* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Reference：
[1] Journal of Medicinal Chemistry, 2008, vol. 51, # 20, p. 6571 - 6580
[2] Recueil des Travaux Chimiques des Pays-Bas, 1950, vol. 69, p. 673,690
Reference：
[1] Journal of Medicinal Chemistry, 2008, vol. 51, # 20, p. 6571 - 6580
[2] Recueil des Travaux Chimiques des Pays-Bas, 1950, vol. 69, p. 673,690
5
[ 116632-24-7 ]
[ 68963-75-7 ]
Yield
Reaction Conditions
Operation in experiment
92%
at 0℃; for 1.08333 h;
2,4-Dichloro-6-hydroxypyridine; Sodium nitrite (64 mg, 0.93 mmol) dissolved in water (0.6 mL), was added dropwise to a stirred solution of 2-amino-4,6-dichloropyridine (prepared according to the method described in Recl. Trav. Chim. Pays-Bas, 1950, 69, 673) (126 mg, 0.77 mmol) in 5percent sulphuric acid (aq) (5 mL) at 0° C., over 5 min. The mixture was stirred at 0° C. for 1 h and then diluted with water (20 mL) and extracted with DCM (3.x.20 mL). The combined extracts were washed with brine (20 mL), dried over MgSO4 and concentrated in vacuo to afford the 2,4-dichloro-6-hydroxypyridine (116 mg, 0.71 mmol, 92percent) M.S. (ESI) (m/z) 164,166 [M+H]+.
92%
at 0℃; for 1.08333 h;
Sodium nitrite (64mg, 0.93mmol) dissolved in water (0.6 ml.) was added dropwise to a stirred solution of 2-amino-4,6-dichloropyridine (prepared according to the method described in Reel. Trav. Chim. Pays-Bas, 1950, 69, 673) (126 mg, 0.77 mmol) in 5percent sulphuric acid (5 ml.) at 0 °C, over 5 min. The mixture was stirred at 0 °C for 1 h and then diluted with water (20 ml.) and extracted with dichloromethane (3 x 20 ml_). The combined extracts were washed with brine (20 ml_), dried (MgSO4) and concentrated in vacuo to afford the product as an orange solid (116 mg, 92 percent).Data for 2,4-dichloro-6-hydroxypyridine: MS (ESI) m/z: 164/166 ([M+H]+).
92%
With sulfuric acid; sodium nitrite In water at 0℃; for 1.08333 h;
Sodium nitrite (64 mg, 0.93 mmol) dissolved in water (0.6 mL) was added dropwise to a stirred solution of 2-amino-4,6-dichloropyridine (prepared according to the method described in Recl. Trav. Chim. Pays-Bas, 1950, 69, 673) (126 mg, 0.77 mmol) in 5percent sulphuric acid (5 mL) at 0 C., over 5 min. The mixture was stirred at 0 C. for 1 h and then diluted with water (20 mL) and extracted with dichloromethane (3 20 mL). The combined extracts were washed with brine (20 mL), dried (MgSO4) and concentrated in vacuo to afford the product as an orange solid (116 mg, 92percent).Data for 2,4-dichloro-6-hydroxypyridine: MS (ESI) m/z:164/166 ([M+H]+).
92%
at 0℃; for 1.08333 h;
Sodium nitrite (64mg, 0.93mmol) dissolved in water (0.6 ml_), was added dropwise to a stirred solution of 2-amino-4,6-dichloropyridine (prepared according to the method described in Reel. Trav. Chim. Pays-Bas, 1950, 69, 673) (126 mg, 0.77 mmol) in 5percent sulphuric acid (aq) (5 ml.) at 0 °C, over 5 min. The mixture was stirred at 0°C for 1 h and then diluted with water (20 ml.) and extracted with DCM (3 x 20 ml_). The combined extracts were washed with brine (20 ml_), dried over MgSO4 and concentrated in vacuo to afford the 2,4-dichloro-6-hydroxypyridine (116 mg, 0.71 mmol, 92 percent) M.S. (ESI) (m/z)164,166 [M+H]+.
7(4.48 g, 27.48 mmol) was joined in batch in concentrated H2SO4(6 ml), and fuming HNO3(1.2 mL) was added slowly under 5 oC. The mixture was stirred at 5 oC for 10h. Upon completion, the reaction mixture was quenched by ice water and modified PH=7 to obtained 3.55 g of the yellow solid 4, washed in methanol(yield: 62.1percent). m.p. 208 °C. 1H-NMR (300 MHz, CDCl3), δ (ppm): 6.84 (s, 1H), 6.25 (br, 2H).
