient elution) to give a white solid as the product.
3-(4-methyl-1,3-dioxoisoindolin-2-yl)-N-(5-phenylpyridin-2-yl)propanamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
54.4%
ntermediate compound (445 mg, 2.86 mmol) and HATU (1.4 g, 3.72 mmol)Dissolved in anhydrous dichloromethane(10 ml), triethylamine (580 muL, 4.22 mmol) was added dropwise.After stirring for 10 min at room temperature, 2-aminophenylpyridine was added.(488 mg, 2.87 mmol), reacted at room temperature for 24 h. filter,The inorganic salt residue is removed, and the filtrate is mixed with 60-100 mesh silica gel and purified by silica gel column.(mobile phase: petroleum ether / ethyl acetate = 20:1 - 10:1 gradient elution),A white solid of 400 mg was obtained in a yield of 54.4%.
General procedure: The intermediate compound (1.93 mmol) and HATU (960 mg, 2.52 mmol) were dissolved in anhydrous dichloromethane (10 ml), and then triethylamine (394 muL, 2.92 mmol) was added dropwise. The mixture was stirred at room temperature for 10 min. 2-Aminophenylpyridine (330 mg, 1.94 mmol) was added afterwards and allowed to react at room temperature for 24 h. After removal of inorganic salt residue by filtration, the filtrate was mixed with 60-100 mesh silica gel, and purified by silica gel column (mobile phase: petroleum ether / ethyl acetate = 20:1 - 10:1 gradient elution) to give a white solid as the product.
<i>N</i>,<i>N</i>-(3-methyl-phthaloyl)-glycine[ No CAS ]
2-(4-methyl-1,3-dioxoisoindolin-2-yl)-N-(5-phenylpyridin-2-yl)acetamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
52.3%
Intermediate compound (420 mg, 2.87 mmol) and HATU (1.4 g, 3.72 mmol)Dissolved in anhydrous dichloromethane(10 ml), triethylamine (580 muL, 4.22 mmol) was added dropwise.After stirring for 10 min at room temperature, 2-aminophenylpyridine was added.(488 mg, 2.87 mmol), reacted at room temperature for 24 h. filter,The inorganic salt residue is removed, and the filtrate is mixed with 60-100 mesh silica gel and purified by silica gel column.(mobile phase: petroleum ether / ethyl acetate = 20:1 - 10:1 gradient elution),370 mg of a white solid were obtained in a yield of 52.3%.
General procedure: The intermediate compound (1.93 mmol) and HATU (960 mg, 2.52 mmol) were dissolved in anhydrous dichloromethane (10 ml), and then triethylamine (394 muL, 2.92 mmol) was added dropwise. The mixture was stirred at room temperature for 10 min. 2-Aminophenylpyridine (330 mg, 1.94 mmol) was added afterwards and allowed to react at room temperature for 24 h. After removal of inorganic salt residue by filtration, the filtrate was mixed with 60-100 mesh silica gel, and purified by silica gel column (mobile phase: petroleum ether / ethyl acetate = 20:1 - 10:1 gradient elution) to give a white solid as the product.
2-(4-methyl-1,3-dioxoisoindolin-2-yl)-N-(5-phenylpyridin-2-yl)propanamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
48%
Intermediate compound (420 mg, 2.72 mmol) and HATU (1.34 g, 3.54 mmol)Dissolved in anhydrous dichloromethane(10 ml), triethylamine (550 muL, 4.09 mmol) was added dropwise.After stirring for 10 min at room temperature, 2-aminophenylpyridine was added.(464 mg, 2.72 mmol), reacted at room temperature for 24 h. filter,The inorganic salt residue is removed, and the filtrate is mixed with 60-100 mesh silica gel and purified by silica gel column.(mobile phase: petroleum ether / ethyl acetate = 20:1 - 10:1 gradient elution),Obtained 388 mg of white solid, yield 48.0%
General procedure: The intermediate compound (1.93 mmol) and HATU (960 mg, 2.52 mmol) were dissolved in anhydrous dichloromethane (10 ml), and then triethylamine (394 muL, 2.92 mmol) was added dropwise. The mixture was stirred at room temperature for 10 min. 2-Aminophenylpyridine (330 mg, 1.94 mmol) was added afterwards and allowed to react at room temperature for 24 h. After removal of inorganic salt residue by filtration, the filtrate was mixed with 60-100 mesh silica gel, and purified by silica gel column (mobile phase: petroleum ether / ethyl acetate = 20:1 - 10:1 gradient elution) to give a white solid as the product.
