* 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 TurboGrignard In tetrahydrofuran at 0℃; for 0.25 h; Inert atmosphere Stage #2: at 0 - 20℃; Inert atmosphere
A round bottomed flask was charged with 5-bromo-2-chloropyridine (5.30 g, 27.6 mmol) in THF under N2 and cooled at 0° C. A solution of 1 M iso-propylmagnesiumchloride-lithium chloride complex in THF (40 mL) was added drop wise over 15 min. After 70 min N-methoxy-N-methylacetamide (4.1 mL, 38 mmol) was added drop wise. After stirring for 5 min at 0° C. the cooling bath was removed. The mixture was left stirring overnight and was then quenched by the addition of 100 mL saturated aqueous NH4Cl solution. The mixture was extracted with 3×100 mL EtOAc. The combined organic layers were washed with water followed by brine and dried over MgSO4. Evaporation of the volatiles at 80° C., 10 mbar for 1 h gave the title compound (3.596 g, 84) sufficiently pure for the next step.
Reference：
[1] Justus Liebigs Annalen der Chemie, 1931, vol. 487, p. 105,115
[2] Bioorganic and Medicinal Chemistry Letters, 2013, vol. 23, # 13, p. 3947 - 3953
3
[ 5350-93-6 ]
[ 53939-30-3 ]
Yield
Reaction Conditions
Operation in experiment
49%
Stage #1: With hydrogen bromide In water at 20℃; Stage #2: With sodium nitrite In water at -10℃; for 2 h; Stage #3: With hydrogen bromide; copper(I) bromide In water at 20℃;
b) Preparation of 5 -bromo-2-chloro-pyridine. 6-Chloro-pyridin-3-ylamine (15 g, 117 mmol) was dissolved slowly with constant stirring in 48percent HBr solution (50 mL) at r.t. and then the solution was chilled to -10 °C. A solution of sodium nitrite (8.9 g, 129 mmol) in cold water (25 mL) was added dropwise at -10 °C with constant stirring over 2 h, followed by a solution of copper (I) bromide (25 g, 176 mmol) in 48percent HBr (40 mL) dropwise. The mixture was- then stirred at r.t. until complete. The mixture was neutralised with sodium carbonate and extracted with ethyl acetate. The organic phase was washed with brine, dried over soldium sulfate and concentrated. The residue was purified by column chromatography on silica gel (60-120 mesh) eluting with 1percent ethyl acetate/petroleum ether to afford 5- bromo-2-chloro-pyridine (ll.l g, 49percent).
3%
With hydrogen bromide; bromine; sodium nitrite In water at -10 - 20℃; for 48 h;
[5-BROMO-2-CHLOROPYRIDINE] To a solution of the available 5-amino-2-chloropyridine (3.0 g, 23.3 [MMOL)] in HBr solution 48percent [AT-10XB0;C] was added a sodium nitrite solution (4.18 g, 60.7 [MMOL)] in [WATER (6 ML). BROMINE (11.2 G, 3 EQ. ) WAS SLOWLY ADDED AND THE REACTION WAS STIRRED] at rt for 48 hours. After addition of a [NAOH] solution (16.8 [G)] in water (42 mL), and extraction with [ET20,] the organic layer was dried over [NA2SO4] and evaporated. After purification by flash chromatography using DCM/Cyclohexane 50/50 as eluent, the title compound was obtained as a white solid (0.135 g, 0.7 [MMOL)] in 3percent yield ; GC/MS: [M+C5H3BRCIN] 192
Reference：
[1] Journal of Medicinal Chemistry, 2007, vol. 50, # 15, p. 3627 - 3644
[2] Patent: WO2008/62182, 2008, A1, . Location in patent: Page/Page column 119
[3] Patent: WO2004/6922, 2004, A1, . Location in patent: Page/Page column 53
[4] Zhurnal Russkago Fiziko-Khimicheskago Obshchestva, 1920, vol. 50, p. 476[5] Chem. Zentralbl., 1923, vol. 94, # III, p. 1020
4
[ 13472-85-0 ]
[ 53939-30-3 ]
Yield
Reaction Conditions
Operation in experiment
76%
With trichlorophosphate In N,N-dimethyl-formamide
a 5-Bromo-2-chloro-pyridine To a solution of 15.0 g (75.8 mmol) 5-bromo-2-methoxypyridine in 90 ml dry N,N-dimethylformamide 21.2 ml (227 mol) phosphorus oxychloride were slowly added at 0° C. After completed addition the reaction mixture was heated to 110° C. over a period of 30 min. At this temperature the reaction started to be exothermic. The heating bath was partly removed such that the internal temperature did not exceed 120° C. When the internal temperature started to drop heating was resumed, and the reaction mixture was kept at an internal temperature of 100-110° C. for 18 h. After cooling to room temperature the reflux condenser was exchanged by a claisen condenser, and the title compound was gained as a mixture with N,N-dimethylformamide by vacuum distillation at 40-50° C. (1-10 mbar). The distillate was diluted with cyclohexane and washed with two portions of water. The combined aqueous layers were extracted with cyclohexane. The combined organic extracts were dried with sodium sulfate and concentrated to give 11.0 g (76percent) of the title compound as a white solid. MS m/e, isotope cluster (percent): 191 (M+, 75), 193 (100), 195 (24).
Reference：
[1] Journal of Organic Chemistry, 2008, vol. 73, # 23, p. 9326 - 9333
[2] Tetrahedron, 2004, vol. 60, # 22, p. 4861 - 4865
[3] Tetrahedron, 2002, vol. 58, # 14, p. 2885 - 2890
[4] Tetrahedron Letters, 2001, vol. 42, # 15, p. 2779 - 2781
[5] Zhurnal Russkago Fiziko-Khimicheskago Obshchestva, 1920, vol. 50, p. 489[6] Chem. Zentralbl., 1923, vol. 94, # III, p. 1021
6
[ 5326-23-8 ]
[ 53939-30-3 ]
Yield
Reaction Conditions
Operation in experiment
45.8%
With bromine; sodium hydrogencarbonate In tetrachloromethane
A. 2-Chloro-5-bromopyridine A suspension of 2 g (12 mmol) of 2-chloro-5-pyridine-carboxylic acid, 4.12 g (19 mmol) of HgO (red) and 1 ml (19 mmol) of bromine in CCl4 was irradiated (flood lamp) under reflux for 2.5 h. The mixture was cooled to room temperature, 30 ml of sat. sodium bicarbonate solution was added, and the mixture was stirred vigorously for 15 min. The biphasic orange suspension was filtered through celite, the organic layer was washed with brine and dried over sodium sulfate. The filtrate was concentrated in vacuo to afford 1.1 g (45.8percent) of 2-chloro-5-bromopyridine, as a white solid, m.p. 67°-69° C.
Reference：
[1] Zhurnal Russkago Fiziko-Khimicheskago Obshchestva, 1920, vol. 50, p. 476[2] Chem. Zentralbl., 1923, vol. 94, # III, p. 1020
[3] Patent: WO2008/62182, 2008, A1,
10
[ 2402-97-3 ]
[ 53939-30-3 ]
[ 52200-48-3 ]
[ 36953-42-1 ]
Reference：
[1] Chemical and Pharmaceutical Bulletin, 1988, vol. 36, p. 2244 - 2247
11
[ 504-29-0 ]
[ 53939-30-3 ]
Reference：
[1] Zhurnal Russkago Fiziko-Khimicheskago Obshchestva, 1920, vol. 50, p. 489[2] Chem. Zentralbl., 1923, vol. 94, # III, p. 1021
12
[ 75-44-5 ]
[ 81971-39-3 ]
[ 53939-30-3 ]
Reference：
[1] Justus Liebigs Annalen der Chemie, 1931, vol. 486, p. 71,78
13
[ 2402-97-3 ]
[ 7791-25-5 ]
[ 53939-30-3 ]
[ 52200-48-3 ]
[ 36953-42-1 ]
Reference：
[1] Recueil des Travaux Chimiques des Pays-Bas, 1951, vol. 70, p. 578
14
[ 53939-30-3 ]
[ 69045-79-0 ]
Reference：
[1] Chemistry - A European Journal, 2010, vol. 16, # 41, p. 12425 - 12433
[2] Journal of the American Chemical Society, 2015, vol. 137, # 33, p. 10480 - 10483
15
[ 2402-97-3 ]
[ 53939-30-3 ]
[ 52200-48-3 ]
[ 36953-42-1 ]
Reference：
[1] Chemical and Pharmaceutical Bulletin, 1988, vol. 36, p. 2244 - 2247
16
[ 2402-97-3 ]
[ 7791-25-5 ]
[ 53939-30-3 ]
[ 52200-48-3 ]
[ 36953-42-1 ]
Reference：
[1] Recueil des Travaux Chimiques des Pays-Bas, 1951, vol. 70, p. 578
17
[ 2402-97-3 ]
[ 53939-30-3 ]
[ 52200-48-3 ]
[ 36953-42-1 ]
Reference：
[1] Chemical and Pharmaceutical Bulletin, 1988, vol. 36, p. 2244 - 2247
18
[ 2402-97-3 ]
[ 7791-25-5 ]
[ 53939-30-3 ]
[ 52200-48-3 ]
[ 36953-42-1 ]
Reference：
[1] Recueil des Travaux Chimiques des Pays-Bas, 1951, vol. 70, p. 578
19
[ 53939-30-3 ]
[ 124-41-4 ]
[ 13472-85-0 ]
Yield
Reaction Conditions
Operation in experiment
33%
at 90℃; for 24 h;
A 0.5 M sodium methoxide methanol solution (NaOMe in MeOH, 10.4 mL, 5.19 mmol) was added to 5-bromo-2-chloropyridine (96, 500 mg, 2.59 mmol) dissolved in methanol (10 mL) at room temperature, stirred at 90° C. for 24 hours, followed by adding water. Organic compounds were extracted with ethyl acetate and evaporated after a treatment with sodium sulfate. Purification was performed by column chromatograph to give the target compound 2-methoxy-5-bromopyridine (97a, 160 mg, 33percent).1H NMR (400 MHz, CDCl3) δ 3.98 (s, 3H), 6.39 (d, J=2.4 Hz, 1H), 7.47 (dd, J=8.8, 2.4 Hz, 1H), 8.16 (d, J=2.4 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 14.1, 53.5, 60.3, 111.6, 112.5, 140.9, 147.4, 162.9.
Reference：
[1] Journal of Medicinal Chemistry, 2010, vol. 53, # 1, p. 77 - 105
21
[ 53939-30-3 ]
[ 593-51-1 ]
[ 84539-30-0 ]
Yield
Reaction Conditions
Operation in experiment
27.4%
at 170℃; for 4 h; Microwave irradiation
A mixture of 5-bromo-2-chloropyridine (3g, 15.5 mmol), methylamine hydrochloride (3.16 g, 46.8 mmol), and DIPEA (8.17 mL, 46.8 mmol) was heated at 170°C under microwave for 4 h. The mixture was diluted with water and extracted with EtOAc. The organic layers was separated and washed with brine. Organic layer was dried over anhydrous Na2SO4 and concentrated. The residue was applied to ISCO (24g silica gel, solid loading, 70-80percent ethyl acetate/hexane) to afford 5-bromo-N-methylpyridin-2- amine (800 mg, 4.28 mmol, 27.4 percent yield) as a brown solid.
Reference：
[1] Journal of Organic Chemistry, 2005, vol. 70, # 7, p. 2494 - 2502
23
[ 53939-30-3 ]
[ 67-63-0 ]
[ 870521-31-6 ]
Yield
Reaction Conditions
Operation in experiment
78%
Stage #1: With sodium hydride In mineral oil at 60℃; for 0.5 h; Inert atmosphere Stage #2: at 80℃; Reflux
General procedure: 60percent NaH in oil (1.5:1, Sodium hydride:Mineral Oil, 5.20 g) was added in two portions to isopropyl alcohol (150 mL) at room temperature under N2. The mixture was stirred at 60° C. for 30 min. 5-bromo-2-chloropyridine (10.00 g, 51.96 mmol) was added in two portions and the mixture was stirred at reflux 4 h and then at 80° C. overnight. The solution was concentrated in vacuo. Water (50 mL) and EtOAc (50 mL) was added and the layers were separated. The aqueous layer was extracted with EtOAc (50 mL). The combined organic layers were washed with brine, dried over MgSO4, filtered and the solvent was removed in vacuo. The crude product was subjected to flash chromatography (silica, 0-50percent EtOAc in heptanes) to give the title compound as a clear oil (8.74 g, 78percent). 1H NMR (600 MHz, DMSO) δ 8.17 (s, 1H), 7.61 (dd, 1H), 6.59 (d, 1H), 5.23 (m, 1H), 1.33 (s, 6H).
Reference：
[1] Patent: US2013/12530, 2013, A1, . Location in patent: Paragraph 0170-0171
[2] Journal of Medicinal Chemistry, 2010, vol. 53, # 1, p. 77 - 105
2-Chloro-5-bromopyridine (64 g, 333 mmol) was suspended in hydrazine monohydrate (250 mL) and the mixture was heated at 70° C. for 72 hours. The reaction mixture was then diluted with water (750 mL) and the resulting precipitate was filtered off and azeotroped, firstly with toluene (*2) then dichloromethane (*2), to afford the title compound as a pale brown solid in 83percent yield, 52 g.
83%
at 70℃; for 72 h;
Preparation 23: (5 -Bromopyridin -2-yl)hydrazine; 2-Chloro-5-bromopyridine (64 g, 333 mmol) was suspended in h ydrazine monohydrate (250 ml_) and the mixture was heated at 70 °C for 72 hours. The reaction mixture was then diluted with water (750 mL) and the resulting precipitate was filtered off and azeotroped, firstly with toluene (x2) then dichloromethane (x2), to afford the title compound as a paie brown solid (52 g, 83percent).
74.4%
for 2 h; Inert atmosphere; Reflux
a) 5-Bromo-2-hydrazinylpyridine. A mixture of 5-bromo-2-chloropyridine (11.5 g, 60 mmol) and hydrazine hydrate (100 mL) was refluxed under Argon for 2 h. The mixture was cooled to room temperature, filtered and the solids were washed with water (50 mL x 3), dried to give the title compound (8.30 g, 74.4percent yield) as yellow solids. MS: m/z 188.0 [M+H+].
74.4%
for 2 h; Reflux; Inert atmosphere
EXAMPLE 13-(2-Methoxyphenyl)-6-(4-methoxyphenyl)-[l,2,4]triazolo[4,3-a]pyridine a) 5-Bromo-2-hydrazinylpyridine. A mixture of 5-bromo-2-chloropyridine (11.5 g, 60 mmol) and hydrazine hydrate (100 mL) was refluxed under Argon for 2 h. The mixture was cooled to room temperature, filtered and the solids were washed with water (50 mL x 3), dried to give the title compound (8.30 g, 74.4percent yield) as yellow solids. MS: m/z 188.0 [M+H+].