58%
at 0 - 4℃; for 120 h;
a) 4,6-Dichloro-3-nitropyridin-2-amine (A91) To 2-amino-4,6-dichloropyridine (1.0 g, 6.1 mmol) was added concentrated H2S04 (5.4 mL) dropwise at 0 °C and the mixture stirred for 10 minutes. To this stirring solution was added concentrated fuming HN03 (0.3 mL) dropwise, and the mixture stood at 4 °C for five days. The reaction mixture was poured onto crushed ice then neutralized with NaHC03. The resulting precipitate was filtered, washed with H20 and dried to give the crude product as a yellow powder. The crude product was adsorbed onto silica gel then purified using silica gel chromatography twice (24 g silica cartridge, 0-10percent MeOH in DCM then 0-5percent MeOH in DCM), evaporated under reduced pressure, then dried to give the title compound as a bright yellow powder (0.744 g, 58percent ).; H NMR (400 MHz, CDCI3): δ 6.83 (s, 1 H), 6.24 (br. s, 2H). LCMS-A: rt 6.21 min, m/z (positive ion) 208.1 [M+H]+.
47%
Stage #1: at -5℃; for 0.5 h; Stage #2: at 0℃; for 96 h;
To a concentrated H2S04 (265mL) added 4,6- dichloropyridin-2-amine (50g, 3O6mmol, 1.Oeq) portionwise at -5 °C and stirred for 30mm followed by addition of nitric acid (16.5OmL) dropwise. Reaction mixture was allowed to stand at 0 °C for 4 days. Upon completion, reaction mixture was slowly transferred into crushed ice. Saturated NaHCO3 solution was added to pH 8. Precipitated solid was filtered off to obtain crude compound. This was purified by column chromatography and compound was eluted in 8percent ethyl acetate in hexane to get pure 1.1 (30g, 47percent).1H NMR (CDC13, 400IVIHz): 6.85 (s, 1H), 6.28 (s, 2H).
With potassium carbonate In 1,4-dioxane; water at 120℃; for 18 h;
To a 10percent aqueous solution of dioxane (0.1 M) was added 4,6-dichloropyridin-2-amine (1.0 equiv.), trimethylboroxine (1.5 equiv.), Pd(PPh3)4 (0.10 equiv.) and K2CO3 (3.0 equiv.). The solution was heated in an oil bath to 120° C. for 18 hrs, cooled to room temperature (not all of starting material was consumed), extracted with EtOAc, dried with Na2SO4, and concentrated. The crude material was purified via SiO2 column chromatography eluting with 5percent MeOH/DCM to yield 4-chloro-6-methylpyridin-2-amine as an off-white solid in 23percent yield. LCMS (m/z): 143 (MH+); LC Rt=1.11 min.
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; caesium carbonate In 1,4-dioxane; water at 100℃; for 18 h;
A suspension of 4,6-dichloropyridin-2-amine (1.63 g, 10 mmol), methylboronic acid (0.6 g, 10 mmol), Cs2C03 (9.75 g, 30 mmol), and Pd(dppf)Cl2 (400 mg) in dioxane/water (4: 1, 50 mL) was stirred for 18 hours at 100 °C. The reaction was diluted with water and extracted with EtOAc (50 mLx3). The combined organic layer was washed with water and brine. The resulting solution was concentrated under reduced pressure and the residue was purified via prep-HPLC to afford 4-chloro-6-methylpyridin-2-amine (100 mg) as brown solid. MS ESI calcd. For C6H7C1N2 [M + H]+ 143, found 143.
6-chloro-4-morpholin-4-yl-pyridin-2-amine[ No CAS ]
[ 1075215-73-4 ]
Yield
Reaction Conditions
Operation in experiment
16%; 72%
In dimethyl sulfoxide; at 170℃; for 0.5h;
A mixture of 2-amino-4,6-dichloro-pyridine (900 mg, 5.52 mmol, described in Rec. Trav. Chim. Pays-Bas 1950, vol. 69, p. 673-690), morpholine (4.80 ml, 55.2 mmol) and DMSO (0.39 ml, 5.52 mmol) was heated in a Personal Chemistry EMRYS Optimizer EXP microwave synthesiser at 170 C. for 30 minutes. After cooling, morpholine was removed in vacuo, the residue was treated with 30% ammonium hydroxide and the resulting mixture was extracted with methylene chloride. Evaporation of the solvent and purification of the residue on silica gel (3 to 4% MeOH in DCM) provided 4-chloro-6-morpholin-4-yl-pyridin-2-amine (890 mg, 72% yield) and its isomer 6-chloro-4-morpholin-4-yl-pyridin-2-amine (190 mg, 16% yield). NMR Spectrum (500 MHz, CDCl3) 3.43-3.45(m, 4 H), 3.76-3.78(m, 4 H), 4.30(bs, 2 H), 5.91(s, 1 H), 5.97(s, 1 H). Mass Spectrum: MH+ 214.
