* 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.
Stage #1: With n-butyllithium In tetrahydrofuran at -78℃; for 0.5 h; Stage #2: for 0.5 h;
Intermediate 161 : 5-methyl-2-pyridinecarbaldehvde; 5 g of 5-bromo-2-methylpyridine (29.1 mmole, Aldrich), dissolved in 60 mL of dry THF.The solution was cooled to -780C. To this solution, were added 15.99 mL of BuLi (32.0 mmole) and the reaction mixture was stirred at -780C for 0.5 h. Then 4.50 mL of dry DMF <n="175"/>(58.1 mmole) were added and stirring was continued for 0.5 h. 30 mL of water were added followed by 100 mL of AcOEt. The organic layer was separated, dried over Na2SO4, filtered and evaporated under vacuum to give a crude that was purified on Isco- Companion (CH/AcOEt 1 :1 to 1 :9) to give the title compound as a yellow oil (1.6 g, 45percent yield). 1H-NMR (400 MHz, CDCI3): δ 1.99 (s, 3H), 7.22 (d, 1 H), 7.43 (d, 1 H), 8.16 (s, 1 H), 9.59 (s, 1 H); m/z (ES): 121.99 [M+H]+.
Stage #1: With n-butyllithium In tetrahydrofuran at -78℃; for 1 h; Stage #2: at -78℃; for 1 h;
To a solution of 5-bromo-2-methylpyridine (151; 10 g, 58.1 mmol) in THF (150 mL) was added n-BuLi (2.5 M, 25.6 mL) at -78 0C. The reaction mixture was stirred at this temperature for Ih. DMF (1.30 mL) was then added and the resulting reaction mixture was stirred for 1 h at -78 °C. The reaction was quenched by the addition of aq. NH4Cl. Upon warming to room temperature, the mixture was extracted with EtOAc. The combined organic layers were dried (Na2SO4) and concentrated under reduced pressure. The resulting residue was purified by chromatography to afford 6-methylnicotinaldehyde 152 (5.0 g, 72percent).
72%
Stage #1: With n-butyllithium In tetrahydrofuran at -78℃; for 1 h; Stage #2: at -78℃; for 1 h;
Example 22. Synthesis of 2-(6-methylpyridin-3-yl)-N-(thiazol-2-yl)-[l,2,4]triazolo[l,5- a]pyridine-8-carboxamide (Compound 210): Step 1) Preparation of 6-methylnicotinaldehyde (93): 91To a solution of 5-bromo-2-methylpyridine (91; 10 g, 58.1 mmol) in THF (150 mL) was added n-BuLi (2.5 M, 25.6 mL) at -78 0C. The reaction mixture was stirred at this temperature for Ih. DMF (1.30 mL) was then added and the resulting reaction mixture was stirred for 1 h at -78 0C. The reaction was quenched by the addition of aq. NH4Cl. Upon warming to room temperature, the mixture was extracted with EtOAc. The combined organic layers were dried (Na2SO4) and concentrated under reduced pressure. The resulting residue was purified by chromatography to afford 6-methylnicotinaldehyde 92 (5.0 g, 72percent).
38%
Stage #1: With n-butyllithium; isopropylmagnesium chloride In tetrahydrofuran; hexane at 10℃; for 1 h; Stage #2: at 20℃; for 2 h;
Step 1 6-Methylnicotinaldehyde: At about 0° C. and under an atmosphere of nitrogen, n-butyllithium (2.5 M in hexane, 20 mL, 1.00 equiv) was added to a solution of isopropylmagnesiumchloride (2.0 M in tetrahydrofuran, 12.5 mL, 0.50 equiv) in tetrahydrofuran (100 mL). The resulting solution was stirred at about 0° C. for about 30 minutes, and then 5-bromo-2-methylpyridine (8.6 g, 50 mmol, 1.00 equiv) was added. After stirring for about 1 hour at about -10° C., dimethylformamide (14.6 g, 200 mmol, 4.00 equiv) was added. The resulting solution was stirred at ambient temperature for about 2 hours, and then saturated ammonium chloride was added. Following standard extractive workup with ethyl acetate (3*50 mL), the crude residue was purified by silica gel column chromotagraphy (ethyl acetate/petroleum ether (1:2)) to give the title product as a light yellow oil (2.3 g; yield=38percent). LC-MS: m/z=122 (MH)+.
4.5 g
Stage #1: With isopropylmagnesium chloride In tetrahydrofuran at 0 - 20℃; for 6 h; Stage #2: at 0 - 20℃;
To a solution of 5-bromo-2-methyl-pyridine (2.0 g, 11.6mmol) in anhydrous THF (20 mL) was added isopropylmagnesium chloride (2M in THF, 9.3 mL, 1.6 eq). dropwise over 30 mins at 0 °C under nitrogen atmosphere, then the reaction mixture was stirred at room temperature for 6 hrs. DMF (1.02 g, 1.2 eq) was added to the reation mixture at 0 °C for 30 mi amd the mixture was the stirred at room temperature for overnight. The reaction mixture was poured into water (50 mL), and the aqueous phase was extracted with EtOAc (50 mL x3). The extracts were washed with brine (50 mL), dried over Na2SO4 and concentrated in vacuum to give 4.5 g of crude 6-methylpyridine-3-carbaldehyde as yellow oil.
4.1.7 5-Bromopyridine-2-carboxylic acid (11) In a 250 mL three-necked flask equipped with a stirrer, a thermometer, and a condenser, 150 mL water and 5-bromo-2-methylpyridine (10) (6.0 g, 35 mmol) was added to it and stirring until the temperature was raised to 80 °C, then KMnO4 (24.8 g, 157 mmol) was added in three batches at intervals of 1 h. The mixture was stirred at the same temperature for 3-4 h. After completion of the reaction, suction filtration to give a clear solution, the solution was adjusted to pH 4-5 with concentrated HCl, some white solid precipitated, the filter cake is a small amount of the product (11), after filtration and concentration in vacuo, an appropriate amount of ethanol was added to the residues to dissolve the residue compound (11), a lot of white solid precipitated, discarded it after subjected to suction filtration again, finally the filtrate was concentrated in vacuo, total yielding (11) (3.0 g, 39percent) as light yellow solid.