44%
With hydrazine hydrate In ethanol at 90℃; for 46 h;
9.3 ml (9.5 g, 190.2 mmol) hydrazine hydrate are added to a solution of 1.8 g (9.5 mmol) 5-bromo-2-chloropyridine in 25 ml ethanol at RT, while stirring, and the mixture is then stirred at 90° C. for 46 h. After concentration of the reaction mixture in vacuo, the residue is stirred in water and the solid is filtered off, washed with water and diethyl ether and dried in vacuo.Yield: 0.8 g (44percent of th.)LC-MS (Method 8): Rt=0.50 min; MS (ESIpos): m/z=188 [M+H]+;1H-NMR (400 MHz, DMSO-d6): δ=8.02 (d, 1H), 7.66 (s, 1H), 7.58 (dd, 1H), 6.69 (d, 1H), 4.16 (s, 2H).
50 percent Aqueous solution of dimethylamine (30 ml) was added to 5-bromo-2-chloropyridine (1.79 g, 10 mmol) and the mixture was stirred at room temperature under argon atmosphere for 5 hrs. Saturated sodium bicarbonate solution (15 ml) was added to the reaction mixture and the mixture was extracted with ethyl acetate. The extract was washed with brine and dried. The solvent was distilled off under reduced pressure and the residue was dried at 40 °C under reduced pressure for 2 hrs. to give 5-bromo-2-dimethylaminopyrimidine (1.83 g, 90 percent) as colorless crystals. m.p.: 81 - 82°C; IR (Nujol): 1586, 1527 cm-1; APCI-MS m/z: 202/204 [M+H]+.
90%
at 20℃; for 5 h; Inert atmosphere
(Preparation 29) 1) 50percent Aqueous solution of dimethylamine (30 ml) was added to 5-bromo-2-chloropyridine (1.79 g, 10 mmol) and the mixture was stirred at room temperature under argon atmosphere for 5 hrs. Saturated sodium bicarbonate solution (15 ml) was added to the reaction mixture and the mixture was extracted with ethyl acetate. The extract was washed with brine and dried. The solvent was distilled off under reduced pressure and the residue was dried at 40° C. under reduced pressure for 2 hrs. to give 5-bromo-2-dimethylaminopyrimidine (1.83 g, 90percent) as colorless crystals. m.p. : 81-82° C.; IR (Nujol) : 1586, 1527 cm-1; APCI-MSm/z: 202/204 [M+H]
Reference：
[1] Organic Letters, 2015, vol. 17, # 8, p. 1866 - 1869
[2] Journal of Organic Chemistry, 2015, vol. 80, # 24, p. 12137 - 12145
29
[ 2591-86-8 ]
[ 53939-30-3 ]
[ 23100-12-1 ]
Yield
Reaction Conditions
Operation in experiment
68%
Stage #1: With n-butyllithium In diethyl ether; hexane at -50 - -45℃; Inert atmosphere Stage #2: at -70 - 20℃;
5-Bromo-2-chloropyridine (T-9) (15.0 g) and diethyl ether (450 ml) were put in a reaction vessel and cooled to -50 °C under an atmosphere of nitrogen. n-Butyllithium (1.57 M in n-hexane; 54.6 ml) was added dropwise in the temperature range of -50 °C to -45 °C, and the stirring was continued for another 90 minutes. After the reaction vessel had been cooled to -70 °C, formylpiperidine (9.70 g) was added dropwise in the temperature range of -70 °C to -65 °C, and the stirring was continued for another 60 minutes while the mixture was allowed to return to room temperature. The resulting reaction mixture was poured into ice-water (500 ml) and mixed with it. Diethyl ether (200 ml) was added to the solution to separate organic and aqueous phases, and extraction was carried out. The combined organic phase was washed with water and dried over anhydrous magnesium sulfate. The resulting solution was concentrated under reduced pressure and the residue was purified with a fractional operation by means of column chromatography (silica gel; toluene). The product was further purified by recrystallization from heptane. The solvent was distilled off and the product was dried, giving 2-chloro-5-formylpyridine (T-10) (7.01 g). The yield based on the compound (T-9) was 68percent.
With potassium carbonate In acetonitrile at 110℃; for 12 h;
General procedure: To 1,4-dioxane (30 mL) were added tert-butyl piperazine-1-carboxylate (2.89 g, 15.51 mmol), 5-bromo-2-chloropyrimidine (2.00 g, 10.34 mmol) and potassium carbonate (2.86 g, 20.68 mmol) sequentially. The mixture was heated to 110 °C, after stirring for 12 hours, the reaction mixture was cooled to room temperature, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (PE/EtOAc (v/v) = 20/1) to give the title compound as a pale yellow solid (3.15 g, 88.7percent).; The title compound was prepared using tert-butyl piperazine-1-carboxylate (1.45 g, 7.79 mmol),5-bromo-2-chloropyridine (1.00 g, 5.20 mmol) and potassium carbonate (1.44 g, 10.39 mmol) in acetonitrile (30 mL) according to the process described in Step 4 of Example 1, and the crude product was purified by silica gel chromatography (PE/EtOAc (v/v) = 20/1) to give the title compound as a pale yellow solid (1.45 g, 8 1.5percent).MS (ESI, pos. ion) m/z: 342.1 [M+H] and‘H NMR (600 MHz, CDC13): (ppm) 8.17 (d, J 2.4 Hz, 1H), 7.52 (dd, J 9.0, 2.5 Hz, 1H), 6.52 (d, J 9.0 Hz, 1H), 3.55 - 3.49 (m, 4H), 3.49 - 3.45 (m, 4H), 1.46 (s, 9H).
58.8%
at 80℃; for 14 h;
To a stirred solution of 1-Boc piperazine (10.6 g, 57.29 mmol, Symax fine chemicals) in dryDMF (lOOmL), TEA (14.43 mL, 103.39 mmol) and 5-bromo-2-chloropyrimidine (10 g, 52.08mmol, Oakwood chemicals) were added and the reaction mixture was stirred at 80°C for 14h. It was cooled down to rt and poured on iced water (100 mL). The resulting precipitatewas filtered and washed with hexane (50 mL) to afford the title compound. Yield: 58.8percent(10 g, off white solid). 1H NMR (400 MHz, DMSO-d6): 68.60(s, IH), 8.13 (dd, J= 8.6, 2.4Hz, IH), 7.54 (dd, J = 8.4, 0.4 Hz, IH), 3.22-3.20 (m, 4H), 2.61-2.59 (m, 4H), 1.42 (5, 9H).LCMS: (Method A) 343.9 (M +2H), Rt. 5.58 mm, 98.9percent (Max).
58.8%
With triethylamine In N,N-dimethyl-formamide at 80℃; for 14 h;
To a stirred solution of 1-Boc piperazine (10.6 g, 57.29 mmol, Symax fine chemicals) in dry DMF (100mL), TEA (14.43 mL, 103.39 mmol) and 5-bromo-2-chloropyridine (10 g, 52.08 mmol, Oakwood chemicals) were added and the reaction mixture was stirred at 80°C for 14 h. It was cooled down to rt and poured on iced water (100 mL). The resulting precipitate was filtered and washed with hexane (50 mL) to afford the title compound. Yield: 58.8percent (10 g, off white solid). 1H NMR (400 MHz, DMSO-d6): δ 8.60 (s, 1 H), 8.13 (dd, J = 8.6, 2.4 Hz, 1 H), 7.54 (dd, J = 8.4, 0.4 Hz, 1 H), 3.22-3.20 (m, 4H), 2.61 -2.59 (m, 4H), 1.42 (s, 9H). LCMS: (Method A) 343.9 (M +2H), Rt. 5.58 min, 98.9percent (Max).
With sodium hydrogensulfide; In N,N-dimethyl-formamide; at 70℃; for 14h;Inert atmosphere;
To a solution of Compound 12A (1.92 g, 10 mmol) in DMF (20 mL) was added NaHS (560 mg, 10.0 mmol). The reaction mixture was stirred at 70 C under nitrogen for 14 hours. The mixture was diluted with water (50 mL) and extracted with ethyl acetate (50 mL x 3). The combined extracts were washed with brine (100 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated to give Compound 12B. LC-MS (ESI) m/z: 190 [M+H]+.
b) Preparation of 5 -bromo-2-chloro-pyridine. 6-Chloro-pyridin-3-ylamine (15 g, 117 mmol) was dissolved slowly with constant stirring in 48% HBr solution (50 mL) at r.t. and then the solution was chilled to -10 C. A solution of sodium nitrite (8.9 g, 129 mmol) in cold water (25 mL) was added dropwise at -10 C with constant stirring over 2 h, followed by a solution of copper (I) bromide (25 g, 176 mmol) in 48% HBr (40 mL) dropwise. The mixture was- then stirred at r.t. until complete. The mixture was neutralised with sodium carbonate and extracted with ethyl acetate. The organic phase was washed with brine, dried over soldium sulfate and concentrated. The residue was purified by column chromatography on silica gel (60-120 mesh) eluting with 1% ethyl acetate/petroleum ether to afford 5- bromo-2-chloro-pyridine (ll.l g, 49%).
3%
With hydrogen bromide; bromine; sodium nitrite; In water; at -10 - 20℃; for 48h;
[5-BROMO-2-CHLOROPYRIDINE] To a solution of the available 5-amino-2-chloropyridine (3.0 g, 23.3 [MMOL)] in HBr solution 48% [AT-10XB0;C] was added a sodium nitrite solution (4.18 g, 60.7 [MMOL)] in [WATER (6 ML). BROMINE (11.2 G, 3 EQ. ) WAS SLOWLY ADDED AND THE REACTION WAS STIRRED] at rt for 48 hours. After addition of a [NAOH] solution (16.8 [G)] in water (42 mL), and extraction with [ET20,] the organic layer was dried over [NA2SO4] and evaporated. After purification by flash chromatography using DCM/Cyclohexane 50/50 as eluent, the title compound was obtained as a white solid (0.135 g, 0.7 [MMOL)] in 3% yield ; GC/MS: [M+C5H3BRCIN] 192
In a flask replaced by nitrogen, tetrahydrofuran solution (80g) containing 5-bromo-2-chloropyridine (9.6g, 50.0mmol) was charged, and cooled at -78C, and then n-hexane solution of n-butyllthium (15% by weight, 24.6g, 57.5mmol) wasadded dropwise at-78C. Next, at-78C,trimethoxyborane (5.7g,55.0mmol) was added dropwise. After 30 minutes from adding dropwise, cooling bath was removed off, and the reaction mixture was stirred at room temperature overnight. Then, 10% byweightofhydrochloricacid (50g) was added under ice cooling condition, and the reaction mixture was stirred for 1. 5 hours, and then neutrali zed by adding 4 0% by weight of sodium hydroxide aqueous solution (15g). Ethyl acetate (50g) was added to the reaction mixture, and the reaction mixture was stirred for 1.0 hour, and then left to stand to separate organic layer. Organic layer was dried with anhydrous magnesium sulfate, and then condensed under reduced pressure to obtain 6-chloro-3-pyridylboronic acid (6.9g, 44.0mmol).
With sodium t-butanolate;tris-(dibenzylideneacetone)dipalladium(0); 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In toluene; at 100℃; for 4h;
(179a) 4-(6-Chloropyridin-3-yl)morpholine Toluene (50 mL), morpholine (0.87 mL, 10 mmol), and tris(dibenzylideneacetone)dipalladium (0.46 g, 0.50 mmol) were added to a mixture of <strong>[53939-30-3]2-chloro-5-bromopyridine</strong> (2.5 g, 13 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.58 g, 1.0 mmol), and sodium t-butoxide (1.4 g, 15 mmol). The reaction solution was heated to 100C under a nitrogen atmosphere and then stirred for 4 hr. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (Yamazen, eluding solvent: hexane/ethyl acetate) to obtain 2.4 g (quantitative yield) of the title compound as a yellow solid. 1H-NMR (400 MHz, CDCl3) delta ppm: 8.02 (1H, d, J = 2.7 Hz), 7.20 (1H, d, J = 8.6 Hz), 7.16 (1H, dd, J = 2.7, 8.6 Hz), 3.87 (4H, t, J = 4.7 Hz), 3.16 (4H, t, J = 4.7 Hz).
2,5-dibromopyridine 20.0g (84.4 mmol) was dissolved in 300ml of diethyl ether and then, at -78 1.6M n-BuLi in hexane 53ml (84.4 mmol) and the mixture was stirred for about 1 hour dongan. Thereafter, it was added to 10.7ml Chlorotrimethylsilane (84.4 mmol) slowly, followed by stirring and stirred for 2 hours at -78 raising the temperature to room temperature for about 18 hours. After completion of reaction, it was then added to 200ml of distilled water, extracted with ethyl acetate 300ml and evaporated under reduced pressure followed by drying the organic layer with magnesium sulfate. A fractional distillation and the resulting intermediate 11-3 obtained therefrom to give about 16.0g (84.0 mmol, 100% yield). The resulting compound was confirmed by LC-MS.
A stirring solution of DIPA (34 mL, 227.7 mmol, 1.1 eq) in dry THF (250 mL) was cooled to -78 C and n-BuLi (85 mL, 207.9 mmol, 1.0 eq, 2.5 M in THF) was added dropwise. The resulting reaction mixture was stirred for 30 mi 5-Bromo- 2-chloropyridine (40 g, 207.9 mmol, 1 eq.) in dry THF (450 mL) was added dropwise and the reaction mixture was stirred at -78 C for 1 h. A solution of iodine (55 g, 207.9 mmol, leq) in THF (250 mL) was added dropwise and the mixture was stirred for 16 h at RT. TLC analysis indicated formation of non-polar spot. The mixture was quenched with sodium thiosulfate solution (500 mL) and extracted with EtOAc (2 x 500 mL). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure gave crude product which was recrystallized from ethanol (120 mL) to afford 5-bromo-2-chloro-4-iodopyridine (50 g, 75.4% yield) as an off white solid. LCMS:[M+Hjb 320.15.
60.3%
A stirred solution of DIP A (4.02 niL, 28.8 mmol, l . leq) in dry THF (50 mL) was cooled to -78C and n-BuLi (10.47 niL, 26.18 mmol, 1.0 eq, 2.5M in hexane) was added dropwise under an argon atmosphere. Then, the reaction mixture was stirred for 30 min. at the same temp., followed by the addition of a solution of 2- chloro-5-bromopyridine (5.0g, 26.178 mmol, 1.0 eq) in dry THF (50mL) and stirred for lh at the same temp. Then, a solution of iodine (6.64g, 26.178 mmol, l .Oeq) in THF (50mL) was added dropwise at -78C. After completion of addition the reaction mixture was allowed to warm to RT over 4h. The reaction progress was monitored by TLC. The reaction mixture was quenched with a saturated aqueous solution of sodium thiosulfate, and extracted with EtOAc (3 x lOOmL). The combined organic layer was dried over Na2S04 and concentrated under reduced pressure to obtain the crude compound. The crude compound was recrystallized from ethanol (20 mL) to give the title compound (5 g, 60.3%) as an off white solid. LCMS: [M+H]+ 317.86.
60%
Step 1: Preparation of 5-bromo-2-chloro-4-iodopyridine. [0790] To a solution of <strong>[53939-30-3]5-bromo-2-chloropyridine</strong> (2.00 g, 10.4 mmol) in anhydrous THF (40 mL) was added LDA (6.2 mL, 2 M in THF) dropwise at -60 C. After the addition, the resulting reaction mixture was stirred at -60 C for 0.5 h. Then NIS (2.34 g, 10.4 mmol) was added into above solution in portions at -60 C. The reaction mixture was warmed to 15 C gradually and further stirred for 1.5 hours under N2 atmosphere. A yellow solution was formed. TLC showed the starting material was consumed completely. The reaction mixture was quenched with sat. aq. NH4CI (20 mL), then extracted with EtOAc (30 mL x3). The combined organic layer was washed with water (20 mL x2), brine (40 mL), dried over anhydrous Na2S04, filtered and concentrated under reduced pressure. The residue was purified by Combi Flash (0% to 10% EtOAc in PE) to give 5-bromo-2-chloro-4-iodopyridine (2.00 g, yield: 60%) as a white solid. NMR (400 MHz, CDCb) d 7.86 (1H, s), 8.47 (1H, s).