N-(3-(naphthalen-1-yl)phenyl)-5-phenylpyridin-2-amine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
83%
With palladium diacetate; sodium t-butanolate; In toluene; at 120℃; for 48h;Inert atmosphere;
(1) in a 500ml three-necked bottle,Add <strong>[33421-40-8]5-phenylpyridin-2-amine</strong> (17.02 g, 100 mmol),1-(3-bromophenyl)naphthalene (28.32 g, 100 mmol), sodium tert-butoxide(28.83 g, 300 mmol) was added 100 g of toluene, and palladium acetate was added under the protection of N2.After reacting at 120 C for 48 h, the reaction was completed by TLC. Wash water (200ml) three times,Decolorization by adding activated carbon, drying and concentration to obtain a gray solidRecrystallized product with ethyl acetateDrying under vacuum to give N-(3-(naphthalen-1-yl)phenyl)-<strong>[33421-40-8]5-phenylpyridin-2-amine</strong>30.92 g, 83% yield.
Intermediate compound (440 mg, 1.57 mmol) and HATU (780 mg, 2.04 mmol)Dissolved in anhydrous dichloromethane(10 ml), triethylamine (318 muL, 2.36 mmol) was added dropwise.After stirring for 10 min at room temperature, 2-aminophenylpyridine was added.(272 mg, 1.57 mmol), reacted at room temperature for 24 h. filter,The inorganic salt residue was removed, and the filtrate was mixed with 60-100 mesh silica gel.Separation and purification on a silica gel column (mobile phase: petroleum ether / ethyl acetate = 20:1 - 10:1 gradient elution)A white solid 331 mg was obtained in a yield of 46.5%.
Intermediate compound (340 mg, 1.4 mmol) and HATU (710 mg, 1.87 mmol)Dissolved in anhydrous dichloromethane(10 ml), triethylamine (225 muL, 2.16 mmol) was added dropwise.After stirring for 10 min at room temperature, 2-aminophenylpyridine was added.(245 mg, 1.44 mmol), reacted at room temperature for 24 h. Filter to remove inorganic salt residue,The filtrate was mixed with 60-100 mesh silica gel and separated by silica gel column.(mobile phase: petroleum ether / ethyl acetate = 20:1 - 10:1 gradient elution),263 mg of a white solid were obtained in a yield of 49.8%.
Intermediate compound (480 mg, 1.62 mmol) and HATU (800 mg, 2.1 mmol)Dissolve in anhydrous dichloromethane (10ml), add triethylamine (332muL, 2.46mmol) dropwise, stir at room temperature for 10min, then add 2-aminophenylpyridine(280 mg, 1.64 mmol), reacted at room temperature for 24 h. filter,The inorganic salt residue is removed, and the filtrate is mixed with 60-100 mesh silica gel and purified by silica gel column.(mobile phase: petroleum ether / ethyl acetate = 20:1 - 10:1 gradient elution),327 mg of a white solid were obtained in a yield of 45.0%.
Intermediate compound (525 mg, 1.70 mmol) and HATU (840 mg, 2.21 mmol)Dissolved in anhydrous dichloromethane(10 ml), triethylamine (344 muL, 2.55 mmol) was added dropwise.After stirring for 10 min at room temperature, 2-aminophenylpyridine was added.(290 mg, 1.70 mmol), reacted at room temperature for 24 h. filter,The inorganic salt residue is removed, and the filtrate is mixed with 60-100 mesh silica gel and purified by silica gel column.(mobile phase: petroleum ether / ethyl acetate = 20:1 - 10:1 gradient elution),378 mg of a white solid were obtained in a yield of 48.1%.