Reference：
[1] Bioorganic and Medicinal Chemistry, 2015, vol. 23, # 13, p. 3228 - 3236
[2] Journal fuer Praktische Chemie (Leipzig), 1932, vol. <2> 133, p. 36,49
[3] Heterocycles, 1981, vol. 15, # 1, p. 213 - 223
[4] Synthesis, 2003, # 4, p. 551 - 554
[5] Patent: US2005/113374, 2005, A1, . Location in patent: Page/Page column 8
Stage #1: With 3-chloro-benzenecarboperoxoic acid In dichloromethane for 2 h;
Part A: Compound 413 (3.5 g, 20.7 mmol) was dissolved in methylene chloride (100 ml) and m-CPBA (4.95 g, 28.9 mmol) was added. The reaction mixture was stirred for two hours and then quenched with saturated sodium carbonate and stirred overnight. The organic layer was dried over sodium sulfate and the concentrated to provide a yellow solid (3.8 g). The solid was placed under argon and trifluoroacetic anhydride (15 mL) was added slowly. The reaction was stirred for 30 minutes at room temperature and then refluxed for 30 minutes. The reaction was cooled to room temperature and quenched slowly with saturated sodium bicarbonate. Methylene chloride was added and the organic layer was washed dried over sodium sulfate and concentrated. Column chromatography (2 to 1 ethyl acetate/hexanes) provided the desired product (3.O g, 78percent).1H NMR (400 MHz, CDCI3) δ 8.65 (d, 1H), 7.8 (m, 1H), 7.2 (d, 1H), 4.7 (s, 2H).
Reference：
[1] Patent: WO2007/84451, 2007, A1, . Location in patent: Page/Page column 146
[2] Journal of Medicinal Chemistry, 1987, vol. 30, # 5, p. 871 - 880
[3] Polyhedron, 2010, vol. 29, # 7, p. 1854 - 1862
[4] Journal of Medicinal Chemistry, 2011, vol. 54, # 13, p. 4721 - 4734
4.1.7 5-Bromopyridine-2-carboxylic acid (11) In a 250 mL three-necked flask equipped with a stirrer, a thermometer, and a condenser, 150 mL water and 5-bromo-2-methylpyridine (10) (6.0 g, 35 mmol) was added to it and stirring until the temperature was raised to 80 C, then KMnO4 (24.8 g, 157 mmol) was added in three batches at intervals of 1 h. The mixture was stirred at the same temperature for 3-4 h. After completion of the reaction, suction filtration to give a clear solution, the solution was adjusted to pH 4-5 with concentrated HCl, some white solid precipitated, the filter cake is a small amount of the product (11), after filtration and concentration in vacuo, an appropriate amount of ethanol was added to the residues to dissolve the residue compound (11), a lot of white solid precipitated, discarded it after subjected to suction filtration again, finally the filtrate was concentrated in vacuo, total yielding (11) (3.0 g, 39%) as light yellow solid.
Pyridine (22) is obtained in two steps from 5-bromo-2-methyl-pyridine (20) by oxidation to 5-bromo-2-pyridinecarboxylic acid (21) as described in G. M. Sanders, M. van Dijk and H. C. van der Plas, Heterocycles 1981, 15, 213-223, and chlorination with SOCl2 followed by reaction with EtOH (see Scheme 6).
5-[[(4-methoxyphenyl)methyl]sulfanyl]-2-methylpyridine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
93%
With tris-(dibenzylideneacetone)dipalladium(0); N-ethyl-N,N-diisopropylamine; 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene In toluene at 110℃; for 3h; Inert atmosphere;
s51.1 Step 1: Synthesis of 5-[[(4-methoxyphenyl)methyl]sulfanyl]-2-methylpyridine.
A mixture of 5-bromo-2-methylpyridine (5.0 g, 29.07 mmol), benzyl mercaptan (3.6 g, 29.07 mmol), DIEA (7.5 g, 58.13 mmol), Pd2(dba)3 (1.3 g, 1.45 mmol) and XantPhos (1.7 g, 2.91 mmol) in toluene (100.0 mL) was stirred at 110 °C for 3 h under N2. After the reaction was completed, the resulting mixture was diluted with H2O and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under vacuum. The residue was purified by flash column chromatography with CH2Cl2/CH3OH (96/4, v/v) to afford 5-[[(4-methoxyphenyl)methyl]sulfanyl]-2-methylpyridine (6.7 g, 93%) as a yellow oil. LCMS (ESI, m/z): [M+H]+ = 246.1.
93%
With tris-(dibenzylideneacetone)dipalladium(0); N-ethyl-N,N-diisopropylamine; 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene In toluene at 110℃; for 3h; Inert atmosphere;
s51.1 Step 1: Synthesis of 5-[[(4-methoxyphenyl)methyl]sulfanyl]-2-methylpyridine.
A mixture of 5-bromo-2-methylpyridine (5.0 g, 29.07 mmol), benzyl mercaptan (3.6 g, 29.07 mmol), DIEA (7.5 g, 58.13 mmol), Pd2(dba)3 (1.3 g, 1.45 mmol) and XantPhos (1.7 g, 2.91 mmol) in toluene (100.0 mL) was stirred at 110 °C for 3 h under N2. After the reaction was completed, the resulting mixture was diluted with H2O and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under vacuum. The residue was purified by flash column chromatography with CH2Cl2/CH3OH (96/4, v/v) to afford 5-[[(4-methoxyphenyl)methyl]sulfanyl]-2-methylpyridine (6.7 g, 93%) as a yellow oil. LCMS (ESI, m/z): [M+H]+ = 246.1.
92%
With C47H54OP2PdSi2; N-ethyl-N,N-diisopropylamine In 1,4-dioxane at 100℃; for 1h; Sealed tube; Inert atmosphere;
85%
With N-ethyl-N,N-diisopropylamine; 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene In 1,4-dioxane for 7h; Heating;
85%
With N-ethyl-N,N-diisopropylamine In 1,4-dioxane for 7h; Heating / reflux;
To a solution of 5-bromo-2-methylpyridine (151; 10 g, 58.1 mmol) in THF (150 mL) was added n-BuLi (2.5 M, 25.6 mL) at -78 0C. The reaction mixture was stirred at this temperature for Ih. DMF (1.30 mL) was then added and the resulting reaction mixture was stirred for 1 h at -78 C. The reaction was quenched by the addition of aq. NH4Cl. Upon warming to room temperature, the mixture was extracted with EtOAc. The combined organic layers were dried (Na2SO4) and concentrated under reduced pressure. The resulting residue was purified by chromatography to afford 6-methylnicotinaldehyde 152 (5.0 g, 72%).
72%
Example 22. Synthesis of 2-(6-methylpyridin-3-yl)-N-(thiazol-2-yl)-[l,2,4]triazolo[l,5- a]pyridine-8-carboxamide (Compound 210): Step 1) Preparation of 6-methylnicotinaldehyde (93): 91To a solution of 5-bromo-2-methylpyridine (91; 10 g, 58.1 mmol) in THF (150 mL) was added n-BuLi (2.5 M, 25.6 mL) at -78 0C. The reaction mixture was stirred at this temperature for Ih. DMF (1.30 mL) was then added and the resulting reaction mixture was stirred for 1 h at -78 0C. The reaction was quenched by the addition of aq. NH4Cl. Upon warming to room temperature, the mixture was extracted with EtOAc. The combined organic layers were dried (Na2SO4) and concentrated under reduced pressure. The resulting residue was purified by chromatography to afford 6-methylnicotinaldehyde 92 (5.0 g, 72%).
