* 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] Synthesis, 1989, # 12, p. 905 - 908
[2] Synthesis, 1989, # 12, p. 905 - 908
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[ 212268-12-7 ]
[ 21717-96-4 ]
Reference：
[1] Patent: CN107827887, 2018, A, . Location in patent: Paragraph 0027; 0028
3
[ 100304-88-9 ]
[ 21717-96-4 ]
Reference：
[1] Synthesis, 1989, # 12, p. 905 - 908
4
[ 31301-51-6 ]
[ 5350-93-6 ]
[ 21717-96-4 ]
Reference：
[1] Synthesis, 1989, # 12, p. 905 - 908
[2] Synthesis, 1989, # 12, p. 905 - 908
5
[ 127773-43-7 ]
[ 21717-96-4 ]
[ 100304-88-9 ]
Reference：
[1] Synthesis, 1989, # 12, p. 905 - 908
6
[ 31301-51-6 ]
[ 21717-96-4 ]
Reference：
[1] Patent: WO2017/74914, 2017, A1,
7
[ 884495-37-8 ]
[ 21717-96-4 ]
Reference：
[1] Patent: CN107827887, 2018, A,
8
[ 136888-21-6 ]
[ 21717-96-4 ]
Reference：
[1] Patent: CN107827887, 2018, A,
9
[ 127773-43-7 ]
[ 21717-96-4 ]
Reference：
[1] Synthesis, 1989, # 12, p. 905 - 908
[2] Synthesis, 1989, # 12, p. 905 - 908
10
[ 4214-76-0 ]
[ 21717-96-4 ]
Reference：
[1] Bioorganic and Medicinal Chemistry, 2008, vol. 16, # 23, p. 9948 - 9956
11
[ 21717-96-4 ]
[ 41404-58-4 ]
Yield
Reaction Conditions
Operation in experiment
66%
Stage #1: With hydrogen bromide; bromine; sodium nitrite In water at 0 - 5℃; for 1 h; Stage #2: With sodium hydroxide In water at 20℃; for 0.333333 h;
EXAMPLE C 2-Bromo-5-fluoro-pyridine; 2-Amino-5-fluoropyridine (6.5 g, 58 mmol) was added in portions to cool (0-5° C.) hydrobromic acid 48percent (28.8 ml, 296 mmol). Bromine (8.9 ml, 174 mmol) and a solution of sodium NaNO2 (10 g, 145 mmol) in 20 ml water were added drop wise at 0-5° C. (N2-evolution.). The reaction mixture was stirred for 1 hr and quenched with conc. NaOH (32percent) (50.5 ml, 0.55 mol). The reaction mixture was stirred at room temperature for 20 minutes and extracted then three times with diethyl ether. The combined organic extracts were washed with brine, dried with sodium sulfate, filtered and evaporated only at 30° C. and 500 mbar (volatile.). The crude product was purified by flash chromatography on silica gel (dichloromethane/pentane 0:100->50:50 gradient). The desired compound was obtained as a light yellow solid (6.7 g, 66percent).
36%
Stage #1: at 0℃; for 0.333333 h; Stage #2: With sodium nitrite In water at -10℃; for 2 h; Stage #3: With sodium hydroxide In water at 5℃; for 0.5 h;
To a 3-neck flask equipped with a dropping ihtmel and thermometer, 48percent BBr (26'.?' mL) was added, S-Fiooropyridia-Z-aittine (6,0 g, 0.05 mol) was added, dropwise at 0 °C. Br2 (8*0 mL, 0.16 mol) was then added at 0 "C dropwise over 20 mm. The reaction mixture was cooled to -1.0 °C and a solution ofNa O^ (9.3 g, 0.14 mol) in water (30 ml) was added over 1.5 hours, 'the resulting mixture was stirred for an. additional 30 minutes. A solutio of NaO (20 g, 0.50 mol) in water (30 mL) was added over 30 mirtutes. The reaction mixture was warmed to 5 °C and then extmcted with ether (3* 100 .mL). The combined organic phases were washed with brine, dried over sodium sulfate, filtered, and concentrated. The concentrate was purified by column chromatography over silica gel (hexane/EiOAc::::lG0. i) to afford the title compound as a colorless liquid (3.37 g, 36percent).. 1H ‘NMR (400 MHz, CDC[4) d 8.27 Cd, J 3.0 Hz, ff1). 7.48 (dd, J =8.7, 4.0 Hz, IFi), 735 - 7,2S (m. I H).
Reference：
[1] Patent: US2007/78155, 2007, A1, . Location in patent: Page/Page column 29
[2] Patent: WO2016/44323, 2016, A1, . Location in patent: Paragraph 0268
[3] Bioorganic and Medicinal Chemistry Letters, 2007, vol. 17, # 19, p. 5349 - 5352
12
[ 21717-96-4 ]
[ 136888-21-6 ]
Reference：
[1] Patent: EP2471792, 2012, A1,
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[ 21717-96-4 ]
[ 571188-59-5 ]
Reference：
[1] Patent: WO2012/97682, 2012, A1,
14
[ 21717-96-4 ]
[ 571189-16-7 ]
Reference：
[1] Patent: WO2012/97682, 2012, A1,
15
[ 21717-96-4 ]
[ 869557-43-7 ]
Yield
Reaction Conditions
Operation in experiment
82%
With sulfuric acid; bromine In water at 30 - 50℃; for 26 h; Large scale
Procedure C: Alternatively the bromination was performed by employing H2S04. In one specific example, to 93percent sulfuric acid (12.5 kg, 119 mol) in water (26 L) in a 50-L reactor was added 2-amino-5-fluoropyridine (6.5 kg, 58 mol). The temperature was adjusted to 30 °C then bromine (10 kg, 63 mol) added in ten portions over three hours. The mixture was stirred at 45 °C for 18 hours, then at 50 °C for 5 hours. The mixture was cooled to 15 °C for work-up in a 400-L reactor. [0260] Four of the above reactions (4 χ 6.5 kg) were combined and quenched in to a mixture of 50percent sodium hydroxide (110 kg, 1375 mol) and sodium thiosulfate (1.8 kg, 11.4 mol) in water (100 L) at -3 °C over one hour. The temperature was adjusted to 32 °C and the slurry filtered and washed with water (80 L) to afford water-wet crude product (62 kg). A second run of three reactions (3 χ 6.5 kg SM) was similarly carried out to afford water-wet crude product (41 kg). The crude products (103 kg) were dissolved (some insolubles) in toluene (280 kg) at 25-30 °C. Brine (20 kg) was added but phase break not possible due to solids. The mixture was filtered through a pad of Celite, washing with toluene, and the layers thenseparated. The organics were concentrated to 347 L volume to azeotrope residual water for the use of the preparation of compound 3a. An aliquot was used to determine product concentration as being 181 g per liter of solution. Yield = 62.8 kg. An additional 600 g was isolated by extraction of the water/brine layer with ethyl acetate (10 L), and subsequent filtration through a pad of magnesol, evaporation and trituration with hexane. Total yield is 82percent
82%
With sulfuric acid; bromine In water at 30 - 50℃; for 26 h;
4-1 a 4-2a [0252] Alternatively the bromination was performed by employing H2S04. In one specific example, to 93percent sulfuric acid (12.5 kg, 119 mol) in water (26 L) in a 50 L reactor was added 2-amino-5-fluoropyridine (6.5 kg, 58 mol). The temperature was adjusted to 30 °C then bromine (10 kg, 63 mol) added in ten portions over three hours [exothermic, temperature kept to 30 °C to 40 °C, vent set up to scrub through aq. NaOH/Na2S203]. The mixture was stirred at 45 °C for 18 hours, then at 50 °C for 5 hours. The mixture was cooled to 15 °C for workup in a 400 L reactor. Four of the above reactions (4 * 6.5 kg) were combined and quenched in to a mixture of 50percent sodium hydroxide (1 10 kg, 1375 mol) and sodium thiosulfate (1.8 kg, 1 1.4 mol) in water (100 L) at -3 °C over one hour. The temperature was adjusted to 32 °C and the slurry filtered and washed with water (80 L) to afford water-wet crude product (62 kg). A second run of three reactions (3 * 6.5 kg SM) was similarly carried out to afford water-wet crude product (41 kg). The crude products (103 kg) were dissolved (some insolubles) in toluene (280 kg) at 25 °C to 30 °C. Brine (20 kg) was added but phase break not possible due to solids. The mixture was filtered through a pad of Celite, washing with toluene, and the layers then separated. The organics were concentrated to 347 L volume to azeotrope residual water for the use of the preparation of compound 4-3a. An aliquot was used to determine product concentration as being 181 g per liter of solution. Yield = 62.8 kg. An additional 600 g was isolated by extraction of the water/brine layer with ethyl acetate (10 L), and subsequent filtration through a pad of magnesol, evaporation and trituration with hexane. Total yield is 82percent.
53%
With N-Bromosuccinimide In acetonitrile at 20℃; for 2 h;
To a solution of 5-fluoropyridin-2-amine (6 g, 53.52 mmol) in acetonitrile (120 mL) was added slowly NBS (12.64 g, 69.60 mmol), and the mixture was stirred at rt for 2 h, then concentrated in vacuo to dry. The residue was purified by silica gel column chromatography (PE/EA (v/v) = 20/1) to give the title compound as a yellow solid (5.4 g, 53percent).MS (ESI, pos.ion) m/z: 193.O[M+H]1H NMR (400 MHz, CDC13) (ppm): 7.95 (d, J = 2.5 Hz, 1H), 7.52 (dd, J = 7.3, 2.6 Hz, 1H), 4.84 (s, 2H).
31%
With N-Bromosuccinimide In acetonitrile at 20℃;
NBS (10 g, 56.2 mmol) was added slowly to a solution of 5-fluoro-pyridin-2- ylamine (12.4 g, 56.2 mmol) in MeCN (200 mL). The reaction mixture was stirred at RT overnight. After completion, the solution was filtered and the filtrate was concentrated to get a residue, which was purified by silica gel chromatography to give the product (5.2 g, 31percent) as a yellow solid.
31%
With N-Bromosuccinimide In acetonitrile at 20℃;
NBS (10 g, 56.2 mmol) was added slowly to a solution of 5-fluoro-pyridin-2- ylamine (55) (12.4 g, 56.2 mmol) in MeCN (200 mL). The reaction mixture was stirred at RT overnight. After completion, the solution was filtered and the filtrate was concentrated to obtain a residue, which was purified by silica gel chromatography (10percent> to 20percent> EtOAc in petroleum ether) to give 3-bromo-5-fluoro-pyridin-2-ylamine (56) (5.2 g, 27.2 mmol, 31percent> yield) as a yellow solid.ESI-MS (M+l): 191 calc. for C5H4BrFN2 190.
28%
With N-Bromosuccinimide In acetonitrile at -10 - 20℃; for 2.75 h; Inert atmosphere
Description 18 (D18); 3-bromo-5-fluoro-2-pyridinamine; To a stirred solution of 2-amino-4-fluropyridine (22.5 g, 0.20 mol) in acetonitrile (400 ml_) at -10C was added N-bromosuccinimide (37.9 g, 0.21 mol) portionwise over 15 min. Reaction mixture was allowed to stir at this temperature for 1 .5 h and at room temperature for a further 1 h. Ethyl acetate (200 ml_) added and the reaction mixture filtered to remove solids. The filtrate was concentrated in vacuo, triturated with ethyl acetate (300 ml_) and filtered the cake was washed with ethyl acetate (2 x 100 ml_). The filtrate washed with 1 M sodium hydroxide (100 ml_), water (50 ml_) and then brine (50 ml_). The combined organics were dried over sodium sulfate and solvent removed in vacuo yielding a solid. Material purified by column chromatography eluting with 25percent ethyl acetate in hexane. The relevant fractions were combined and solvent removed in vacuo yielding a light brown solid (20.4 g) which was recrystallised from hexane to furnish the title compound (10.8 g, 28percent).1H NMR: (300 MHz, CDCI3) δ 7.92 (d, 1 H), 7.50 (dd, 1 H), 4.80 (s, 2H).
Synthesis of compound 207.2. A solution of 207.1 (6.0g, 53.51mmol, l .Oeq) in concentrated H2SO4 (60 ml) was cooled at 0 °C (A). Further in another flask hydrogen peroxide (13 ml) was added to concentrated sulphuric acid at 0 °C (B). Further solution (A) was added dropwise to solution (B) at 0 °C. The reaction was stirred at room temperature for 16 h. After completion of reaction, reaction mixture was poured in ice cold water and product was extracted with EtOAc. Organic layers were combined, dried over sodium sulphate and evaporated to obtain pure compound 207.2 (3.0g, 39.45percent). MS (ES): m/z 142.09 [M+H]+.
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2007, vol. 17, # 19, p. 5349 - 5352
18
[ 21717-96-4 ]
[ 212268-12-7 ]
Yield
Reaction Conditions
Operation in experiment
3.6%
With nitric acid In methanol; diethyl ether; dichloromethane; sulfuric acid; Petroleum ether
Example 2.4 Synthesis of 2-amino-5-fluoro-3-nitropyridine To a solution of 2-amino-5-fluoropyridine (8.6 g, 77 mmol) in conc. sulfuric acid (40 ml) was added dropwise (30 min) fuming nitric acid (3.25 ml, 77 mmol) at a temperature of +3° C. The reaction mixture was stirred at room temperature for 1 h and at +55° C. for 1 h. The mixture was poured onto ice and neutralized with 10 M sodium hydroxide and was extracted with methylene chloride. The organic layer was separated, dried over sodium sulfate and evaporated under reduced pressure. The residue was purified twice by column chromatography on silica gel, using (i) methanol:methylene chloride (1:20) and (ii) diethyl ether:petroleum ether (1:1) as eluent to give the title compound (0.44 g, 3.6percent). 1H-NMR (300 MHz, CDCl3): δ6.65 (bs, 2H), 8.20 (dd, 1H), 8.35 (d, 1H)
With sulfuric acid; iodine; periodic acid In water; acetic acid at 80 - 82℃; Large scale
H2S04 (120 mL) was added, dropwise, to a solution of 2-amino-5-fluoropyridine (1 kg, 8.9 mol) in AcOH (4 L) and H20 (1 L) over 5 minutes. Periodic acid (H5I06; 450 g, 1.97 mol, 0.22 eq) and I2 (1 kg, 3.94 mol, 0.44 eq) were added and the reaction mixture was stirred at 82 °C (internal) overnight. A sample (diluted with H20, made alkaline with 30percent NaOH, extracted with EtOAc, cone.) showed 13-15percent starting material. More Η5Ι06 (80 g) and I2 (180 g) were added and stirring was continued at 80 °C overnight. The external heating was removed and the reaction mixture was stirred at RT overnight. The reaction mixture was poured over ice-water (8 L), made alkaline with 33percent aq. NaOH (-6.5 L needed) and stirred for 2 h. The precipitated product was collected by filtration, and washed with hot H20 (8 x 3L). The filter wash left overnight after which the product was washed with heptanes (3x). The product was dried in the stove at 45 °C over the weekend. Compound 2b (1390 g, 65percent yield) was obtained as a black solid. H20 was added to the heptanes layer and it was left over the weekend. The dark aqueous layer was separated from the light-yellow organic layer, which was concentrated to dryness. More compound 2b (95 g, 70percent total yield) was thus obtained as a yellow solid. NMR (DMSO-c/6, 300 MHz): δ 7.95-7.88 (m, 2H) ppm. NMR (CDC13, 300 MHz): 57.95-7.90 (m, 1H); 7.68-7.62 (m, 1H); 4.85 (s, NH2) ppm
60%
With sodium periodate; sulfuric acid; sodium iodide In water at 100℃; for 1 h; Heating / reflux
Step 1:Sodium periodate (1.53 g, 7.16 mmol) was added to a stirred solution of 5-fluoro-2- aminopyridine (2.0 g, 17.9 mmol) in aqueous sulphuric acid (2.0 M, 30 mL) and the reaction heated to 100 0C. A solution of sodium iodide (2.68 g, 17.9 mmol) in water (10 mL) was added dropwise to the reaction mixture. After completion of addition, the mixture was refluxed for 1 h and then cooled to room temperature. Saturated aqueous sodium bicarbonate solution was added dropwise to adjust pH -7.0 and the mixture was extracted with dichloromethane (3 x). The combined organic layers were washed with aqueous sodium bisulfite solution, brine, dried and concentrated in vacuo. The residue was subjected to column chromatography (hexane/ethyl acetate 4:1) to afford the desired compound (2.56 g, 60percent).1HNMR (300MHz, CDCl3) δ 4.70-5.03 (brs, 2H), 7.69 (dd, J=7.2, 2.1 Hz, IH), 7.93 (d, J =2.1 Hz, IH)MS (ESI+) m/z 239 (M+l)
58%
Stage #1: at 100℃; Stage #2: With potassium iodide In water for 1.5 h;
Step 1 : 5-Fluoro-3-iodo-pyridin-2-ylamine A stirred solution of 5-fluoro-pyridin-2-ylamine (50 g, 0.45 mol) in 2M sulfuric acid (250 mL) was treated portionwise with potassium iodate (48 g, 0.22 mol) and the mixture heated to 100 °C. A solution of potassium iodide (41 g, 0.24 mol) in water (100 mL) was added dropwise over ca. 1 hour. The mixture was allowed to stir for a further 30 minutes then cooled to ambient temperature. The pH of the aqueous phase was adjusted to 8-9 and the mixture extracted with ethyl acetate (x 3). The combined organic layer was washed with aqueous sodium thiosulfate solution, water and brine, dried (Na2S04), filtered and evaporated to afford the title compound as a yellow solid (61.2 g, 58percent). NMR (400 MHz, CDC13): 7.94 (d, J = 2.7 Hz, 1H), 7.68 (dd, J = 7.2, 2.7 Hz, 1H), 4.85 (s, 2H).