51.5%
To a stirred solution of DIPA (18mL, 105.2mmol) in dry THF (150 mL) was cooled to -78 C and -BuLi (42 mL, 105.2 mmol, 2.5 M in THF) was drop wise added under Argon atm. Then, the reaction mixture was stirred for 30 min. at the same temp. Followed by the addition of a solution of <strong>[53939-30-3]2-chloro-5-bromopyridine</strong> (20g, 105.2mmol) in dry THF (50 mL) and stirred for 1 hour at the same temp. Then, a solution of iodine (26g, 105.2mmol) in THF (80 mL) was added drop wise at -78 C , after completion of addition the reaction mixture was allowed to RT over 16 hours. The reaction mixture was quenched with saturated aqueous solution of sodium thiosulfate (500 mL), extracted with EtOAc (2 x 500 mL). The combined organic layer was dried over Na2S04 and concentrated under reduced pressure to get crude compound. The crude compound was recrystallized from ethanol (120 mL) to give the title compound (17g, 51.5%) as an off white solid. LCMS [M+H]+ = 319.9 g/mol.
19.3 g (77%)
With n-butyllithium; iodine; sodium thiosulfate; diisopropylamine; In tetrahydrofuran; n-heptane;
b 5-Bromo-2-chloro-4-iodo-pyridine To a solution of 12 ml (83 mmol) diisopropylamine in 80 ml dry tetrahydrofuran 52 ml of a solution of n-butyllithium in hexanes (1.6 M, 83 mmol) was added at -78 C. over a period of 15 min under argon. The mixture was stirred at -78 C. for 10 min. A solution of 15.2 g (79.0 mmol) <strong>[53939-30-3]5-bromo-2-chloro-pyridine</strong> in 160 ml dry tetrahydrofuran was added at a rate such that the internal temperature did not exceed -70 C. After completed addition the reaction mixture was stirred at -78 C. for 5 h. A solution of 24 g (95 mmol) iodine in 160 ml dry tetrahydrofuran was added at a rate such that the internal temperature did not exceed -70 C. The reaction mixture was stirred for another 30 min at -78 C. The reaction mixture was allowed to warm to -10 C. and treated with 120 ml of an aqueous solution of sodium thiosulfate (1 M, 120 mmol). The layers were separated and the aqueous layer was extracted with two portions of ethyl acetate. The combined organic layers were washed twice with saturated ammonium hydroxide solution, dried with sodium sulfate and concentrated. The residue was dissolved in hot heptane and allowed to stand over night. Filtration of the precipitate and drying in vacuo gave 19.3 g (77%) of the title compound as a light brown solid. MS m/e (%): 318 (M+, 100).
In a 300 mL eggplant flask,diisopropylamine (2.9001 g, 28.66 mmol) and anhydrous THF (30 mL) were put andreplaced with argon. At -78C, n- butyl lithium (1.58 M n- hexane solution; 18.2mL, 28.76 mmol) was added dropwise slowly, and the mixture was stirred for 10minutes at the same temperature. At the same temperature,<strong>[53939-30-3]2-chloro-5-bromopyridine</strong> (7) (5.2429 g, 27.24 mmol) dissolved in anhydrous THF(50 mL) was added dropwise slowly and stirred for 5 hours at the sametemperature. at the same temperature, Iodine (8.3550 g, 32.92 mmol) dissolvedin anhydrous THF (15 cm 3) was added dropwise, and after stirringfor 30 minutes at the same temperature, it was allowed to warm slowly. 1M aqueoussodium thiosulfate solution (40 mL) was added at 0C, and extracted 3 timeswith ethyl acetate and dried over anhydrous sodium sulfate, and then solventwas distilled off. When obtained residue was recrystallized from ethanol, palebrown powder of Compound 8 (5.8389 g, 18.34 mmol) was obtained. Furthermoreconcentrate of the filtrate was purified by silica gel column chromatography(BW-200, 40 g, eluent; 10% ? 20% ? 40% benzene / n-hexane) to give theremaining compound 8 (1.2299 g, 3.863 mmol). total of 7.0688 g (22.21 mmol,82%). Further, by repeating recrystallization from MeOH, colorless needles wereobtained.
With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In ethanol; water; toluene; at 80℃; for 1.5h;
Step c: Preparation of 2-chloro-5-phenylpyridine A solution of 0.7 g (5.7 mmol) of phenylboronic acid in 3 mL of ethanol is added to a mixture of 0.18 g (0.15 mmol) of tetrakis(triphenylphosphine)palladium, 1 g (5.15 mmol) of <strong>[53939-30-3]5-bromo-2-chloropyridine</strong>, 5.7 mL of an aqueous solution of 2M sodium carbonate and 10 mL of toluene. The mixture is stirred vigorously and heated to 80 C. for 90 minutes. After returning to ambient temperature, the reaction medium is extracted with 20 mL of ethyl acetate, then washed with 10 mL of water. The organic phase is dried over magnesium sulfate, filtered and concentrated under a vacuum. The chestnut brown oil obtained is purified by silica gel chromatography (elution with an ethyl acetate/heptane gradient) to produce 0.7 g (70%) of 2-chloro-5-phenylpyridine in the form of white crystals. Rf=0.6 heptane/ethyl acetate 2/1 1H NMR (DMSO d6): 8.7 (multiplet, 1H); 8.1 (multiplet, 1H); 7.8 to 7.65 (unresolved peaks, 2H); 7.6 (multiplet, 1H); 7.55 to 7.35 (unresolved peaks, 3H)
5.75 g
6.65 g (54.56 mmol) of phenylboronic acid,10 g (51.96 mmol) of <strong>[53939-30-3]5-bromo-2-chloropyridine</strong>, 17.95 g (129.9 mmol) of potassium carbonate and 100 mL of toluene were placed in a 300 mL eggplant type flask successively and stirred at room temperature under a nitrogen atmosphere.After stirring for 15 minutes, 1.8 g (1.56 mmol) of tetrakistriphenylphosphine palladium was added. The temperature was raised to 90 C. with an oil bath and stirred for 4 hours. Progress of the reaction was confirmed by TLC and cooled to room temperature. 100 mL of water was added to the reaction solution, and the liquid separation operation was carried out to recover the toluene layer. The recovered toluene layer was concentrated, and a mixed solution of hexane and ethyl acetate was used as a developing solvent, And purification was carried out by silica gel column chromatography. After concentrating the eluted portion of the target product, hexane was added. After insoluble matter was removed by filtration, hexane was distilled off.crystalAfter recovering the target product, 5.75 g (30.32 mmol) of the desired product of pale yellowish white crystals was obtained by drying.
With indium(III) oxide; ammonia; water; sulfur; In ethanol; at 60℃;Green chemistry;
General procedure: A mixture of alkyl/aryl halide, 1 (1.2 mmol), ammonium hydroxide (1 mmol) and nanosulfur powder (3 mmol, 96 mg) was stirred in 5mL of solvent (ethanol/water (2:1)) at 60 C. Under this stirring condition indium oxide nanoparticles (3 mol-%) were added to it and the reaction was stirred for a period of 10 min to 1 h at 60 C. After completion of the reaction as indicated by thin layer chromatography (TLC), the reaction mixture was cooled to room temperature and a 2:1 mixture of ethyl acetate/water (15 mL) was added and indium oxide was removed by centrifuge. The combined organic extracts were dried with anhydrous sodium sulfate and concentrated to give desired product in high purity.
50 % Aqueous solution of dimethylamine (30 ml) was added to 5-bromo-2-chloropyridine (1.79 g, 10 mmol) and the mixture was stirred at room temperature under argon atmosphere for 5 hrs. Saturated sodium bicarbonate solution (15 ml) was added to the reaction mixture and the mixture was extracted with ethyl acetate. The extract was washed with brine and dried. The solvent was distilled off under reduced pressure and the residue was dried at 40 C under reduced pressure for 2 hrs. to give 5-bromo-2-dimethylaminopyrimidine (1.83 g, 90 %) as colorless crystals. m.p.: 81 - 82C; IR (Nujol): 1586, 1527 cm-1; APCI-MS m/z: 202/204 [M+H]+.
90%
In water; at 20℃; for 5h;Inert atmosphere;
(Preparation 29) 1) 50% Aqueous solution of dimethylamine (30 ml) was added to 5-bromo-2-chloropyridine (1.79 g, 10 mmol) and the mixture was stirred at room temperature under argon atmosphere for 5 hrs. Saturated sodium bicarbonate solution (15 ml) was added to the reaction mixture and the mixture was extracted with ethyl acetate. The extract was washed with brine and dried. The solvent was distilled off under reduced pressure and the residue was dried at 40 C. under reduced pressure for 2 hrs. to give 5-bromo-2-dimethylaminopyrimidine (1.83 g, 90%) as colorless crystals. m.p. : 81-82 C.; IR (Nujol) : 1586, 1527 cm-1; APCI-MSm/z: 202/204 [M+H]
With 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; sodium t-butanolate;tris-(dibenzylideneacetone)dipalladium(0); In toluene; at 110℃; for 18h;
EXAMPLE 41A (1S, 5R)-3-(6-Chloro-pyridin-3-yl)-3,6-diaza-bicyclo[3.2.0]heptane-6-carboxylic Acid Tert-Butyl Ester The product of Example 37G (2.0 g, 10 mmol), was coupled with 5-Bromo-2-chloro-pyridine (Aldrich, 2.3 g, 12 mmol) catalyzed by Pd2(dba)3 (Strem, 90 mg, 0.1 mmol) and racemic-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (BINAP, Strem, 200 mg, 0.3 mmol) with t-BuONa (1.0 g, 10 mmol) in toluene (30 mL) at 110 C. under N2 for ~18 h. After the reaction went to completion, the mixture was cooled to ambient temperature and quenched with 50 mL of water. The layers were separated and the aqueous layer was extracted with CHCl3 (3*25 mL). The extracts were combined and concentrated. The residue was purified by chromatography (SiO2, 90:10:2 CH2Cl2: MeOH:NH4OH, Rf. 0.20) and the title compound was obtained as an oil (2.0 g, 6.4 mmol, 65% yield). 1H NMR (MeOH-d4, 300 MHz) delta 1.44 (s, 9H), 2.84-2.94 (m, 1H), 2.98 (dd, J=6.4 Hz, J=10.5 Hz, 1H), 3.16-3.30 (m, 1H), 3.51-3.67 (m, 1H), 3.76 (d, J=9.8 Hz, 1H), 3.84-3.99 (m, 1H), 4.02-4.15 (m, 1H), 7.24-7.29 (m, 2H), 7.85 (s, 1H); MS (DCI/NH3) m/z 310 (M+H)+, 312 (M+H)+.
25%
EXAMPLE 80B tert-butyl (1S,5R)-3-(6-chloro-3-pyridinyl)-3,6-diazabicyclo[3.2.0]heptane-6-carboxylate The product of Example 80A (198 mg, 1.0 mmol) and <strong>[53939-30-3]5-bromo-2-chloropyridine</strong> were processed according to the procedure described in Example 1E. The crude product was purified by chromatography (SiO2, hexane: EtOAc, 50:50, Rf 0.3) to provide the title compound (80 mg, 25% yield). 1H NMR (MeOH-d4, 300 MHz) delta 1.48 (s, 9H), 2.90 (dd, J=10.6, 4.1 Hz, 1H), 3.00 (dd, J=10.2, 6.4 Hz, 1H), 3.27 (m, 2H), 3.60 (m, 1H), 3.77 (d, J=10.2 Hz, 1H), 3.92 (m, 1H), 4.08 (m, 1H), 7.26 (d, J=1.7 Hz, 2H), 7.85 (t, J=1.8 Hz, 4 1H); MS (DCI/NH3) m/z 329 M+2+NH4)+, 327 (M+NH4)+.
With sodium t-butanolate;tris-(dibenzylideneacetone)dipalladium(0); 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; In toluene; at 85℃; for 20h;
Example 156A 5-(6-Chloro-pyridin-3-yl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic Acid tert-butyl Ester The product of Example 6C (5 g, 23.6 mmol), <strong>[53939-30-3]5-bromo-2-chloropyridine</strong> (Aldrich, 5.02 g, 28.3 mmol), tris(dibenzylideneacetone)dipalladium (0) (Pd2(dba)3, Strem, 0.43 g, 0.47 mmol), 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (BINAP, Strem, 0.59 g, 0.94 mmol) and tert-BuONa (3.63 g, 37.8 mmol) in 50 mL toluene was warmed to 85 C. and allowed to stir for 20 h. The mixture was cooled to ambient temperature, filtered and concentrated under reduced pressure. The crude material was purified by column chromatography (SiO2, 50% hexanes-EtOAc) to give 3.86 g of the title compound (12 mmol, 42% yield) as the major product. MS (DCl/NH3) m/z 324 (M+H)+.
2-Chloro-5-bromopyridine (64 g, 333 mmol) was suspended in hydrazine monohydrate (250 mL) and the mixture was heated at 70 C. for 72 hours. The reaction mixture was then diluted with water (750 mL) and the resulting precipitate was filtered off and azeotroped, firstly with toluene (*2) then dichloromethane (*2), to afford the title compound as a pale brown solid in 83% yield, 52 g.
83%
With hydrazine; at 70℃; for 72h;
Preparation 23: (5 -Bromopyridin -2-yl)hydrazine; 2-Chloro-5-bromopyridine (64 g, 333 mmol) was suspended in h ydrazine monohydrate (250 ml_) and the mixture was heated at 70 C for 72 hours. The reaction mixture was then diluted with water (750 mL) and the resulting precipitate was filtered off and azeotroped, firstly with toluene (x2) then dichloromethane (x2), to afford the title compound as a paie brown solid (52 g, 83%).
74.4%
With hydrazine hydrate; for 2h;Inert atmosphere; Reflux;
a) 5-Bromo-2-hydrazinylpyridine. A mixture of <strong>[53939-30-3]5-bromo-2-chloropyridine</strong> (11.5 g, 60 mmol) and hydrazine hydrate (100 mL) was refluxed under Argon for 2 h. The mixture was cooled to room temperature, filtered and the solids were washed with water (50 mL x 3), dried to give the title compound (8.30 g, 74.4% yield) as yellow solids. MS: m/z 188.0 [M+H+].
74.4%
With hydrazine hydrate; for 2h;Reflux; Inert atmosphere;
EXAMPLE 13-(2-Methoxyphenyl)-6-(4-methoxyphenyl)-[l,2,4]triazolo[4,3-a]pyridine a) 5-Bromo-2-hydrazinylpyridine. A mixture of <strong>[53939-30-3]5-bromo-2-chloropyridine</strong> (11.5 g, 60 mmol) and hydrazine hydrate (100 mL) was refluxed under Argon for 2 h. The mixture was cooled to room temperature, filtered and the solids were washed with water (50 mL x 3), dried to give the title compound (8.30 g, 74.4% yield) as yellow solids. MS: m/z 188.0 [M+H+].