38%
Step 1 6-Methylnicotinaldehyde: At about 0 C. and under an atmosphere of nitrogen, n-butyllithium (2.5 M in hexane, 20 mL, 1.00 equiv) was added to a solution of isopropylmagnesiumchloride (2.0 M in tetrahydrofuran, 12.5 mL, 0.50 equiv) in tetrahydrofuran (100 mL). The resulting solution was stirred at about 0 C. for about 30 minutes, and then 5-bromo-2-methylpyridine (8.6 g, 50 mmol, 1.00 equiv) was added. After stirring for about 1 hour at about -10 C., dimethylformamide (14.6 g, 200 mmol, 4.00 equiv) was added. The resulting solution was stirred at ambient temperature for about 2 hours, and then saturated ammonium chloride was added. Following standard extractive workup with ethyl acetate (3*50 mL), the crude residue was purified by silica gel column chromotagraphy (ethyl acetate/petroleum ether (1:2)) to give the title product as a light yellow oil (2.3 g; yield=38%). LC-MS: m/z=122 (MH)+.
4.5 g
To a solution of 5-bromo-2-methyl-pyridine (2.0 g, 11.6mmol) in anhydrous THF (20 mL) was added isopropylmagnesium chloride (2M in THF, 9.3 mL, 1.6 eq). dropwise over 30 mins at 0 C under nitrogen atmosphere, then the reaction mixture was stirred at room temperature for 6 hrs. DMF (1.02 g, 1.2 eq) was added to the reation mixture at 0 C for 30 mi amd the mixture was the stirred at room temperature for overnight. The reaction mixture was poured into water (50 mL), and the aqueous phase was extracted with EtOAc (50 mL x3). The extracts were washed with brine (50 mL), dried over Na2SO4 and concentrated in vacuum to give 4.5 g of crude 6-methylpyridine-3-carbaldehyde as yellow oil.
2-methyl-5-(1-trityl-1<i>H</i>-imidazol-4-yl)-pyridine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
To a solution of 4-IODO-L-TRITYL-LH-IMIDAZOLE (1 eq) in THF at room temperature was added ethylmagnesium bromide (1.2 eq) under dry conditions. After stirring for 90 minutes, zinc chloride (1.2 eq) was added to the reaction mixture. After stirring for another 90 minutes, tetrakis (triphenylphosphine) palladium (10%) and 5- bromo-2-methylpyridine (1.2 eq) were added to the reaction mixture. Following that, the reaction mixture was heated in a 70C oil bath overnight. Upon cooling, the reaction was diluted with dichloromethane and washed with a EDTA buffer (at approximately pH 9), NaCl, dried over sodium sulfate, filtered and concentrated. The crude product was disolved in ethanol and concentrated HCl was added to the solution at room temperature. The reaction mixture was heated in a 50C oil bath for 2 hours. Upon cooling, the reaction was filtered and washed with ethyl ether to yield 5- (1H- imidazol-4-yl) -2-methyl-pyridine (63%). MH+ (160)
To a solution of 4-IODO-L-TRITYL-LH- imidazole (15.0 g, 34 mmoles) in THF (150 ml) at room temperature was added ethylmagnesium bromide (41 ml, 40.7 mmoles) under dry conditions. After stirring for 90 minutes, zinc chloride (5.6 g, 40.7 mmoles) was added to the reaction mixture. After stirring for another 90 minutes, tetrakis (RIPHENYLPHOSPHINE) palladium (4.0 g, 3.43 mmoles) and 5-bromo-2-methylpyridine (7.0 g, 40.7 mmoles) were added to the reaction mixture. Following that, the reaction mixture was heated in a 70C oil bath overnight. Upon cooling, the reaction was diluted with dichloromethane and washed with an EDTA buffer (at APPROIMATE pH 9) (2x 300 ML), NACI (sat. ) (300 ml), dried over sodium sulfate, filtered, and concentrated. The crude product was dissolved in ethanol (250 ml) and concentrated HCl (13.6 ml) was added to the solution at room temperature. The reaction mixture was heated in a 50C oil bath for 2 hours. Upon cooling, the reaction was filtered and washed with ethyl ether (25 ml) to yield 5- (1H- imidazol-4-yl) -2-methyl-pyridine (5.815g, 63%). MH+ (160).
With sodium carbonate;palladium diacetate; triphenylphosphine; In propan-1-ol; for 1.5h;Heating / reflux;
Preparation 56: 2,4-Dimethoxy-5-(6-methyl-pyridin-3-yl)-pyrimidine (Prep56); 2,4-Dimethoxy-pyrimidine-5-boronic acid (commercially available from Aldrich, 830 mg, 4.5 mmol) was dissolved in degassed n-PrOH (10 ml.) and then 3-bromo-6- methylpyridine (600 mg, 3.5 mmol), Na2CO3 (956 mg, 9 mmol), PPh3 (90 mg, 0.35 mmol) and Pd(OAc)2 (78 mg, 0.35 mmol) were added. The suspension was stirred at reflux for 1.5 hours. The solvent was evaporated under vacuum and the crude was partitioned between water and ethyl acetate. The organic phase was dried (Na2SO4) and evaporated. The crude was purified by SCX cartridge washing with MeOH and then collecting the product with MeOH-NH4OH (95-5) to give 500 mg of the title compound (62% yield). MS (ES) {mlz): 232.3 [M+H]+.
A.A-4
General Procedure 2 (GP2): Sonogashira Reaction; The halide (1.0 eq.) is dissolved in DMF or THF and PdCl2(PPh3)2 (0.1 eq.) and CuI (0.1 eq.) are added. Subsequently, triethylamine (10.0 eq.) and finally the alkyne (1.5 eq.) are added and the reaction mixture is stirred at 65 0C. The reaction is monitored byLC-MS. If the iodide is not completed converted after 4 h, additional amounts of alkyne are added in small portions. The product either precipitates from the reaction mixture (and is filtered off and if necessary re-crystallized) and/or, after removal of the solvent, is purified by preparative RP-HPLC.; A-4) 2-Methyl-5-trimethylsilanylethynyl-pyridine; The title compound is synthesized according to general procedure GP2 starting from 2.0 g (11.6 mmol) 5-bromo-2-methy-pyridine and 2.3 niL (16.3 mmol) 1-trimethylsilyl-ethyne using 68 mg (0.36 mmol) CuI, 305 mg (1.2 mmol) triphenylphosphine, 213 mg (0.30 mmol) PdCl2(PPh3)2 and 18 mL (127 mmol) triethylamine in 18 mL dry THF. For the work-up the reaction mixture is diluted with ethyl acetate, the organic phase is extracted with water and brine. The product is purified by chromatography on silica gel using a hexane/ethyl acetate gradient. Yield: 1.5 g (68 %).