20.4%
for 95 h; Heating / reflux
Preparation 21 A; 2-Amiπo-5-fluoro-3-iodψDyridiπe; The following procedure is a modification of that of Dinnell (US2002 22624A1) for iodination of δ-chloro^-aminopyridine. A mixture of 2-amino-5-fluoropyridine (5.0 g, 45 mmol), iodine (11.3 g, 45 mmol) and Ag2SO4 (14.0 g, 45 mmol) in ethanol was heated at reflux for 95 h, cooled, and filtered. The filtrate was concentrated and partitioned between600 mL DCM and 200 mL 2N NaOH. The organic layer was separated, washed with water and dried giving a solid (4.6 g). The aqueous NaOH layer was extracted with 500 mL 4:1 DCM-2-propanol, dried and concentrated. The residue (1.1 g) was combined with the other solid. SGC (loaded in DCM, eluted with 20percent EtOAc-hexanes) giving an orange solid. Yield2.19 g, 20.4percent. 1H NMR (CDCI3) δ 7.91 (d, 1H, J = 2.7 Hz)1 7.65 (dd, 1H, J = 2.7, 7.3 Hz)14.83 (br, 2H). MS (ES+) m/e 239 (MH+).
Stage #1: With sodium hydride In tetrahydrofuran at 20 - 40℃; for 0.5 h; Stage #2: at -40 - 20℃;
To a suspension of sodium hydride (60percent dispersion in mineral oil, 117.8 mg, 4.91 mmol) in tetrahydrofuran (25 ml) was added a solution of 5- fluoropyridin-2-amine (500 mg, 4.46 mmol) in tetrahydrofuran (25 ml) at room temperature and the reaction mixture was stirred at 40 °C for 30 min. Then to the reaction mixture was added methyl iodide (696.9 mg, 4.91 mmol) at -40 °C and the resulting mixture was stand at room temperature overnight with stirring. The reaction was quenched by the addition of water and whole mixture was extracted with ethyl acetate. The organic extracts were dried over sodium sulfate and concentrated. The residue was purified by flush column chromatography on silica gel eluting with hexane/ethyl acetate (4/1) to afford 129 mg (23percent) of the title compound: (at)H-NMR (CDCI3) 5 7.97 (1 H, d, J = 2.6 Hz), 7.28-7.17 (1 H, m), 6.34 (1 H, dd, J = 3.5,9.1 Hz), 2.90 (3H, d, J = 5.1 Hz).
To a solution of 2-amino-5-fluoropyridine (10 g) in ethanol (200 mL), a solution of chloroacetaldehyde 50percent in water (56 mL, 4.0 equiv.) was added. The reaction mixture was heated at reflux 2 Hrs, then was concentrated under reduced pressure to 100 mL. The residue was diluted in AcOEt (100 mL) and washed with a saturated aqueous solution of NaHCO3 (2* 150 mL). The combined aqueous were saturated with NaHCO3 and extracted back with AcOEt (2*100 mL). The combined organic layers were washed with brine (100 mL), dried over Na2SO4 and concentrated under reduced pressure. Purification by flash-chromatography (MeOH 2.5percent in CH2Cl2) afforded the product as a cream solid (8.7 g, 72percent). M/Z (M+H)+ = 137.
429A-Preparation of 5-Fluoro-2-nitro-pyridine To concentrated H2SO4 at 0 C. was added 4 ml of 3% H2O2. To this solution at 0 C. was added 5-fluoro-2-amino-pyridine (250 mg, 2.23 mmol). The mixture was warmed to room temperature and stirred for 20 hr, then poured onto ice. The aqueous solution was extracted with EtOAc (3*30 ml). The combined organic layers were washed with water, brine and dried with Na2SO4. Removal of the solvent gave a light brown oil (245 mg, 77%). The product was used for next step without further purification.
76%
With sulfuric acid; dihydrogen peroxide; at 0℃; for 24h;
H2O2 (37%, 50ml) was drop wise added to concentrated H2SO4 (200 ml) at 0 C in open air and after 5 min stirring at same temperature, 5-fluoropyridin-2-amine (11, 20.0 g, 0.139 mol) in conc. H2SO4 (200 ml) was slowly added and stirred for 24 h. The reaction mixture was diluted with water (300 ml) and extracted with DCM (3 x 300 ml). The organic layers were combined, washed with 5% of aqueous sodium bi-sulphate (200 ml), dried (Na2SO4) and concentrated in vacuo. The residue was purified by flash column chromatography [normal phase, silica gel (100-200 mesh) and gradient 3% to10% ethyl acetate in hexane] and then triturated with pentane (100 ml) to give 5-fluoro-2-nitropyridine (12, 14.0 g, 76%) as an off-white solid.1H-NMR (400 MHz; CDCl3): d 7.70 - 7.77 (m, 1H), 8.32 - 8.38 (m, 1H), 7.48 (d, J = 2.6 Hz,1H).
39.45%
With sulfuric acid; dihydrogen peroxide; at 0 - 20℃; for 16h;
Synthesis of compound 207.2. A solution of 207.1 (6.0g, 53.51mmol, l .Oeq) in concentrated H2SO4 (60 ml) was cooled at 0 C (A). Further in another flask hydrogen peroxide (13 ml) was added to concentrated sulphuric acid at 0 C (B). Further solution (A) was added dropwise to solution (B) at 0 C. The reaction was stirred at room temperature for 16 h. After completion of reaction, reaction mixture was poured in ice cold water and product was extracted with EtOAc. Organic layers were combined, dried over sodium sulphate and evaporated to obtain pure compound 207.2 (3.0g, 39.45%). MS (ES): m/z 142.09 [M+H]+.
Preparation 25-Fluoro-2-nitro-pyridineTo sulfuric acid (46 mL) at 0 C. add 25% hydrogen peroxide (26.98 mL) in the open air. After 5 min add a cold solution of 2-amino-5-fluoropyridine (9 g) in concentrated sulfuric acid (46 mL) drop wise with an addition funnel Stir the resulting dark solution at 0 C. to RT in the bath overnight. Pour over 200 mL ice-water and extract with DCM. Wash combined organic layers with 5% aqueous solution of sodium bisulfite and dry over anhydrous sodium sulfate. Remove the solvent under vacuum and purify by silica gel column chromatography eluting with DCM to afford 7.5 g of the title compound. MS (ES+): m/z=143 (M+H)+.
With sulfuric acid; dihydrogen peroxide; In water; at 0 - 20℃; for 16h;
EXAMPLE 103 7-(2-chlorophenoxy)-5-{ [5-(piperazin-l-yl)pyridin-2-yl]amino}pyrido[3,4-d]pyridazin-4(3H)-one EXAMPLE 103 A 5 -fluoro-2-nitropy ridine To concentrated sulfuric acid (6 mL) at 0C was added dropwise 30% aqueous hydrogen peroxide (2.5 mL). To the mixture was added a pre-cooled solution of 5- fluoropyridin-2-amine (1 g, 8.9 mmol) in concentrated sulfuric acid (6 mL). The mixture was stirred at ambient temperature for 16 hours, poured into ice-water and extracted with ethy l acetate. The combined organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by flash chromatography on silica gel (200-300 mesh) eluting with 98/2 dichloromethane/methanol to give the title compound. MS: 143 (Mu+Iota-Gamma).
EXAMPLE C 2-Bromo-5-fluoro-pyridine; <strong>[21717-96-4]2-Amino-5-fluoropyridine</strong> (6.5 g, 58 mmol) was added in portions to cool (0-5 C.) hydrobromic acid 48% (28.8 ml, 296 mmol). Bromine (8.9 ml, 174 mmol) and a solution of sodium NaNO2 (10 g, 145 mmol) in 20 ml water were added drop wise at 0-5 C. (N2-evolution.). The reaction mixture was stirred for 1 hr and quenched with conc. NaOH (32%) (50.5 ml, 0.55 mol). The reaction mixture was stirred at room temperature for 20 minutes and extracted then three times with diethyl ether. The combined organic extracts were washed with brine, dried with sodium sulfate, filtered and evaporated only at 30 C. and 500 mbar (volatile.). The crude product was purified by flash chromatography on silica gel (dichloromethane/pentane 0:100->50:50 gradient). The desired compound was obtained as a light yellow solid (6.7 g, 66%).
36%
To a 3-neck flask equipped with a dropping ihtmel and thermometer, 48% BBr (26'.?' mL) was added, S-Fiooropyridia-Z-aittine (6,0 g, 0.05 mol) was added, dropwise at 0 C. Br2 (8*0 mL, 0.16 mol) was then added at 0 "C dropwise over 20 mm. The reaction mixture was cooled to -1.0 C and a solution ofNa O^ (9.3 g, 0.14 mol) in water (30 ml) was added over 1.5 hours, 'the resulting mixture was stirred for an. additional 30 minutes. A solutio of NaO (20 g, 0.50 mol) in water (30 mL) was added over 30 mirtutes. The reaction mixture was warmed to 5 C and then extmcted with ether (3* 100 .mL). The combined organic phases were washed with brine, dried over sodium sulfate, filtered, and concentrated. The concentrate was purified by column chromatography over silica gel (hexane/EiOAc::::lG0. i) to afford the title compound as a colorless liquid (3.37 g, 36%).. 1H ?NMR (400 MHz, CDC[4) d 8.27 Cd, J 3.0 Hz, ff1). 7.48 (dd, J =8.7, 4.0 Hz, IFi), 735 - 7,2S (m. I H).
With triethylamine; In dichloromethane; at 15 - 20℃;
INTERMEDIATES (EXAMPLES 54-61) a) N- (5-FLUORO-PYRIDIN-2-YL)-2, 2-DIMETHYL-PROPIONAMIDE To a solution of 33.6 mL triethylamine and 22.5 <strong>[21717-96-4]2-amino-5-fluoropyridine</strong> (0.201 mol) in 200 mL dichloromethane was added dropwise a solution of 28 mL pivaloyl chloride (0.201 mol) in 50 mL dichloromethane at such a rate that the temperature did not exceed 15C (ice bath cooling). The mixture was then stirred overnight with thawing to room temperature. To the resulting brown-black suspension was added 5 g charcoal and the mixture was stirred at room temperature for 30 min and filtered through dicalite. The orange-yellow mother liquor was purified by filtration over a layer of silica gel (400g) with heptane: ethyl acetate = 4 : L, The slightly yellow product fractions were evaporated and the oily residue was distilled in a kugelrohr apparatus at 100C and 0.5 mbar. The compound crystallized on standing at room temperature. Yield: 33.400 g N- (5-FLUORO-PYRIDIN-2-YL)-2, 2-DIMETHYL-PROPIONAMIDE as colorless crystals (84. 8%) ; m. p.: 33.4-35. 2 C.
To a 0 oC solution of 2-AMINO-5-FLUOROPYRIDINE (1.00 g, 8.92 mmol) and triethylamine (1.35 g, 13.4 mmol) in dichloromethane (30 mL) was added trimethylacetyl chloride (1.29 g, 10.7 mmol) and DMAP (0.11 g, 0. 89 MMOL). The solution was allowed to warm to room temperature. After 4 h, saturated aqueous NAHC03 was added, the layers separated and the aqueous phase backwashed with DCM. The combined organics were dried over magnesium sulfate, filtered and concentrated and the residue purified by silica gel chromatography (5% # 40% ETOAC/HEXANES) to give the title compound (1.34 g). MS 197.3 (M+1).
With dmap; triethylamine; In dichloromethane; at 0 - 20℃; for 4h;
To a 0 0C solution of <strong>[21717-96-4]2-amino-5-fluoropyridine</strong> (1.00 g, 8.92 mmol) and triethylamine (1.35 g, 13.4 mmol) in dichloromethane (30 mL) was added trimethylacetyl chloride (1.29 g, 10.7 mmol) and DMAP (0.11 g, 0.89 mmol). The solution was allowed to warm to room temperature. After 4 h, saturated aqueous NuaEtaCtheta3 was added, the layers separated and the aqueous phase backwashed with DCM. The combined organics were dried over magnesium sulfate, filtered and concentrated and the residue purified by silica gel chromatography (5% -> 40% EtOAc /Jiexanes) to give the title compound (1.34 g). MS: m/z = 197.3 (M+l).
With triethylamine; In dichloromethane; at 20℃; for 21h;
Stage 1 Preparation of N-(5-fluoro-pyridin-2-ylV2,2-dimethylpropionamide; To a stirred solution of <strong>[21717-96-4]2-amino-5-fluoropyridine</strong> (50.Og, commercially available) and triethylamine (93ml) in dichloromethane (600ml) was added pivaloyl chloride (56ml) at ambient temperature. The slurry that formed was stirred for 3 hours, stored for 18 hours then washed with water (200ml), brine (100ml) then dried over magnesium sulfate, filtered and evaporated under reduced pressure to give the required product as a brown oil, 86g. 1HNMR (CDO3) delta: 8.30(lEta, dd), 8.10(1H, d), 8.00(1H, bs), 7.42(lH, m), 1.30(9H, s).
With dmap; triethylamine; In dichloromethane; at 0 - 20℃; for 4h;
INTERMEDIATE 4 4-Fluoro-2-oxo-l-(4-piperidinylV2,3-dihydro-lH-imidazo[4,5-b]pyridine Step A. iV-(5-Fluoropyridin-2-yl)-2,2-dimethylpropanamide; To a 0 C solution of <strong>[21717-96-4]2-amino-5-fluoropyridine</strong> (1.00 g, 8.92 mmol) and triethylamine (1.35 g, 13.4 mmol) in dichloromethane (30 mL) was added trimethylacetyl chloride (1.29 g, 10.7 mmol) and DMAP (0.11 g, 0.89 mmol). The solution was allowed to warm to room temperature. After 4 h, saturated aqueous NaHCO3 was added, the layers separated and the aqueous phase backwashed with DCM. The combined organics were dried over magnesium sulfate, filtered and concentrated and the residue purified by silica gel chromatography (5% -> 40% EtOAc / hexanes) to give the title compound (1.34 g). MS 197.3 (M+l).
With dmap; triethylamine; In dichloromethane; at 0 - 20℃; for 4h;
To a 0 0C solution of <strong>[21717-96-4]2-amino-5-fluoropyridine</strong> (1.00 g, 8.92 mmol) and triethylamine (1.35 g, 13.4 mmol) in dichloromethane (30 inL) was added trimethylacetyl chloride (1.29 g, 10.7 mmol) and DMAP (0.11 g, 0.89 mmol). The solution was allowed to warm to room temperature. After 4 h, saturated aqueous NuaHCtheta3 was added, the layers separated and the aqueous phase backwashed with DCM. The combined organics were dried over magnesium sulfate, filtered and concentrated and the residue purified by silica gel chromatography (5% ->? 40% EtOAc / hexanes) to give the title compound (1.34 g). MS 197.3 (M+l).