Intermediate compound (478 mg, 1.61 mmol) and HATU (800 mg, 2.1 mmol)Dissolved in anhydrous dichloromethane(10 ml), triethylamine (332 muL, 2.46 mmol) was added dropwise.After stirring for 10 min at room temperature, 2-aminophenylpyridine was added.(280 mg, 1.64 mmol), reacted at room temperature for 24 h. Filter to remove inorganic salt residue,The filtrate was mixed with 60-100 mesh silica gel and separated by silica gel column.(mobile phase: petroleum ether / ethyl acetate = 20:1 - 10:1 gradient elution),333 mg of a white solid were obtained in a yield of 46.1%.
Intermediate compound (520 mg, 1.70 mmol) and HATU (840 mg, 2.21 mmol)Dissolved in anhydrous dichloromethane(10 ml), triethylamine (344 muL, 2.55 mmol) was added dropwise.After stirring for 10 min at room temperature, 2-aminophenylpyridine was added.(290 mg, 1.70 mmol), reacted at room temperature for 24 h. filter,The inorganic salt residue was removed, and the filtrate was mixed with 60-100 mesh silica gel.Separation and purification on a silica gel column (mobile phase: petroleum ether / ethyl acetate = 20:1 - 10:1 gradient elution)370 mg of a white solid were obtained in a yield of 47.6%.
The intermediate compound (525 mg, 1.83 mmol) and HATU (905 mg, 2.38 mmol)Dissolved in anhydrous dichloromethane (10 ml), triethylamine (370 muL, 2.75 mmol) was added dropwise.After stirring for 10 min at room temperature, 2-aminophenylpyridine was added.(311 mg, 1.83 mmol), reacted at room temperature for 24 h. Filter to remove inorganic salt residue,The filtrate was mixed with 60-100 mesh silica gel and separated by silica gel column.(mobile phase: petroleum ether / ethyl acetate = 20:1 - 10:1 gradient elution),396 mg of a white solid were obtained in a yield of 49.3%.
The intermediate compound (525 mg, 1.83 mmol) and HATU (905 mg, 2.38 mmol)Dissolved in anhydrous dichloromethane (10 ml), triethylamine (370 muL, 2.75 mmol) was added dropwise.After stirring for 10 min at room temperature, 2-aminophenylpyridine was added.(311 mg, 1.83 mmol), reacted at room temperature for 24 h. Filter to remove inorganic salt residue,The filtrate was mixed with 60-100 mesh silica gel and separated by silica gel column.(mobile phase: petroleum ether / ethyl acetate = 20:1 - 10:1 gradient elution),396 mg of a white solid were obtained in a yield of 49.3%.
Intermediate compound (376 mg, 1.61 mmol) and HATU (800 mg, 2.1 mmol)Dissolve in anhydrous dichloromethane (10ml), add triethylamine (332muL, 2.46mmol) dropwise, stir at room temperature for 10min, then add 2-aminophenylpyridine(280 mg, 1.64 mmol), reacted at room temperature for 24 h. filter,The inorganic salt residue is removed, and the filtrate is mixed with 60-100 mesh silica gel and purified by silica gel column.(mobile phase: petroleum ether / ethyl acetate = 20:1 - 10:1 gradient elution),333 mg of a white solid were obtained in a yield of 46.1%.
Intermediate compound (400 mg, 1.61 mmol) and HATU (800 mg, 2.1 mmol)Dissolved in anhydrous dichloromethane (10 ml), triethylamine (332 muL, 2.46 mmol) was added dropwise.After stirring for 10 min at room temperature, 2-aminophenylpyridine was added.(280 mg, 1.64 mmol), reacted at room temperature for 24 h. filter,The inorganic salt residue was removed, and the filtrate was mixed with 60-100 mesh silica gel.Separation and purification on a silica gel column (mobile phase: petroleum ether / ethyl acetate = 20:1 - 10:1 gradient elution)A white solid 313 mg was obtained in a yield of 52.1%.