68%
With triethylamine In tetrahydrofuran at 55 - 65℃;
A.A-2
General Procedure GPl: Sonogashira Reaction; The halide (1.0 eq.) is dissolved in DMF or THF and PdCl2(PPh3)2 (0.1 eq.) and CuI (0.1 eq.) are added. Subsequently, triethylamine (10.0 eq.) and finally the alkyne (1.5 eq.) are added and the reaction mixture is stirred at 55-65 ºC. The reaction is monitored by LC-MS. If the iodide is not completed converted after 4 h, additional amounts of alkyne are added in small portions.; A-2) 2-Methyl-5-trimethylsilanylethynyl-pyridine; The title compound is synthesized according to general procedure GP2 starting from 2.0 g (11.6 mmol) 5-bromo-2-methyl-pyridine and 2.3 mL (16.3 mmol) 1-trimethylsilyl-ethyne using 68 mg (0.36 mmol) CuI, 305 mg (1.2 mmol) triphenylphosphine, 213 mg (0.30 mmol) PdCl2(PPh3)2 and 18 mL (127 mmol) triethylamine in 18 mL dry THF. For the work-up the reaction mixture is diluted with ethyl acetate, the organic phase is extracted with water and brine. The product is purified by chromatography on silica gel using a hexane/ethyl acetate gradient. Yield: 1.5 g (68 %). Note: Sublimation of the product is observed at 40 °C/40 mbar.
68%
With triethylamine In tetrahydrofuran at 65℃;
The halide (1.0 eq.) is dissolved in DMF or THF and 0.1 eq. Pd-catalyst (e.g.PdCl2(PPh3)2 or Pd(PPh3)4) and Cul (0.1 eq.) are added. Subsequently, triethylamine (10.0 eq.) and finally the alkyne (1.5 eq.) are added and the reaction mixture is stirred at 65 °C. The reaction is monitored by LC-MS. If the iodide is not completed converted after 4 h, additional amounts of alkyne are added in small portions. The product either precipitates from the reaction mixture (and is filtered off and if necessary re-crystallized) and/or, after removal of the solvent, is purified by preparative RP-HPLC orchromatography on slica gel.; The title compound is synthesized according to general procedure GP2 starting from 2.0 g (11.6 mmol) 5-bromo-pyridin-2-ylamine and 2.3 mL (16.3 mmol) 1-trimethylsilyl- ethyne using 68 mg (0.36 mmol) Cul, 305 mg (1.2 mmol) triphenylphosphine, 213 mg (0.30 mmol) PdCl2(PPh3)2 and 18 mL (127 mmol) triethylamine in 18 mL dry THF. For the work-up the reaction mixture is diluted with ethyl acetate, the organic phase is extracted with water and brine. The product is purified by chromatography on silica gel using a hexane/ethyl acetate gradient. Yield: 1.5 g (68 %).
68%
With copper(l) iodide; triethylamine In tetrahydrofuran at 65℃;
A-10
The title compound is synthesized according to general procedure GP2 starting from 2.0 g (11.6 mmol) 5-bromo-pyridin-2-ylamine and 2.3 mL (16.3 mmol) 1-trimethylsilyl-ethyne using 68 mg (0.36 mmol) CuI, 305 mg (1.2 mmol) triphenylphosphine, 213 mg (0.30 mmol) PdCl2(PPh3)2 and 18 mL (127 mmol) triethylamine in 18 mL dry THF. For the work-up the reaction mixture is diluted with ethyl acetate, the organic phase is extracted with water and brine. The product is purified by chromatography on silica gel using a hexane/ethyl acetate gradient. Yield: 1.5 g (68%).
With diisopropylamine In 1,4-dioxane for 1h;
7
Example 7: N-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-4-methyl- 3- [4- (6-methyl-pyridin-3-yl)- [1, 2,3] triazol-1-yl]-benzamide; In a flask under N2 were added 87 mg (0.23 mmoL) of (CH3CN) 2PdCI2 and 36 mg (0.19 mmol) of Cul, followed by 5 mL of dioxane, 131 mg (0.454 mmol) of t-BuP-HBF4, 649 mg (3.77 mmol) of 2-methyl-5-bromo pyridine (Fluka), 1.3 mL (9.4 mmol) of Me3SiCCH, and finally 0.64 mL (4.5 mmol) of i-Pr2NH. The mixture was stirred for one hour, filtered through celite, and the celite was washed with EtOAc. The filtrate was washed with water and brine, and the washes were extracted once with EtOAc. The combined extracts were dried with Na2S04, filtered, concentrated, and chromatographed (0-2% MeOH in CH2CI2) to provide 646 mg of 2-methyl-5- trimethylsilanylethynyl-pyridine.
With copper(l) iodide; N-ethyl-N,N-diisopropylamine In 1-methyl-pyrrolidin-2-one at 65℃; for 2h;
2.1
To a NMP solution (20 mL) of 5-bromo-2-methyl-pyridine (1.0 g) were added trimethylsilylacetylene (1.2 mL), tetrakis(triphenylphosphine)palladium(0) (130 mg), copper(I) iodide (44 mg), and N,N-diisopropylethylamine (2.0 mL), which was stirred under a nitrogen atmosphere for 2 hours at 65°C. Water was added at room temperature to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate and filtered, after which the solvent was evaporated from the filtrate under a reduced pressure. The residue was purified by silica gel column chromatography (heptane:ethyl acetate = 5:1) to obtain a mixture (810 mg) of 5-bromo-2-methyl-pyridine and 2-methyl-5-trimethylsilanylethynyl-pyridine Then, to a solution of THF (10 mL) and ethanol (5 mL) of the mixture (810 mg) of 5-bromo-2-methyl-pyridine and 2-methyl-5-trimethylsilanylethynyl-pyridine was added potassium carbonate (1.2 g) at room temperature, which was stirred for 2 hours and 30 minutes at room temperature. Water was added at room temperature to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and filtered, after which the solvent was evaporated from the filtrate under a reduced pressure, and the residue was purified by silica gel column chromatography (heptane:ethyl acetate = 5:1) to obtain the titled compound (55 mg). 1H-NMR spectrum (DMSO-d6) δ (ppm): 2.26 (3H, s), 4.13 (1H, s), 7.06 (1H, d, J = 8.1 Hz), 7.56 (1 H, dd, J = 2.2 Hz, 8.1 Hz), 8.32 (1 H, d, J = 1.7 Hz)
Intermediate 161 : 5-methyl-2-pyridinecarbaldehvde; 5 g of 5-bromo-2-methylpyridine (29.1 mmole, Aldrich), dissolved in 60 mL of dry THF.The solution was cooled to -780C. To this solution, were added 15.99 mL of BuLi (32.0 mmole) and the reaction mixture was stirred at -780C for 0.5 h. Then 4.50 mL of dry DMF <n="175"/>(58.1 mmole) were added and stirring was continued for 0.5 h. 30 mL of water were added followed by 100 mL of AcOEt. The organic layer was separated, dried over Na2SO4, filtered and evaporated under vacuum to give a crude that was purified on Isco- Companion (CH/AcOEt 1 :1 to 1 :9) to give the title compound as a yellow oil (1.6 g, 45% yield). 1H-NMR (400 MHz, CDCI3): delta 1.99 (s, 3H), 7.22 (d, 1 H), 7.43 (d, 1 H), 8.16 (s, 1 H), 9.59 (s, 1 H); m/z (ES): 121.99 [M+H]+.