With triethylamine; In dichloromethane; at 20℃; for 5h;Inert atmosphere;
Step 3: Into a 5-L 4-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed 5-fluoropyridin-2-amine (230 g, 2.05 mol), TEA (415 g, 4.10 mol), and dichloromethane (3000 mL). This was followed by the addition of 2,2-dimethylpropanoyl chloride (271 g, 2.25 mol, 1.10 equiv) dropwise with stirring. The resulting solution was stirred for 5 h at RT. The resulting mixture was washed with water and brine, dried over anhydrous sodium sulfate and concentrated under vacuum to afford N-(5-fluoropyridin-2-yl)-2,2- dimethylpropanamide as a solid.
With triethylamine; In dichloromethane; at 20℃; for 21h;
To a stirred solution of <strong>[21717-96-4]2-amino-5-fluoropyridine</strong> (50.Og, commercially available) and triethylamine (93ml) in dichloromethane (600ml) was added pivaloyl chloride (56ml) at ambient temperature. The slurry that formed was stirred for 3 hours, stored for 18 hours then washed with water (200ml), brine (100ml) then dried over magnesium sulfate, filtered and evaporated under reduced pressure to give the required product as a brown oil, 86g. 1HNMR (CDCl3) delta: 8.3O(1eta, dd), 8.10(1H, d), 8.00(1H, bs), 7.42(lH, m), 1.30(9H, s).
With nitric acid; In methanol; diethyl ether; dichloromethane; sulfuric acid; Petroleum ether;
Example 2.4 Synthesis of 2-amino-5-fluoro-3-nitropyridine To a solution of 2-amino-5-fluoropyridine (8.6 g, 77 mmol) in conc. sulfuric acid (40 ml) was added dropwise (30 min) fuming nitric acid (3.25 ml, 77 mmol) at a temperature of +3 C. The reaction mixture was stirred at room temperature for 1 h and at +55 C. for 1 h. The mixture was poured onto ice and neutralized with 10 M sodium hydroxide and was extracted with methylene chloride. The organic layer was separated, dried over sodium sulfate and evaporated under reduced pressure. The residue was purified twice by column chromatography on silica gel, using (i) methanol:methylene chloride (1:20) and (ii) diethyl ether:petroleum ether (1:1) as eluent to give the title compound (0.44 g, 3.6%). 1H-NMR (300 MHz, CDCl3): delta6.65 (bs, 2H), 8.20 (dd, 1H), 8.35 (d, 1H)
(Reference Example 2-1) Under ice cooling, to 5-fluoropyridine-2-amine (10.36 g) was added concentrated sulfuric acid (48 ml), followed by stirring for 10 minutes, and then fuming nitric acid (3.83 ml) was added dropwise over 30 minutes. Stirring was carried out at room temperature for 1 hour, and further at 55C for 90 minutes. Ice was poured thereinto, and neutralized with a 10 N aqueous sodium hydroxide solution, followed by concentration under reduced pressure. The residue was dissolved in dichloromethane (600 ml), followed by stirring for 30 minutes, and then the insolubles were filtered off to concentrate the filtrate under reduced pressure. The residue was purified by silica gel column chromatography to afford 5-fluoro-3-nitropyridine-2-amine (2.66 g). 1H NMR (500 MHz, CDCl3) delta: 6.61 (br s, 2H), 8.17 (dd, 1H, J = 7.6, 3.1 Hz), 8.31 (d, 1H, J = 3.1 Hz).
With sulfuric acid; iodine; periodic acid; In water; acetic acid; at 80 - 82℃;Large scale;
H2S04 (120 mL) was added, dropwise, to a solution of 2-amino-5-fluoropyridine (1 kg, 8.9 mol) in AcOH (4 L) and H20 (1 L) over 5 minutes. Periodic acid (H5I06; 450 g, 1.97 mol, 0.22 eq) and I2 (1 kg, 3.94 mol, 0.44 eq) were added and the reaction mixture was stirred at 82 C (internal) overnight. A sample (diluted with H20, made alkaline with 30% NaOH, extracted with EtOAc, cone.) showed 13-15% starting material. More Eta5Iota06 (80 g) and I2 (180 g) were added and stirring was continued at 80 C overnight. The external heating was removed and the reaction mixture was stirred at RT overnight. The reaction mixture was poured over ice-water (8 L), made alkaline with 33% aq. NaOH (-6.5 L needed) and stirred for 2 h. The precipitated product was collected by filtration, and washed with hot H20 (8 x 3L). The filter wash left overnight after which the product was washed with heptanes (3x). The product was dried in the stove at 45 C over the weekend. Compound 2b (1390 g, 65% yield) was obtained as a black solid. H20 was added to the heptanes layer and it was left over the weekend. The dark aqueous layer was separated from the light-yellow organic layer, which was concentrated to dryness. More compound 2b (95 g, 70% total yield) was thus obtained as a yellow solid. NMR (DMSO-c/6, 300 MHz): delta 7.95-7.88 (m, 2H) ppm. NMR (CDC13, 300 MHz): 57.95-7.90 (m, 1H); 7.68-7.62 (m, 1H); 4.85 (s, NH2) ppm
60%
With sodium periodate; sulfuric acid; sodium iodide; In water; at 100℃; for 1h;Heating / reflux;
Step 1:Sodium periodate (1.53 g, 7.16 mmol) was added to a stirred solution of 5-fluoro-2- aminopyridine (2.0 g, 17.9 mmol) in aqueous sulphuric acid (2.0 M, 30 mL) and the reaction heated to 100 0C. A solution of sodium iodide (2.68 g, 17.9 mmol) in water (10 mL) was added dropwise to the reaction mixture. After completion of addition, the mixture was refluxed for 1 h and then cooled to room temperature. Saturated aqueous sodium bicarbonate solution was added dropwise to adjust pH -7.0 and the mixture was extracted with dichloromethane (3 x). The combined organic layers were washed with aqueous sodium bisulfite solution, brine, dried and concentrated in vacuo. The residue was subjected to column chromatography (hexane/ethyl acetate 4:1) to afford the desired compound (2.56 g, 60%).1HNMR (300MHz, CDCl3) delta 4.70-5.03 (brs, 2H), 7.69 (dd, J=7.2, 2.1 Hz, IH), 7.93 (d, J =2.1 Hz, IH)MS (ESI+) m/z 239 (M+l)
58%
Step 1 : 5-Fluoro-3-iodo-pyridin-2-ylamine A stirred solution of 5-fluoro-pyridin-2-ylamine (50 g, 0.45 mol) in 2M sulfuric acid (250 mL) was treated portionwise with potassium iodate (48 g, 0.22 mol) and the mixture heated to 100 C. A solution of potassium iodide (41 g, 0.24 mol) in water (100 mL) was added dropwise over ca. 1 hour. The mixture was allowed to stir for a further 30 minutes then cooled to ambient temperature. The pH of the aqueous phase was adjusted to 8-9 and the mixture extracted with ethyl acetate (x 3). The combined organic layer was washed with aqueous sodium thiosulfate solution, water and brine, dried (Na2S04), filtered and evaporated to afford the title compound as a yellow solid (61.2 g, 58%). NMR (400 MHz, CDC13): 7.94 (d, J = 2.7 Hz, 1H), 7.68 (dd, J = 7.2, 2.7 Hz, 1H), 4.85 (s, 2H).
56%
With sodium periodate; sulfuric acid; sodium iodide; In water; at 0 - 100℃; for 3h;
To a stirred solution of 5-fluoropyridin-2-amine (1) (10 g, 89.28 mmol) in 2 M aq.H2SO4 (150 mL) was added sodium meta periodate (7.5 g, 35 mmol) at 0 C and heated at 100 C. Then, sodium iodide (13.5 g, 89.28 mmol) in water (30 mL) was added drop wise at same temp and maintained for 3 h. After consumption of starting material, the mixture was poured into ice cold water (300 mL), basified with solid NaHCO3 (pH~8) and extracted with ethyl acetate (2 x 500 mL). The combined organic layer was washed with sodium thiosulfate solution (2 x 200 mL), water (200 mL) followed by brine solution (100 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude compound was purified by column chromatography using 100-200 silica and eluted with 15-20% ethyl acetate in pet ether to afford 5-fluoro-3-iodopyridin-2-amine (2) (12 g, 50 mmol, 56%) as brown solid. TLC system: 30% EtOAc in hexane Rf: 0.5 LCMS (ESI): m/z 239 [M+H]+
56%
With sodium periodate; sulfuric acid; sodium iodide; In water; at 0 - 100℃; for 2h;
To a stirred solution of 5-fluoropyridin-2-amine (1) (10 g, 89.28 mmol) in 2 M aq.H2SO4 (150 mL) was added sodium meta periodate (7.5 g, 35 mmol) at 0 C and heated at 100 C. Then, sodium iodide (13.5 g, 89.28 mmol) in water (30 mL) was added drop wise at same temp and maintained for 2 h. After consumption of starting material, the mixture was poured into ice cold water (300 mL), basified with solid NaHCO3 (pH~8) and extracted with ethyl acetate (2 x 500 mL). The combined organic layer was washed with sodium thiosulfate solution (2 x 200 mL), water (200 mL) followed by brine solution (100 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude compound was purified by column chromatography using 100-200 silica and eluted with 15-20% ethyl acetate in pet ether to afford 5-fluoro-3-iodopyridin-2-amine (2) (12 g, 50 mmol, 56%) as brown solid. TLC system: 30% EtOAc in hexane Rf: 0.5 LCMS (ESI): m/z 239 [M+H]+
20.4%
With iodine; silver sulfate; for 95h;Heating / reflux;
Preparation 21 A; 2-Ami?o-5-fluoro-3-iodthetaDyridi?e; The following procedure is a modification of that of Dinnell (US2002 22624A1) for iodination of delta-chloro^-aminopyridine. A mixture of 2-amino-5-fluoropyridine (5.0 g, 45 mmol), iodine (11.3 g, 45 mmol) and Ag2SO4 (14.0 g, 45 mmol) in ethanol was heated at reflux for 95 h, cooled, and filtered. The filtrate was concentrated and partitioned between600 mL DCM and 200 mL 2N NaOH. The organic layer was separated, washed with water and dried giving a solid (4.6 g). The aqueous NaOH layer was extracted with 500 mL 4:1 DCM-2-propanol, dried and concentrated. The residue (1.1 g) was combined with the other solid. SGC (loaded in DCM, eluted with 20% EtOAc-hexanes) giving an orange solid. Yield2.19 g, 20.4%. 1H NMR (CDCI3) delta 7.91 (d, 1H, J = 2.7 Hz)1 7.65 (dd, 1H, J = 2.7, 7.3 Hz)14.83 (br, 2H). MS (ES+) m/e 239 (MH+).
c) 5-Fluoro-3-iodopyridin-2-ylamine can be prepared as in example 103e: But using 5 g of 5-fluoropyridin-2-ylamine and 11.04 g of N-iodosuccinimide in 250 ml of glacial acetic acid. 6.1 g of 5-fluoro-3-iodopyridin-2-ylamine are thus obtained in the form of a solid, the characteristics of which are as follows: Melting point: 70 C. (Koefler bench) Mass spectrum (CI): m/z=239 [M+H]+ (base peak) ; l) 5-Fluoro-3-iodo-pyrid-2-ylamine may be prepared in the following manner: A mixture of 9.9 g of 5-fluoropyrid-3-ylamine and 21.85 g of N-iodosuccinimide in 400 cm3 of acetic acid is stirred for about 6 hours at a temperature in the region of 70 C. After concentrating to dryness under reduced pressure (13 kPa), the residue is taken up in 250 cm3 of water; the pH is brought to about 8 by addition of sodium hydrogen carbonate. The aqueous phase is extracted with 5 times 150 cm3 of dichloromethane. The combined organic phases are washed with three times 100 cm3 of water and then with 5 times 50 cm3 of aqueous 10% sodium thiosulfate solution, dried over sodium sulfate, filtered and concentrated to dryness under reduced pressure (13 kPa). 11 g of 5-fluoro-3-iodo-pyrid-2-ylamine are thus obtained, after flash chromatography on a column of silica (eluent: dichloromethane), in the form of a solid, the characteristics of which are as follows: Melting point: melting at 76 C. (Koefler block) 1H NMR spectrum (300 MHz, (CD3)2SO d6, delta in ppm): 5.98 (broad s, 2H); from 7.93 to 7.98 (m, 2H). Mass spectrum (EI): m/z=238 (M)+
With iodine; silver sulfate; In ethanol; at 20℃; for 24h;
EXAMPLE 12Compound 15N-(1-methyl-1H-benzimidazol-5-yl)-5-fluoro-1-[(3-fluorophenyl)methyl]-1H-pyrrolo[2,3-b]pyridine-2-carboxamide12.1 2-amino-3-iodo-5-fluoropyridine; 5 g (44.6 mmol) of 2-amino-5-fluoropyridine, 13.9 g (44.6 mmol) of silver sulfate and 400 ml of ethanol are placed in a 500 ml two-necked flask equipped with a magnetic stirrer. 11.31 g (44.6 mmol) of iodine powder are then added portionwise. Stirring is continued at room temperature for 24 hours. The resulting yellow suspension is filtered, the precipitate is rinsed with ethanol and the filtrate is concentrated under reduced pressure. The residue thus obtained is taken up in a mixture of ethyl acetate (200 ml) and sodium carbonate solution (200 ml). After separation, the organic phase is successively washed with aqueous 25% sodium thiosulfate solution, with saturated aqueous sodium chloride solution and then dried over sodium sulfate and concentrated under reduced pressure. The resulting solid is purified by chromatography on a column of silica, eluting with a mixture of n-heptane and ethyl acetate. 2.67 g (11.22 mmol) of the expected product are obtained.1H NMR (DMSO D6), delta (ppm): 7.95 (s, 1H); 7.85 (s, 1H); 5.9 (s, NH2).
With iodine; silver sulfate; In ethanol; at 20℃; for 24h;
21.1 2-amino-3-iodo-5-fluoropyridine 5 g (44.6 mmol) of 2-amino-5-fluoropyridine, 13.9 g (44.6 mmol) of silver sulphate and 400 ml of ethanol are introduced into a 500 ml two-necked flask equipped with a magnetic stirrer. 11.31 g (44.6 mmol) of powdered iodine are subsequently added in small portions. The stirring is continued at ambient temperature for 24 hours. The insoluble material is removed by filtration and washed with ethanol and the filtrate is concentrated under reduced pressure. The residue thus obtained is taken up in a mixture of ethyl acetate (200 ml) and of a solution of sodium carbonate (200 ml). After separation, the organic phase is washed successively with a 25% aqueous solution of sodium thiosulphate and then with a saturated aqueous solution of sodium chloride, and then dried over sodium sulphate and concentrated under reduced pressure. The resulting solid is purified by silica column chromatography, elution being carried out with a mixture of n-heptane and ethyl acetate. 2.67 g (11.22 mmol) of the expected product are obtained. 1H NMR (DMSO D6), delta (ppm): 7.95 (s, 1H); 7.85 (s, 1H); 5.9 (s, NH2).
With iodine; silver sulfate; In ethanol; at 20℃;
Example 1; Compound 1N-(2-methyl benzothiazol-5-yl)-5-fluoro-1-[(4-pyridyl)methyl]-1H-pyrrolo[2,3-b]pyridine-2-carboxamide; 1.1 2-amino-3-iodo-5-fluoropyridine; 5 g (44.6 mmol) of 2-amino-5-fluoropyridine, 13.9 g (44.6 mmol) of silver sulfate and 400 mL of ethanol are introduced into a 500 mL two-necked flask equipped with a magnetic stirrer. 11.31 g (44.6 mmol) of iodine powder are then added portionwise. Stirring is continued at room temperature for 24 hours. The resulting yellow suspension is filtered, the precipitate is rinsed with ethanol and the filtrate is concentrated under reduced pressure. The residue thus obtained is taken up in a mixture of ethyl acetate (200 mL) and saturated sodium carbonate solution (200 mL). After separation, the organic phase is successively washed with aqueous 25% sodium thiosulfate solution and with saturated aqueous sodium chloride solution and then dried over sodium sulfate and concentrated under reduced pressure. The resulting solid is purified by chromatography on a column of silica, eluting with a mixture of n-heptane and ethyl acetate. 2.67 g of the expected product are obtained.1H NMR (DMSO D6), delta (ppm): 7.9 (m, 2H); 5.9 (s, 2H).