16%; 72%
In dimethyl sulfoxide; at 170℃; for 0.5h;Microwave irradiation;
4-chloro-6-morpholin-4-yl-pyridin-2-amineA mixture of 2-amino-4,6-dichloro-pyridine (900 mg, 5.52 mmol, described in Rec. Trav. Chim. Pays-Bas 1950, vol. 69, p. 673-690), morpholine (4.80 ml, 55.2 mmol) and DMSO (0.39 ml, 5.52 mmol) was heated on a Personal Chemistry EMRYS Optimizer EXP microwave synthesisor at 1700C for 30 minutes. After cooling, morpholine was removed in vacuo, the residue was treated with 30% ammonium hydroxide and the resulting mixture was extracted with methylene chloride. Evaporation of the solvent and purification of the residue on silica gel (3 to 4% MeOH in CH2Cl2) provided 4-chloro-6-morpholin-4-yl-pyridin-2-amine (890 mg, 72% yield) and its isomer6-chloro-4-morpholin-4-yl-pyridin-2-amine (190 mg, 16% yield). NMR Spectrum (500 MHz, CDC13) 3.43-3.45 (m, 4H), 3.76-3.78 (m, 4H), 4.30 (bs, 2H), 5.91 (s, IH), 5.97 (s, IH). Mass Spectrum: MH+ 214.
In dimethyl sulfoxide; at 220℃; for 0.333333h;Microwave irradiation;
4,6-dimorpholin-4-ylpyridin-2-amineA mixture of 2-amino-4,6-dichloro-pyridine (2.0 g, 12.2 mmol), morpholine (10.7 ml, 123 mmol) and DMSO (0.87 ml, 12 mmol) was heated on a Personal Chemistry EMRYS Optimizer EXP microwave synthesisor at 2200C for 20 minutes. After cooling, morpholine was removed in vacuo, the residue was treated with 30% ammonium hydroxide and the resulting mixture was extracted with methylene chloride. Evaporation of the solvent and purification of the residue on silica gel (3 to 4% MeOH in CH2Cl2) provided a gum that was triturated in ether to give 4,6-dimorpholin-4-ylpyridin-2-amine (900 mg, 28% yield). NMR Spectrum (500 MHz, CDC13) 3.20-3.22 (m, 4H), 3.40-3.42 (m, 4H), 3.79-3.81 (m, 8H), 4.20 (bs, 2H), 5.44 (s, IH), 5.46 (s, IH). Mass Spectrum: MH+ 265.
Preparation of 4-(4-aminophenoxy)-6-chloropyridin-2-amine A stirred solution of 4-aminophenol (335 mg, 3.1 mmol) in anhydrous DMSO (8 ml) was flushed with nitrogen and treated with 1M KOBut/THF solution (3.1 ml, 3.1 mmol). The mixture was stirred at room temperature under nitrogen for 10 minutes. <strong>[116632-24-7]4,6-dichloropyridin-2-ylamine</strong> (500 mg, 3.1 mmol) was added and the mixture was heated at 88 C. for 16 hours, cooled to room temperature and poured into 100 ml of water. The resulting precipitates were filtered, washed with water and dried to give the crude product, which was purified by silica gel chromatography with 2-5% MeOH/CHCl3 to give 4-(4-aminophenoxy)-6-chloropyridin-2-amine as light brown solid. Yield: 350 mg, 49%.
49%
Preparation of 4-(4-aminophenoxy)-6-chloropyridin-2-amineA stirred solution of 4-aminophenol (335mg, 3.1mmol) in anhydrous DMSO (8ml) was flushed with nitrogen and treated with 1M KOBut / THF solution (3.1ml, 3.1mmol). The mixture was stirred at room temperature under nitrogen for 10 minutes. <strong>[116632-24-7]4,6-dichloropyridin-2-ylamine</strong> (500mg, 3.1mmol) was added and the mixture was heated at 88C for 16 hours, cooled to room temperature and poured into 100ml of water. The resulting precipitates were filtered, washed with water and dried to give the crude product, which was purified by silica gel chromatography with 2~5% MeOH/CHCl3 to give 4-(4-aminophenoxy)-6-chloropyridin-2-amine as light brown solid. Yield: 350mg, 49%.
In N,N-dimethyl-formamide; butan-1-ol; at 130℃; for 0.75h;Microwave irradiation;
To a solution of 2-amino~4i6-dichloropyridine (1 ) (3.26 g, 20.0 mmoi) in 1-butanol (10 mL) and DMF (1 mL) was added a solution of sodium butoxide (22.0 mL, 1 .0 M solution in butanol). The reaction mixture was heated in the microwave at130C for 45 min and was then poured onto a saturated solution of NH4CI (50 mL) and EtOAc (50 mL). The layers were separated, and the organic layer was washed with brine (30 mL). The organic layer was dried, filtered, and concentrated in vacuo. The crude oil was purified by flash column chromatography(CH2Cl2/EtOAc) to give 1 .9 g of 2.2: H-NMR: 300 MHz, (CDCI3) d: 6.11 (s, 1 H), 6.07 (s, 1 H), 4.40 (br s, 2H), 4.17 (t, 2H, J = 1 Hz), 1 .72 (m, 2H, J = 7 Hz), 1 .47 (m, 2H, J = 7 Hz), 0.97 (t, 3H, J = 7 Hz).LCMS-ESi+: calc'd for C9H14CIN2O: 201 .1 (M+H+); Found: 20 .0 (M+H).