Intermediate compound (400 mg, 1.61 mmol) and HATU (800 mg, 2.1 mmol)Dissolved in anhydrous dichloromethane(10 ml), triethylamine (332 muL, 2.46 mmol) was added dropwise.After stirring for 10 min at room temperature, 2-aminophenylpyridine was added.(280 mg, 1.64 mmol), reacted at room temperature for 24 h. filter,The inorganic salt residue is removed, and the filtrate is mixed with 60-100 mesh silica gel and purified by silica gel column.(mobile phase: petroleum ether / ethyl acetate = 20:1 - 10:1 gradient elution),Obtained 313 mg of a white solid, yield 52.1%
Intermediate compound (385 mg, 1.6 mmol) and HATU (800 mg, 2.1 mmol)Dissolved in anhydrous dichloromethane(10 ml), triethylamine (332 muL, 2.46 mmol) was added dropwise.After stirring for 10 min at room temperature, 2-aminophenylpyridine was added.(280 mg, 1.64 mmol), reacted at room temperature for 24 h. Filter to remove inorganic salt residue,The filtrate was mixed with 60-100 mesh silica gel and separated by silica gel column.(mobile phase: petroleum ether / ethyl acetate = 20:1 - 10:1 gradient elution),A white solid of 320 mg was obtained in a yield of 50.2%.
Intermediate compound (430 mg, 1.93 mmol) and HATU (950 mg, 2.5 mmol)Dissolved in anhydrous dichloromethane(10 ml), triethylamine (390 muL, 2.88 mmol) was added dropwise.After stirring for 10 min at room temperature, 2-aminophenylpyridine was added.(335 mg, 1.93 mmol), reacted at room temperature for 24 h. filter,The inorganic salt residue is removed, the filtrate is spun dry, and the ethyl acetate is thermally dissolved.Filtration under low temperature for 2 h gave a pale yellow solid.The dry weight was about 430 mg, and the yield was 55.0%.
The intermediate compound (425 mg, 1.92 mmol) and HATU (950 mg, 2.5 mmol) were dissolved in anhydrous dichloromethane(10 ml), triethylamine (390 muL, 2.88 mmol) was added dropwise, and stirred at room temperature for 10 min, then 2-aminophenylpyridine was added.(330 mg, 1.92 mmol), reacted at room temperature for 24 h. Filtration, removal of inorganic salt filter residue, filtrate spin dry, ethyl acetate thermally dissolved, low temperatureIt was filtered for 2 h to give a pale yellow solid, dried and weighed about 450 mg, yield 57.8%.
The intermediate compound (450 mg, 1.9 mmol) and HATU (940 mg, 2.47 mmol) were dissolved in anhydrous dichloromethane(10 ml), triethylamine (385 muL, 2.85 mmol) was added dropwise, and stirred at room temperature for 10 min, then 2-aminophenylpyridine was added.(323 mg, 1.9 mmol), reacted at room temperature for 24 h. Filtration, removal of inorganic salt residue, the filtrate was mixed with 60-100 mesh silica gel, and purified by silica gel column (mobile phase: petroleum ether / ethyl acetate = 20:1 - 10:1 gradient elution) to give a white solid, dry It weighed about 415 mg and the yield was 56.1%.
Intermediate compound (450 mg, 1.9 mmol) and HATU (940 mg, 2.47 mmol)Dissolved in anhydrous dichloromethane(10 ml), triethylamine (385 muL, 2.85 mmol) was added dropwise, and stirred at room temperature for 10 min, then 2-aminophenylpyridine was added.(323 mg, 1.9 mmol), reacted at room temperature for 24 h. filter,The inorganic salt residue is removed, and the filtrate is mixed with 60-100 mesh silica gel and purified by silica gel column.(mobile phase: petroleum ether / ethyl acetate = 20:1 - 10:1 gradient elution),A white solid was obtained which was dried and weighed about 485 mg, yield 66.1%.
The intermediate compound (450 mg, 1.9 mmol) and HATU (940 mg, 2.47 mmol)Dissolved in anhydrous dichloromethane(10 ml), triethylamine (385 muL, 2.85 mmol) was added dropwise.After stirring for 10 min at room temperature, 2-aminophenylpyridine was added.(323 mg, 1.9 mmol), reacted at room temperature for 24 h. Filter to remove inorganic salt residue,The filtrate was mixed with 60-100 mesh silica gel and purified by silica gel column (mobile phase: petroleum ether / ethyl acetate = 20:1 - 10:1 gradient elution).A white solid was obtained which was dried and weighed about 485 mg, yield 66.1%.