44%
With hydrazine hydrate; In ethanol; at 90℃; for 46h;
9.3 ml (9.5 g, 190.2 mmol) hydrazine hydrate are added to a solution of 1.8 g (9.5 mmol) <strong>[53939-30-3]5-bromo-2-chloropyridine</strong> in 25 ml ethanol at RT, while stirring, and the mixture is then stirred at 90 C. for 46 h. After concentration of the reaction mixture in vacuo, the residue is stirred in water and the solid is filtered off, washed with water and diethyl ether and dried in vacuo.Yield: 0.8 g (44% of th.)LC-MS (Method 8): Rt=0.50 min; MS (ESIpos): m/z=188 [M+H]+;1H-NMR (400 MHz, DMSO-d6): delta=8.02 (d, 1H), 7.66 (s, 1H), 7.58 (dd, 1H), 6.69 (d, 1H), 4.16 (s, 2H).
EXAMPLE 2 N-(2,5-difluorobenzyl)-3-[4-(4-methylpiperazin-l-yl)phenyl][l ,2,4]triazolo[4,3-a]pyridin amine5 -Bromo-2-hydrazinylpyridine (2-2) Hydrazine (1,633 mL, 52.0 mmol) was mixed with a stirred, room temperature of 5-bromo-2- chloropyridine (2000 mg, 10.39 mmol) in dioxane (13 mL). The reaction mixture was stirred for 110 C for overnight. The reaction mixture was quenched with aqueous sodium hydrogen carbonate (saturated, 50 mL). The reaction mixture was extracted with EtOAc (3 x 30mL). The combined organic fractions were washed with brine (saturated, 40 mL), dried and filtered. The solvent was evaporated under reduced pressure to provide the title compound; MS (ES) m/z M calc'd; 188, found: 188.
Example 52(a) 2-Ben?ylsulfanyl-5-bromo-pyridine; Potassium fert-butoxide (2.79 g, 24.84 mmol) was dissolved in DMF (10 mL) and benizylmercaptane (2.57 g, 20.70 mmol) was added dropwise at 0 C. The mixture was stirred at room temperature for 15 min and then cooled to 0 C. 5-Bromo-2-chloro-pyridine (3.98 g, 20.70 mmol) dissolved in DMF ( 4 mL) was added dropwise at 0 0C and the mixture was heated at 80 0C for 1.5 hours. The mixture was poured into water (100 mL) and extracted with ether (3 x 100 mL). The combined organic phases were washed with brine (100 mL), water (100 mL) and dried (Na2SO4). Concentration afforded the title compound (5.52 g, 95%). MS (ESI) m/z 281 (M + 1).
1-(6-chloro-3-pyridinyl)-4-ethylpiperazine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
269 mg (60%)
With sodium t-butanolate; In ethyl acetate; toluene;
REFERENCE EXAMPLE 85 1-(6-Chloro-3-pyridinyl)-4-ethylpiperazine A mixture of 5-bromo-2-chloropyridine (384 mg, 2.0 mmol), 1-ethylpiperazine (228 mg, 2.0 mmol), sodium tert-butoxide (576 mg, 6 mrnmol), tris(dibenzylideneacetone) dipalladium(0) (18.3 mg, 0.02 mmol), and 2-dicyclohexylphosphino-2'-(N,N-dimethylamino) biphenyl (23.6 mg, 0.06 mmol) in 10 mL of toluene was heated at reflux for 1 hour and concentrated. The residue was purified by flash column chromatography, eluding with 5% methanol in ethyl acetate to provide 269 mg (60%) of 1-(6-chloro-3-pyridinyl)-4-ethylpiperazine as a brown semi-solid: MS 225.9 (M+H) +.
With sodium t-butanolate;tris-(dibenzylideneacetone)dipalladium(0); 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In toluene; at 100℃; for 5h;
As reported in Ji, J.; Li, T.;Bunnelle, W. H., Org. Lett. 2003, 5, (24), 4611-4614, f-butyl 1-piperazinecarboxylate (11.18 g, 60 mmol), sodium t-butoxide (8.64 g, 90 mmol), Pd2(dba)3 (1.10 g, 1.20 mmol), and XantPhos (2.08 g, 3.6 mmol) were added to a solution of <strong>[53939-30-3]5-bromo-2-chloropyridine</strong> (11.54 g, 60 mmol) in toluene (300 mL). The mixture was evacuated and purged with argon (3 cycles), then heated at 100 0C for 5 h. The reaction mixture was then cooled to room temperature, diluted with ethyl acetate (1200 mL) and washed with water (300 mL). The organic solution was concentrated under pressure, and the residue was purified by flash chromatography on silica gel eluting with 17% ethyl acetate in hexane to give compound 5 as a light yellow solid (14.56 g, 82%). 1H NMR (400 MHz, CDCl3) delta 8.02 (IH, s), 7.19 - 7.18 (2H, m), 3.59 (4H, dd, J = 12 Hz, J = 4 Hz), 3.14 (4H, dd, J = 12 Hz, J = 4 Hz), 1.49 (9H, s) ppm; LCMS-ESI (POS), M/Z, M+l: Found 298.1, Calculated 298.1.
72%
With sodium t-butanolate;tris-(dibenzylideneacetone)dipalladium(0); 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In toluene; at 100℃;Inert atmosphere;
tert-Butyl 4-(6-chloropyridin-3-yl)piperazine-l-carboxylate (67) A 250 mL single- necked round bottom flask was charged with <strong>[53939-30-3]5-bromo-2-chloropyridine</strong> (11.4 g, 59.2 mmol), /ert-butyl 1-piperazinecarboxylate (11.0 g, 59.2 mmol), tris(dibenzylideneacetone)dipalladium (o) (0.542 g, 0.592 mmol), 9,9-dimethyl-4,5- bis(diphenylphosphino)xanthene (1.03 g, 1.78 mmol), and sodium /-butoxide (8.54 g, 88.9 mmol). The flask was subjected to 3 cycles of evacuation and back-filling with N2 before toluene (100 mL) was introduced under N2. The resulting mixture was stirred at 100 0C overnight. After cooling, the product was purified by combi-flash column chromatography (EtOAc/Hexanes) to give /ert-butyl 4-(6-chloropyridin-3-yl)piperazine- 1-carboxylate (66) (12.7 g, 72.0% yield) as an off-white solid. 1H NMR (500 MHz, DMSO-d6) delta ppm 8.08 (1 H, d, J=3.2 Hz), 7.43 (1 H, dd, J=8.8, 3.2 Hz), 7.31 (1 H, d, J=8.8 Hz), 3.42 - 3.49 (4 H, m), 3.14 - 3.21 (4 H, m), 1.42 (9 H, s). LCMS-ESI (POS), M/Z, M+l: Found 298.1
53%
With sodium t-butanolate;tris-(dibenzylideneacetone)dipalladium(0); 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In toluene; at 20℃; for 4h;Heating / reflux;
Intermediate 18; 4-(6-Chloropyridin-3-yl)pipcrazinc-l-carboxylic acid tert-butyl ester; A mixture of <strong>[53939-30-3]2-chloro-5-bromopyridine</strong> (1.Og, 5.2 mmol), 1-boc-piperazine (0.967g, 5.2 mmol), sodium tert-butoxide (0.749g, 7.8 mmol), 9,9-dimethyl-4,5- bis(diphenylphosphino)xanthene (0.179g, 0.31 mmol) in toluene (3OmL) was treated with Pd2(dba)3 (0.095g, 0.1 mmol) at rt. The mixture was refluxed for 4h. The reaction was cooled and filtered through celite. The organic layer was diluted with EtOAc (10OmL) then washed with saturated Na2CO3 solution, brine, dried (MgSO4) and the solvent removed in vacuo. The crude mixture was purified by flash chromatography with 20% EtOAc / Hexane as eluent to afford the title compound (0.82g, 53%): RT = 3.40 min; m/z (ES+) = 298.2 [M+ H]+
A suspension of <strong>[53939-30-3]5-bromo-2-chloropyridine</strong> al30 (0.75 g, 3.9 mmol, 1 eq), (5S)- 5-(piperidin-l-ylmethyl)pyrrolidin-2-one al5 (0.85 g, 4.67 mmol, 1.2 eq), cesium carbonate (1.78 g, 5.46 mmol, 1.4 eq), Xanphos (0.17 g, 0.29 mmol, 0.075 eq), and tris(dibenzylideneacetone) dipalladium (0) (89 mg, 0.097 mmol, 0.025 eq) in dioxane (25 ml) is stirred under an argon atmosphere in a sealed tube for 12 h at 100 C. The mixture is left to cool to room temperature and filtered through a pad of Celite. The solid is washed with ethyl acetate and the resulting soluble fractions are combined and concentrated to dryness. The residue is taken up in ethyl acetate and washed twice with a saturated aqueous solution of sodium hydrogenocarbonate. The organic phase is then <n="88"/>dried over magnesium sulfate and concentrated to afford 1.4 g of crude mixture. Purification by chromatography over silicagel (dichloromethane/rnethanol/ammonia gradient) affords 0.5 g of (5S)-l-(6-chloropyridin-3-yl)-5-(piperidin-l- ylmethyl)pyrrolidin-2-one al31. Yield: 44 %.LC-MS (MH+): 294/296.
To a a solution of <strong>[1018297-63-6][3-(4-fluoro-phenyl)-5-methyl-isoxazol-4-yl]-methanol</strong> (500 mg, 2.41 mmol) in THF (5 mL) at room temperature was added sodium hydride (55% dispersion in mineral oil, 137 mg, 3.1 mmol) and the reaction mixture stirred at room temperature for 1 h. Then a solution of 2-chloro-5-bromo-pyridine (484 mg, 2.41 mmol) in THF (5 mL) was added at room temperature and the reaction mixture was stirred at room temperature for 2 h. The reaction mixture was then diluted with methanol and water and the mixture was extracted with ethyl acetate. The combined organic layers were then washed with water and brine and then dried over sodium sulfate, filtered and evaporated. Purification by chromatography (SiO2, heptane:ethyl acetate=9:1 to 4:1) afforded the title compound (128 mg, 15%) which was obtained as a colourless oil. MS: m/e=363.1/365.1 [M+H]+.
With sodium t-butanolate;tris-(dibenzylideneacetone)dipalladium(0); 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In toluene; at 100℃; for 3h;
<strong>[53939-30-3]5-Bromo-2-chloropyridine</strong> (3.15 g, 16.4 mmol), compound 246 (4.00 g, 16.4 mmol), Pd2(dba)3 (0.749 g, 0.818 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethyl-9H-xanthene (0.947 g, 1.64 mmol) and sodium terf-butoxide (1.82 g, 19.0 mmol) were combined in a screw cap vial and solvated under argon atmosphere with degassed toluene (44 mL). The reaction was briefly sparged with argon, then sealed and stirred at 100 C. After 3 h, the reaction contents were poured into saturated sodium bicarbonate (100 mL) and extracted with 10% methanol in dichloromethane (3 x 200 mL). The combined organics were dried with sodium sulfate and concentrated in vacuo. Silica gel chromatography (gradient elution 0 to 100% ethyl acetate in hexanes switching to 3% methanol in DCM) afforded compound 247 (5.40 g, 92.7% yield). IH NMR (500 MHz, CDCl3) delta 0.08 (s, 6 H) 0.91 (s, 9 H) 2.60 (t, J= 5.87 Hz, 2 H) 2.70 (br. s., 4 H) 3.20 (d, J= 4.40 Hz, 4 H) 3.80 (t, J= 6.11 Hz, 2 H) 7.17 (d, J= 1.71 Hz, 2 H) 8.02 (s, 1 H) ppm.
3-Hydroxy quinuclidine (Aldrich, 3.2 g, 25 mmol) in DMF (anhydrous, 30 mL) was treated with NaH (Aldrich, 99%, 1.2 g, 50 mmol) at ambient temperature for 1 hour. The mixture was then treated with <strong>[53939-30-3]2-chloro-5-bromopyridine</strong> (7.1 g, 30 mmol) and stirred at 100 C. for 6 hours. The mixture reaction was treated with Na2CO3 (2M, 10 mL) at 10 C. and extracted with ethyl acetate (2×50 mL). The extracts were combined and concentrated under reduced pressure. The title compound was purified by chromatography (SiO2, CH2Cl2:MeOH:NH3.H2O, 90:10:2, Rf. 0.20) as oil (5.3 g, yield, 75%). 1H NMR (MeOH-d4, 300 MHz) delta 1.46-1.58 (m, 1H), 1.60-1.88 (m, 2H), 1.96-2.10 (m, 1H), 2.24-2.30 (m, 1H), 2.72-2.98 (m, 5H), 3.42-3.46 (m, 1H), 5.00-5.08 (m, 1H), 6.75 (d, J=8.8 Hz, 1H), 7.77 (dd, J=8.9, 2.4 Hz, 1H), 8.16 (d, J=2.7, 1H) ppm. MS (DCl/NH3) m/z 283 (M+H)+, 285 (M+H)+.
75%
Example 28A 3-[(5-phenoxypyridin-2-yl)oxy]quinuclidine 3-Hydroxy quinuclidine (Aldrich, 3.2 g, 25 mmol)) in DMF (anhydrous, 30 mL) was treated with NaH (Aldrich, 99%, 1.2 g, 50 mmol) at ambient temperature for 1 hour. 2-Chloro-5-bromopyridine (7.1 g, 30 mmol) was added and the mixture was stirred at 100 C. for 6 hours. The mixture was allowed to cool to room temperature, treated with Na2CO3 (2M, 10 mL) at 10 C., and extracted with ethyl acetate (2*50 mL). The extracts were combined and concentrated under reduced pressure. The title compound was purified by chromatography (SiO2, CH2Cl2:MeOH:NH3H2O, 90:10:2, Rf. 0.20) as oil (5.3 g, yield, 75%). 1H NMR (MeOH-d4, 300 MHz) delta 1.46-1.58 (m, 1H), 1.60-1.88 (m, 2H), 1.96-2.10 (m, 1H), 2.24-2.30 (m, 1H), 2.72-2.98 (m, 5H), 3.42-3.46 (m, 1H), 5.00-5.08 (m, 1H), 6.75 (d, J=8.8 Hz, 1H), 7.77 (dd, J=8.9, 2.4 Hz, 1H), 8.16 (d, J=2.7, 1H) ppm. MS (DCl/NH3) m/z 283 (M+H)+, 285 (M+H)+.
75%
Example 12A 3-[(5-bromopyridin-2-yl)oxy]quinuclidine 3-Hydroxy quinuclidine (Aldrich, 3.2 g, 25 mmol) in DMF (anhydrous, 30 mL) was treated with NaH (Aldrich, 99%, 1.2 g, 50 mmol) at ambient temperature for 1 hour. The mixture was then treated with <strong>[53939-30-3]2-chloro-5-bromopyridine</strong> (7.1 g, 30 mmol) and stirred at 100' C. for 6 hours. The mixture reaction was treated with Na2CO3 (2M, 10 mL) at 10' C. and extracted with ethyl acetate (2*50 mL). The extracts were combined and concentrated under reduced pressure. The title compound was purified by chromatography (SiO2, CH2Cl2:MeOH:NH3-H2O, 90:10:2, Rf. 0.20) as oil (5.3 g, yield, 75%). 1H NMR (MeOH-d4, 300 MHz) delta 1.46-1.58 (m, 1H), 1.60-1.88 (m, 2H), 1.96-2.10 (m, 1H), 2.24-2.30 (m, 1H), 2.72-2.98 (m, 5H), 3.42-3.46 (m, 1H), 5.00-5.08 (m, 1H), 6.75 (d, J=8.8 Hz, 1H), 7.77 (dd, J=8.9, 2.4 Hz, 1H), 8.16 (d, J=2.7, 1H) ppm. MS (DCl/NH3) m/z 283 (M+H)+, 285 (M+H)+.