A mixture of <strong>[116632-24-7]2-amino-4,6-dichloropyridine</strong> (1.0 g, 6.1 mmol) and isopropylamine (5.0 mL. 61.1 mmol) was heated to 140 C in a microwave for 12h. The reaction was cooled to room temperature, concentrated and the crude residue was purified by FCC (40 g SiO2, 0 to 30% EtOAc : hexane) to afford 4-chloro-N2-isopropylpyridine-2,6-diamine (0.46 g, 40%). MS (ESI): mass calcd. for C8H12ClN3, 185.1; m/z found, 186.1 [M+H]+. 1H NMR (CDCl3): 5.80 (d, J = 1.4 Hz, 1H), 5.75 (d, J = 1.4 Hz, 1H), 4.28 - 4.18 (m, 3H), 3.77 - 3.67 (m, 1H), 1.19 (d, J = 6.4 Hz, 6H).To a solution of 4-chloro-N2-isopropylpyridine-2,6-diamine (100 mg, 0.54 mmol) in i-PrOH (1.0 mL) was added N-methylpiperazine (108 mg. 1.1 mmol) and ytterbium trifluoromethanesulfonate hydrate (378 mg. 0.59 mmol). The reaction was heated to 160 C in a microwave for 2h. The reaction was cooled to room temperature, concentrated and the crude residue was purified by FCC (12 g SiO2, 0 to 10% 2.0 M ammonia in MeOH : CH2Cl2) to afford the title compound 8a (30 mg, 22%). MS (ESI): mass calcd. for C13H23N5, 249.2; m/z found, 250.2 [M+H]+. 1H NMR (CDCl3): 5.36 (d, J = 1.8 Hz, 1H), 5.26 (d, J = 1.8 Hz, 1H), 4.07 - 3.95 (m, 3H), 3.77 - 3.65 (m, 1H), 3.28 - 3.20 (m, 4H), 2.54 - 2.45 (m, 4H), 2.32 (s, 3H), 1.19 (d, J = 6.3 Hz, 6H).
A mixture of <strong>[116632-24-7]2-amino-4,6-dichloropyridine</strong> (1.0 g, 6.1 mmol) and isopropylamine (5.0 mL. 61.1 mmol) was heated to 140 C in a microwave for 12h. The reaction was cooled to room temperature, concentrated and the crude residue was purified by FCC (40 g SiO2, 0 to 30% EtOAc : hexane) to afford 4-chloro-N2-isopropylpyridine-2,6-diamine (0.46 g, 40%). MS (ESI): mass calcd. for C8H12ClN3, 185.1; m/z found, 186.1 [M+H]+. 1H NMR (CDCl3): 5.80 (d, J = 1.4 Hz, 1H), 5.75 (d, J = 1.4 Hz, 1H), 4.28 - 4.18 (m, 3H), 3.77 - 3.67 (m, 1H), 1.19 (d, J = 6.4 Hz, 6H).To a solution of 4-chloro-N2-isopropylpyridine-2,6-diamine (100 mg, 0.54 mmol) in i-PrOH (1.0 mL) was added N-methylpiperazine (108 mg. 1.1 mmol) and ytterbium trifluoromethanesulfonate hydrate (378 mg. 0.59 mmol). The reaction was heated to 160 C in a microwave for 2h. The reaction was cooled to room temperature, concentrated and the crude residue was purified by FCC (12 g SiO2, 0 to 10% 2.0 M ammonia in MeOH : CH2Cl2) to afford the title compound 8a (30 mg, 22%). MS (ESI): mass calcd. for C13H23N5, 249.2; m/z found, 250.2 [M+H]+. 1H NMR (CDCl3): 5.36 (d, J = 1.8 Hz, 1H), 5.26 (d, J = 1.8 Hz, 1H), 4.07 - 3.95 (m, 3H), 3.77 - 3.65 (m, 1H), 3.28 - 3.20 (m, 4H), 2.54 - 2.45 (m, 4H), 2.32 (s, 3H), 1.19 (d, J = 6.3 Hz, 6H).