The intermediate compound (410 mg, 1.9 mmol) and HATU (940 mg, 2.47 mmol) were dissolved in anhydrous dichloromethane(10 ml), triethylamine (385 muL, 2.85 mmol) was added dropwise, and stirred at room temperature for 10 min, then 2-aminophenylpyridine was added.(323 mg, 1.9 mmol), reacted at room temperature for 24 h. filterThe inorganic salt residue is removed, and the filtrate is mixed with 60-100 mesh silica gel.Separation and purification on a silica gel column (mobile phase: petroleum ether / ethyl acetate = 20:1 - 10:1 gradient elution)A white solid was obtained which weighed about 455 mg, yield 56.1%.
Intermediate compound (450 mg, 1.9 mmol) and HATU (940 mg, 2.47 mmol)Dissolved in anhydrous dichloromethane(10 ml), triethylamine (385 muL, 2.85 mmol) was added dropwise.After stirring for 10 min at room temperature, 2-aminophenylpyridine was added.(323 mg, 1.9 mmol), reacted at room temperature for 24 h. Filter to remove inorganic salt residue,The filtrate was mixed with 60-100 mesh silica gel and separated by silica gel column.(mobile phase: petroleum ether / ethyl acetate = 20:1 - 10:1 gradient elution),A white solid was obtained which weighed approximately 414 mg, yield 56.1%.
The intermediate compound (400 mg, 1.33 mmol) and HATU (925 mg, 2.43 mmol) were dissolved in anhydrous dichloromethane(10 ml), triethylamine (378 muL, 2.81 mmol) was added dropwise, stirring at room temperature for 10 min, then adding 2-aminophenylpyridine(310 mg, 1.8 mmol), reacted at room temperature for 24 h. filter,The inorganic salt residue was removed, and the filtrate was mixed with 60-100 mesh silica gel.Separation and purification on a silica gel column (mobile phase: petroleum ether / ethyl acetate = 20:1 - 10:1 gradient elution)A white solid was obtained which was dried and weighed about 363 mg, yield 60.0%.
Stage #1: 4-phthalimidobenzoic acid With triethylamine; O-(benzotriazol-1-yl)-N,N,N,N-tetramethyluroniumhexafluorophosphate In dichloromethane at 20℃; for 0.166667h;
Stage #2: 5-phenyl-pyridin-2-ylamine In dichloromethane at 20℃; for 18h;
17
The intermediate compound (750 mg, 2.83 mmol) and HATU (1180 mg, 3.68 mmol)Dissolved in anhydrous dichloromethane(10 ml), triethylamine (482 μL, 3.57 mmol) was added dropwise.After stirring for 10 min at room temperature, 2-aminophenylpyridine was added.(481 mg, 2.83 mmol), reacted at room temperature for 18 h. filter,The inorganic salt residue was removed, and the filtrate was spun dry to give an oil.Filtration, spin dry the filtrate to give an oil;After cooling at low temperature for 2 h, suction filtration gave a white solid.After drying, the weight was weighed 560 mg, and the yield was 47.3%.
Intermediate compound (400 mg, 1.93 mmol) and HATU (960 mg, 2.52 mmol)Dissolved in anhydrous dichloromethane (10 ml), triethylamine (394 muL, 2.92 mmol) was added dropwise.After stirring for 10 minutes under the room, join2-Aminophenylpyridine (330 mg, 1.94 mmol) was reacted at room temperature for 24 h. Filtration, removal of inorganic salt residue, the filtrate was mixed with 60-100 mesh silica gel, and purified by silica gel column (mobile phase: petroleum ether / ethyl acetate = 20:1 - 10:1 gradient elution) to obtain 510 mg of white solid. The rate is 68.1%.