(Step 4) 2-Benzylsulfanyl-5-bromo-pyridine (0332) (0333) 5-Bromo-2-chloro-pyridine (80.0 g, 645 mmol) was dissolved in tetrahydrofuran (600 ml), sodium hydride (60% wt in mineral oil, 45.0 g, 1.13 mol) was added thereto over 20 minutes, and the resulting mixture was stirred at room temperature for 30 minutes. Benzyl thiol (123 g, 640 mmol) was added to the reaction liquid, and the resulting mixture was stirred at room temperature for 3 hours. The reaction liquid was diluted with water, extracted with diethyl ether, the extracts were combined, and washed with a saturated aqueous solution of sodium hydrogen carbonate, and a saturated saline solution. The obtained residue was dried over magnesium sulfate, and the solvent was removed under reduced pressure to obtain the title compound (148 g, 82%).
80%
Phenylmethanethiol (80.0 g, 645 mmol) was dissolved in anhydrous tetrahydrofuran (600 ml), and 60% sodium hydride (45.0 g, 1.13 mol) was added thereto, followed by stirring at room temperature for 30 minutes. To this reaction solution, <strong>[53939-30-3]5-bromo-2-chloropyridine</strong> (123 g, 640 mmol) was added, followed by stirring at room temperature for 3 hours. The reaction solution was diluted with water, followed by extraction with diethyl ether. The extraction liquids were combined, washed with a saturated aqueous sodium hydrogen carbonate solution and saturated aqueous sodium chloride, and dried over anhydrous sodium sulfate. Then, the solvent was removed. A compound (250 g, 0.90 mol) obtained by repeating the-above described process was suspended in a mixture solvent of acetic acid (2250 ml) and water (750 ml), and N-chlorosuccinimide (340 g, 2.60 mol) was added thereto, followed by stirring at room temperature for 2 hours. The reaction solution was diluted with water, followed by extraction with methylene chloride. The extraction liquids were combined, washed with a saturated aqueous sodium hydrogen carbonate solution and water, and dried over anhydrous sodium sulfate. Then, the solvent was removed. The obtained residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=30:1). The obtained compound (47.0 g, 185 mmol) and methyl 4-amino-2,6-difluorobenzoate (26.0 g, 139 mmol) were suspended in methylene chloride (1000 ml), and pyridine (30 ml) was added thereto, followed by stirring at room temperature for 12 hours. The reaction solution was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=4:1) to obtain the title compound (50 g, 15% over three steps).
69%
Step A Preparation of mt 2-1 Potassium tert-butoxide (2.8 g, 24.84 mmol) was dissolved in DMF (10 mL) and benzylthiol (2.6 g, 20.70 mmol) was added dropwise at 0C. The mixture was allowed to stir at room temperature for 15 minutes and then cooled to 0C, a solution of <strong>[53939-30-3]5-bromo-2-chloropyridine</strong>(4.0 g, 20.70 mmol) in DMF (4 mL) was added dropwise at 0C and the mixture was heated at80C for 1.5 hours. The mixture was poured into water (100 mL) and extracted with ethyl estate(3 x 100 mL). The combined organic phases were washed with brine (100 mL), water (100 mL)and dried (Na2504). Concentrated in vacuo to provide the residue, which was purified withcolumn chromatography (petroleum ether : EtOAc = 10:1) to provide mt 2-1 (4.0 g, 69%). MS(ES): m/z (M+H) 280.
69%
Potassium tert-butoxide (2.8 g, 24.84 mmol) was dissolved in DMF (10 mL) andbenzylthiol (2.6 g, 20.70 mmol) was added dropwise at 0C. The mixture was allowed to stir atroom temperature for 15 minutes and then cooled to 0C, a solution of <strong>[53939-30-3]5-bromo-2-chloropyridine</strong>15 (4.0 g, 20.70 mmol) in DMF (4 mL) was added dropwise at 0C and the mixture was heated at80C for 1.5 hours. The mixture was poured into water (100 mL) and extracted with ethyl estate(3 x 100 mL). The combined organic phases were washed with brine (100 mL), water (100 mL)and dried (Na2S04). Concentrated in vacuo to provide the residue, which was purified withcolumn chromatography (petroleum ether: EtOAc = 10:1) to provide Int 2-1 (4.0 g, 69%). MS20 (ESI): mlz (M+Ht 280.
69%
Step A Preparation of mt 2-1 10262] Potassium tert-butoxide (2.8 g, 24.84 mmol) was dissolved in DMF (10 mE) and benzylthiol (2.6 g, 20.70 mmol) was added dropwise at 00 C. The mixture was allowed to stir at room temperature for 15 minutes and then cooled to 00 C., a solution of <strong>[53939-30-3]5-bromo-2-chloropyridine</strong> (4.0 g, 20.70 mmol) in DMF (4 mE) was added dropwise at 00 C. and the mixture was heated at 80 C. for 1.5 hours. The mixture was poured into water (100 mE) and extracted with ethyl estate (3x 100 mE). The combined organic phases were washed with brine (100 mE), water (100 mE) and dried (Na2SO4). Concentrated in vacuo to provide the residue, which was purified with column chromatography (petroleum ether:EtOAc10:1) to provide mt 2-1 (4.0 g, 69%). MS (ESI): mlz (M+H) 280.
69%
Potassium tert-butoxide (2.8 g, 24.84 mmol) was dissolved in DMF (10 mL) and benzylthiol (2.6 g, 20.70 mmol) was added dropwise at 0 C. The mixture was allowed to stir at room temperature for 15 minutes and then cooled to 0 C., a solution of <strong>[53939-30-3]5-bromo-2-chloropyridine</strong> (4.0 g, 20.70 mmol) in DMF (4 mL) was added dropwise at 0 C. and the mixture was heated at 80 C. for 1.5 hours. The mixture was poured into water (100 mL) and extracted with ethyl estate (3×100 mL). The combined organic phases were washed with brine (100 mL), water (100 mL) and dried (Na2SO4). Concentrated in vacuo to provide the residue, which was purified with column chromatography (petroleum ether:EtOAc=10:1) to provide Int 2-1 (4.0 g, 69%). MS (ESI): m/z (M+H)+ 280.
A solution of phenylmethanethiol (1 ml, 8 mmol) in N,N-dimethylformamide (15 ml) under an atmosphere of argon was treated with sodium hydride (352 mg, 8.8 mmol, 60% dispersion in oil). After stirring at room temperature for 15 minutes a solution of <strong>[53939-30-3]5-bromo-2-chloropyridine</strong> (1.84 g, 9.6 mmol) in N,N-dimethylformamide (5 ml) was added. After 2 hours, water and ethyl acetate were added. The organic layer was separated and washed with water, brine and dried over anhydrous magnesium sulfate and concentrated in vacua. The residue was then purified by chromatography on silica gel eluting with 5% ethyl acetate in pentane to give the title compound. MS (ES+) 280/282 [M+H]+.
Step 1 - 2-Benzylsulfanyl-5-bromo pyridine (0436) [00297] To a solution of sodium tert-butoxide (4.99 g, 51.9 mmol) in anhydrous N,N- dimethylformamide (100 mL) was added phenylmethanethiol (6.45 g, 51.9 mmol) dropwise at 0 C. The mixture was stirred at 30 C for 30 min and then cooled to 0 C again. To the cooled mixture was added <strong>[53939-30-3]5-bromo-2-chloro-pyridine</strong> (10.0 g, 51.9 mmol) dissolved in anhydrous N,N- dimethylformamide (150 mL) dropwise, while the temperature was kept below 5 C. Afterwards, the mixture was heated to 80 C and stirred at for 1.5 hrs. On completion, the reaction mixture was concentrated in vacuo to remove most of the solvent. The resulting mixture was poured into water (250 mL) and extracted with ethyl acetate (3 x 150 mL). The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, concentrated in vacuo, and the residue was purified by column chromatography (petroleum ether:ethyl acetate = 40:1) to give the title compound. 1H NMR (400MHz, DMSO-d6) delta = 8.58 (d, J = 2.1 Hz, 1H), 7.83 (dd, J = 2.4, 8.5 Hz, 1H), 7.40 (d, J = 7.3 Hz, 2H), 7.33 - 7.27 (m, 3H), 7.26 - 7.20 (m, 1H), 4.41 (s, 2H).
With potassium carbonate;tetrakis(triphenylphosphine) palladium(0); In ethanol; water; toluene; at 80℃; for 4h;Inert atmosphere;
2-Chloro-5-(3-isopropyl-phenyl)-pyridine; To a stirred solution of <strong>[53939-30-3]5-bromo-2-chloropyridine</strong> (1.27 g, 6.63 mmol) in toluene (30 mL) was added an ethanolic solution (10 mL) of 3-isopropyl-phenylboronic acid (1.8 g, 11.28 mmol) followed by water (10 mL) and potassium carbonate (2.76 g, 20.0 mmol). The resulting mixture was degassed for 15 min (by purging with argon). At this time, Pd(PPh3)4 (0.613 g, 0.53 mmol) was added under argon and the reaction mixture was heated at 80 C. for 4 h. The reaction mixture was then cooled to room temperature and extracted with ethyl acetate (3×10 mL). The combined organic layers were washed with water (2×10 mL), dried over Na2SO4 and concentrated in vacuo to obtain the crude product, which was purified over silica gel (Biotage column chromatography, 2% ethyl acetate in hexane) to afford 0.900 g (59%) of 2-chloro-5-(3-isopropyl-phenyl)-pyridine.
With potassium carbonate; In N,N-dimethyl-formamide; at 120℃;
Into a 1-L round-bottom flask, was placed a solution of 5- bromo-2-chloropyridine (50 g, 259.82 mmol, 1.00 equiv) inN,N-dimethylformamide (300 mL), morpholine (91 g, 1.04 mol, 4.00 equiv), potassium carbonate (108 g, 781.42 mmol, 3.00 equiv). The resulting solution was stirred overnight at 120 C. The resulting solution was extracted with 5x150 mL of ethyl acetate and the organic layers were combined. The resulting mixture was washed with 3x100 mL of brine. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The resulting mixture was washed with PE:EA=1 :5. This resulted in 80 g (63%) of 4-(5-bromopyridin-2-yl)morpholine as a white solid. MS (ES, m/z): 243 (M+H); ?HNMR (CDC13, 300 MHz) : 8.22 (s, 1 H), 7.57 (d, J4.5Hz, 1 H), 6.54 (d, J2.4Hz, 1 H), 3.82 (t, J5.1 Hz, 4 H), 3.48 (t, J5.1Hz, 4 H).
63%
With potassium carbonate; In N,N-dimethyl-formamide; at 120℃;
Into a 1-L round-bottom flask, was placed a solution of 5- bromo-2-chloropyridine (50 g, 259.82 mmol, 1.00 equiv) in N,N-dimethylformamide (300 mL), morpholine (91 g, 1.04 mol, 4.00 equiv), potassium carbonate (108 g, 781.42 mmol, 3.00 equiv). The resulting solution was stirred overnight at 120oC. The resulting solution was extracted with 5x150 mL of ethyl acetate and the organic layers combined. The resulting mixture was washed with 3x100 mL of brine. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The resulting mixture was washed with PE:EA=1:5. This resulted in 80 g (63%) of 4-(5-bromopyridin-2-yl)morpholine as a white solid. MS (ES, m/z): 243 (M+H); 1H NMR (CDCl3, 300 MHz) delta: 8.22 (s, 1 H), 7.57 (d, J=4.5Hz, 1 H), 6.54 (d, J=2.4Hz, 1 H), 3.82 (t, J=5.1 Hz, 4 H), 3.48 (t, J=5.1Hz, 4 H).
63%
With potassium carbonate; In N,N-dimethyl-formamide; at 120℃;
Into a 1-L round-bottom flask, was placed a solution of 5- bromo-2-chloropyridine (50 g, 259.82 mmol, 1.00 equiv) in N,N-dimethylformamide (300 mL), morpholine (91 g, 1.04 mol, 4.00 equiv), potassium carbonate (108 g, 781.42 mmol, 3.00 equiv). The resulting solution was stirred overnight at 120 oC. The resulting solution was extracted with 5x150 mL of ethyl acetate and the organic layers were combined. The resulting mixture was washed with 3x100 mL of brine. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The resulting mixture was washed with PE:EA=1:5. This resulted in 80 g (63%) of 4-(5-bromopyridin-2-yl)morpholine as a white solid. MS (ES, m/z): 243 (M+H); 1H NMR (CDCl3, 300 MHz) delta: 8.22 (s, 1 H), 7.57 (d, J=4.5Hz, 1 H), 6.54 (d, J=2.4Hz, 1 H), 3.82 (t, J=5.1 Hz, 4 H), 3.48 (t, J=5.1Hz, 4 H).
<strong>[53939-30-3]2-chloro-5-bromopyridine</strong> (4.0 mmol) was added to CHC13 (40 mL), stirred under nitrogen, and BPO (0.08 mmol) and NBS (4.4 mmol) were added to the mixture. The reaction was heated to reflux for 5 h and cooled.The solvent was distilled off under reduced pressure to give a crude product.A solution of morpholine (0.50 mol) in ethanol was added to the crude product of the previous step under nitrogen and stirred at room temperature overnight.The solvent was removed under reduced pressure.The crude product was purified by column chromatography to give 4-(4-bromo-2-fluorophenyl)morpholine.
General procedure: 60% NaH in oil (1.5:1, Sodium hydride:Mineral Oil, 5.20 g) was added in two portions to isopropyl alcohol (150 mL) at room temperature under N2. The mixture was stirred at 60 C. for 30 min. <strong>[53939-30-3]5-bromo-2-chloropyridine</strong> (10.00 g, 51.96 mmol) was added in two portions and the mixture was stirred at reflux 4 h and then at 80 C. overnight. The solution was concentrated in vacuo. Water (50 mL) and EtOAc (50 mL) was added and the layers were separated. The aqueous layer was extracted with EtOAc (50 mL). The combined organic layers were washed with brine, dried over MgSO4, filtered and the solvent was removed in vacuo. The crude product was subjected to flash chromatography (silica, 0-50% EtOAc in heptanes) to give the title compound as a clear oil (8.74 g, 78%). 1H NMR (600 MHz, DMSO) delta 8.17 (s, 1H), 7.61 (dd, 1H), 6.59 (d, 1H), 5.23 (m, 1H), 1.33 (s, 6H).
2-Trifluoromethoxyaniline (0.8Og, 5.0mmol) and sodium hydride (60% dispersion in mineral oil, 1.7eq) were stirred in dry DMF at room temperature for 2 hours, and 5-bromo- 2-chloropyridine (1.0Og, 5.0mmol) was added and the mixture stirred at room temperature overnight. Iced water was added slowly to the mixture, and the mixture was extracted with DCM (3x). The DCM was washed with 2M HCl solution (2x), dried (MgSO4), and concentrated. The residue was purified by column chromatography eluting using a gradient (EtOAc/hexanes 1 :9 v/v).