With iodine; silver sulfate; In ethanol; at 20℃;
5.1 2-Amino-3-iodo-5-fluoropyridine; 5 g (44.6 mmol) of 2-amino-5-fluoropyridine, 13.9 g (44.6 mmol) of silver sulfate and 400 mL of ethanol are put in a 500-mL two-necked flask equipped with a magnetic stirrer. Then 11.31 g (44.6 mmol) of iodine powder is added, in small portions. It is stirred at room temperature for 24 hours. The insoluble matter is removed by filtration and is washed with ethanol, and the filtrate is concentrated at reduced pressure. The residue thus obtained is taken up in a mixture of ethyl acetate (200 mL) and sodium carbonate solution (200 mL). After separation, the organic phase is washed successively with a 25% aqueous solution of sodium thiosulfate then with a saturated aqueous solution of sodium chloride, then it is dried over sodium sulfate and concentrated at reduced pressure. The resultant solid is purified by chromatography on a silica column, eluting with a mixture of n-heptane and ethyl acetate. We obtain 2.67 g (11.22 mmol) of the expected product.1H NMR (DMSO D6), delta (ppm): 7.95 (s, 1H); 7.85 (s, 1H); 5.9 (s, NH2).
With sulfuric acid; iodine; acetic acid; periodic acid; In water; at 80 - 82℃;Large scale;
H2S04 (120 mL) was added, dropwise, to a solution of 2-amino-5-fluoropyridine (4-la) (1 kg, 8.9 mol) in AcOH (4 L) and H20 (1 L) over 5 minutes. Periodic acid (H5I06; 450 g, 1.97 mol, 0.22 eq) and I2 (1 kg, 3.94 mol, 0.44 eq) were added and the reaction mixture was stirred at 82 C (internal) overnight. A sample (diluted with H20, made alkaline with 30% NaOH, extracted with EtOAc, cone.) showed 13-15% starting material. More H I06 (80 g) and I2 (180 g) were added and stirring was continued at 80 C overnight. The external heating was removed and the reaction mixture was stirred at RT overnight. The reaction mixture was poured over ice-water (8 L), made alkaline with 33% aq. NaOH (-6.5 L needed) and stirred for 2 h. The precipitated product was collected by filtration, and washed with hot H20 (8 chi 3L). The filter wash left overnight after which the product was washed with heptanes (3x). The product was dried in the stove at 45 C over the weekend. Compound 2b (1390 g, 65% yield) was obtained as a black solid. H20 was added to the heptanes layer and it was left over the weekend. The dark aqueous layer was separated from the light-yellow organic layer, which was concentrated to dryness. More compound 2b (95 g, 70% total yield) was thus obtained as a yellow solid. NMR (DMSO-<, 300 MHz): delta 7.95-7.88 (m, 2H) ppm. 'H NMR (CDC13, 300 MHz): 67.95-7.90 (m, 1H); 7.68-7.62 (m, 1H); 4.85 (s, NH2) ppm.
With 2-chloro-1-methyl-pyridinium iodide; N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; at 20℃; for 48h;
2-Chloro-l-methylpyridinium iodide (2.2 g, 9.8 mmol) and DIPEA (1 ml) were added to a mixture of 5-fluoropyridin-2-amine 1 (554 mg, 4.9 mmol) and <strong>[6311-35-9]6-bromonicotinic acid</strong> 2 (1 g, 4.9 mmol) in THF. The reaction mixture was stirred at rt for 2 days. At the conclusion of the reaction, the reaction mixture was concentrated to 1/3 of its volume and the precipitated product was filtered off. The filtrate was concentrated, diluted with chloroform (100 ml), washed with water and brine and then dried over Na2SO4. Evaporation of the solvent gave a crude yellow product, which crystallized in EtOAc to give 6-bromo-N-(5-fluoropyridin-2- yl)nicotinamide 3 (1.05g, 71 %) as a white solid. Mp. 173-174 0C.1H-NMR (400 MHz, CDCl3): delta = 11.27 (s, IH), 8.94 (s, IH), 8.43 (s, IH), 8.27 (d, J = 8.0 Hz, IH), 8.2 (d, J = 12 Hz, IH), 7.83 (m, 2H). <n="65"/>MS (ESI): m/z = (297, M+H).
EXAMPLE 604-(aminomethyl)-N-(5-fluoropyridin-2-yl)-l-(7H-pyrrolor2,3-dlpyrimidin-4-yl)piperidine- 4-carboxamide 6OA. tert-butyl 4-cvano-4-(5-fluoropyridin-2-ylcarbamoyl)piperidine- 1 -carboxylate; <n="186"/>HATU (1121 mg, 2.95 mmol) was added in one portion to l-(tert-butoxycarbonyl)-4- cyanopiperidine-4-carboxylic acid (Example 26A) (500mg, 1.97 mmol) and DIPEA (1.030 ml, 5.90 mmol) in DMA (5ml) at 2O0C under nitrogen. The resulting solution was stirred at 20 0C for 10 minutes then <strong>[21717-96-4]2-Amino-5-fluoropyridine</strong> (265 mg, 2.36 mmol) added. The reaction mixture was stirred at 50 0C for 6 hours then at 20 0C for 18 hours. The reaction mixture was diluted with EtOAc (50 mL), and washed sequentially with water (2 x 50 mL) and saturated brine (50 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 10 to 50% EtOAc in isohexane. Pure fractions were evaporated to dryness to afford and triturated with diethyl ether to afford tert-butyl 4- cyano-4-(5-fluoropyridin-2-ylcarbamoyl)piperidine-l-carboxylate (611 mg, 89 %) as a white solid.IH NMR (400.13 MHz, DMSO-d6) delta 1.42 (9H, s), 1.97 - 2.05 (2H, m), 2.21 - 2.24 (2H, m), 2.97 (2H, s), 4.01 - 4.05 (2H, m), 7.78 - 7.83 (IH, m), 8.00 - 8.03 (IH, m), 8.41 (IH, d), 10.98 (IH, s) MS m/e M-H 347
To a suspension of sodium hydride (60% dispersion in mineral oil, 117.8 mg, 4.91 mmol) in tetrahydrofuran (25 ml) was added a solution of 5- fluoropyridin-2-amine (500 mg, 4.46 mmol) in tetrahydrofuran (25 ml) at room temperature and the reaction mixture was stirred at 40 C for 30 min. Then to the reaction mixture was added methyl iodide (696.9 mg, 4.91 mmol) at -40 C and the resulting mixture was stand at room temperature overnight with stirring. The reaction was quenched by the addition of water and whole mixture was extracted with ethyl acetate. The organic extracts were dried over sodium sulfate and concentrated. The residue was purified by flush column chromatography on silica gel eluting with hexane/ethyl acetate (4/1) to afford 129 mg (23%) of the title compound: (at)H-NMR (CDCI3) 5 7.97 (1 H, d, J = 2.6 Hz), 7.28-7.17 (1 H, m), 6.34 (1 H, dd, J = 3.5,9.1 Hz), 2.90 (3H, d, J = 5.1 Hz).
To a stirred solution of <strong>[203866-14-2](2S,4R)-1-(tert-butoxycarbonyl)-4-fluoropyrrolidine-2-carboxylic acid</strong> (250 mg, 1.07 mmole) in 10 mL of CH2Cl2, was added 1-methyl imidazole (0.21 mL, 2.5 equiv.) at 0-5 C. under nitrogen atmosphere. The reaction mixture was stirred for 10 min at 0-5 C. and then added methane sulfonyl chloride (0.1 mL, 1.2 equiv) at the same temperature. It was stirred for 1 h at 0-50 C. Then 5-fluoropyridin-2-amine (200 mg, 1 equiv) was added, and stirred for 18h at room temperature. Water (10 mL) was added to the reaction mixture, layers were separated and aqueous layer was extracted with DCM (3×10 mL). The combined organic layer was washed with 1N HCl (10 mL), followed by Sat NaHCO3 (10 mL) and then with brine (10 mL). Combined organic layer was dried over Na2SO4, concentrated and 430 mg (quantitative yield) of titled compound was obtained.
71%
With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 0 - 20℃; for 16h;
To a DMF solution (15 mL) of Boc-L-Pro-4-F-OH (2.5 g, 10.73 mmol, 1 equiv) Hunig's base (Diisopropylethylamine, abbrev. DIEA) (6.73 mL, 38.61 mmol, 3.6 eq) is added and the mixture cooled to 0 C. This is followed by the addition of 2-Amino-5-fluoro pyridine (1.44 g, 12.87 mmol, 1.2 equiv), and HATU (4.89 g, 12.87 mmol, 1.2 equiv) at 0 C. The resulting mixture is stirred at room temperature for 16 h. The mixture is partitioned between excess ethyl acetate and 10% citric acid. The organic layer is washed with brine and sat. NaHCO3, dried over anhydrous Na2SO4, filtered, and concentrated. The residue is purified by silica gel chromatography (Hexanes:Ethyl acetate=1:0-7:3) to give the title compound as a colorless syrup (2.5 g, 71%).
With sulfuric acid; bromine; In water; at 30 - 50℃; for 26h;Large scale;
Procedure C: Alternatively the bromination was performed by employing H2S04. In one specific example, to 93% sulfuric acid (12.5 kg, 119 mol) in water (26 L) in a 50-L reactor was added 2-amino-5-fluoropyridine (6.5 kg, 58 mol). The temperature was adjusted to 30 C then bromine (10 kg, 63 mol) added in ten portions over three hours. The mixture was stirred at 45 C for 18 hours, then at 50 C for 5 hours. The mixture was cooled to 15 C for work-up in a 400-L reactor. [0260] Four of the above reactions (4 chi 6.5 kg) were combined and quenched in to a mixture of 50% sodium hydroxide (110 kg, 1375 mol) and sodium thiosulfate (1.8 kg, 11.4 mol) in water (100 L) at -3 C over one hour. The temperature was adjusted to 32 C and the slurry filtered and washed with water (80 L) to afford water-wet crude product (62 kg). A second run of three reactions (3 chi 6.5 kg SM) was similarly carried out to afford water-wet crude product (41 kg). The crude products (103 kg) were dissolved (some insolubles) in toluene (280 kg) at 25-30 C. Brine (20 kg) was added but phase break not possible due to solids. The mixture was filtered through a pad of Celite, washing with toluene, and the layers thenseparated. The organics were concentrated to 347 L volume to azeotrope residual water for the use of the preparation of compound 3a. An aliquot was used to determine product concentration as being 181 g per liter of solution. Yield = 62.8 kg. An additional 600 g was isolated by extraction of the water/brine layer with ethyl acetate (10 L), and subsequent filtration through a pad of magnesol, evaporation and trituration with hexane. Total yield is 82%
82%
With sulfuric acid; bromine; In water; at 30 - 50℃; for 26h;
4-1 a 4-2a [0252] Alternatively the bromination was performed by employing H2S04. In one specific example, to 93% sulfuric acid (12.5 kg, 119 mol) in water (26 L) in a 50 L reactor was added 2-amino-5-fluoropyridine (6.5 kg, 58 mol). The temperature was adjusted to 30 C then bromine (10 kg, 63 mol) added in ten portions over three hours [exothermic, temperature kept to 30 C to 40 C, vent set up to scrub through aq. NaOH/Na2S203]. The mixture was stirred at 45 C for 18 hours, then at 50 C for 5 hours. The mixture was cooled to 15 C for workup in a 400 L reactor. Four of the above reactions (4 * 6.5 kg) were combined and quenched in to a mixture of 50% sodium hydroxide (1 10 kg, 1375 mol) and sodium thiosulfate (1.8 kg, 1 1.4 mol) in water (100 L) at -3 C over one hour. The temperature was adjusted to 32 C and the slurry filtered and washed with water (80 L) to afford water-wet crude product (62 kg). A second run of three reactions (3 * 6.5 kg SM) was similarly carried out to afford water-wet crude product (41 kg). The crude products (103 kg) were dissolved (some insolubles) in toluene (280 kg) at 25 C to 30 C. Brine (20 kg) was added but phase break not possible due to solids. The mixture was filtered through a pad of Celite, washing with toluene, and the layers then separated. The organics were concentrated to 347 L volume to azeotrope residual water for the use of the preparation of compound 4-3a. An aliquot was used to determine product concentration as being 181 g per liter of solution. Yield = 62.8 kg. An additional 600 g was isolated by extraction of the water/brine layer with ethyl acetate (10 L), and subsequent filtration through a pad of magnesol, evaporation and trituration with hexane. Total yield is 82%.
53%
With N-Bromosuccinimide; In acetonitrile; at 20℃; for 2h;
To a solution of 5-fluoropyridin-2-amine (6 g, 53.52 mmol) in acetonitrile (120 mL) was added slowly NBS (12.64 g, 69.60 mmol), and the mixture was stirred at rt for 2 h, then concentrated in vacuo to dry. The residue was purified by silica gel column chromatography (PE/EA (v/v) = 20/1) to give the title compound as a yellow solid (5.4 g, 53%).MS (ESI, pos.ion) m/z: 193.O[M+H]1H NMR (400 MHz, CDC13) (ppm): 7.95 (d, J = 2.5 Hz, 1H), 7.52 (dd, J = 7.3, 2.6 Hz, 1H), 4.84 (s, 2H).
31%
With N-Bromosuccinimide; In acetonitrile; at 20℃;
NBS (10 g, 56.2 mmol) was added slowly to a solution of 5-fluoro-pyridin-2- ylamine (12.4 g, 56.2 mmol) in MeCN (200 mL). The reaction mixture was stirred at RT overnight. After completion, the solution was filtered and the filtrate was concentrated to get a residue, which was purified by silica gel chromatography to give the product (5.2 g, 31%) as a yellow solid.
31%
With N-Bromosuccinimide; In acetonitrile; at 20℃;
NBS (10 g, 56.2 mmol) was added slowly to a solution of 5-fluoro-pyridin-2- ylamine (55) (12.4 g, 56.2 mmol) in MeCN (200 mL). The reaction mixture was stirred at RT overnight. After completion, the solution was filtered and the filtrate was concentrated to obtain a residue, which was purified by silica gel chromatography (10%> to 20%> EtOAc in petroleum ether) to give 3-bromo-5-fluoro-pyridin-2-ylamine (56) (5.2 g, 27.2 mmol, 31%> yield) as a yellow solid.ESI-MS (M+l): 191 calc. for C5H4BrFN2 190.
28%
With N-Bromosuccinimide; In acetonitrile; at -10 - 20℃; for 2.75h;Inert atmosphere;
Description 18 (D18); 3-bromo-5-fluoro-2-pyridinamine; To a stirred solution of 2-amino-4-fluropyridine (22.5 g, 0.20 mol) in acetonitrile (400 ml_) at -10C was added N-bromosuccinimide (37.9 g, 0.21 mol) portionwise over 15 min. Reaction mixture was allowed to stir at this temperature for 1 .5 h and at room temperature for a further 1 h. Ethyl acetate (200 ml_) added and the reaction mixture filtered to remove solids. The filtrate was concentrated in vacuo, triturated with ethyl acetate (300 ml_) and filtered the cake was washed with ethyl acetate (2 x 100 ml_). The filtrate washed with 1 M sodium hydroxide (100 ml_), water (50 ml_) and then brine (50 ml_). The combined organics were dried over sodium sulfate and solvent removed in vacuo yielding a solid. Material purified by column chromatography eluting with 25% ethyl acetate in hexane. The relevant fractions were combined and solvent removed in vacuo yielding a light brown solid (20.4 g) which was recrystallised from hexane to furnish the title compound (10.8 g, 28%).1H NMR: (300 MHz, CDCI3) delta 7.92 (d, 1 H), 7.50 (dd, 1 H), 4.80 (s, 2H).
3.5 ml of bromine was added to a mixture of 5.11 g of 2-amino-5-fluoropyridine and 20 ml of acetic acid, and the obtained mixture was stirred at 80C for 30 minutes. Thereafter, a saturated sodium bisulfite aqueous solution and a saturated sodium bicarbonate aqueous solution were added to the reaction mixture, and the obtained mixture was then extracted with ethyl acetate. The organic layer was washed with a saturated saline solution, and it was then dried over anhydrous sodium sulfate, followed by concentration under reduced pressure. The obtained residue was subjected to silica gel column chromatography, so as to obtain 6.07 g of 2-amino-3-bromo-5-fluoropyridine.2-amino-3-bromo-5-fluoropyridine [Show Image] 1H-NMR (CDCl3) delta: 4.80 (2H, br s), 7.50 (1H, dd, J = 7.5, 2.4 Hz), 7.93 (1H, d, J = 2.4 Hz).