A mixture of <strong>[116632-24-7]2-amino-4,6-dichloropyridine</strong> (1.0 g, 6.1 mmol) and isopropylamine (5.0 mL. 61.1 mmol) was heated to 140 C in a microwave for 12h. The reaction was cooled to room temperature, concentrated and the crude residue was purified by FCC (40 g SiO2, 0 to 30% EtOAc : hexane) to afford 4-chloro-N2-isopropylpyridine-2,6-diamine (0.46 g, 40%). MS (ESI): mass calcd. for C8H12ClN3, 185.1; m/z found, 186.1 [M+H]+. 1H NMR (CDCl3): 5.80 (d, J = 1.4 Hz, 1H), 5.75 (d, J = 1.4 Hz, 1H), 4.28 - 4.18 (m, 3H), 3.77 - 3.67 (m, 1H), 1.19 (d, J = 6.4 Hz, 6H).To a solution of 4-chloro-N2-isopropylpyridine-2,6-diamine (100 mg, 0.54 mmol) in i-PrOH (1.0 mL) was added N-methylpiperazine (108 mg. 1.1 mmol) and ytterbium trifluoromethanesulfonate hydrate (378 mg. 0.59 mmol). The reaction was heated to 160 C in a microwave for 2h. The reaction was cooled to room temperature, concentrated and the crude residue was purified by FCC (12 g SiO2, 0 to 10% 2.0 M ammonia in MeOH : CH2Cl2) to afford the title compound 8a (30 mg, 22%). MS (ESI): mass calcd. for C13H23N5, 249.2; m/z found, 250.2 [M+H]+. 1H NMR (CDCl3): 5.36 (d, J = 1.8 Hz, 1H), 5.26 (d, J = 1.8 Hz, 1H), 4.07 - 3.95 (m, 3H), 3.77 - 3.65 (m, 1H), 3.28 - 3.20 (m, 4H), 2.54 - 2.45 (m, 4H), 2.32 (s, 3H), 1.19 (d, J = 6.3 Hz, 6H).
A mixture of <strong>[116632-24-7]2-amino-4,6-dichloropyridine</strong> (1.0 g, 6.1 mmol) and isopropylamine (5.0 mL. 61.1 mmol) was heated to 140 C in a microwave for 12h. The reaction was cooled to room temperature, concentrated and the crude residue was purified by FCC (40 g SiO2, 0 to 30% EtOAc : hexane) to afford 4-chloro-N2-isopropylpyridine-2,6-diamine (0.46 g, 40%). MS (ESI): mass calcd. for C8H12ClN3, 185.1; m/z found, 186.1 [M+H]+. 1H NMR (CDCl3): 5.80 (d, J = 1.4 Hz, 1H), 5.75 (d, J = 1.4 Hz, 1H), 4.28 - 4.18 (m, 3H), 3.77 - 3.67 (m, 1H), 1.19 (d, J = 6.4 Hz, 6H).To a solution of 4-chloro-N2-isopropylpyridine-2,6-diamine (100 mg, 0.54 mmol) in i-PrOH (1.0 mL) was added N-methylpiperazine (108 mg. 1.1 mmol) and ytterbium trifluoromethanesulfonate hydrate (378 mg. 0.59 mmol). The reaction was heated to 160 C in a microwave for 2h. The reaction was cooled to room temperature, concentrated and the crude residue was purified by FCC (12 g SiO2, 0 to 10% 2.0 M ammonia in MeOH : CH2Cl2) to afford the title compound 8a (30 mg, 22%). MS (ESI): mass calcd. for C13H23N5, 249.2; m/z found, 250.2 [M+H]+. 1H NMR (CDCl3): 5.36 (d, J = 1.8 Hz, 1H), 5.26 (d, J = 1.8 Hz, 1H), 4.07 - 3.95 (m, 3H), 3.77 - 3.65 (m, 1H), 3.28 - 3.20 (m, 4H), 2.54 - 2.45 (m, 4H), 2.32 (s, 3H), 1.19 (d, J = 6.3 Hz, 6H).
at 140℃; for 12h;Microwave irradiation; Neat (no solvent);
A mixture of <strong>[116632-24-7]2-amino-4,6-dichloropyridine</strong> (1.0 g, 6.1 mmol) and isopropylamine (5.0 mL. 61.1 mmol) was heated to 140 C in a microwave for 12h. The reaction was cooled to room temperature, concentrated and the crude residue was purified by FCC (40 g SiO2, 0 to 30% EtOAc : hexane) to afford 4-chloro-N2-isopropylpyridine-2,6-diamine (0.46 g, 40%). MS (ESI): mass calcd. for C8H12ClN3, 185.1; m/z found, 186.1 [M+H]+. 1H NMR (CDCl3): 5.80 (d, J = 1.4 Hz, 1H), 5.75 (d, J = 1.4 Hz, 1H), 4.28 - 4.18 (m, 3H), 3.77 - 3.67 (m, 1H), 1.19 (d, J = 6.4 Hz, 6H).To a solution of 4-chloro-N2-isopropylpyridine-2,6-diamine (100 mg, 0.54 mmol) in i-PrOH (1.0 mL) was added N-methylpiperazine (108 mg. 1.1 mmol) and ytterbium trifluoromethanesulfonate hydrate (378 mg. 0.59 mmol). The reaction was heated to 160 C in a microwave for 2h. The reaction was cooled to room temperature, concentrated and the crude residue was purified by FCC (12 g SiO2, 0 to 10% 2.0 M ammonia in MeOH : CH2Cl2) to afford the title compound 8a (30 mg, 22%). MS (ESI): mass calcd. for C13H23N5, 249.2; m/z found, 250.2 [M+H]+. 1H NMR (CDCl3): 5.36 (d, J = 1.8 Hz, 1H), 5.26 (d, J = 1.8 Hz, 1H), 4.07 - 3.95 (m, 3H), 3.77 - 3.65 (m, 1H), 3.28 - 3.20 (m, 4H), 2.54 - 2.45 (m, 4H), 2.32 (s, 3H), 1.19 (d, J = 6.3 Hz, 6H).