The same operation as example 1 was carried out except chlorobenzene (5.6g, 50.0mmol) was used instead of bromobenzene, to obtain 6-chloro-3-phenylpyridine as 40% of yield.
In a 300mL inner volume flask replaced by nitrogen, 30. 3g of tetrahydrofuran solution containing 19.5% by weight of isopropylmagnesium chloride (57.5mmol as isopropylmagnesium chloride) as a magnesiation reagent was charged, and cooled at 10C, and then 20g of tetrahydrofuran solution containing <strong>[53939-30-3]5-bromo-2-chloropyridine</strong> (9.6g, 50.0mmol) as a 2,5-dihalogenopyridine derivative (I), was added dropwise in the range of 10 to 20C for 1.0 hour. After adding dropwise, the reaction mixture was stirred in the range of 10 to 20C for 1.5 hours, and then added dropwise to the solution of tetrahydrofuran (20g) containing bromobenzene(7.9g, 50.0 mmol) as a halogenoaryl derivative (II), and [1,1'-bis-(diphenylphosphino)ferrocene]dichloropalladium(II)(0.20g, 0.25mmol)) as a palladium compound in the range of 10 to 20C for 2.0 hours. After adding dropwise, the reaction mixture was stirred in the range of 10 to 20C for 4.0 hours, and then saturated aqueous solution of ammonium chloride (50g) was added. Toluene (50g) was added to the reaction mixture, and after stirring for 1.0 hour, the reaction mixture was left to stand to separate the organic layer. After washing the organic layer with saturated sodium chloride solution (10g), it was condensed under reduced pressure to obtain crude 6-chloro-3-phenylpyridine (6.5g, purity: 82%, yield: 60%).
A dry solution of 4-hydroxypiperidine- 1-carboxylic acid isopropyl ester (Preparation 2, 1Og, 53mmol) in DMF, under argon, was cooled to 00C. Sodium hydride (60% in mineral oil, 2.54g, 64mmol) was added in one portion. The reaction was allowed to reach r.t. before stirring for a further 45 min. 5-Bromo-2-chloropyridine (12.32g, 64mmol) was added and the reaction was heated to 600C for 4Oh. The reaction mixture was allowed to cool to r.t. then EtOAc was added. The organic solution was washed with brine, dried (MgSO4) and solvent was removed in vacuo. The crude material was triturated from o-hexane (2 x 6mL) then diethyl ether to afford the title compound: RT = 3.98 min; mlz (ES+) = 343.0, 345.0 [M + H]+.
2-Methoxy-ethanol (3.08 ml, 39 mmol) was added dropwise to a stirred suspension of a 60%) dispersion of sodium hydride in mineral oils (1.46 g, 36.4 mmol) in DMSO (50 ml). The mixture was stirred at RT for 30 min. and then <strong>[53939-30-3]5-bromo-2-chloro-pyridine</strong> (5 g, 26 mmol) was added. The mixture was stirred at 60 C for 1 h. and then diluted with heptane and washed with water. The organic layer was separated, dried (Na2S04), filtered and the solvents evaporated in vacuo. The crude product was purified by flash column chromatography (silica; DCM in heptane 30/70 to 70/30). The desired fractions were collected and evaporated in vacuo to yield intermediate 48 (4.55 g, 75 %) as a colourless oil.
75%
Example A48 5-Bromo-2-(2-methoxy-ethoxy)-pyridine 2-Methoxy-ethanol (3.08 ml, 39 mmol) was added dropwise to a stirred suspension of a 60% dispersion of sodium hydride in mineral oils (1.46 g, 36.4 mmol) in DMSO (50 ml). The mixture was stirred at RT for 30 min. and then <strong>[53939-30-3]5-bromo-2-chloro-pyridine</strong> (5 g, 26 mmol) was added. The mixture was stirred at 60 C. for 1 h. and then diluted with heptane and washed with water. The organic layer was separated, dried (Na2SO4), filtered and the solvents evaporated in vacuo. The crude product was purified by flash column chromatography (silica; DCM in heptane 30/70 to 70/30). The desired fractions were collected and evaporated in vacuo to yield intermediate 48 (4.55 g, 75%) as a colourless oil.
73%
With potassium tert-butylate; In 1,4-dioxane;Inert atmosphere; Reflux;
2-Methoxyethanol (5.12 mL, 65.0 mmol) was dissolved in 1,4-dioxane (125 mL). Potassium tert-butoxide (7.00 g, 62.4 mmol) was added under N2. The mixture was stirred for 10 minutes. <strong>[53939-30-3]5-Bromo-2-chloropyridine</strong> (10.0 g, 52.0 mmol) was added and the resulting mixture was refluxed for 2 hours. The mixture was poured into brine and extracted with EtOAc. The organic layer was washed with brine, dried over MgSO4 and evaporated to dryness. Purification by flash chromatography (silica, heptanes/EtOAc 4:1) gave the title compound as a colorless oil (8.74 g, 73%) sufficiently pure for the next step.
43.3%
With sodium hydride; In dimethyl sulfoxide; at 20 - 60℃; for 1.5h;Inert atmosphere;
n a three-necked flask, 0.15 g (3.75 mmol)NaH was dissolved in 10 mLIn the refined DMS0,Under the protection of nitrogen, ethylene glycol monomethyl ether 0.3 mL (3.8 mmol)After stirring at room temperature for 30 min,5-bromo-2-0.5 g (2.6 mmol) of chlorambidine,60 C reaction lh,The reaction was terminated with dichloromethane and water,Drying the organic layer,Concentrated after the crude product,Crude silica gel column(Eluent: ethyl acetate / petroleum ether = 1: 1, V: V) to give 0.5 g of white oil as an intermediate 43.3%
A mixture of NaH 55% (133 mg, 3 06 mmol) in DME (3 ml) was cooled to 0 C, then 2- methoxyethanol (Aldrich, Buchs, Switzerland, 0 362 ml, 4.58 mmol) was added. The solution was stirred at rt for 15 mm After that 5-bromo-2-chtoropyridine (Aldnch, Buchs, Switzerland, 294 mg, 1.528 mmol) was added and the RM was heated by microwaves at 150 C for 10 mm Then the RM was quenched with saturated aqueous NaHCOj (50 ml) and extracted with EtOAc (2x) The combined organic layers were washed with brine (2x), dned over Na2SO4, filtered and evaporated. The residue was absorbed on silica gel and purified by MPLC (hexane/EtOAc 0 to 30%). The fractions containing product were evaporated together to give the title compound as a colorless oil (LC-MS tR 1 20 mm (Method B); M+H = 232, 234 (Br- pattern) MS-ES. 1H-NMR (d6-DMSO, 400 MHz) 8.28.8 21 (m, 1H), 7 91-7 84 (m, 1H), 6 86- 6 79 (m, 1H), 4 31 (t, 2H), 3.62 (t, 2H) 3 26 (s, 3H)).
<strong>[53939-30-3]5-Bromo-2-chloropyridine</strong> (T-9) (15.0 g) and diethyl ether (450 ml) were put in a reaction vessel and cooled to -50 C under an atmosphere of nitrogen. n-Butyllithium (1.57 M in n-hexane; 54.6 ml) was added dropwise in the temperature range of -50 C to -45 C, and the stirring was continued for another 90 minutes. After the reaction vessel had been cooled to -70 C, formylpiperidine (9.70 g) was added dropwise in the temperature range of -70 C to -65 C, and the stirring was continued for another 60 minutes while the mixture was allowed to return to room temperature. The resulting reaction mixture was poured into ice-water (500 ml) and mixed with it. Diethyl ether (200 ml) was added to the solution to separate organic and aqueous phases, and extraction was carried out. The combined organic phase was washed with water and dried over anhydrous magnesium sulfate. The resulting solution was concentrated under reduced pressure and the residue was purified with a fractional operation by means of column chromatography (silica gel; toluene). The product was further purified by recrystallization from heptane. The solvent was distilled off and the product was dried, giving 2-chloro-5-formylpyridine (T-10) (7.01 g). The yield based on the compound (T-9) was 68%.
85 ml of 15% BuLi in n-hexane are added to a solution of pyridine (1) (25.0 g; 120 mmol) in 300 ml of diethyl ether under nitrogen at -70 C.After 90 minutes, 13.7 ml (120 mmol) of the formylpiperidine (2) solution at the same temperature is added to the batch. After an additional hour, the batch is warmed to -10 [deg.] C, water is added and the mixture is diluted with MTB ether.The organic phase is dried over sodium sulfate and evaporated. The residue obtained is passed through silica gel (MTB ether / n-heptane 1: 1). The product is then crystallized with n-heptane at -20 deg C.
With copper(l) iodide; potassium carbonate; N,N`-dimethylethylenediamine; In acetonitrile; at 70℃; for 8h;Inert atmosphere;
General procedure: Inside a N2 filled glovebox, benzenesulfonamide (250 mg, 1.590 mmol) and copper(I) iodide (15.14 mg, 0.080 mmol), 4-toluene bromide (326mg, 1.91 mmol), potassium carbonate (550 mg, 3.98 mmol), Acetonitrile (4 mL), and N1,N2dimethylethane-1,2-diamine (70.1 mg, 0.795 mmol) was charged into a vial. The vial was then heated to 70 oC for 8hr, LC indicated >97% conversion of benzenesulfonamide. The reaction mixture was then cooled to room temperature. 2N HCl (4mL) was added slowly, followed by EtOAc extraction (5mL x 3). The organic layers were combined, concentrated, and flash chromatographed (SiO2, 20:1--> 3:1 Heptane:EtOAc) to give N(p-tolyl) benzene sulfonamide as white solids (380 mg, 97%).
4-(5-bromopyridin-2-yloxy)piperidine-1-carboxylic acid tert-butyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
89%
j00390j To a solution of 4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (5.75 g, 28.6 mmol) in DMF (50 mL) was sodium hydride, 60% disp. in mineral oil (1.35 g, 33.8mmol) in portion. After stirred for 10 mm, to the reaction was added <strong>[53939-30-3]5-bromo-2-chloro-pyridine</strong> (5.00 g, 26.0 mmol) followed by K2C03 (3.59 g, 26.0 mmol). The reaction was heated at 105 C for 16 h and cooled to room temp. It was carefully quenched with H20 (100 mL), extracted with EtOAc (3 x 300 mL). The combined organic layers were washed with H20, brine, dried(Na2504) and concentrated. The residue was chromatography on silica gel (0-20% EtOAc/Hexanes) to give a white solid 8.30 g (89%).
With potassium phosphate;copper(l) iodide; N,N-dimethylethylenediamine; In 1,4-dioxane; for 15h;Reflux;
Intermediate 51N-(5-Bromopyridin-2-yl)-<strong>[18063-03-1]2,6-difluorobenzamide</strong>To a mixture of 2-chloro-5-bromopyridine (370 mg, 1.9 mmol, 1.2 eq) and 2,6- difluorobenzamide (250 mg, 1.5 mmol, 1.0 eq) in dioxane (10 mL), copper iodide (151 mg, 0.75 mmol, 0.5 eq), potassium phosphate (670 mg, 3.15 mmol, 2.1 eq) and N,N- dimethylethylene diamine (0.1 mL, 1.05 mmol, 0.7 eq) were added sequentially. The resulting mixture was stirred at reflux for 15 h. The reaction was cooled to room temperature, filtered to remove the solid components and the filtrate was concentrated under vacuum. The residue was dissolved in ethyl acetate (50 mL), washed with water (20 mL), brine (20 mL), dried ( a2S04) and filtered. The filtrate was concentrated under vacuum and the crude product was purified by flash column chromatography (silica gel, ethyl acetate and hexane) to afford 300 mg of the solid product as a white solid. 1HNMR (400 MHz, DMSO-<¾ delta 1 1.22 (s, 1H, D20 exchangeable), 8.70 (d, J = 2.5 Hz, 1H), 8.18 (dd, J = 8.0, 2.5 Hz, 1H), 7.67-7.59 (m, 1H), 7.55 (d, J = 8.0 Hz, 1H), 7.29 (t, J= 8.0 Hz, 2H); ESI-MS (m/z) 313, 315 [(MH)+ Br79' 81].
With potassium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; water; at 100℃; for 20h;Inert atmosphere;
a) 2-Chloro-5-(4-methoxyphenyl)pyridine. A flask was charged with 4- methoxyphenylboronic acid (1.0 g, 6.8 mmol), <strong>[53939-30-3]5-bromo-2-chloropyridine</strong> (1.0 g, 5.2 mmol), Pd(PPh3)4 (50 mg, 0.043 mmol), potassium carbonate (1.08 g, 7.8 mmol), 1,4-dioxane (40 mL) and water (4 mL). The mixture was stirred at 100C under Argon for 20 h, and evaporated to afford a crude product. The crude product was purified by chromatography on silica gel(petroleum ether: ethyl acetate = 40: 1) to give the title compound (1.0 g, 88% yield) as white solids. MS: m/z 220.0 [M+H+].
88%
With potassium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; water; at 100℃; for 20h;Inert atmosphere;
EXAMPLE 573-(4-Chloro-2-methoxyphenyl)-6-(4-methoxyphenyl)-[l,2,4]triazolo[4,3-a]pyridine a) 2-Chloro-5-(4-methoxyphenyl)pyridine. A flask was charged with 4- methoxyphenylboronic acid (1.0 g, 6.8 mmol), <strong>[53939-30-3]5-bromo-2-chloropyridine</strong> (1.0 g, 5.2 mmol), Pd(PPh3)4 (50 mg, 0.043 mmol), potassium carbonate (1.08 g, 7.8 mmol), 1,4-dioxane (40 mL) and water (4 mL). The mixture was stirred at 100C under Argon for 20 h, and evaporated to afford a crude product. The crude product was purified by chromatography on silica gel(petroleum ether: ethyl acetate = 40: 1) to give the title compound (1.0 g, 88% yield) as white solids. MS: m/z 220.0 [M+H+].
With potassium tert-butylate; In tetrahydrofuran; at 120℃; for 0.5h;Microwave irradiation; Autoclave;
General procedure: Potassium tert-butoxide (1.85 g, 16.5 mmol) was added to a mixture of <strong>[53939-30-3]5-bromo-2-chloropyridine</strong> (2.89 g, 15.0 mmol) and 1-propanol (1.230 mL, 16.5 mmol) in THF (15 mL). The reaction mixture was heated at 120 C. for 30 minutes in a microwave reactor. The mixture was poured into a mixture of water (50 mL) and EtOAc (100 mL). The organic layer was washed with brine, dried over MgSO4 and evaporated to dryness. Flash chromatography (silica, 0-20% EtOAc in heptanes) gave the title compound as a yellow oil (3.13 g, 97%) sufficiently pure for the next step.