With bromine; acetic acid; at 80℃; for 1h;
To a solution of 5-Fluoro-pyridin-2-ylamine (3.00 g, 26.8 mmol) in acetic acid (30.0 mL, 528 mmol) at 80 0C was added bromine (5.50 mL, 107 mmol) in acetic acid (5.50 mL, 96.7 mmol). The temperature was maintained for one hour. The reaction was poured over ice, neutralized, and extracted with EtOAc. The organic layer was purified with ISCO silica gel chromatography to afford 3-bromo-5-fluoro-pyridine-2-ylamine. 6-Fluoro-8- bromo-[l,2,4]triazolo[l,5-a]pyridin-2-ylamine was prepared from 3-bromo-5-fluoro- pyridine-2-ylamine in a manner analogous to Steps 2a-b to afford a white solid (80%). MP = 243-246 0C. 1H NMR (400 MHz, (D3C)2SO, delta, ppm): 8.97 (s, IH), 7.99 (d, J= 8.5 Hz, IH), 6.28 (bs, 2H). MS = 231.0 (MH)+.
With hydrogen bromide; bromine; In water; at 12 - 24℃;Large scale;
To a slurry of 2-amino-5-fluoropyridine (6 kg, 53.6 mol) in water (24 L) at 14 C was added over 10 minutes 48% hydrobromic acid (18.5 kg, 110 mol). The reaction was exothermic and the temperature went up to 24 C. The mixture was re-cooled to 12 C then bromine (9 kg, 56.3 mol) was added in nine portions over 50 minutes (exothermic, kept at 20 C). The mixture was stirred at 22 C overnight, and monitored by 'HNMR of a quenched aliquot (quenched 5 drops in to mix of 1 ml 20% K2C03, 0.3 ml 10% Na2S203 and 0.7 ml DCM. Organic layer evaporated and assayed). The mixture was cooled to 10 C then quenched by addition of sodium bisulfite (560 g, 5.4 mol) in water (2 L), and further cooled to 0 C. This mixture was added to a cold (-4 C) mixture of DCM (18 L) and 5.4M sodium hydroxide (35 L, 189 mol). The bottom -35 L was filtered through a pad of Celite and then the phase break was made. The aqueous layer was re-extracted with DCM (10 L). The organics were filtered through a pad of 3 kg magnesol, washing with DCM (8 L). The filtrate was evaporated, triturated with hexane and filtered. Despite the in-process assay indicating 97% completion, this initial product from all four runs typically contained -10% SM. These were combined and triturated in hexane (2 L per kg material) at 50 C, then cooled to 15 C and filtered to afford Compound 2a (30.0 kg, -95% purity, 149 mol, 67%). Mother liquors from the initial trituration and the re- purification were chromatographed (20 kg silica, eluent 25-50% EtOAc in hexane) to afford additional Compound 2a (4.7 kg, -99% purity, 24.4 mol, 1 1%).
With 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; triethylamine; In dichloromethane; at 20℃;Cooling with ice;
To a stirred and ice-cooled solution of commercial 2-(3,4-dichloro- phenyl)-quinoline-4-carboxylic acid (INT-1 ; 3.000 g, 9.4293 mmol) and 5-fluoro- pyridin-2-ylamine (1 .374 g, 12.2581 mmol) in dichloromethane (35 ml), triethylamine (6.679 g, -22.5 ml, 66.0051 mmol) is added, followed by portion-wise addition of 1 -propanephosphonic acid cyclic anhydride (24.002 g, 37.7172 mmol) and the mixture is allowed to attain room temperature spontaneously overnight. The resulting mixture is diluted with dichloromethane (-40 ml), washed with water and brine, dried (MgSO4), and evaporated to afford a reddish gummy residue (3.900 g, 100% mass balance). This is purified by crystallization from chloroform and hexane, to obtain the title compound as a yellow solid (2.000 g, -55% yield). M.p. 203.6-205.00C.
~ 55%
With 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; triethylamine; In dichloromethane; at 20℃;Cooling with ice;
To a stirred and ice-cooled solution of commercial 2-(3,4-dichloro-phenyl)-quinoline-4-carboxylic acid (INT-1; 3.000 g, 9.4293 mmol) and <strong>[21717-96-4]5-fluoro-pyridin-2-ylamine</strong> (1.374 g, 12.2581 mmol) in dichloromethane (35 ml), triethylamine (6.679 g, 22.5 ml, 66.0051 mmol) is added, followed by portion-wise addition of 1-propanephosphonic acid cyclic anhydride (24.002 g, 37.7172 mmol) and the mixture is allowed to attain room temperature spontaneously overnight. The resulting mixture is diluted with dichloromethane (40 ml), washed with water and brine, dried (MgSO4), and evaporated to afford a reddish gummy residue (3.900 g, 100% mass balance). This is purified by crystallization from chloroform and hexane, to obtain the title compound as a yellow solid (2.000 g, 55% yield). M.p. 203.6-205.0 C
Example 15 beta-fluoro-imidazofl ,2-alpha]pydine (26)Synthesis of beta-fluoro-imidazofl ,2-alpha]pydine (26) is shown schematically in Fig. 5. Concentrated HCI (34 ml_, 345 mmol) was added drop-wise to 2-bromo-1 ,1-diethoxyethane 17 (26.37g, 133.8 mmol) at room temperature in a 250-mL three neck round bottomed flask. The mixture was then heated at 550C for 30 minutes. The pale yellow mixture was then cooled to O0C and excess anhydrous Na2SO4 (64g) added and the reaction stirred for 1.0 hr. The reaction mixture now containing crude bromoacetaldehyde 18 was filtered into a three neck 1000 ml. round bottomed flask and the cake washed with ethanol (100 ml_). The flask was then cooled to O0C and 2-amino-5-fluoropyridine (10.Og, 50 mmol) added portion-wise followed by the addition of NaHCO3 (42g, 500 mmol). There was evolution of gas. After the bubbling had ceased, the mixture was refluxed at 7O0C for 1.0 hour. The reaction mixture was then cooled to room temperature, filtered and concentrated under reduced pressure. CH2CI2 was added to the residue at O0C and 40% NaOH (30 ml.) added to pH 10. The mixture was then diluted with water (100 ml.) and the organic phase separated, dried (Na2SO4 ) and concentrated under reduced pressure. Purification on silica gel (CombiFlash, Heptanes/EtOAc elution) afforded 6-fluoro-imidazo[1 ,2-alpha]pyridine 26 as a brown solid. 5.52g, 85%, yield.1H NMR (300 MHz, CDCI3, 297K) delta 7.06 (m, 1 H), 7.56 (m, 3H), 8.04 (m, 1 H).19F NMR (282.2 MHz, CDCI3, 297K) delta:21.61.ESI MS (MeOH) calcd for C7H5FN2 136.13, found m/z (M++1 ) 137.
To a solution of 2-amino-5-fluoropyridine (10 g) in ethanol (200 mL), a solution of chloroacetaldehyde 50% in water (56 mL, 4.0 equiv.) was added. The reaction mixture was heated at reflux 2 Hrs, then was concentrated under reduced pressure to 100 mL. The residue was diluted in AcOEt (100 mL) and washed with a saturated aqueous solution of NaHCO3 (2* 150 mL). The combined aqueous were saturated with NaHCO3 and extracted back with AcOEt (2*100 mL). The combined organic layers were washed with brine (100 mL), dried over Na2SO4 and concentrated under reduced pressure. Purification by flash-chromatography (MeOH 2.5% in CH2Cl2) afforded the product as a cream solid (8.7 g, 72%). M/Z (M+H)+ = 137.
With perchloric acid; In ethanol; at 20℃; for 20h;Inert atmosphere;
The preparation of (2,6-dimethylphenyl)-(6-fluoro-2-(2-thiazol-2-ylphenyl)-imidazo[1,2-a]pyridin-3-yl]amine (A1) is carried out analogously to the following scheme:118 mg (1.0 mmol) of 2-amino-5-fluoropyridine and 189 mg (1.0 mmol) of <strong>[223575-69-7]2-thiazol-2-ylbenzaldehyde</strong> are dissolved successively in 5 ml of ethanol at RT under inert gas. 137 mg (1.0 mmol) of 2,6-dimethyiphenyl isocyanide are then added, 0.043 ml of 70% perchloric acid is added dropwise, and the mixture is stirred at RT for a further 20 h. 10 ml of petroleum ether are subsequently added, and the precipitated solid is filtered off with suction. This is triturated with a little ethyl acetate and filtered off with suction again, giving 177 mg (43%) of (2,6-dimethylphenyl)-[6-fluoro-2-(2-thiazol-2-yl-phenyl)imidazo[1,2-a]pyridin-3-yl]amine (A1) as solid; MS-FAB (M+H+)=415.7; Rf (polar method): 1.98 min;1H-NMR (DMSO-d6) d [ppm] 8.43 (1H, s), 8.03-8.07 (1H, m), 7.96 (1H, d, J=8.1 Hz), 7.92 (1H, d, J=3.3 Hz), 7.81 (1H, d, J=8.1 Hz), 7.77 (1H, d, J=3.3 Hz), 7.69 (1H, dd, J=9.7 and 5.1 Hz), 7.42 (1H, t, J=8.0 Hz), 7.29 (1H, ddd, J=2.4, 8.0 and 9.9 Hz), 7.28 (1H, s), 6.86 (2H, d, J=7.5 Hz), 6.65 (1H, t, J=7.5 Hz), 1.90 (6H, s).
With caesium carbonate;tris-(dibenzylideneacetone)dipalladium(0); 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In toluene; at 100℃; for 16h;Inert atmosphere;
Reference Example 55 methyl { (3S) -6- [ { (3S) -7- [ (5-fluoropyridin-2-yl) amino] -2,3- dihydro-l-benzofuran-3-yl} (trifluoroacetyl) amino] -2, 3-dihydro- 1-benzofuran-3-yl } acetate; [0371]A solution of methyl [ (3S) -6-{ [ (3S) -7-bromo-2, 3-dihydro- l-benzofuran-3-yl] (trifluoroacetyl) amino}-2, 3-dihydro-l- benzofuran-3-yl] acetate (0.200 g, 0.400 mmol) , 5- fluoropyridin-2-amine (53.8 mg, 0.480 mmol) and cesium carbonate (0.261 g, 0.800 mmol) in toluene (4 mL) was substituted with argon, and tris (dibenzylideneacetone) dipalladium (0) (14.6 mg, 0.0160 mmol) and 4, 5-bis (diphenylphosphino) -9, 9-dimethylxanthene(18.5 mg, 0.0320 mmol) were added. The reaction mixture was stirred under an argon atmosphere at 1000C for 16 hr. The reaction mixture was cooled, water was added and the mixture was extracted with ethyl acetate. The extract was dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography(hexane: ethyl acetate = 95:5 - 65:35) to give the title compound (0.186 mg, yield 88%) as a brown oil. MS m/z 532 (M + H)+.
5-(2-(5-fluoropyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid[ No CAS ]
[ 21717-96-4 ]
[ 1260842-16-7 ]
Yield
Reaction Conditions
Operation in experiment
78%
With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 70℃;
Example 95; (R)-N-(5 -fluoropyridin-2-yl)-5 -(2-(5 -fluoropyridin-3 -vDpyrrolidin- 1 -vDpyrazolo [1,5- alpyrimidine-3 -carboxamide; To a DMF (0.25 mL) solution of (R)-5 -(2-(5 -fluoropyridin-3 -yl)pyrrolidin-l - yl)pyrazolo[l,5-a]pyrimidine-3-carboxylic acid (Preparation I, 25 mg, 0.076 mmol) and HATU (35 mg, 0.092 mmol) was added 5-fluoropyridin-2-amine (10 mg, 0.092 mmol), followed by drop-wise addition of DIEA (0.040 mL, 0.23 mmol) at ambient temperature. The reaction was heated at 70 0C overnight, cooled, and directly purified by reverse-phase chromatography (5 to 66% acetonitrile/water) to yield the final product as white solid (25 mg, 78%). LCMS (apci) m/z = 422.0 (M+H).
To a mixture of 1,1-dimethylethyl (2S, 5 S)-2-formyl-5 -methyl- 1 -piperidinecarboxylate D3 (122 mg, 0.537 mmol) and 5-fluoro-2-pyridinamine (72.2 mg, 0.644 mmol) in dry DCE under Nitrogen, a drop of AcOH was added and then was stirred at room temperature for 30 min. Sodium triacetoxyborohydride (228 mg, 1.073 mmol) was then added and the resulting reaction mixture was stirred for 3 hours, quenched with NaHCO3 (saturated aqueous solution) and extracted with DCM. The organic layers were combined, dried (Na2SO4) and concentrated in vacuo. The crude product was purified by flash chromatography on silica gel (20 g column, eluting with a gradient from DCM/MeOH 99.5:0.5 to 99:1) affording the title compound D16 (61 mg, 0.189 mmol, 35.1 % yield). UPLC (Acid FINAL QC): rt = 0.72 min, peak observed: 324 (M+l). C17H26FN3O2 requires 323.
1-Bromopyrrolidine-2,5-dione (15.8 g, 89.2 mmol) was added portionwise to a cooled (ice-bath), stirred solution of (£)-3-methoxyacrylonitrile (7.49 mL, 89.2 mmol) in 1 ,4- dioxane/water (3:1 , 600 mL). The solution was stirred for 30 minutes at 0 C and then 5-fluoropyridin-2-amine (5.0 g, 44.6 mmol) was added. The mixture was warmed to ambient temperature over 2 hours and then was heated to 60 C and stirred for 16 hours at 60 C. The organic solvent was removed under reduced pressure and the residue was partitioned between ethyl acetate and aqueous sodium hydrogencarbonate solution. The organic phase was dried, filtered and evaporated to dryness. The crude product was purified by flash chromatography (15-50% ethyl acetate/hexane) to give the title compound (94%) as a brown solid.LRMS (m/z): 162 (M+1)+.1H-NMR delta (DMSO-c/6): 7.71 (ddd, 1 H), 7.93 (dd, 1 H), 8.49 (s, 1 H), 8.98 (bs, 1 H).
94%
1-Bromopyrrolidine-2,5-dione (15.8 g, 89.2 mmol) was added portionwise to a cooled (ice-bath), stirred solution of (E)-3-methoxyacrylonitrile (7.49 mL, 89.2 mmol) in 1,4-dioxane/ water (3:1, 600 mL). The solution was stirred for 30 minutes at 0 C and then 5-fluoropyridin-2-amine (5.0 g, 44.6 mmol) was added. The mixture was warmed to ambient temperature over 2 hours and then was heated to 60 C and stirred for 16 hours at 60 C. The organic solvent was removed under reduced pressure and the residue was partitioned between ethyl acetate and aqueous sodium hydrogencarbonate solution. The organic phase was dried, filtered and evaporated to dryness. The crude product was purified by flash chromatography (15-50% ethyl acetate/hexane) to give the title compound (94%) as a brown solid.LRMS (m/z): 162 (M+1)+.1H-NMR delta (DMSO-d6): 7.71 (ddd, 1 H), 7.93 (dd, 1 H), 8.49 (s, 1 H), 8.98 (bs, 1 H).
94%
1-Bromopyrrolidine-2,5-dione (15.8 g, 89.2mmol) was added in portions to a solution of (E)-3-methoxyacrylonitrile (7.49mL, 89.2 mmol) in a 3:1 mixture of dioxane/water (600 mL) at 0 C. The solution was stirred for 30minutes at 0 C and then 5- fluoropyridin-2-amine (5.0 g, 44.6 mmol) was added. Temperature was allowed to increase to ambient temperature during 2h and themixture was stirred for 16h at 60 C. The organic solvent was removed underreduced pressure and the crude was partitioned between ethyl acetate andaqueous sodium hydrogencarbonate solution. The organic phase was separated, driedover sodium sulfate, filtered and the solvent was evaporated to dryness. Thecrude product was purified by flash chromatography (15 to 50% ethyl acetate inhexanes) to give the title compound as a brown solid (6.7 g, 94%). LRMS (m/z): 162 (M+1 )+ 1H NMR delta (300 MHz, DMSO-d6): 7.71 (ddd, 1 H), 7.93 (dd, 1 H), 8.49 (s, 1 H), 8.98 (bs, 1 H).
With 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; triethylamine In ethyl acetate at 100℃; for 7h; Cooling with ice; Inert atmosphere;
4.2
0.149 g of 12, 0.112 g of 2-amino-5-fluoropyridine 4, 0.209 g of 2-(2-formyl-3-methoxyphenoxy)acetamide 3, 0.286 ml of triethylamine and, dropwise, 2.5 ml of T3P [=propylphosphonic anhydride (50% solution in ethyl acetate)] are introduced successively into a flask with ice-cooling and under an inert gas. The reaction mixture is stirred at 100° C. for 7 h. The mixture is subsequently subjected to conventional work-up, giving 0.2 g (40%) of “A1”.