In tetrahydrofuran; N,N-dimethyl-formamide at 20 - 100℃; Inert atmosphere;
7
Example 7 Preparation of 2-methyl-5-vmyl-pyϖdme[0372] The title compound was prepared by following general procedure 2 5-Bromo-2- methyl pyridine (5 g, 29 0 mmol) was dissolved in DMF THF (3 1, 35 mL) tϖbutylvmyltm (10 2 g, 31 9 mmol) and Pd(PPh3)4 (044 g, 0432 mmol) was added to this solution at RT under nitrogen and was heated at 100 0C for 2 h After completion of the reaction (TLC), the reaction mixture was cooled to RT and diluted with water (350 mL) and extracted with ethyl acetate (3 x 200 mL) The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure using rotary evaporator below 400C The crude was purified through column chromatography (6% ethylacetate hexane in silica 100-200 mesh, Diameter of column - 2 5cm, Height of silica - approx 5 inch) to provide 2-methyl-5-vmylpyϖdme as a light yellow oil (1 6 g, 47% yield)
B. Preparation of [1-(t-butoxycarbonyl)azetidin-3-yl]methyl}(iodo)zinc (C71). Zinc powder (116.5 g, 1.78 mol) was suspended in dimethylacetamide (300 mL) under argon. A mixture of trimethylsilyl chloride and 1,2-dibromoethane (7:5 v/v, 34.5 mL) was added and the mixture was stirred for 20 mins. A solution of C70 (426.8 g, 1.437 mol) in dimethylacetamide (650 mL) was added under water cooling and the reaction mixture was stirred overnight. The concentration of the resulting solution of compound C71 was about 1 mol/L and this was used in the next step.; C. Preparation of t-butyl 3-[(6-methylpyridin-3-yl)methyl]azetidine-1-carboxylate (C72). 5-Bromo-2-methylpyridine (25 g, 0.145 mol) was dissolved in dimethylacetamide (150 mL) and the solution was degassed. To the solution was added tetrakis(triphenylphosphine)palladium(0) (5 g, 4.4 mmol), copper iodide (1.7 g, 8.7 mmol) and the 1 mol/L solution of compound C71 (170 mL) under an atmosphere of argon. The reaction mixture was stirred at 50 C. for 12 h; during this time, partial decomposition of the catalyst was observed and additional amounts of tetrakis(triphenylphosphine)palladium(0) (5 g, 4.4 mmol) and copper iodide (0.9 g, 4.7 mmol) were added. The reaction mixture was stirred at 50 C. for 48 h, cooled and poured into a mixture of a saturated aqueous solution of ammonium chloride (600 mL) and diethyl ether (600 mL). The resulting mixture was stirred for 30 mins and filtered through a layer of Celite to remove insoluble impurities. The organic layer was separated and the aqueous layer was extracted with diethyl ether (4*300 mL). The combined organic extracts were dried over anhydrous sodium sulfate and evaporated. The residue was purified by silica gel chromatography (Eluant: EtOAc) to afford compound C72. Yield: 27.9 g, 0.106 mol, 73%.
With sodium t-butanolate;1,1'-bis-(diphenylphosphino)ferrocene; bis(dibenzylideneacetone)-palladium(0); In toluene; at 80℃;
Description 294-(6-methyl-pyridin-3-yl)-3,4-dihydro-2H-benzo[1,4]oxazine (D29)A nitrogen stream was bubbled through a mixture of 5-bromo-2-methylpyridine (3.818 g, 22.195 mmol) in toluene (28 ml), then, tBuONa (6.186 g, 64.365 mmol), 1,1'- bis(diphenylphosphino)ferrocene (0.615 g, 1.11 mmol), bis(dibenzylideneacetonato)palladium (0.383 g, 0.666 mmol) and 3,4-dihydro-2H-l,4- benzoxazino [CA.S. 5735-53-5] (1.77 g, 13.097 mmol) were added. The reaction mixture was heated at 80 0C overnight. After cooling to room temperature, the reaction mixture was filtered through diatomaceous earth and washed with EtOAc. The solvent was evaporated in vacuo. The residue was purified by column chromatography (silica gel; eluent: DCM/EtOAc from 100/0 to 80/10 as eluent). The desired fractions were collected and the solvent was evaporated in vacuo to yield intermediate compound D29 (3.812 g, 75 %) as a yellow oil.
With caesium carbonate; triphenylphosphine In water at 75 - 80℃; for 19h; Inert atmosphere;
1.1C
Example 1C; 2-methyl-5-vinylpyridineWater (10 mL) was added to a mixture of potassium vinyltrifluoroborate (6.35 g, 47.4 mmol, Aldrich), 5-bromo-2-methylpyridine (8.00 g, 46.5 mmol,), triphenylphosphine (0.732 g, 2.79 mmol) and Cs2CO3 (45.5 g, 140 mmol) in a 500 mL round-bottom flask with stir bar. The flask was evacuated and purged with nitrogen (3 cycles), and the mixture was heated under nitrogen at 75-80° C. for 19 hours, and then cooled to room temperature. The mixture was diluted with water (100 mL) and hexanes (50 mL), and the aqueous layer was drawn off and extracted with ether-hexanes (4:1, 50 mL). The combined organic phases were washed with brine (25 mL), dried over Na2SO4 and distilled at atmospheric pressure to a volume of ca. 10 mL. The residue was distilled under vacuum (90-100° C./20 Torr) to provide the title compound: 1H NMR (400 MHz, methanol-d4) δ ppm 2.51 (s, 3H) 5.35 (d, J=11.1 Hz, 1H) 5.86 (d, J=17.8 Hz, 1H) 6.74 (dd, J=17.8, 11.1 Hz, 1H) 7.27 (d, J=7.9 Hz, 1H) 7.84 (dd, J=8.3, 2.4 Hz, 1H) 8.40 (d, J=2.0 Hz, 1H).