1.5 g
With potassium tert-butylate; In tetrahydrofuran; at 120℃;
To a solution of <strong>[53939-30-3]5-bromo-2-chloropyridine</strong> (3.0 g, i5.59 mmol) in THF (iO mL) was added N-propyl alcohol (i.2 mL, i6.0 mmol), potassium tert-butoxide (i.90 g, i6.96 mmol). Thereaction mixture was heated at i20C for 5-6 h. The reaction mixture was quenched in water, extracted with ethyl acetate. The organic layers were dried over Na2504 and concentrated to afford i.5 g of title compound. ?H NMR (300 MHz, DMSO-d6): 8.26 (s, 1H), 7.89-7.85 (dd, J= 3.0 Hz, iH), 6.82-6.79 (d, J= 8.7 Hz, iH), 4.i9-4.i4 (t, J= 6.6 Hz, 2H), i.73-i.66 (dq J=7.2 Hz, 2H), 0.94-0.9i (t, J = 7.2 Hz, 3H); MS [M+Hj: 2i6.
A round bottomed flask was charged with 5-bromo-2-chloropyridine (5.30 g, 27.6 mmol) in THF under N2 and cooled at 0 C. A solution of 1 M iso-propylmagnesiumchloride-lithium chloride complex in THF (40 mL) was added drop wise over 15 min. After 70 min N-methoxy-N-methylacetamide (4.1 mL, 38 mmol) was added drop wise. After stirring for 5 min at 0 C. the cooling bath was removed. The mixture was left stirring overnight and was then quenched by the addition of 100 mL saturated aqueous NH4Cl solution. The mixture was extracted with 3×100 mL EtOAc. The combined organic layers were washed with water followed by brine and dried over MgSO4. Evaporation of the volatiles at 80 C., 10 mbar for 1 h gave the title compound (3.596 g, 84) sufficiently pure for the next step.
With potassium tert-butylate; In tetrahydrofuran; for 12h;Reflux;
<strong>[6154-04-7]2-methyl-2H-tetrazole-5-amine</strong> (7.7 g, 78 mmol), 2-chloro-5-bromopyridine (10 g, 52 mmol), and potassium tert-butylate (11.6 g, 104 mmol) were dissolved in 100 mL THF, heated under reflux and reacted for 12 h. Water was added, extracted with ethyl acetate, and the organic phase was dried, concentrated, and the solid was separated by a silica gel column (dichloromethane: methanol = 100: 1) to obtain 5-bromo-N-(2-methyl-2H-tetrazol-5-yl) pyridine-2-amine 200 mg, at a yield of 1.5%.
A mixture of 2-chloro-5-bromo-pyridine (9.80 g, 50.0 mmol, CAS No.: 53939-30-3) and sodium methanethiolate (5.25 g, 75.0 mmol, CAS No.: 5 188-07-8) in N,N-dimethylformamide (25 mL) was stirred at room temperature for 3 hours. The reaction mixture was diluted with water (50 mL) and then extracted with ethyl acetate (60 mL x 3). The combined organic layer was washed with brine (100 mL x 2), and then dried over sodium sulfate and then concentrated in vacuo to afford a mixture of 5-bromo-2-(methylsulfanyl)pyridine and 2,5- bis(methylsulfanyl)pyridine, which was used directly for the next step.
With N-ethyl-N,N-diisopropylamine; at 170℃; for 4h;Microwave irradiation;
A mixture of 5-bromo-2-chloropyridine (3g, 15.5 mmol), methylamine hydrochloride (3.16 g, 46.8 mmol), and DIPEA (8.17 mL, 46.8 mmol) was heated at 170C under microwave for 4 h. The mixture was diluted with water and extracted with EtOAc. The organic layers was separated and washed with brine. Organic layer was dried over anhydrous Na2SO4 and concentrated. The residue was applied to ISCO (24g silica gel, solid loading, 70-80% ethyl acetate/hexane) to afford 5-bromo-N-methylpyridin-2- amine (800 mg, 4.28 mmol, 27.4 % yield) as a brown solid.
5-bromo-2-chloropyridine-4-carboxaldehyde[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
85%
A solution of diisopropylamine (31.3 g, 0.31 mol) in tetrahydrofuran (600 mL) was treated with 2.5 n-butyllithium (109 mL, 0.27 mol) in hexane for 30 min at -78 C, followed by the addition of a solution of 5-bromo-2- chloropyridine (35 g, 0.18 mol) in tetrahydrofuran (200 mL). The resulting solution was stirred for 30 min at -78 C, then N,N-dimethylformamide (40.4 g, 0.55 mol) was added. After additional 30 min at -60 C, The reaction mixture was quenched by saturated aqueous solution of ammonium chloride (1 L) and extracted with ethyl acetate (3 x 500 mL). The combined organic layers was washed with brine (2 x 500 mL) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography, eluted with 1-10% ethyl acetate in petroleum ether to afford 5-bromo-2-chloroisonicotinaldehyde as a light yellow solid: MS (ESI, m/z): 220.2, 222.1 [M + 1]+; 1H MR (400 MHz, CDC13) delta 10.31 (s, 1H), 8.70 (s, 1H), 7.74 (s, 1H).
61%
Diisopropylamine (8.95 g, 88 mmol) was dissolved in dried THF (100 mL) under N2, then the mixture was cooled to -78 C. N-butyllithium (50 mL, 78 mmol) was added dropwise, and then the mixture was stirred at 0 C. for 10 min. The mixture was cooled to -78 C., then <strong>[53939-30-3]2-chloro-5-bromopyridine</strong> (10.0 g, 52 mmol) was added, the mixture was stirred at -78 C. for 1 h, then dried DMF (11.4 g, 0.16 mol) was added dropwise, the mixture was stirred at this temperature for another 1 h. A ammonium chloride solution was added to quench the reaction, and the mixture was diluted with EtOAc (300 mL), washed for three times with water (50 mL), washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtrated, concentrated and separated by column chromatography (Fluent:PE/EtOAc 9:1) to obtain compound 5-bromo-2-chloroisonicotinaldehyde (7.0 g, yield: 61%). 1H NMR (400 CDCl3): delta 10.3 (s, 1H), 8.69 (s, 1H), 7.73 (s, 1H). MS m/z (ESI): 252.0, 254.0, 256.0 [M+MeOH+H]+.
28%
To a solution of LDA (2 M in THF, 296 mL) in THF (500 mL) was added a solution of <strong>[53939-30-3]5-bromo-2-chloropyridine</strong> (95.0 g, 493 mmol) in THF (200 mL) dropwise at -75 C over a period of 2.5 h under N2. The reaction mixture was stirred at -75 C for 1 hour. DMF (49 mL, 641 mmol) was then added over a period of 1 hour and the reaction mixture was stirred for 1.5 h. A black solution was formed. TLC showed the starting material was consumed completely. The reaction was quenched by the addition of acetic acid (50 wt% in THF, 100 mL) at -75C followed by warming to between -40 and -30 C over 2 h. The reaction was added H2O (300 mL) slowly and then extracted with EtOAc (500 mL x3). The combined organic phase was dried over anhydrous Na2S04, filtered and concentrated. The residue was purified by Combi Flash (5% EtOAc in pentane) to give impure product (50 g) as a yellow solid. The solid was washed with PE (50 mL x3) to give 5-bromo-2-chloroisonicotinaldehyde (30.0 g, yield: 28%) as an off-white solid. (1140) NMR (400 MHz, DMSO-rie) d 7.81 (1H, s), 8.85 (1H, s), 10.10 (1H, s).
6.34 g
After a solution prepared by dissolving 10.6 mL of diisopropylamine in 100 mL of THF was cooled to -78 C., 22.7 mL of n-butyllithium was added thereto slowly dropwise. After the reaction solution was stirred for 1 hour, a solution obtained by dissolving 9.7 g of <strong>[53939-30-3]5-bromo-2-chloropyridine</strong> in 50 mL of THF was added slowly dropwise, and the reaction solution was stirred for another hour. Afterwards, 10 mL of N,N-dimethylformamide (DMF) was added dropwise. After this mixed solution was stirred for 1 hour at -78 C., 30 mL of 2 M hydrochloric acid was added, and temperature was raised slowly to room temperature, followed by stirring for 30 minutes at room temperature. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with brine, then dried and concentrated in vacuo. 10 mL of dichloromethane was added to the residue, purification was carried out by a conventional method to obtain 3.23 g of <strong>[53939-30-3]5-bromo-2-chloropyridine</strong>-4-carbaldehyde. In addition, after the filtrate was concentrated in vacuo, the residue was purified by silica gel chromatography (hexane:ethyl acetate=9:1) to give 6.34 g of <strong>[53939-30-3]5-bromo-2-chloropyridine</strong>-4-carbaldehyde. (0124) 1H-NMR (400 MHz, CDCl3) delta (ppm): 7.72 (1H, s), 8.68 (1H, s), 10.30 (1H, s)
With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In 1,2-dimethoxyethane; water; at 84℃; for 16h;Inert atmosphere; Sealed tube;
Into a 500ml pressure flask, <strong>[53939-30-3]2-chloro-5-bromopyridine</strong> (9.6 g, 50mmol) and 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (10.0 g, 65mmol ) are added into ethylene glycol dimethyl ether (225 ml) and 2M aqueous sodium carbonate solution (75 ml), and forming a two-phase hybrid system. Under the nitrogen atmosphere, added the Tetrakis (triphenylphosphine) palladium (0) (2.9 g, 2.5mmol) to the mixture. Subsequently, the pressure bottle is sealed; the reaction is stirred at 84 C for 16 hours. The reaction mixture is diluted with 150 ml of water and 150 ml of ethyl acetate, by filtration removed the white solid. After separation of the two phases, the aqueous phase is extracted with 40 ml of ethyl acetate; the combined organic phases are dried over anhydrous magnesium sulfate, filtered, and concentrated to about 20 ml by steaming, after column chromatography obtained 2-chloro-5-vinylpyridine 5.7g, a colorless liquid, yield 81%.
62%
With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In tetrahydrofuran; water; at 75℃;Inert atmosphere;
2-Chloro-5-vinylpyridine To a solution of <strong>[53939-30-3]5-bromo-2-chloropyridine</strong> (1.92 g, 10 mmol) in THF:H2O=4:1 (100 mL) were added 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (2.31 g, 15 mmol), tetrakis(triphenylphosphine)palladium (231 mg, 0.2 mmol), and sodium carbonate (6.9 g, 50 mmol). The mixture was stirred at 75 C. under Ar for overnight. The crude product was purified by silica gel chromatography (eluted with petroleum:DCM=10:1) to give the titled compound (0.87 g, 62%) as an oil. MS: m/e=140 [M+H]+.
5-bromo-2-chloropyridine 10.0g (52.5 mmol) was dissolved in 500ml tetrahydrofuran and then, Tetrakistriphenylphosphine Pd (0) 3.0g (2.6 mmol) was added at the room temperature was stirred for about 5 minutes dongan. Thereafter, by the addition of 2,4,6-Trimethylphenyl boronic acid 9.5g (57.89 mmol) of potassium carbonate and 21.8g (157.5 mmol). Then, 250ml of distilled water was added and heated under reflux for one day at 80 . When the reaction is complete, the extract was added to 200ml of ethyl acetate, and distilled under reduced pressure the organic layer was dried over magnesium sulfate. Purification of the results obtained therefrom separated by column chromatography to yield the intermediate 9-3 that raepi about 11.0g (47.3 mmol, 90percent yield). The resulting compound was confirmed by LC-MS.
Under nitrogen, to 2-fluorobenzylalcohol (1.64 g, 13.0 mmol, 1.30 equiv) in DMF (5 mL) at 0 C. was added NaH (299 mg, 13.0 mmol, 1.30 equiv). After stirring for 5 min at 23 C., 5-bromo-2-chloropyridine (1.92 g, 10.0 mmol, 1.00 equiv) was added. After further stirring for 20 min at 85 C., water (20 mL) was added to the reaction mixture. The phases were separated and the aqueous phase was extracted with Et2O (3*20 mL). The combined organic phases were washed with brine (20 mL) and dried (MgSO4). The filtrate was concentrated in vacuo and the residue was purified by column chromatography on silica gel eluting with hexanes/EtOAc to afford 2.6 g of the title compound (92% yield). NMR Spectroscopy: 1H NMR (400 MHz, CDCl3, 23 C., delta): 8.21 (br s, 1H), 7.66 (d, J=8.8 Hz, 1H), 7.50-7.42 (m, 1H), 7.35-7.28 (m, 1H), 7.18-7.06 (m, 2H), 6.73 (d, J=8.8 Hz, 1H), 5.42 (s, 2H). 19F NMR (375 MHz, CDCl3, 23 C., delta): -118.2 (m, 1F).
With potassium carbonate; In acetonitrile; at 110℃; for 12h;
General procedure: To 1,4-dioxane (30 mL) were added tert-butyl piperazine-1-carboxylate (2.89 g, 15.51 mmol), 5-bromo-2-chloropyrimidine (2.00 g, 10.34 mmol) and potassium carbonate (2.86 g, 20.68 mmol) sequentially. The mixture was heated to 110 C, after stirring for 12 hours, the reaction mixture was cooled to room temperature, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (PE/EtOAc (v/v) = 20/1) to give the title compound as a pale yellow solid (3.15 g, 88.7%).; The title compound was prepared using tert-butyl piperazine-1-carboxylate (1.45 g, 7.79 mmol),<strong>[53939-30-3]5-bromo-2-chloropyridine</strong> (1.00 g, 5.20 mmol) and potassium carbonate (1.44 g, 10.39 mmol) in acetonitrile (30 mL) according to the process described in Step 4 of Example 1, and the crude product was purified by silica gel chromatography (PE/EtOAc (v/v) = 20/1) to give the title compound as a pale yellow solid (1.45 g, 8 1.5%).MS (ESI, pos. ion) m/z: 342.1 [M+H] and?H NMR (600 MHz, CDC13): (ppm) 8.17 (d, J 2.4 Hz, 1H), 7.52 (dd, J 9.0, 2.5 Hz, 1H), 6.52 (d, J 9.0 Hz, 1H), 3.55 - 3.49 (m, 4H), 3.49 - 3.45 (m, 4H), 1.46 (s, 9H).
58.8%
In N,N-dimethyl-formamide; at 80℃; for 14h;
To a stirred solution of 1-Boc piperazine (10.6 g, 57.29 mmol, Symax fine chemicals) in dryDMF (lOOmL), TEA (14.43 mL, 103.39 mmol) and 5-bromo-2-chloropyrimidine (10 g, 52.08mmol, Oakwood chemicals) were added and the reaction mixture was stirred at 80C for 14h. It was cooled down to rt and poured on iced water (100 mL). The resulting precipitatewas filtered and washed with hexane (50 mL) to afford the title compound. Yield: 58.8%(10 g, off white solid). 1H NMR (400 MHz, DMSO-d6): 68.60(s, IH), 8.13 (dd, J= 8.6, 2.4Hz, IH), 7.54 (dd, J = 8.4, 0.4 Hz, IH), 3.22-3.20 (m, 4H), 2.61-2.59 (m, 4H), 1.42 (5, 9H).LCMS: (Method A) 343.9 (M +2H), Rt. 5.58 mm, 98.9% (Max).