A mixture of <strong>[116632-24-7]2-amino-4,6-dichloropyridine</strong> (1.0 g, 6.1 mmol) and isopropylamine (5.0 mL. 61.1 mmol) was heated to 140 C in a microwave for 12h. The reaction was cooled to room temperature, concentrated and the crude residue was purified by FCC (40 g SiO2, 0 to 30% EtOAc : hexane) to afford 4-chloro-N2-isopropylpyridine-2,6-diamine (0.46 g, 40%). MS (ESI): mass calcd. for C8H12ClN3, 185.1; m/z found, 186.1 [M+H]+. 1H NMR (CDCl3): 5.80 (d, J = 1.4 Hz, 1H), 5.75 (d, J = 1.4 Hz, 1H), 4.28 - 4.18 (m, 3H), 3.77 - 3.67 (m, 1H), 1.19 (d, J = 6.4 Hz, 6H).To a solution of 4-chloro-N2-isopropylpyridine-2,6-diamine (100 mg, 0.54 mmol) in i-PrOH (1.0 mL) was added N-methylpiperazine (108 mg. 1.1 mmol) and ytterbium trifluoromethanesulfonate hydrate (378 mg. 0.59 mmol). The reaction was heated to 160 C in a microwave for 2h. The reaction was cooled to room temperature, concentrated and the crude residue was purified by FCC (12 g SiO2, 0 to 10% 2.0 M ammonia in MeOH : CH2Cl2) to afford the title compound 8a (30 mg, 22%). MS (ESI): mass calcd. for C13H23N5, 249.2; m/z found, 250.2 [M+H]+. 1H NMR (CDCl3): 5.36 (d, J = 1.8 Hz, 1H), 5.26 (d, J = 1.8 Hz, 1H), 4.07 - 3.95 (m, 3H), 3.77 - 3.65 (m, 1H), 3.28 - 3.20 (m, 4H), 2.54 - 2.45 (m, 4H), 2.32 (s, 3H), 1.19 (d, J = 6.3 Hz, 6H).
A mixture of <strong>[116632-24-7]2-amino-4,6-dichloropyridine</strong> (1.0 g, 6.1 mmol) and isopropylamine (5.0 mL. 61.1 mmol) was heated to 140 C in a microwave for 12h. The reaction was cooled to room temperature, concentrated and the crude residue was purified by FCC (40 g SiO2, 0 to 30% EtOAc : hexane) to afford 4-chloro-N2-isopropylpyridine-2,6-diamine (0.46 g, 40%). MS (ESI): mass calcd. for C8H12ClN3, 185.1; m/z found, 186.1 [M+H]+. 1H NMR (CDCl3): 5.80 (d, J = 1.4 Hz, 1H), 5.75 (d, J = 1.4 Hz, 1H), 4.28 - 4.18 (m, 3H), 3.77 - 3.67 (m, 1H), 1.19 (d, J = 6.4 Hz, 6H).To a solution of 4-chloro-N2-isopropylpyridine-2,6-diamine (100 mg, 0.54 mmol) in i-PrOH (1.0 mL) was added N-methylpiperazine (108 mg. 1.1 mmol) and ytterbium trifluoromethanesulfonate hydrate (378 mg. 0.59 mmol). The reaction was heated to 160 C in a microwave for 2h. The reaction was cooled to room temperature, concentrated and the crude residue was purified by FCC (12 g SiO2, 0 to 10% 2.0 M ammonia in MeOH : CH2Cl2) to afford the title compound 8a (30 mg, 22%). MS (ESI): mass calcd. for C13H23N5, 249.2; m/z found, 250.2 [M+H]+. 1H NMR (CDCl3): 5.36 (d, J = 1.8 Hz, 1H), 5.26 (d, J = 1.8 Hz, 1H), 4.07 - 3.95 (m, 3H), 3.77 - 3.65 (m, 1H), 3.28 - 3.20 (m, 4H), 2.54 - 2.45 (m, 4H), 2.32 (s, 3H), 1.19 (d, J = 6.3 Hz, 6H).