Intermediate compound (353 mg, 1.64 mmol) and HATU (810 mg, 2.14 mmol)Dissolved in anhydrous dichloromethane(10 ml), triethylamine (332 muL, 2.46 mmol) was added dropwise.After stirring for 10 min at room temperature, 2-aminophenylpyridine was added.(280 mg, 1.64 mmol), reacted at room temperature for 24 h. filterThe inorganic salt residue is removed, and the filtrate is mixed with 60-100 mesh silica gel and separated by silica gel column.(mobile phase: petroleum ether / ethyl acetate = 20:1 - 10:1 gradient elution),A white solid of 200 mg was obtained in a yield of 32.8%.
Stage #1: 2-(4-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)phenyl)acetic acid With triethylamine; O-(benzotriazol-1-yl)-N,N,N,N-tetramethyluroniumhexafluorophosphate In dichloromethane at 20℃; for 0.166667h;
Stage #2: 5-phenyl-pyridin-2-ylamine In dichloromethane at 20℃; for 24h;
29
Intermediate compound (380 mg, 1.64 mmol) and HATU (810 mg, 2.14 mmol)Dissolved in anhydrous dichloromethane(10 ml), triethylamine (332 μL, 2.46 mmol) was added dropwise.After stirring for 10 min at room temperature, 2-aminophenylpyridine was added.(280 mg, 1.64 mmol), reacted at room temperature for 24 h. filter,The inorganic salt residue was removed, and the filtrate was mixed with 60-100 mesh silica gel.Separation and purification on a silica gel column (mobile phase: petroleum ether / ethyl acetate = 20:1 - 10:1 gradient elution)Obtained 314mg of white solidThe rate is 50.0%.
3-methoxy-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-carboxylic acid[ No CAS ]
3-methoxy-N-(5-phenylpyridin-2-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-carboxamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
66%
3-Methoy-6.7.8.9-tetrahydro-5//-benzo| 7 |annulene-2-carboxylic acid (25 mg, 0.113 mmol) was dissolved in DMF and to this solution, diethyl phosphorocyanidate (18.51 mg, 0.113 mmol) was added followed by Et3N (0.016 mL, 0.113 mmol). The reaction mass was stirred at room temperature for 10 min. After which, <strong>[33421-40-8]5-phenylpyridin-2-amine</strong> (23.18 mg, 0.136 mmol) was added to the reaction mass and it was again stirred for 6 hours. The reaction mixture was diluted with 1N HC1 and extracted with EtOAc. The organic layer was dried over anhydrous Na2S04, filtered and concentrated under reduced pressure followed by purification on a pre-packed Silica gel column using Teledyne ISCO flash chromatographic system by Hexanes:EtOAc (7:3). Yield: 28.5 mg (66%). 'H NMR (400 MHz, CDCb) d 10.43 (s, 1H), 8.63 - 8.37 (m, 2H), 8.00 (s, 2H), 7.68 - 7.53 (m, 2H), 7.47 (t, J= 7.7 Hz, 2H), 7.38 (s, 1H), 6.80 (s, 1H), 4.19 - 3.83 (m, 3H), 2.97 - 2.65 (m, 4H), 1.85 (s, 2H), 1.75 - 1.58 (m, 4H). HR-ESIMS: m/z 373.1838 [M+H]+ calcd for C24H25N2O2, found 373.1904. HPLC Purity: 99.9% (Retention Time = 20.5 min).
Stage #1: 2-(3,5-dichloro-4-oxopyridine-1(4H)-yl)acetic acid With triethylamine; O-(benzotriazol-1-yl)-N,N,N,N-tetramethyluroniumhexafluorophosphate In dichloromethane for 0.166667h;
Stage #2: 5-phenyl-pyridin-2-ylamine In dichloromethane at 20℃; for 24h;
2 Compound 3
Dissolve 2-(3,5-dichloro-4-oxopyridine-1(4H)-yl)acetic acid (445mg, 2.0mmol) and HATU (990mg, 2.0mmol) in dry dichloromethane (10mL) , Triethylamine (404 μL, 3.0 mmol)) was added dropwise, after 10 min, 2-amino-5-phenylpyridine (340 mg, 2.0 mmol) was added, and the reaction was carried out at room temperature for 24 h. Filter, discard the filtrate, wash the filtrate repeatedly with saturated NaHCO3 aqueous solution and dichloromethane, dry and weigh the white powdery solid 450mg, yield 60.2%.
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