58.8%
With triethylamine; In N,N-dimethyl-formamide; at 80℃; for 14h;
To a stirred solution of 1-Boc piperazine (10.6 g, 57.29 mmol, Symax fine chemicals) in dry DMF (100mL), TEA (14.43 mL, 103.39 mmol) and <strong>[53939-30-3]5-bromo-2-chloropyridine</strong> (10 g, 52.08 mmol, Oakwood chemicals) were added and the reaction mixture was stirred at 80C for 14 h. It was cooled down to rt and poured on iced water (100 mL). The resulting precipitate was filtered and washed with hexane (50 mL) to afford the title compound. Yield: 58.8% (10 g, off white solid). 1H NMR (400 MHz, DMSO-d6): delta 8.60 (s, 1 H), 8.13 (dd, J = 8.6, 2.4 Hz, 1 H), 7.54 (dd, J = 8.4, 0.4 Hz, 1 H), 3.22-3.20 (m, 4H), 2.61 -2.59 (m, 4H), 1.42 (s, 9H). LCMS: (Method A) 343.9 (M +2H), Rt. 5.58 min, 98.9% (Max).
With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In toluene; at 60℃; for 60h;
0.7 g of tetrakis (triphenylphosphine) palladium, 8.2 g (50 mmol) of boronic acid (16) and 9.6 g (50 mmol) of pyridine (1) are added to a mixture of 100 ml of toluene and 50 ml of 2 N sodium carbonate solution.After 60 hours at 60 DEG C,The reaction mixture is diluted with MTB ether.The organic phase is evaporated.The residue is filtered through silica gel (n-heptane).
With potassium carbonate; In N,N-dimethyl-formamide; at 90℃; for 6h;
Step 1: (2S, 6R)-2,6-dimethylmorpholine (4.0 g, 34.8 mmol) and potassium carbonate (8.0 g, 58 mmol) wereadded into a solution of <strong>[53939-30-3]5-bromo-2-chloro-pyridine</strong> (5.0 g, 26.2 mmol) in DMF (18 mL). The reaction mixture was stirredat 90C for 6h and filtrated, the filtrate cake was washed with EtOAc. The filtrate was concentrated, the crude productwas purified by silica gel column chromatography to deliver compound 158-2 (6 g, yield 84.9%) as yellow oil. MS ESIcalcd for C11H15BrN2O [M+H]+ 271, found 271.
12%
With potassium carbonate; In N,N-dimethyl-formamide; at 90℃; for 12h;
To a solution of commercially available <strong>[53939-30-3]5-bromo-2-chloro-pyridine</strong> (1 g, 5.19 mmol) and ((2S,6R)- 2,6-dimethylmorpholine (0.778 g, 6.75 mmol) in DMF (5 mL) potassum carbonate (1 .57 g, 1 1.43 mmol ) was added and the mixture was heated to 90 C for 12 h. The reaction mixture was diluted with ethyl acetate (50 mL) and water (30 mL). The organic phase was separated and the aqueous phase was extracted with ethyl acetate two more times. The combined organic phase was dried over Na2SC>4, filtered and the solvents were evaporated under reduced pressure. The crude purified on HP-Sil column (Biotage), by employing a ethyl acetate/petroleum ether gradient (30/70) to afford title compound (0.17 g, 12%).1H-NMR (400 MHz, CDCI3) d 8.20 (d, J = 2.00 Hz, 1 H), 7.54-7.54 (m, 1 H), 6.54 (d, J = 8.80 Hz, 1 H), 3.97-3.97 (m, 2H), 3.69-3.70 (m, 2H), 2.49-2.51 (m, 2H), 1.27 (d, J = 6.40 Hz, 6H).MS: 271.1 (M +H)+.
diethyl 2-(6-chloro-3-pyridinyl)malonate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
83%
With benz<b>oxazole; potassium phosphate; copper(l) iodide; In dimethyl sulfoxide; at 50℃; for 6h;Inert atmosphere; Sealed tube;
General procedure: Under Ar atmosphere, DMSO (2 mL), ArBr 1 (1.0 mmol), diethyl malonate 2 (1.5 mmol), CuI (0.1mmol), benzoxazole (0.2 mmol) and K3PO4 (3 mmol) were successively added into a sealed tube.The mixture was stirred at 50C for about 3-9 h. When the reaction completed indicated by TLC,the reaction mixture was poured into saturated ammonium chloride aqueous solution (20 mL)and extracted with ethyl acetate (3×20 mL).The combined organic phase was washed with saturated ammonium chloride aqueous solution(2×20 mL) and water (2×20 mL). Then the separated organic layer was dried over anhydroussodium sulfate, filtered and concentrated under reduced pressure. The residue waschromatographed on silica gel using hexane/ethyl acetate to afford the desired product.
70%
With benz<b>oxazole; copper(l) iodide; triethylamine; In 1,4-dioxane; at 60℃; for 0.0833333h;
(1) 2-Chloro-5-bromopyridine was dissolved in dioxane at a concentration of 1 mol / L to give solution a;(2) The molar ratio of diethyl malonate, ligand benzoxazole and triethylamine in dioxane was determined. The molar ratio of diethyl malonate to <strong>[53939-30-3]2-chloro-5-bromopyridine</strong> was1.5: 1, the molar ratio of benzoxazole to <strong>[53939-30-3]2-chloro-5-bromopyridine</strong> is 0.4: 1, the molar ratio of triethylamine to <strong>[53939-30-3]2-chloro-5-bromopyridine</strong> is4: 1, the solution b; the solid catalyst cuprous iodide added to the fixed bed microchannel reaction device, and <strong>[53939-30-3]2-chloro-5-bromopyridine</strong> (4) the solution a and the solution b are simultaneously pumped into the fixed bed microchannel reaction after the treatment in step (3) And then into the microreactor in the reaction apparatus. The flow rate ratio of solution a and solution b is controlled at 1: 1 Hold the residence time 5min, at 60 to carry out the reaction; collecting out of liquid, EA / water extraction, combined organic phase, add anhydrous sulfuric acid Dried in water and filtered, and the residue was separated by silica gel column chromatography. The mobile phase was separated with petroleum ether / ethyl acetate. Quality, the product was pure, the yield of 70%
With tris-(dibenzylideneacetone)dipalladium(0); N-ethyl-N,N-diisopropylamine; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane; at 80℃; under 760.051 Torr; for 1.5h;Inert atmosphere;
A 500 mL round bottomed flask was charged with 5-bromo-2- chioropyridine (10 g, 52.0 mmol), Xantphos (3.01 g, 5.20 mmol), Pd2(dba)3 (2.379 g, 2.60 mmol), 1,4-dioxane (208 ml), Hunig?s base (18.15 ml, 104 mmol). The flask was evacuated and backfilled three times with N2 and then heated at 80 C for 1.5 h. LCMS showed full conversion. 200 ml of Me-THF was added as the reaction cooled and after stirring overnight the reaction was filtered over CELITE to provide an orange oil that was purified by MPLC (340g SnapUltra, 0-30% EtOAc/heptane) to provide 5- (benzylthio)-2-chloropyridine (8.95 g, 38.0 mmol, 73.1 % yield) as a yellow oil. 1H NMR (400 MHz, CHLOROFORM-d) oe ppm 4.09 (s, 2 H) 7.19 (dd, J8.29, 0.73 Hz, 1 H) 7.24- 7.34 (m, 5 H) 7.49 (dd, J8.29, 2.49 Hz, 1 H) 8.28 (dd, J=2.59, 0.62 Hz, 1 H).
To a solution of 2-(benzhydrylideneamino)acetonitrile (6.87 g, 31.18 mmol) in DMF (60 mL) was added NaH (1.37 g, 34.3 mmol). The mixture was stirred at 0 °C for 20 mins, and then A-23 was added (6 g, 31.18 mmol). The resulting mixture was stirred at 15 °C for 16 hours. Saturated NH4C1 aqueous (120 mL) and EtOAc (150 mL) were added, and the organic layer was washed with brine (60 mL x 2), dried over anhydrous Na2S04, filtered and concentrated to give the crude product, which was purified by flash chromatography on silica gel (EtOAc in PE = 0percent to 10percent to 30percent) afford A-24 (2200 mg, 5.85 mmol) as an oil. H NMR (400MHz
2-((1,4-dioxan-2-yl)methoxy)-5-bromopyridine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With sodium hydride; In dimethyl sulfoxide; at 20 - 60℃; for 10h;Inert atmosphere;
To a solution of(l, 4-dioxan-2-yl) methanol (2.4 g) in dimethylsulfoxide (24 mL) was added 5-bromo-2-chloropyridine (3.91 g) and sodium hydride (0.81 g) at 20 C under nitrogen flow. Thereaction mixture was stirred at 60 C for 10 hours under nitrogen atmosphere. The reaction was diluted with water (40 mL) at 25 C and extracted with ethyl acetate (3 x 40 mL). The combined organic layers were washed with brine (5 x 20 mL) and dried over sodium sulfate. After filtration, the filtrate was concentrated to give a residue which was purified by colunm chromatography on silica gel (eluted with petroleum ether:ethyl acetate = 100:1 to 20:1) to give the title compound. ?H NMR (400 MHz, CDC13) 6ppm 8.15 (d, 1H), 7.63 (dd, 1H), 6.70 (d, 111) 4.38-4.49 (m, 2H), 3.78-3.85 (m, 2H), 3.59-3.71 (m, 6H),3.52 (dd, 2H), 3.35 (s, 311).
tert-butyl 7-(6-chloro-3-pyridyl)-4,7-diazaspiro[2.5]octane-4-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
77.5%
With dichloro[4,5-bis(diphenylphosphino)-9,9?-dimethylxanthene]palladium(II); sodium t-butanolate; In 2-methyltetrahydrofuran; at 70℃; for 1.25h;
5-Bromo-2-chloropyridine (85.0 g, 442 mmol), tert-butyl 4,7-diazaspiro[2.5]octane-4- carboxylate (102 g, 442 mmol) and Me-THF (722 g) were charged into a reaction vessel. After 10 minutes stirring, most of the solids were dissolved and [Pd(Xantphos)Cl2] (3.34 g) was added followed after 5 minutes by a solution of sodium tert-butanolate (56.3 g, 574 mmol) in Me-THF (173 g). The reaction mixture was stirred at 70 C for 1.25 hours, cooled to room temperature and water (595 g) and 1-propylacetate (378 g) were added. After vigorous stirring, the phases were separated, the organic phase was washed with a second portion of water (425 g) and with a mixture of water (425 g) and brine (25 mL). The organic phase was treated with active charcoal (6.8 g), filtered and concentrated under reduced pressure to afford a brown oil, which was dissolved in tert-amyl-methyl-ether (347 g) at reflux. The solution was cooled slowly to room temperature. After stirring 18 hours at room temperature, n-heptane (205 g) was added and the suspension was further cooled to -10 C. The precipitate was filtered off and dried under high vacuum to afford tert-butyl 7-(6-chloro-3-pyridyl)-4,7-diazaspiro[2.5]octane-4-carboxylate (110.9 g, 77.5%) as a beige solid. (0249) -NuMuRhonu (CDC13, 600 MHz): 7.95 (d, 1H); 7.18 - 7.14 (m, 1H); 7.13 - 7.09 (m, 1H); 3.79 - 3.63 (m, 2H); 3.24 - 3.12 (m, 2H); 2.96 (s, 2H); 1.47 (s, 9H); 1.11 - 1.04 (m, 2H); 0.90 - 0.79 (m, 2H); LCMS: 324.15, 326.15 (M+H+)
4-(4-(6-chloropyridin-3-yl)benzyl)morpholine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
80.22%
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate; In 1,4-dioxane; water; at 80℃; for 4h;Inert atmosphere;
The resulting 4-(morpholin-1-ylmethyl)phenylboronic acid and 1.07 g (5.6 mmol) of 5-bromo-2-chloropyridine, 0.34 g (0.47 mmol) of Pd(dppf)Cl2 after dissolving 1.28 g (9.3 mmol) of potassium carbonate in a mixed solution of 1,4 dioxane (30 mL) and water (20 mL), N2 substitution was performed. The temperature was raised to T=80 C for 4 h, and water was added after the reaction was completed. Extraction with ethyl acetate, drying (Na2SO4), filtration, concentrated and purified by column to obtain 4-(4-(6-chloropyridin-3-yl)benzyl)morpholine 1.08 g. The yield was 80.22%.
1-(4-(6-chloropyridin-3-yl)phenyl)-N,N-dimethylmethylamine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
59.45%
With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In 1,4-dioxane; water; at 80℃; for 4h;Inert atmosphere;
The resulting <strong>[70799-12-1]4-((dimethylamino)methyl)phenylboronic acid</strong> and 1.07 g (5.6 mmol) of 5-bromo-2-chloropyridine, 0.54 g (0.47 mmol) of Pd(PPh3)4, 1.28 g (9.3 mmol) of potassium carbonate was dissolved in a mixed solution of 1,4 dioxane (30 mL) and water (10 mL), and then subjected to N2 replacement. The temperature was raised to T=80 C for 4 h, and water was added after the reaction was completed.Extracted with ethyl acetate, dried (Na2SO4), filtered, concentrated.Purification of the product by 1-(4-(6-chloropyridin-3-yl)phenyl)-N,N-dimethylmethylamine 0.68 g, The yield was 59.45%.
4-(6-chloropyridin-3-yl)piperidine-1-carboxylic acid tert-butyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
58.23%
With tetrakis(triphenylphosphine) palladium(0); caesium carbonate; In 1,4-dioxane; water; at 80℃; for 4h;Inert atmosphere;
The obtained 3 g (9.65 mmol) of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)piperidine-1-carboxylic acid butyl ester and 2.2g (11.6mmol) 5-bromo-2-chloropyridine, 1.15 g (1 mmol) of Pd(PPh3)4, 6.3 g (19.3 mmol) of cesium carbonate was dissolved in a mixed solution o f 1,4 dioxane (30 mL) and water (10 mL), followed by N2 replacement. The temperature was raised to T=80 C for 4 h, and water was added after the reaction was completed.Extracted with ethyl acetate, dried (Na 2 SO 4 ), filtered, concentrated. Purification of the product 4-(6-chloropyridin-3-yl)piperidine-1-carboxylic acid tert-butyl ester 1.67 g, The yield was 58.23%.
5-(6-chloropyridin-3-yl)-4-methylthiazole[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
99%
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.
5-(6-chloropyridin-3-yl)-2-methylthiazole[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
68%
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.
With potassium carbonate; In N,N-dimethyl-formamide; at 90℃; for 12h;
To a solution of commercially available 5-bromo-2-chloro-pyridine (0.83 g, 4.34 mmol) and 4- methoxy piperidine (0.5 g, 4.34 mmol) in DMF( 5 mL) potassium carbonate (1.79 g, 13.02 mmol) was added and the mixture was heated to 90 C for 12 h. The reaction mixture was diluted with ethyl acetate (50 mL) and water (30 mL). The organic phase was separated and the aqueous phase was extracted with ethyl acetate two more times. The combined organic phase was dried over Na2SC>4, filtered and the solvents were evaporated under reduced pressure. The crude purified on HP-Sil column (Biotage), by employing a ethyl acetate/petroleum ether gradient (30/70) to afford title compound (0.5 g, 42%).1H-NMR (400 MHz, DMSO-c/6) d 8.14-8.15 (m, 1 H), 7.63-7.64 (m, 1 H), 6.85 (d, J = 9.12 Hz, 1 H), 3.86-3.87 (m, 2H), 3.39-3.40 (m, 1 H), 3.27 (s, 3H), 3.14-3.15 (m, 2H), 1.84-1.85 (m, 2H), 1.35- 1.36 (m, 2H).MS: 273.1 (M +2H)+.
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