With caesium carbonate;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In 1,2-dimethoxyethane; water; at 80℃; for 24h;Inert atmosphere;
Step A: 4-Chloro-6-(2-trifluoromethyl-phenyl)-pyridin-2-ylamine A solution of <strong>[116632-24-7]4,6-dichloro-pyridin-2-ylamine</strong> (1.00 g, 6.14 mmol) in DME (75 mL) and water (50 mL) was treated with Cs2CO3 (6.00 g, 18.4 mmol) and 2-(trifluoromethyl)phenylboronic acid (1.52 g, 7.98 mmol). The resulting mixture was degassed by heating under a stream of Ar. Cl2Pd(dppf).DCM (270 mg, 0.368 mmol) was added, and the mixture was heated to 80 C. for 24 h. The cooled mixture was diluted with EtOAc (70 mL) and washed twice with water (50 mL). The combined aqueous layers were extracted twice with EtOAc (50 mL). The combined organic extracts were dried over MgSO4 and concentrated in vacuo. The residue was purified on a 115-g SEPRA Si 35 SPE silica column (Flow rate=30 mL/min; Eluent=EtOAc-hexanes, 1:19 for 15 min, 1:19 to 1:3 over 40 min, then 1:3 until product eluted) to yield 4-chloro-6-(2-trifluoromethyl-phenyl)-pyridin-2-ylamine as an off-white solid. 1H-NMR (400 MHz, CDCl3) delta: 7.74 (d, J=7.6 Hz, 1H), 7.59 (t, J=7.5 Hz, 1H), 7.50 (t, J=7.7 Hz, 1H), 7.45 (d, J=7.6 Hz, 1H), 6.77 (d, J=1.5 Hz, 1H), 6.53 (d, J=1.5 Hz, 1H), 4.59 (br. s., 2H). Mass Spectrum (LCMS, ESI pos.): Calculated for C12H8N2ClF3: 273.0 (M+H); Measured: 273.0.
A stirred solution of <strong>[116632-24-7]4,6-dichloropyridin-2-amine</strong> (0.1 g, 0.61 mmol) in morpho- line (0.080 g, 0.92 mmol) was stirred at 23C for 115 h. After which, water was added to the mixture and extracted with ethyl acetate. The combined organics were concentrated in vacuo. The crude mixture was purified on alumina (0-30% ethyl acetate in hexane) to give the desired product 4-chloro-6-morpholino- pyridin-2-amine. Mass Spectrum (ESI) m/e = 214.1 (M + 1).
Ethoxycarbonyl isothiocyanate (2 g, 16 mmol) was added to a solution of <strong>[116632-24-7]4,6-dichloropyridin-2-amine</strong> (2.2 g, 13 mmol) in 1,4-dioxane (100 mL) and stirred at rt for 18 h. LCMS showed desired product. The reaction mixture was concentrated in vacuo and the residue azeotroped with EtOAc (3×20 mL) to give a cream solid, which was triturated with EtOAc to give the desired product as a white solid (2.9 g, 76%). 1H NMR (DMSO) delta 12.31 (s, 1H), 11.77 (s, 1H), 8.86 (d, J=1.1 Hz, 1H), 7.66 (d, J=1.5 Hz, 1H), 4.25 (q, J=7.1 Hz, 2H), 1.28 (t, J=7.1 Hz, 3H). m/z [M+H]+=293.88
With sodium carbonate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In 1,4-dioxane; water;Inert atmosphere; Reflux;
1 14 Compound 14: To a solution of the <strong>[116632-24-7]4,6-dichloropyridin-2-amine</strong> (1.636 g, 10.04 mmol, Small Molecules, Inc.) in dioxane (100 mL) was added 2-(4-(4-fluorophenoxy)phenyl)- 4,4,5,5-tetramethyl-l ,3,2-dioxaborolane (compound 1, 3.157 g, 10.05 mmol), 2M aqueous Na2C03 solution (10.0 mL, 20.0 mmol) and PdCl2(dppf) (0.413 g, 0.51 mmol). The vessel was heated at reflux under nitrogen overnight. After cooling, the reaction was partitioned between 100 mL EtOAc and 50 mL water. The organics were isolated and the aqueous extracted once more with 25 mL EtOAc. The combined organic layers were washed once with 25 mL brine, dried over MgS04, filtered and concentrated in vacuo. The residue was chromatographed over silica gel eluting with 10-40% EtOAc in hexanes. The product fractions were isolated and evaporated in vacuo to yield 4-chloro-6-(4-(4- fluorophenoxy)phenyl)pyridin-2-amine (compound 14) as a thick yellow oil (2.215 g, 7.04 mmol, 70% yield, LC/MS: m/z = 315.1 [M+H]+).
With bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide; triethylamine; In tetrahydrofuran; acetonitrile; at 90℃; for 17h;Inert atmosphere;
4-chloro-6-(2-phenylethynyl)pyridin-2-amine Dichlorobis(triphenylphosphine)palladium(II) (2.5 g, 3.06 mmol) is added to a mixture of <strong>[116632-24-7]2-amino-4,6-dichloropyridine</strong> (5 g, 30.7 mmol), ethynylbenzene (7.05 g, 69 mmol), copper(I) iodide (0.58 g, 3.07 mmol), triethylamine (10.8 ml, 78 mmol), THF (25 ml) and ACN (50 ml) under argon atmosphere and is stirred at 90C for 17 h. The mixture is diluted with water (100 ml) and extracted with EtOAc. The combined organic layers are dried over MgSC^ and concentrated in vacuo. The product is purified by NP chromatography. Yield: 3.52 g (50%). HPLC-MS: M+H=229; tR=1.85 min (METHOD l).
50%
With bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide; triethylamine; In tetrahydrofuran; acetonitrile; at 90℃; for 17h;Inert atmosphere;
F1) 4-chloro-6-(2-phenylethynyl)pyridin-2-amine [0163] Dichlorobis(triphenylphosphine)palladium(II) (2.5 g, 3.06 mmol) is added to a mixture of <strong>[116632-24-7]2-amino-4,6-dichloropyridine</strong> (5 g, 30.7 mmol), ethynylbenzene (7.05 g, 69 mmol), copper(I) iodide (0.58 g, 3.07 mmol), triethylamine (10.8 ml, 78 mmol), THF (25 ml) and ACN (50 ml) under argon atmosphere and is stirred at 90 C. for 17 h. The mixture is diluted with water (100 ml) and extracted with EtOAc. The combined organic layers are dried over MgSO4 and concentrated in vacuo. The product is purified by NP chromatography. Yield: 3.52 g (50%). HPLC-MS: M+H=229; tR=1.85 min (METHOD-1).
43%
With copper(l) iodide; dichlorobis(triphenylphosphine)palladium(II); triethylamine; In tetrahydrofuran; acetonitrile; at 90℃; for 6h;Inert atmosphere;
A mixture of <strong>[116632-24-7]4,6-dichloropyridin-2-amine</strong> (2.0 g, 12.3 mmol), ethynylbenzene (2.51 g, 24.5 mmol), copper(I) iodide (234 mg, 1.23 mmol), Dichlorobis(triphenylphosphine)- palladium(II) (1.0 g, 1.23 mmol) and triethylamine (4.3 ml, 31 mmol) is stirred under argon atmosphere in ACN (20 ml) with THF (10 ml) for 6 h at 90C. The mixture is diluted with water and extracted with EtOAc. The combined organic layers are dried over MgS04, concentrated in vacuo and the product purified by NP chromatography. Yield: 1.2 g (43%). HPLC-MS: M+H=229; tR=l .96 min (*Method_2).
43%
With bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide; triethylamine; In tetrahydrofuran; acetonitrile; at 90℃; for 6h;Inert atmosphere;
A mixture of <strong>[116632-24-7]4,6-dichloropyridin-2-amine</strong> (2.0 g, 12.3 mmol), ethynylbenzene (2.51 g, 24.5 mmol), copper(I) iodide (234 mg, 1.23 mmol), Dichlorobis(triphenylphosphine)-palladium(II) (1.0 g, 1.23 mmol) and triethylamine (4.3 ml, 31 mmol) is stirred under argon atmosphere in ACN (20 ml) with THF (10 ml) for 6 h at 90 C. The mixture is diluted with water and extracted with EtOAc. The combined organic layers are dried over MgSO4, concentrated in vacuo and the product purified by NP chromatography. Yield: 1.2 g (43%). HPLC-MS: M+H=229; tR=1.96 min (*Method-2).
General procedure: A mixture of a 2-aminopyridine (1 mmol), phthalaldehyde (2) (1 mmol), and TMSCN (3)(1 mmol) in CH3CN (10 mL) was refluxed for the appropriate amount of time.After completion of the reaction, as indicated by TLC (EtOAc/n-hexane, 4:1), themixture was filtered and the residue purified by washing with n-hexane(5 mL), and then crystallized from EtOH or CH3CN to give pure crystallineproducts 4a-i.
With sodium hexamethyldisilazane; In tetrahydrofuran; at -78 - 20℃; for 12h;
To a stirred solution of <strong>[116632-24-7]4,6-dichloropyridin-2-amine</strong> (5.0 g, 30.6 mmol) in THF (100.0 mL) was added NaHMDS (67.5 mL, 1M solution in THF, 67.0 mmol) at -78 C followed by Boc anhydride (8.08 g, 36.7 mmol) and allowed to warm to room temperature over 12 h. After confirming the completion of starting material by TLC, the reaction mixture was quenched with saturated ammonium chloride solution extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous Na2SO4, filtered, concentrated under reduced pressure to get crude product which was purified by column chromatography (hexanes:ethyl acetate=9: 1) to afford desired product. 1H NMR (ppm, 400 MHz, DMSO-d6): delta 10.48 (s, 1H),7.85 (s, 1H), 7.36 (s, 1H), 1.46 (s, 9H), MS ES calc?d. for C10H12Cl2N2O2 [M+H]+ 263, Found: 263.
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