With caesium carbonate; triphenylphosphine In water at 75 - 80℃; for 19h; Inert atmosphere;
1.B 2-methyl-5-vinylpyridine
Example 1B 2-methyl-5-vinylpyridine Water (10 mL) was added to a mixture of potassium vinyltrifluoroborate (6.35 g, 47.4 mmol, Aldrich), 5-bromo-2-methylpyridine (8.00 g, 46.5 mmol,), triphenylphosphine (0.732 g, 2.79 mmol) and Cs2CO3 (45.5 g, 140 mmol) in a 500 mL round-bottom flask with stir bar. The flask was evacuated and purged with nitrogen (3 cycles), and the mixture was then heated under nitrogen at 75-80° C. for 19 hours, and then cooled to room temperature. The mixture was diluted with water (100 mL) and hexanes (50 mL), and the aqueous layer was drawn off and extracted with ether-hexanes (4:1, 50 mL). The combined organic phases were washed with brine (25 mL), dried over Na2SO4and distilled at atmospheric pressure to a volume of ca. 10 mL. The residue was distilled under vacuum (90-100° C/20 Torr) to provide the title compound: 1H NMR (400 MHz, methanol-d4) δ ppm 2.51 (s, 3H) 5.35 (d, J=11.1 Hz, 1H) 5.86 (d, J=17.8 Hz, 1H) 6.74 (dd, J=17.8, 11.1 Hz, 1H) 7.27 (d, J=7.9 Hz, 1H) 7.84 (dd, J=8.3, 2.4 Hz, 1H) 8.40 (d, J=2.0 Hz, 1H).
With caesium carbonate In water at 75 - 80℃; for 19h; Inert atmosphere;
1B
Water (10 mL) was added to a mixture of potassium vinyltrifluoroborate (6.35 g, 47.4 mmol, Aldrich), 5-bromo-2-methylpyridine (8.00 g, 46.5 mmol,), triphenylphosphine (0.732 g, 2.79 mmol) and Cs2CO3 (45.5 g, 140 mmol) in a 500 mL round-bottom flask with stir bar. The flask was evacuated and purged with nitrogen (3 cycles), and the mixture was then heated under nitrogen at 75-80° C. for 19 hours, and then cooled to room temperature. The mixture was diluted with water (100 mL) and hexanes (50 mL), and the aqueous layer was drawn off and extracted with ether-hexanes (4:1, 50 mL). The combined organic phases were washed with brine (25 mL), dried over Na2SO4 and distilled at atmospheric pressure to a volume of ca. 10 mL. The residue was distilled under vacuum (90-100° C./20 Torr) to provide the title compound: 1H NMR (400 MHz, methanol-d4) δ ppm 2.51 (s, 3H) 5.35 (d, J=11.1 Hz, 1H) 5.86 (d, J=17.8 Hz, 1H) 6.74 (dd, J=17.8, 11.1 Hz, 1H) 7.27 (d, J=7.9 Hz, 1H) 7.84 (dd, J=8.3, 2.4 Hz, 1H) 8.40 (d, J=2.0 Hz, 1H).
A 2.5 M solution of n-butyllithium in pentane (6.97 ml, 17.44 mmol) was added dropwise to a solution of DIPEA (3.29 ml, 23.25 mmol) in THF (50 ml). The mixture was stirred at 0 C for 30 min., cooled down to -78 C and then a solution of 5-bromo- 2-methylpyridine (2.0 g, 11.63 mmol) in THF (50 ml) was added. The mixture was stirred at -78 C for a further 2h. and then DMF (8.5 g, 116.26 mmol) was added dropwise. The mixture was stirred at -78 C for 2 h, at 0 C for 30 min. and finally allowed to warm to RT. MeOH (25 ml) and sodium borohydride (0.439 g, 11.6 mmol) were added and the mixture was stirred at RT for a further 30 min. A saturated solution of ammonium chloride was added and the organic layer was separated. The aqueous layer was extracted with EtOAc and the combined organic extracts were dried(Na2S04), filtered and the solvents evaporated in vacuo to yield intermediate 51 (2.8 g, 87%) as a colourless oil.
87%
Example A51 2-(5-Bromo-pyridin-2-yl)-ethanol A 2.5 M solution of n-butyllithium in pentane (6.97 ml, 17.44 mmol) was added dropwise to a solution of DIPEA (3.29 ml, 23.25 mmol) in THF (50 ml). The mixture was stirred at 0 C. for 30 min., cooled down to -78 C. and then a solution of 5-bromo-2-methylpyridine (2.0 g, 11.63 mmol) in THF (50 ml) was added. The mixture was stirred at -78 C. for a further 2 h. and then DMF (8.5 g, 116.26 mmol) was added dropwise. The mixture was stirred at -78 C. for 2 h, at 0 C. for 30 min. and finally allowed to warm to RT. MeOH (25 ml) and sodium borohydride (0.439 g, 11.6 mmol) were added and the mixture was stirred at RT for a further 30 min. A saturated solution of ammonium chloride was added and the organic layer was separated. The aqueous layer was extracted with EtOAc and the combined organic extracts were dried (Na2SO4), filtered and the solvents evaporated in vacuo to yield intermediate 51 (2.8 g, 87%) as a colourless oil.
35%
A two-necked round-bottommed flask equipped with thermometer was charged with anh. THF (2.0 mL) and cooled to -78 C. Then, LDA (2 M in THF/heptane/ethylbenzene, 1.74 mL, 1.5 eq.) was added dropwise at -78 C. The resulting mixture was stirred for 15 min and then solution of 5-bromo-2-methylpyridine (0.4 g, 1.0 eq.) in anh. THF (4.0 mL) was dropped in slowly at -78 C and the reaction mixture was stirred for 1.5 h at -78 C. Afterwards, DMF (1.8 mL, 10.0 eq.) was added dropwise and stirring was continued for 1 h at -78 C. Subsequently, the mixture was allowed to warm to RT and MeOH (4.5 mL) was added followed by NaBH4 (0.089 g, 1.0 eq.). During NaBH4 addition generation of heat was observed, temperature increased to 30 C. The reaction was continued for 30 min at RT and then quenched with saturated NH4Cl aq. solu- tion. The resulting mixture was extracted with EtOAc (3 x). The combined organic layers were washed with brine, dried over anh. Na2SO4, filtered and concentrated in vacuo. The residue was purified by two consecutive FCC (SiHP; DCM:MeOH) and (SiHP; hexane:EtOAc) to give the product (0.204 g, 35% yield) as a yellowish oil. ESI-MS: 202.0 [M+H]+.