With caesium carbonate;tris-(dibenzylideneacetone)dipalladium(0); 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane; for 15h;Inert atmosphere; Reflux;
A 100-mL single-neck round-bottomed flask equipped with a magnetic stirrer and reflux condenser was charged with 1,4-dioxane (50 mL), 5-fluoropyridin-2-amine (0.67 g, 6 mmol), 3,5-dibromo-l-methylpyridin-2(lH)-one (1.34 g, 5 mmol) and cesium carbonate (4.89 g, 15 mmol). After bubbling nitrogen through the resulting solution for 30 minutes, XantPhos (576 mg, 1 mmol) and tris(dibenzylideneacetone)dipalladium(0) (460 mg, 0.5 mmol) were added, and the reaction mixture was heated at reflux for 15 h. After this time the reaction was cooled to room temperature, partitioned between ethyl acetate (100 mL) and water (100 mL) and filtered. The aqueous layer was separated and extracted with ethyl acetate (50 mL x 2). The organic layers were combined and washed with brine (50 mL) and dried over sodium sulfate. The drying agent was removed by filtration and the filtrate was concentrated under reduced pressure. The residue was washed with acetonitrile (30 mL) and filtered to afford 148a (900 mg, 61%). MS: [M+H]+ 298.
PREPARATION 25 3-(4-Chloro-5-nitropyrimidin-2-yl)-6-fluoroimidazo[1,2-a]pyridine [Show Image]a) 6-Fluoroimidazo[1,2-a]pyridine-3-carbonitrile N-bromosuccinimide (15.88 g, 89.20 mmol) was added portion wise to a cooled (0 C), stirred solution of methoxyacrylonitrile (7.50 mL, 89.20 mmol) in 3:1 dioxane/water (600 mL). The mixture was stirred at 0 C for a further 30 minutes and then <strong>[21717-96-4]2-amino-5-fluoropyridine</strong> (5.00 g, 44.60 mmol) was added. The mixture was warmed to room temperature, stirred for 2 hours and then heated to 60 C and stirring was continued at this temperature for 16 hours. The solvent was evaporated under vacuum and saturated aqueous sodium hydrogencarbonate was added. The aqueous layer was extracted with ethyl acetate (x3) and the combined organic extract was dried (Na2SO4), filtered and the solvent was evaporated. The residue was dissolved in methanol and purified by flash chromatography (hexanes/ethyl acetate) to give the title compound (6.80 g, 94%) as a brown solid. LRMS (m/z): 162 (M+1)+.1H NMR (300 MHz, CDCl3) delta ppm 7.39 (m, 1H), 7.78 (dd, 1H), 8.18 (s, 1H), 8.39 (t, 1H).
94%
PREPARATION 25 3-(4-Chloro-5-nitropyrimidin-2-yl)-6-fluoroimidazo[1,2-a]pyridine a) 6-Fluoroimidazo[1,2-a]pyridine-3-carbonitrile N-bromosuccinimide (15.88 g, 89.20 mmol) was added portion wise to a cooled (0 C), stirred solution of methoxyacrylonitrile (7.50 mL, 89.20 mmol) in 3:1 dioxane/water (600 mL). The mixture was stirred at 0 C for a further 30 minutes and then <strong>[21717-96-4]2-amino-5-fluoropyridine</strong> (5.00 g, 44.60 mmol) was added. The mixture was warmed to room temperature, stirred for 2 hours and then heated to 60 C and stirring was continued at this temperature for 16 hours. The solvent was evaporated under vacuum and saturated aqueous sodium hydrogencarbonate was added. The aqueous layer was extracted with ethyl acetate (x3) and the combined organic extract was dried (Na2SO4), filtered and the solvent was evaporated. The residue was dissolved in methanol and purified by flash chromatography (hexanes/ethyl acetate) to give the title compound (6.80 g, 94%) as a brown solid. LRMS (m/z): 162 (M+1)+.1H NMR (300 MHz, CDCl3) delta ppm 7.39 (m, 1H), 7.78 (dd, 1H), 8.18 (s, 1H), 8.39 (t, 1H).
With N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; at 10 - 60℃; for 2h;
Example 95Synthesis of (1R,2S)-2-[(2,4-dimethylpyrimidin-5-yl)oxy]methyl}-2-(3-fluorophenyl)-N-(5-fluoropyridin-2-yl)cyclopropanecarboxamide (95)The carboxylic acid Prep 14-6 (226 mg) was dissolved in dichloromethane (10 ml), and oxalyl chloride (122 ul) and DMF (several droplets) were then added to the obtained solution. The obtained mixture was stirred at room temperature for 1 hour. Thereafter, the reaction solution was concentrated under reduced pressure, so as to obtain a crude acid chloride. N,N-diisopropylethylamine (283 ul) was added to a THF solution (10 ml) of 2-amino-5-fluoropyridine (96.1 mg), and the temperature of the solution was then heated to 60 C. A THF solution of the crude acid chloride was added dropwise to the reaction solution, and the obtained mixture was stirred for 1 hour while maintaining the temperature. Thereafter, the reaction mixture was cooled to room temperature, and the reaction solution was then stirred for 1 hour. Thereafter, the reaction solution was concentrated under reduced pressure, and was then partitioned between ethyl acetate and water, so as to separate an organic layer. The organic layer was dried over anhydrous magnesium sulfate, and the filtrate was then concentrated under reduced pressure. The residue was purified by NH-silica gel column chromatography (n-heptane:ethyl acetate=2:1), and diethyl ether was then added to the obtained product of interest. The precipitated solid was collected by filtration and was then dried, so as to obtain the title compound (130 mg).1H-NMR (400 MHz, d-DMSO) delta (ppm): 1.46-1.50 (m, 1H), 1.68 (t, J=6.0 Hz, 1H), 2.01 (s, 3H), 2.36 (s, 3H), 2.59-2.63 (m, 1H), 4.27 (d, J=10.4 Hz, 1H), 4.66 (d, J=10.4 Hz, 1'-1), 7.06-7.11 (m, 1H), 7.37-7.44 (m, 3H), 7.60-7.65 (m, 1H), 7.85-7.89 (m, 1H), 8.11 (s, 1H), 8.30 (d, J=3.2 Hz, 1H), 11.20 (brs, 1H)MS [M+H]+=411
Step A: 2-Amino-1-(4-ethoxy-3,4-dioxobutan-2-yl)-5-fluoropyridin-1-ium bromide (5-C). A solution 2-amino-5-fluoropyridine (5-A, 3.04 g, 27.1 mmol) and <strong>[57332-84-0]ethyl 3-bromo-2-oxobutanoate</strong> (5-B, 5.67 g, 27.1 mmol) in DME (15 mL) was stirred at rt for 1 day. The resultant solid precipitate was collected by filtration, and washed with Et2O, to afford compound 5-C as an off-white solid (5.35 g, 82%), which was used without purification in the subsequent step.
With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 20℃; for 2h;Inert atmosphere;
Example 23: Synthesis of 2-[(3S)-12-[[4-(dimethylamino)cyclohexyl]oxy]-7-thia- 9,ll-diazatricyclo[6.4.0.0[2,6]]dodeca-l(8),2(6),9,ll-tetraen-3-yl]-N-(5-fluoropyridin-2-Page 274 of 4072009184-0008 [00621] Synthesis of compound 24a. To a solution of intermediate Ga (200 mg, 0.43 mmol, 1.00 equiv) in distilled DMF (8 mL) at room temperature under nitrogen was added 5- fluoropyridin-2-amine (55 mg, 0.49 mmol, 1.13 equiv), HATU (200 mg) and DIPEA (170 mg). The resulting solution was stirred for 2 h at room temperature and quenched with water and extracted with ethyl acetate (3 x 30 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was loaded onto a silica gel column with ethyl acetate/petroleum ether (1 :2 to 3:5) and purified to give tert- butyl N-(4-[[(3S)-3-[[(5-fluoropyridin-2-yl)carbamoyl]methyl]-7-thia-9, l 1- diazatricyclo[6.4.0.0[2,6]]dodeca-l(8),2(6),9,l l-tetraen-12-yl]oxy]cyclohexyl)-N- methylcarbamate (24a, 195 mg, 81 %) as a yellow oil. MS: m/z 556 (M+H)[00622] Synthesis of Compound. To a 25-mL round-bottom flask containing a solution of 24a (195 mg, 0.35 mmol, 1.00 equiv) in dichloromethane (15 mL) was added hydrochloric acid (12 M, 2 mL) at 0 C under nitrogen. The resulting solution was stirred for 2 h at room temperature and concentrated under vacuum. The resulting N-(5-fluoropyridin-2-yl)-2-[(3S)- 12- [[4-(methylamino)cyclohexyl]oxy]-7-thia-9, l l-diazatricyclo[6.4.0.0[2,6]]dodeca- l(8),2(6),9,l l- tetraen-3-yl]acetamide hydrochloride (130 mg, crude) was used in the next step directly without further purification. A solution of this material (130 mg, crude) and HCHO (37%, 1 mL) in methanol (10 mL) was stirred at room temperature for 30 min., whereupon aBHsCN (55 mg, 0.78 mmol, 3.06 equiv) was added and the mixture stirred for an additional 2 h at room temperature. The reaction was then quenched by the addition of 20 mL of water and extracted with 3 x 30 mL of ethyl acetate. The combined organic layers were concentrated under vacuum. The crude product (70 mg) was purified by preparative HPLC (SHIMADZU) under the following conditions: column: Xbridge Prep C18 5 um, 19* 150 mm; mobile phase: water (0.05% NH4HCO3) and CH3CN (6.0% CH3CN up to 50.0% in 25 min); UV detection at 254 and 220 nm. The fractions were collected and evaporated under reduced pressure to give the 2-[(3S)- 12-[[4- (dimethylamino)cyclohexyl]oxy]-7-thia-9, 1 1 -diazatricyclo[6.4.0.0[2,6]]dodeca- 1 (8),2(6),9, 1 1 - tetraen-3-yl]-N-(5-fluoropyridin-2-yl)acetamide (21.4 mg) as a white solid. NMR (300 MHz, CDCI3) delta 8.49 (s, 1H), 8.20 (m, 2H),7.63 (m, 1H), 5.28 (m, 1H), 3.93 (t, 1H), 3.33 (m, 2H), 3.03 (m, 1H), 2.82 (m, 1H), 2.77 (m, 1H), 2.55 (m, 10H), 2.03 (m, 2H), 1.55 (m, 4H). MS: m z 470 (M+H)+.
With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 20℃; for 2h;Inert atmosphere;
Example 36: Synthesis of 2-[(3 ?)-12-[[4-(dimethylamino)cyclohexyl]oxy]-7- thia-9,ll-diazatricyclo[6.4.0.0[2,6]]-dodeca-l(8),2(6),9,ll-tetraen-3-yl]-N-(5-KbPage 287 of 4072009184-0008 37b[00653] Synthesis of compound 37b. A solution of Kb (200 mg, 0.43 mmol, 1.00 equiv), 5-fluoropyridin-2-amine (55 mg, 0.49 mmol, 1.13 equiv), HATU (200 mg) and DIPEA ( 170 mg) in distilled DMF (8 mL) was stirred at room temperature under nitrogen for 2 h. The reaction was then quenched with water and extracted with ethyl acetate (3 x 30 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was loaded onto a silica gel column with ethyl acetate/petroleum ether (1 :2 to 3:5) to give ½ri-butyl N-(4-[[(-?R)-3-[[(5- fluoropyridin-2-yl)carbamoyl]methyl]-7-thia-9,l l-diazatricyclo[6.4.0.0[2,6]]dodeca- l (8),2(6),9, l l-tetraen-12-yl]oxy]cyclohexyl)-N-methylcarbamate (37b, 200 mg, 83%) as a yellow oil. MS: /z 556 (M+H)+.[00654] Synthesis of Compound. To a 25-mL round-bottom flask containing a solution of 37b (200 mg, 0.36 mmol, 1.00 equiv) in dichloromethane (15 mL) was added hydrochloric acid ( 12 M, 2 mL) at 0 C under nitrogen. The resulting solution was stirred for 2 h at room temperature and concentrated under vacuum to afford N-(5-fluoropyridin-2- yl)-2-[(3R)-12-[[4-(methylamino)cyclohexyl]oxy]-7-thia-9, l l- diazatricyclo[6.4.0.0A[2,6]]dodeca- l (8),2(6),9, l l-tetraen-3-yl]acetamide hydrochloride (130 mg, crude), which was used in the next step without further purification.A solution of this compound ( 130 mg, crude) and HCHO (37%, 1 mL) in methanol ( 10 mL) was stirred at room temperature for 30 min., whereupon NaBHaCN (55 mg, 0.78 mmol, 3.06 equiv) was added to the mixture and stirring was continued for an additional 2 h at room temperature. The reaction was then quenched by the addition of 20 mL of water and extracted with 3 x 30 mL of ethyl acetate. The combined organic layers were concentrated under vacuum. The crude product (70 mg) was purified by preparative HPLCPage 288 of 4072009184-0008 (SHIMADZU) under the following conditions: column: Xbridge Prep C I 8 5 urn, 19* 150 mm; mobile phase: water (0.05% NH4HCO3 solution) and CH3CN (start at 6.0% CH3CN then ramp up to 50.0% over 25 min); UV detection at 254 and 220 nm. The fractions were collected and evaporated under reduced pressure to give Compound 1-37 (33.4 mg) as a white solid. NMR (300 MHz, CD3OD) delta 8.49 (s, 1H), 8.20 (m, 2H), 7.63 (m, 1 H), 5.29 (m, 1 H), 3.91 (t, 1H), 3.32 (m, 2H), 3.03 (m, 1H), 2.82 (m, 1H), 2.77 (m, 1H), 2.55 (m, 10H), 2.03 (m, 2H), 1.55 (m, 4H). MS: mJz 470 (M+H)+.
With trichlorophosphate; In pyridine; at 0 - 15℃; for 1.5h;Large scale;
A solution of 6-methyl-4-(pyrimidin-5-yloxy)pyridine-2-carboxylic acid (11, 2.2 kg, 9.51 mol) in pyridine (33.0 L, 15 V) was stirred at25-30 C for 15-20 min. <strong>[21717-96-4]5-fluoro-2-aminopyridine</strong> (12, 1.386 kg, 12.36 mol)was added to the reaction mass at 25-30 C and stirred at 25-30 C for 45 min.Reaction mass was cooled to 0-5 C, phosphorus oxychloride (1.33 L,14.27 mol) was added drop wise over a period of 1 h by maintaining thetemperature between 0 and 5 C. The reaction mass was stirred at 10-15 C for30 min. The reaction completion was monitored by HPLC. After reactioncompletion, reaction mass was quenched with water (44.0 L, 20 V) andneutralized with 10% potassium carbonate solution (22.0 L, 10 V) at 0-5 C.The suspension was stirred at 0-5 C for 1 h. Solid was filtered, washed withwater (22.0 L, 10 vol.) and dried under vacuum. Crude material was dissolvedin DCM (22.0 L, 10 vol.) and washed with water (6 10 V) to remove pyridinetraces. Organic layer was dried over sodium sulfate and evaporated undervacuum to get desired product as beige solid (1.8 kg, 58.2%). 1H NMR (400 MHz,DMSO-d6) d 10.48 (s, 1H), 9.18 (s, 1H), 8.88 (s, 2H), 8.40 (d, J = 3.0 Hz, 1H), 8.27(dd, J = 9.2 Hz, 4.10 Hz, 1H), 7.86 (td, J = 8.6, 3.1 Hz, 1H), 7.55 (d, J = 2.3 Hz, 1H),7.29 (d, J = 2.3 Hz, 1H), 2.58 (s, 3H); 13C NMR (100 MHz, DMSO-d6) d = 165.15,161.11, 160.57, 156.12 (d, J(C,F) = 249.0 Hz), 155.41, 150.29, 150.07, 149.01,146.92 (d, J(C,F) = 2.1 Hz), 135.94 (d, J(C,F) = 25.5 Hz), 125.83 (d, J(C,F) =19.9 Hz), 114.56, 114.27 (d, J(C,F) = 4.7 Hz), 108.01, 23.84 ppm; LCMS(Method 2): RT = 0.727 min, m/z = 326.2 [M+H]+; HRMS, calc?d forC16H12FN5O2 [M], 325.0975; found 325.0979.