With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile); In tetrachloromethane;Reflux;
INTERMEDIATE 766-(Aminomethyl)pyridine-3-carbonitrile<strong>[3222-48-8]5-Cyano-2-methylpyridine</strong> (3.50 g, 29.6 mmol), AIBN (1 .47 g, 9.00 mmol) and N-bromosuccinimide (5.60 g, 31 .1 mmol) were dissolved in carbon tetrachloride (30 mL) and heated at reflux overnight. The reaction mixture was diluted with DCM (40 mL) and was washed sat aq NaHC03 (3 x 100 mL), dried (MgS04) and concentrated in vacuo. The product was purified by column chromatography. The residue was dissolved in THF (20 mL) and added to a stirring suspension of NaH (0.78 g, 19.5 mmol) in THF (20 mL) at 5C. After 5 min a solution of di-tert-butyl iminodicarboxylate (3.87 g, 17.8 mmol) in THF (20 mL) was added and the reaction mixture warmed to room temperature and stirred overnight. The reaction mixture was concentrated in vacuo and partitioned between EtOAc (100 mL) and water (50 mL). The organic phase was washed with water (2 x 50 mL) and brine (50 mL), dried (MgS04) and the residue was purified by column chromatography. The residue was dissolved in MeOH (50 mL) and cooled to 0C. HCI gas was bubbled through for 15 min and the resulting suspension stirred at room temperature for 3 h. The reaction mixture was concentrated in vacuo and the product triturated with hexane to afford the title compound (1 .5 g, 97 %) as a white solid. LCMS: ES+ 134.0 [MH]+ No..
4-methyl-2-(6-methylpyridin-3-yl)oxazole[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
53%
To a solution of <strong>[693-93-6]<strong>[693-93-6]4-methyloxazol</strong>e</strong> (254 mg) in THF (2 ml) was added at -78 C a solution of n- BuLi (1.6 M in THF, 2.3 ml) followed by zinc chloride (2 M in 2-methyl-tetrahydrofuran, 2.3 and stirring was continued at 22 C for 30 min. 5-Bromo-2-methylpyridine (526 mg) and tetrakis(triphenylphosphine)palladium(0) (353 mg) were added and stirring was continued at 60 C for 2 h. The mixture was partitioned between water and EtOAc, the organic layer was dried, evaporated and the residue purified by flash chromatography (silica gel, gradient, 20% to 70% EtOAc in n-heptane) to give the title compound (283 mg, 53%) as a light yellow solid. MS (ESI, m/z): 175.5 [(M+H)+].
Example 0734 0734-1 A mixture of 5-bromo-2-methylpyridine (258 mg), bis(pinacolato)diboron (396 mg), potassium acetate (282 mg), (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride-dichloromethane adduct (49 mg), and 1,4-dioxane (5 mL) was stirred at 100 C. for 2.5 hours. 3-Bromo-1-methyl-1H-pyrazole (200 mg), sodium carbonate (254 mg), bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (42 mg), and water (0.5 mL) were added thereto, followed by stirring at 100 C. for 6 hours. The reaction mixture was cooled to room temperature, the solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate, NH silica), thereby obtaining 2-methyl-5-(1-methyl-1H-pyrazol-3-yl)pyridine (190 mg) as yellow oily substance. MS m/z (M+H): 174.
5-(1-isopropyl-1H-pyrazol-4-yl)-2-methylpyridine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; sodium carbonate; In 1,2-dimethoxyethane; water; at 95℃;Inert atmosphere;
To a solution of the product from Step 2 (3.2 g, 0.014 mol) ,5-bromo-2-methylpyridine (1.93 g, 0.01 mol) , and Na2CO3(3.6 g, 0.03 mol) in DME/H2O (3: 1, 10 mL) was added Pd (dppf) Cl2(0.5 g, 7 mmol) . The resulting mixture was heated at 95 under N2overnight. After cooling to RT, the mixture was filtered and the filtrate wasconcentrated in vacuo. The residue was purified by silica gel columnchromatography (20EtOAc in petroleum ether) to givethe title compound. LRMS m/z (M+H) 202.2 found, 202.2 required.
2-methyl-5-(5-(pyridin-3-yl)thiophen-2-yl)pyridine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
275 mg
With palladium diacetate In 1,4-dioxane at 100℃; for 12h; Inert atmosphere; Sealed tube;
4.4. General procedure for the preparation of compounds 6 and 8 to19
General procedure: To a sealed flask containing cesium carbonate (3 equiv.), palladium acetate (0.05 equiv.), pivalic acid (0.4 equiv.) and tricyclohexylphosphine(0.4 equiv.) were successively added. Then,under N2 atmosphere, dioxane (4 mL), the first appropriate bromo(hetero)cycle (300 mg, 1 equiv.) and thiophene 1 (10 equiv.)were successively injected. The solution was stirred under N2 at100 C. After 3 h, the excess of thiophene and dioxane were evaporated,and the crude residue was washed with CH2Cl2 (5 mL).Then, the second appropriate bromo(hetero)cycle (1.5 equiv.),palladium acetate (0.05 equiv.) and dioxane (4 mL) were added tothe flask under N2 atmosphere. The solution was stirred at 100 Cfor 12 h.Waterwas then added and the mixturewas extracted withEtOAc (3 20 mL). The organic layer was washed with water(5 200 mL), dried over Na2SO4, filtered and evaporated. The cruderesidue was purified by flash chromatography (Snap Ultra 25 g,appropriate eluent) to give the corresponding coupling products (6and 8e19). Each yield was calculated based on the first bromo(-hetero)cycle added in the mixture.
With copper(l) iodide; potassium carbonate; 2,3-butane diamine; In 1,4-dioxane; at 115℃; for 12h;Inert atmosphere;
To a solution of 41(3.0 g, 17.44 mmol, 1 eq) in1,4-dioxane (150 mE), 41.1 (2.30 g, 20.92 mmol, 1.2 eq) was added. The reaction mixture was degassed for 10 mm under argon atmosphere followed by addition of potassium carbonate (6.0 g, 43.6 mmol, 2.5 eq), N,N-dimethylethylenediamine (0.384 g, 4.36 mmol, 0.25 eq), and copper iodide (0.497 g, 2.61 mmol, 0.15 eq). The reaction mixture was heated at 115 C. for 12 h. Afier completion of reaction, reaction mixture was transferred to ice cold water and product was extracted with ethylacetate. Organic layer was combined, washed with brine solution, dried over sodium sulphate and concentrated under reduced pressure to obtain crude material. This was further purified by 5% methanol in dichloromethane to obtain 41.2. (1.56 g, Yield: 44.45%). MS (ES): mlz 202.09 [M+H]
2-methyl-5-(6-methylpyridin-3-yl)thiazole[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
73%
With C82H77Cl2N3O2Pd; potassium carbonate; Trimethylacetic acid; In N,N-dimethyl acetamide; at 130℃; for 4h;
General procedure: Typically, (hetero)aryl bromide (1.0 mmol), thiazole derivatives(2.0 mmol), Pd-PEPPSI complexes (0.01e0.5 mol%), base (2 mmol),acid additive (0.3 mmol), and 3mL of DMAc solvent were addedinto a parallel reactor. After heating at 130 C for 4 h, the resultingmixture was cooled to room temperature. Subsequently, 25mL ofwater and 20 mL of dichloromethane were added into the reactor,and the mixture was stirred for another several minutes, followedby extraction three times with dichloromethane (3 x 5 mL). Theorganic layer was then combined, dried over anhydrous sodiumsulfate, filtered, and evaporated under reduced pressure to give thecrude products. The crude products were then purified by silica-gelcolumn chromatography using petroleum etheredichloromethane(15/1) as the eluent. The obtained pure products were characterizedby 1H NMR and 13C NMR spectroscopy, and the spectra can be foundin the Supporting Information. And the isolated yields of productswere obtained based on the amounts of (hetero)aryl bromides.