36%
With pyridine; trichlorophosphate; at -15℃; for 0.5h;
f. PREPARATION OF N-(5-FLUOROPYRIDIN-2-YL)-6-METHYL-4-(PYRI IDIN-5-YLOXY)PICOLINAMIDE.[00401] 6-methyl-4-(pyrimidin-5-yloxy)picolinic acid (610 mg, 2.64 mmol, 1 eq) and 5-fluoro-2- aminopyridine (296 mg, 2.64 mmol, 1 eq) were dissolved in pyridine (40 mL) in a flame-dried round- bottom flask. The reaction was cooled to -15 C and phosphorus oxychloride (270 mu, 2.90 mmol, 1 .1 eq) was added dropwise while keeping the temperature below -15 C. After stirring for 30 minutes at -15 C and the reaction was quenched with ice- water and neutralized with 10% K2CO3. The mixture was extracted with EtOAc (3x) and the combined organics were dried (MgSO,), filtered, and concentrated in vacuo. Purification by flash chromatography on silica gel afforded 310 mg (36%) of the title compound as a white solid. NMR (400 MHz, DMSO-c¾) delta 10.48 (s, 1 H), 9.18 (s, 1 H), 8.88 (s, 2H), 8.40 (d, J = 3.0 Hz, 1 H), 8.27 (dd, J = 9.2 Hz, 4.10 Hz, 1 H), 7.86 (td, 7 = 8.6, 3.1 Hz, 1 H), 7.55 (d, J= 2.3 Hz, 1 H), 7.29 (d, J= 2.3 Hz, 1 H), 2.58 (s, 3H); ES-MS [M+l ]+: 326.2
<strong>[109466-87-7]2-Nitro-4-(trifluoromethyl)benzaldehyde</strong> (219 mg) was dissolved in toluene (4 ml), and thereto was added 2-amino-5-fluoropyridine (123 mg), and the mixture solution was refluxed under heating. After the solution was stirred for 3 h, it was kept standing to cool to room temperature, and the solvent was distilled off in vacuo. To the residue was added triethyl phosphite (3 ml), and the residue was heated to 150 C. After the residue was stirred for 4 h, it was kept standing to cool to room temperature, and the residue was purified by the silica gel column chromatography affording the crude product of the compound 2. To the crude product was added hexane (2 ml), and the precipitated material was collected by filtration as the compound 2 (116 mg).MS m/z 282 [M+H]+, APCI(+)
Stage #1: 2-amino-5-fluoropyridine With n-butyllithium In tetrahydrofuran at -78 - -40℃; for 0.333333h;
Stage #2: 3-cyano-4-methylpyridine In tetrahydrofuran at -78 - 20℃; for 18h;
22.A Step A. N-(5-Fluoro-pyridin-2-yl)-4-methyl-nicotinamidine
n-Butyllithium (1.6 M, 3.33 mL, 0.00534 mol) was added slowly for a period of 5 min at a temperature of at -78 °C to a solution of 5-fluoro-pyridin-2-ylamine (0.3 g, 0.00267 mol) in anhydrous tetrahydrofuran (20 mL). Then the temperature raised to -40 °C and the reaction mixture was stirred for 15 min. The reaction mixture was cooled to - 78 °C and 4-methyl-nicotinonitrile (0.316 g, 0.00267 mol) in tetrahydrofuran (5 mL) was added. The temperature was raised to RT and stirred for 18 h. The reaction mixture quenched with a saturated aqueous ammonium chloride solution (25 mL) and then extracted with ethyl acetate (2 x 50 mL). The combined organic layer were dried over sodium sulphate and concentrated under vacuum to afford the crude product, N-(5-fluoro- pyridin-2-yl)-4-methyl-nicotinamidine, which was used without further purification in the next step. MS (M+l): 231.1.
With copper(l) iodide; In N,N-dimethyl-formamide; at 80℃; for 24h;Green chemistry;
General procedure: A test tube was charged with 1a (0.47 mmol), 2a (0.34 mmol) and CuI (5.73mg, 0.03mmol). Then 2 mL DMF was added to the reaction system. The reaction was stirred at 80 for 24 h. After cooling to room temperature, the solvent was diluted with 10 mL ethyl acetate and washed with 5 mL brine and dried over anhydrous Na2SO4. After the solvent was evaporated in vacuo, the residue were purified by column chromatography, eluting with petroleum ether/EtOAc (5:1) to afford 62 mg(92%) pure 3aa as yellow solid.
G. Preparation of Compounds of Formula IX (lR,2S)-2-(((2,4-dimethylpyrimidin-5-yl)oxy)methyl)-2-(3-fluorophenyl)-N-(S- fluoropyridin-2-yl)cyclopropanecarboxamide (14). (lR,2S)-2-(((2,4-dimethylpyrimidin- 5-yl)oxy)methyl)-2-(3-fluorophenyl)-cyclopropanecarboxylic acid (13, 12.80 g, 0.040 mol, 1.0 equiv.), and 2-amino-5-fluoiOpyridine (4.76 g, 0.0425 mol, 1.05 equiv.) were dissolved in ethyl acetate (102.4 mL), under nitrogen. The solution was cooled to 0-5 C, and N,N- diisopropylethylamine (14.10 mL, 0.081 mol, 2.0 equiv.) was added to the reaction mixture while maintaining the internal temperature at 0-15 C. The reaction mixture was stirred at 0-10 C for 20-30 minutes. n-Propylphosphonic anhydride (T3P; 50% w/w solution in ethyl acetate, 36.1 g, 1.4 equiv.) was added to the reaction mixture while maintaining the internal temperature at 0-15 C. The reaction was stirred at 20-25 C for at least 20-24 hour and monitored by HPLC and TLC (EtO Ac/Heptane = 1/1). Upon completion of the reaction, the reaction mixture was cooled to 0-5 C and then was quenched with water (64.0 mL) while maintaining the internal temperature below 10-15 C. The aqueous layer was back extracted once with MTBE (76.8 mL). The organic layers were combined and washed once with saturated aqueous NaHC03 solution (38.4 mL) and once with water (38.4 mL). The organic layer was polish filtered and the filter rinsed with MTBE (12,8 mL). The organic layer was then concentrated under reduced pressure to a minimum stirrable volume. Ethyl acetate (60.8 mL) was added to the reaction mixture and the mixture was heated to no more than 50 C to achieve a clear solution. n-Heptane (86.3 mL) was added slowly with agitation. The reaction mixture was cooled to 20-25 C, and the suspension was stirred for at least 1 h at 20-25 C and then stirred at least for 1 h at 0-5 C. The suspension was filtered and the cake was washed two times with 5 : 1 heptane/ethyl acetate (2 x 12.8 mL). The cake was dried under nitrogen and/or vacuum to provide the title compound, (lR,2S)-2-(((2,4-dimethylpyrimidin-5-yl)oxy)methyl)-2-(3-fluoiOphenyl)-N-(5-fiuoropyridin^ yl)cyclopropanecarboxamide, (14, 12.54 g, >99% ee) as a white to off white solid. (lR,2S)-2-(((2,4-dimethylpyrimidin-5-yl)oxy)methyl)-2-(3-fluoiOphenyl)-N-(5- fluoropyridin-2-yl)cyclopropanecarboxamide: 1H NMR (500 MHz, DMSO-d6) delta 11.19 (s, 1H), 8.31 (d, J = 3.0 Hz, 1H), 8.12 (s, 1H), 7.94 - 7.85 (m, 1H), 7.62 (tt, J = 8.7, 3.1 Hz, 1H), 7.44 (dd, J = 10.6, 1.5 Hz, 1H), 7.41 - 7.40 (m, 1H), 7.39 (s, 1H), 7.14 - 7.06 (m, 1H), 4.67 (d, J = 10.2 Hz, 1H), 4.29 (t, J= 9.9 Hz, 1H), 2.63 (t, J= 7.0 Hz, 1H), 2.38 (s, 3H), 2.03 (s, 3H), 1.76 - 1.64 (m, 1H), 1.49 (dd, J = 8.0, 4.8 Hz, 1H); 13C NMR (125 MHz, DMSO-d6) delta 168.68, 161.98 (d, JcF = 242.3 Hz), 158.46, 155.15, 155.38 (d, JCF = 247.9 Hz), 148.90, 148.51, 145.00 (d, JCF = 7.7 Hz), 139.37, 135.15 (d, JCF = 24.9 Hz), 130.06 (d, JCF = 8.4 Hz), 125.05 (d, JCF = 19.5 Hz), 124.70 (d, JCF = 2.6 Hz), 115.71 (d, JCF = 21.7 Hz), 114.20 (d, JCF = 4.1 Hz), 113.70 (d, JCF = 20.9 Hz), 70.80, 34.09 (d, JCF = 1.9 Hz), 26.90, 24.38, 18.37, 17.78. HRMS Calculated for C22H21F2N402 [M+H]+ 411.1627; found 411.1632.
2-(3,4-dimethoxyphenyl)-7-fluoro-4H-pyrido[1,2-a]pyrimidin-4-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
56%
With toluene-4-sulfonic acid; at 150℃; for 1h;
Step A: A mixture of <strong>[4687-37-0]ethyl 3-(3,4-dimethoxyphenyl)-3-oxopropanoate</strong> (2.02 g, 8.0 mmol), 2- amino-5-fluoropyridine (0.897 g, 8.0 mmol) andp-TsOH (152 mg, 0.8 mmol) was heated at 150 C. The mixture was melted and then solidified. Afterl hour, the mixture was cooled to room temperature and washed with MeCN to give 2-(3,4-dimethoxyphenyl)-7-fluoro-4H- pyrido[1,2-a]pyrimidin-4-one as a yellow solid (1.356 g, 56%). MS m/z 367.5 [M+H] ?H NMR (500 MHz, DMSO-d6): oe 8.92 (1H, dd, J= 2.9 Hz, 4.8 Hz), 8.11-8.07 (1H, m), 7.85-7.82 (1H, m),7.77 (1H, d, J= 2.1 Hz), 7.09 (1H, d, J= 8.6 Hz), 7.06 (1H, s), 6.93 (1H, s), 3.88 (3H, s), 3.84 (3H, s),
2-(4-methoxyphenyl)-7-fluoro-4H-pyrido[1,2-a]pyrimidin-4-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
65%
With polyphosphoric acid at 120℃; for 0.5h;
4.A
[001183] Step A: A mixture of ethyl 3-(3-methoxyphenyl)-3-oxopropanoate (2.68 mL, 14.0 mmol) and 2-amino-5-fluoropyridine (1.12 g, 10.0 mmol) in PPA (5 g) was heated at 120 °C. After 0.5 hours, the dark purple mixture was cooled to room temperature and treated with ice- water. The precipitate was filtered, washed with water and MeCN to give 2-(4-methoxyphenyl)- 7-fluoro-4H-pyrido[1 ,2-a]pyrimidin-4-one as a slightly yellow solid (1.758 g, 65%). MS m/z271.2 [M+H].
ethyl 3-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-3-oxopropanoate[ No CAS ]
[ 21717-96-4 ]
2-(4,6-dimethylpyrazolo [1,5-a]pyrazin-2-yl)-7-fluoro-4H-pyrido[1,2-a]pyrimidin-4-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
71%
With pyridinium p-toluenesulfonate; at 130℃; for 8h;
[001222] Step G: A mixture of <strong>[21717-96-4]2-amino-5-fluoro-pyridine</strong> (134 mg, 1.2 mmol), ethyl 3-(4,6- dimethylpyrazolo [1,5 -a]pyrazin-2-yl)-3 -oxopropanoate (261 mg, 1.0 mmol) and PPTs (12.6 mg, 0.05 mmol) was heated at 130 C. After 8 hours, the mixture was cooled to room temperature and chromatographed to give 2-(4,6-dimethylpyrazolo [1,5 -a]pyrazin-2-yl)-7-fluoro-4H-0 +1pyrido[1,2-a]pyrimidin-4-one as a yellow solid (220 mg, 71 /o). MS m/z 310.2 [M+H] ; H NMR(500 MHz, DMSO-d6): oe 8.97-8.95 (1H, m), 8.55 (1H, s), 8.16-8.12 (1H, m), 7.87-7.85 (1H, m), 7.56 (1H, s), 7.03 (1H, s), 2.73, (3H, s), 2.43 (3H, s).
71%
With pyridinium p-toluenesulfonate; at 130℃; for 8h;
Step G: A mixture of <strong>[21717-96-4]2-amino-5-fluoro-pyridine</strong> (134 mg, 1.2 mmol), ethyl 3-(4,6- dimethylpyrazolo[l,5-a]pyrazin-2-yl)-3-oxopropanoate (261 mg, 1.0 mmol) and PPTs (12.6 mg, 0.05 mmol) was heated at 130 oC. After 8 h, the mixture was cooled to rt and chromato graphed to give 2-(4,6-dimethylpyrazolo[ 1 ,5-a]pyrazin-2-yl)-7-fluoro-4H-pyrido[ 1 ,2-a]pyrimidin-4-one as a yellow solid (220 mg, 71%). MS m/z 310.2 [M+H]+; IH NMR (500 MHz, DMSO-d6): delta 8.97-8.95 (IH, m), 8.55 (IH, s), 8.16-8.12 (IH, m), 7.87-7.85 (IH, m), 7.56 (IH, s), 7.03 (IH, s), 2.73, (3H, s), 2.43 (3H, s).
71%
With pyridinium p-toluenesulfonate; at 130℃; for 8h;
A mixture of <strong>[21717-96-4]2-amino-5-fluoro-pyridine</strong> (134 mg, 1.2 mmol), ethyl 3-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-3-oxopropanoate (261 mg, 1.0 mmol) and PPTs (12.6 mg, 0.05 mmol) was heated at 130 C. After 8 h, the mixture was cooled to rt and chromatographed to give 2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-7-fluoro-4H-pyrido[1,2-a]pyrimidin-4-one as a yellow solid (220 mg, 71%). MS m/z 310.2 [M+H]+; 1H NMR (500 MHz, DMSO-d6): delta 8.97-8.95 (1H, m), 8.55 (1H, s), 8.16-8.12 (1H, m), 7.87-7.85 (1H, m), 7.56 (1H, s), 7.03 (1H, s), 2.73, (3H, s), 2.43 (3H, s).
14.1.A
[001253] Part 1, Step A: A mixture of 2-amino-5-fluoropyridine (11.20 g, 0.10 mol) and dimethyl malonate (57.0 mL, 0.50 mol) was heated at 230 °C for 1.5 hours. After cooling to room temperature, the precipitate was filtered and washed with ACN (3x) to give 7-fluoro-2- hydroxy-4H-pyrido[1,2-a]pyrimidin-4-one as a dark solid (14 g), which was used directly in the+next step. MS m/z 181.3 [M+H]
at 230℃; for 1.5h;
1.a
a) 2-chloro-7-fluoro-pyridor 1 ,2-a1pyrimidin-4-one A mixture of 2-amino-5-fluoropyridine (11.20 g, 0.10 mol) and dimethyl malonate (57.0 mL, 0.50 mol) was heated at 230 °C for 1.5 h. After cooling to room temperature, the precipitate was filtered and washed with ACN (3x) to give 7-fluoro-2-hydroxy-4H-pyrido[l,2-a]pyrimidin- 4-one as a dark solid (14 g), which was used directly in the next step. MS m/z 181.3 [M+H]+. A dark mixture of crude 7-fluoro-2-hydroxy-4H-pyrido[l,2-a]pyrimidin-4-one (14g, -77 mmol) in POCl3 (50 mL) and DIPEA (13.3 mL, 77 mmol) was heated at 110 °C for 15 hours. The solvent was removed and the dark residue was treated with ice-water, washed with water (3x) and dried to give a brown solid. The crude brown solid was chromatographed (5% MeOH in CH2C12) to give 2-chloro-7-fluoro-4H-pyrido[l,2-a]pyrimidin-4-one as a yellow solid (9.84 g, 50%, 2 steps), MS m/z 199.2 [M+H]+.