To a solution of 5-bromo-2-methylpyridine (1.00 g, 5.81 mmol) in CHCb (15 mL) was added mCPBA (1.10 g, 6.39 mmol). The reaction mixture was stirred at room temperature for 4 h, then washed with saturated aqueous Na2C03 solution (50 mL) and extracted with DCM (2 x 40 mL). The organic layer was separated, dried over anhydrous Na2S04 and concentrated in vacuo. The resulting pale yellow solid was redissolved in acetonitrile (28 mL) at room temperature, then trimethylsilyl cyanide (2.24 mL, 17.9 mmol) and trimethylamine (1.10 mL, 13.4 mmol) were added. The reaction mixture was stirred at l00C for 16 h, then cooled to room temperature and concentrated in vacuo. The crude residue was purified by column chromatography (silica, 100-200 mesh, 20% EtOAc in hexanes) to afford the title compound (0.7 g, 66%) as a pale yellow solid. 6n (400 MHz, CDCb) 2.58 (s, 3H), 7.26 (d, J 8.8 Hz, 1H), 7.88 (d, J 8.4 Hz, 1H).
2-(5-bromopyridin-2-yl)-1-(3-methoxyphenyl)ethan-1-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
36%
With lithium hexamethyldisilazane In tetrahydrofuran at 0 - 25℃; for 16h;
45-a (Example 45-a) 2-(5-Bromopyridin-2-yl)-1-(3- methoxyphenyl) ethan-1-one
To a solution of methyl 3-methoxybenzoate (1.93 g,11.6 mmol) and 5-bromo-2-methyl-pyridine (2.0 g,11.6 mmol) in THE (20 mL) was added LiHMDS (1 M, 11.6 mi,11.6 rnmol) at 0°C. The mixture was stirred at 25°C for16 h. The reaction mixture was quenched by addition saturate NH4C1 solution (30 mL) and extracted with EtOAc (20 mL x 3) . The combined organic phase was washed with brine (30 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue.The residue was purified by column chromatography on silica gel (PE/EtOAc=0 to 20:1) to give the title compound (1.35 g, 4.19 mmol, yield: 36.0%) as an oil. LCMS (ES) : m/z 305 [M+H.
2-(5-bromopyridin-2-yl)-1-(2-(trifluoromethyl)phenyl)ethan-1-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
Stage #1: 5-bromo-2-methylpyridine With lithium hexamethyldisilazane In tetrahydrofuran at -78 - 20℃; for 2h; Inert atmosphere;
Stage #2: 2-trifluoromethyl-benzoic acid methyl ester In tetrahydrofuran at 20℃;
23 Step 1 : 2-(5-Bromopyridin-2-yl)-1 -(2-(trifluoromethyl)phenyl)ethan-1 -one (Int 23b)
To a solution of 5-bromo-2-methylpyridine (3.81 g, 22.3 mmol) in THF (100 ml_) at -78 °C was added LHMDS (67 ml_, 1 M in THF, 66.8 mmol) under Ar. The mixture was stirred at rt for 2 h. Then methyl 2-(trifluoromethyl)benzoate (Int 23a) (5.00 g, 24.5 mmol) was added and the mixture was stirred at rt overnight. Aqueous NH4CI was added and the aqueous layer was extracted with EtOAc (3 x 40 ml_). The combined organic layers were dried over anhydrous Na2S04, filtered and concentrated to dryness. The residue was purified by column chromatography on silica gel (PE/EtOAc = 3:1 ) to give the title compound as a yellow solid.
Stage #1: 5-bromo-2-methylpyridine; methanol In sulfuric acid at 70℃; for 0.25h;
Stage #2: With ammonium persulfate In sulfuric acid; water at 70℃; for 0.5h;
1-11
The compound (5-bromo-2-methylpyridin-4-yl)methanol is synthesized using the technical route shown in formula (4), and the specific steps are:Compound 1 (100g, 0.58mol, 1.0eq) was dissolved in 1000mL methanol,Add 10ml concentrated sulfuric acid and heat to 70 and reflux for 15min;Add ammonium persulfate (265g, 1.16mol, 2.0eq) aqueous solution (500mL) dropwise,Continue to reflux at 70°C for 30 minutes;When the dot panel shows most of the reaction, flush into ice water;Adjust alkali with sodium bicarbonate, extract 3 times with EA, and combine the organic phases.After drying with saturated saline and anhydrous sodium sulfate,Concentrate the organic phase, mix the sample through the column,Product 2 (55g, 0.27mol, yield: 46.83%) was obtained,Its nuclear magnetic 1H-NMR spectrum is shown in Figure 1.
With [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II); potassium carbonate In 1,4-dioxane at 110℃; for 24h; Inert atmosphere; Sealed tube;
Synthesis of 5-(4-amino-2-methylphenyl)pyridin-2-amine (67):
General procedure: To a stirred solution of 5-bromopyridin-2-amine (66, 1.00 g, 5.81 mmol), 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (39, 2.03 g, 8.72 mmol) in 1,4-dioxane (7 mL): H2O (3 mL) was added K2CO3 (2.0 g, 14.53 mmol). After addition completed, resulting reaction mixture was purged with N2 gas for 5 min. then PdCl2(dppf) (0.21 g, 0.29 mmol) was added and again purged with N2 gas for 1 min. The reaction mixture was sealed and heated at 110 °C for 24 h. After this time the reaction mixture was allowed to cool to room temperature, filtered through celite bed, washed with EtOAc (100 x 2 mL). The filtrate was washed with H2O (100 x 2 mL) and brine (100 mL). The organic layer was separated, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude was purified by column chromatography (silica gel, 70% ethyl acetate in hexanes) to afford 5-(4-amino-2-methylphenyl)pyridin-2-amine (67, 0.52 g, yield 45%) as an off white solid; ESI (m/z) 200 [C12H13N3 + H] +.
Stage #1: 5-bromo-2-methylpyridine With n-butyllithium; N-ethyl-N,N-diisopropylamine In tetrahydrofuran; hexane at -78℃; for 0.5h; Inert atmosphere;
Stage #2: Diethyl carbonate In tetrahydrofuran; hexane for 2h; Inert atmosphere;
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