14 g
In neat (no solvent) at 230℃; for 1.5h;
at 230℃; for 1.5h; Inert atmosphere;
at 230℃; for 1.5h;
1 a) 7-fluoro-2-hydroxy-pyrido [1,2-al pyrimidin-4-one
A mixture of 2-amino-5-fluoropyridine (11.20 g, 0.10 mol) and dimethyl malonate (57.0 mL, 0.50 mol) was heated at 230 °C for 1.5 h. After cooling to room temperature, the precipitate was filtered and washed with ACN (3x) to give 7-fluoro-2-hydroxy-4H-pyrido[1,2-a]pyrimidin-4-one as a dark solid (14 g), which was used directly in the next step (mlz: 181.3 [M+H]j.
at 230℃; for 1.5h;
a a) 2-chloro-7-fluoro-pyrido [1,2-al pyrimidin-4-one
A mixture of 2-amino-5-fluoropyridine (11.20 g, 0.10 mol) and dimethyl malonate (57.0mL, 0.50 mol) was heated at 230 °C for 1.5 h. After cooling to room temperature, the precipitatewas filtered and washed with ACN (3x) to give 7-fluoro-2-hydroxy-4H-pyrido[1,2-a]pyrimidin-4-one as a dark solid (14 g), which was used directly in the next step. MS m/z 181.3 [M+H].
at 230℃; for 1.5h;
1.a
A mixture of 2-amino-5-fluoropyridine (11.20 g, 0.10 mol) and dimethyl malonate (57.0 mL, 0.50 mol) was heated at 230 °C for 1.5 h. After cooling to room temperature, the precipitate was filtered and washed with ACN (3x) to give 7-fluoro-2-hydroxy-4H-pyrido[1,2-a]pyrimidin- 4-one as a dark solid (14 g), which was used directly in the next step. MS m/z 181.3 [M+H].
at 230℃; for 1.5h;
a a) 2-chloro-7-fluoro-pyrido[1,2-a]pyrimidin-4-one
A mixture of 2-amino-5-fluoropyridine (11.20 g, 0.10 mol) and dimethyl malonate (57.0 mL, 0.50 mol) was heated at 230° C. for 1.5 h. After cooling to room temperature, the precipitate was filtered and washed with ACN (3*) to give 7-fluoro-2-hydroxy-4H-pyrido[1,2-a]pyrimidin-4-one as a dark solid (14 g), which was used directly in the next step. MS m/z 181.3 [M+H]+.
2 Step 2:
Step 2: methyl 6-fluoro-3-methylimidazo[1,2-a]pyridine-2-carboxylate The methyl 3-bromo-2-oxobutanoate (1.502 g, 7.70 mmol) was dissolved in DME (9 mL). The solution was cooled in an ice-water bath. 5-Fluoropyridin-2-amine (0.785 g, 7.00 mmol) was added, and the ice bath was removed. The mixture was stirred at RT for 2 days. The thick suspension was filtered through a fine frit, rinsing the solid with DME (15 mL). The recovered solid (1.535 g) was suspended in MeOH (19 mL). The vessel was sealed and heated in an 80° C. oil bath. After 2.5 h, the reaction was cooled and concentrated. The yellow solid was triturated with diethyl ether and dried under vacuum to afford the title compound (777 mg, 48%).
With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In N,N-dimethyl acetamide; at 145℃; for 0.5h;Inert atmosphere;
Step 2[00164j 5-Fluoropyridin-2-amine (1.195 g, 10.66 mmol) was combined withIntermediate 6(1.00 g, 5.33 mmol). To the vessel was added DMA (20 mL) followed byPd2dba3 (488 mg, 0.533 mmol), Xantphos (617 mg, 1.07 mmol) and cesium carbonate(3.47 g, 107 mmol). The vessel was then evacuated and backfilled with nitrogen three times and then heated to 145 C for 30 minutes. The crude reaction was diluted with methanol and filtered (rinsing with methanol). The filtrate was concentrated to minimal volume using a rotary evaporator connected to an oil pump. To the viscous oil was added iN HC1 (aqueous) to a pH 2 resulting in a precipitate which was then sonicated andfiltered off, rinsing with cold water. The solid was collected, dried and suspended in diethyl ether. The slurry was sonicated and subsequently filtered, rinsing with diethyl ether. The solid was once again collected and this time suspended in 1:1 dichloromethane:ether and again sonicated. Filtration followed by a 1:1 dichloromethane:ether rinse and a hexanes rinse yielded the Intermediate 7 (1.31 g, 94%).?H NMR (400MHz, DMSO-d6) oe 8.60 (s, 1H), 8.35 (d, J=3.1 Hz, 1H), 7.86 (td, J=8.6, 2.8 Hz, 1H), 7.57 (d, J=5.9 Hz, 1H), 7.16 (s, 1H), 3.96 (s, 3H). LC retention time 0.50 mm [J]. MS(E) m/z: 264 (MHj.
6-chloro-4-((2-methoxypyridin-3-yl)amino)-N-methylnicotinamide[ No CAS ]
[ 21717-96-4 ]
[ 1609529-56-7 ]
Yield
Reaction Conditions
Operation in experiment
97%
With tris-(dibenzylideneacetone)dipalladium(0); dicyclohexyl-(2?,4?,6?-triisopropyl-3,6-dimethoxy-[1,1?-biphenyl]-2-yl)phosphine; lithium hexamethyldisilazane; In tetrahydrofuran; 1,4-dioxane; at 110℃; for 1.5h;Inert atmosphere;
[00240j A reaction vial was charged with 6-chloro-4-((2-methoxypyridin-3 -yl)amino)N-methylnicotinamide (15 mg, 0.05 1 mmol), 5-fluoropyridin-2-amine (8.04 mg, 0.072mmol), 2-(dicyclohexylphosphino)3 ,6-dimethoxy-2 ?,4?,6?-triisopropyl- 1,1 ?-biphenyl (BrettPhos, 4.13 mg, 7.69 jimol) and tris(dibenzylideneacetone)dipalladium(0) (Pd2dba3, 4.69 mg, 5.12 jimol). After flushing the contents with nitrogen, dioxane (0.3 mL) was added followed by the addition of LiHMDS (1 M in THF) (0.113 mL, 0.113 mmol) affording a dark amber colored solution. This solution was heated in a preheated heatingblock at 110 C for 1.5 h, then cooled to room temperature. The reaction mixture was quenched with 0.1 mL of methanol, concentrated to remove the residual solvents, diluted with DMF, filtered through a Millipore filter, and the crude material was purified viapreparative LC/MS. Fractions containing the desired product were combined and driedvia centrifugal evaporation to afford 18.9 mg (97%) of Example 313. LCMS (Method E)RT = 1.39 minutes; LCMS (Method G) R = 0.97 minutes. LCMS observed MH+ =369.1. ?H NMR (500MHz, DMSO-d6)oe 10.50 (s, 1H), 9.80 (s, 1H), 8.50 (d, J=4.3 Hz,1H), 8.46 (s, 1H), 8.16 (d, J=2.4 Hz, 1H), 7.86 (d, J=4.9 Hz, 1H), 7.83 (d, J7.3 Hz, 1H),7.74 - 7.57 (m, 3H), 7.09 (dd, J7.3, 5.5 Hz, 1H), 3.94 (s, 3H), 2.77 (d, J=4.3 Hz, 3H).
3-((2-((5-fluoropyridin-2-yl)amino)-5-(methylcarbamoyl)-pyridin-4-yl)amino)-2-methoxy-benzoic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
97%
With tris-(dibenzylideneacetone)dipalladium(0); dicyclohexyl-(2?,4?,6?-triisopropyl-3,6-dimethoxy-[1,1?-biphenyl]-2-yl)phosphine; lithium hexamethyldisilazane; In tetrahydrofuran; 1,4-dioxane; N,N-dimethyl acetamide; at 110℃; for 2h;Inert atmosphere;
[00245j A reaction vial was charged with 3-((2-chloro-5-(methylcarbamoyl)pyridin-4- yl)amino)-2-methoxybenzoic acid (600 mg, 1.787 mmol), 5-fluoro-4-methylpyridin-2- amine (316 mg, 2.502 mmol), BrettPhos (38.4 mg, 0.071 mmol) and Pd2(dba)3 (32.7 mg, 0.03 6 mmol) and the contents were flushed with nitrogen before adding dioxane (2 mL) and DMA (1 mL). The resulting slurry was sparged with additional nitrogen for 1minutes, then LiHMDS (1 M in THF) (3.93 mL, 3.93 mmol) was added and the resulting dark amber colored solution was heated in a preheated heating block at 110 C for 2h, then cooled to room temperature. The reaction mixture was added to water (80 mL) and the pH was adjusted with aq. iN HC1 to 3 causing a solid to precipitate from solution. After stirring the slurry at room temperature for 4 h, the solid was collected by vacuumfiltration, rinsed with water, and dried on the filter to afford 3-((2-((5-fluoro-4-methylpyridin-2-yl)amino)-5 -(methylcarbamoyl)pyridin-4-yl)amino)-2-methoxybenzoicacid (736 mg, 1.730 mmol, 97% yield) as a beige solid. HPLC (Method N) RT = 2.45minutes. LCMS (m+1) = 426.
5-Fluoropyridin-2-amine (1) (1 .Og, 8.9mmol), 5-chloro-3-methyl-1 ,2,4-thiadiazole(2) (1.19g, 8.9mmol), Xantphos (0.516g, 0.89mmol), and Cs2003 (4.35g,13.3mmol) were combined in dry 1,4-dioxane (l5mL). The reaction mixture wasdegassed with N2(g) and placed under vacuum for 10mm. Pd2(dba)3 (0.41g,0.44mmol) was then added and the resulting reaction mixture was heated at90C for 30h. It was then poured onto demineralized water (200mL), and extracted with EtOAc (3 x lOOmL). The organic phases were combined, dried over Na2504, filtered and subsequently evaporated under vacuum. The resultingresidue was purified by flash chromatography, eluting with EtOAc/Hexane (3:7) to provide N-(5-fluoropyridin-2-yl)-3-methyl-1 ,2,4-thiadiazol-5-amine (3) as a yellow solid (1 .2g, 67%).LCMS (ES): Found 211.1 [MH]+.
67%
With tris-(dibenzylideneacetone)dipalladium(0); 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane; at 90℃; for 30h;Inert atmosphere;
5-Fluoropyridin-2-amine (1) (1 .Og, 8.9mmol), 5-chloro-3-methyl-1, 2, 4-thiadiazole (2) (1.19g, 8.9mmol), Xantphos (0.52g, 0.89mmol), and Cs2003 (4.35g, 13.3mmol) were combined in dry 1,4-dioxane (l5mL). The reaction mixture was degassed with N2(g) and placed under vacuum for 10mm. Pd2(dba)3 (0.41g, 0.44mmol) was then added and the resulting reaction mixture was heated at 90C for 30h. The reactionmixture was then poured onto demineralized water (200mL), and extracted with EtOAc (3 x lOOmL). The organic phases were combined, dried over Na2504, filtered and subsequently concentrated in vacuo. The resulting residue was purified by flash chromatography with EtOAc/Hexane (3:7) to provide N-(5-fluoropyridin-2-yl)-3- methyl-i, 2, 4-thiadiazol-5-amine (3) as a yellow solid (1.2g, 67%).LCMS (ES): Found 211.1 [M+H].
67%
With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane; at 90℃; for 30h;Inert atmosphere;
5-Fluoropyridin-2-amine (1 ) (1 .0g, 8.9mmol), 5-chloro-3-methyl-1 , 2, 4- thiadiazole (2) (1 .19g, 8.9mmol), Xantphos (0.52g, 0.89mmol), and Cs2C03 (4.35g, 13.3mmol) were combined in dry 1 ,4-dioxane (15mL). The reaction mixture was degassed with N2(g) and placed under vacuum for 10min. Pd2(dba)3 (0.41 g, 0.44mmol) was then added and the resulting reaction mixture was heated at 90C for 30h. The reaction mixture was then poured onto demineralized water (200ml_), and extracted with EtOAc (3 x 100ml_). The organic phases were combined, dried over Na2S04, filtered and subsequently concentrated in vacuo. The resulting residue was purified by flash chromatography with EtOAc/Hexane (3:7) to provide N-(5-fluoropyridin-2-yl)-3- methyl-1 , 2, 4-thiadiazol-5-amine (3) as a yellow solid (1 .2g, 67%). LCMS (ES): Found 21 1 .1 [M+H]+
67%
Example R (0359) 4-(((5-Fluoropyridin-2-yl)(3-methyl-1 ,2,4-thiadiazol-5-yl)amino)methyl)-N- hydroxybenzamide (0360) (0361) 5-Fluoropyridin-2-amine (1 ) (1.0g, 8.9mmol), 5-chloro-3-methyl-1 ,2,4-thiadiazole (2) (1.19g, 8.9mmol), Xantphos (0.52g, 0.89mmol) and Cs2C03 (4.35g, 13.3mmol) were combined in dry 1 ,4-dioxane (15mL). The reaction mixture was degassed with N2(g) and placed under vacuum for 10min. Pd2(dba)3 (0.41 g, 0.44mmol) was then added and the resulting reaction mixture was heated at 90C for 30h. The reaction mixture was then poured onto demineralised water (200ml_), and extracted with EtOAc (3 x 100ml_). The organic phases were combined, dried over Na2S04, filtered and subsequently concentrated in vacuo. The resulting residue was purified by flash chromatography with EtOAc/Hexane (3:7) to provide N-(5-fluoropyridin-2-yl)-3- methyl-1 ,2,4-thiadiazol-5-amine (3) as a yellow solid (1.2g, 67%). (0362) LCMS (ES): Found 21 1.1 [M+H]+.
5-Fluoropyridin-2-amine (1) (1 .Og, 8.9mmol), 5-chloro-3-(trifluoromethyl)1 2,4- thiadiazole (2) (1.68g, 8.9mmol), Xantphos (0.52g, 0.89mmol), and C52CO3 (4.35g, 13.3mmol) were combined in dry 1,4-dioxane (l5mL). The reaction mixture was degassed with N2(g) and placed under vacuum for I 0mm. Pd2(dba)3 (0.41g, 0.44mmol) was then added and the resulting reaction mixture was heated at 90C for 30h. It was then poured onto demineralized water (200mL),and extracted with EtOAc (3 x 100mL). The organic phases were combined, dried over Na2SO4, filtered and subsequently evaporated under vacuum. The resulting residue was purified by flash chromatography, eluting with EtOAc/Hexane (3:7) to provide N-(5-fl uoropyridin-2-yl)-3-(trifl uoromethyl) 1,2,4- thiadiazol-5-amine (3) as a yellow solid (900mg, 38%).LCMS (ES): Found 265.1 [MH]+.
38%
With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane; at 90℃; for 30h;Inert atmosphere;
5-Fluoropyridin-2-amine (1) (1 .Og, 8.9mmol), 5-chloro-3-(trifluoromethyl)-1, 2, 4-thiadiazole (2) (1.68g, 8.9mmol), Xantphos (0.52g, 0.89mmol), and 0s2003 (4.35g,13.3mmol) were combined in dry 1,4-dioxane (l5mL). The reaction mixture was degassed with N2(g) and placed under vacuum for 10mm. Pd2(dba)3 (0.41g, 0.44mmol) was then added and the resulting reaction mixture was heated at 90C for 30h. It was then poured onto demineralized water (200mL), and extracted with EtOAc (3 x lOOmL). The organic phases were combined, dried over Na2SO4, filtered and subsequently concentrated in vacuo. The resulting residue was purified by flash chromatography with EtOAc/Hexane (3:7) to provide N-(5-fluoropyridin-2-yl)-3-(trifluoromethyl)-1, 2, 4-thiadiazol-5-amine (3) as a yellow solid (900mg, 38%). LCMS (ES): Found 265.1 [M+H].
38%
With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane; at 90℃; for 30h;Inert atmosphere;
5-Fluoropyridin-2-amine (1 ) (1 .0g, 8.9mmol), 5-chloro-3-(trifluoromethyl)-1 , 2, 4- thiadiazole (2) (1 .68g, 8.9mmol), Xantphos (0.52g, 0.89mmol), and Cs2C03 (4.35g, 13.3mmol) were combined in dry 1 ,4-dioxane (15mL). The reaction mixture was degassed with N2(g) and placed under vacuum for 10min. Pd2(dba)3 (0.41 g, 0.44mmol) was then added and the resulting reaction mixture was heated at 90C for 30h. It was then poured onto demineralized water (200ml_), and extracted with EtOAc (3 x 100ml_). The organic phases were combined, dried over Na2S04, filtered and subsequently concentrated in vacuo. The resulting residue was purified by flash chromatography with EtOAc/Hexane (3:7) to provide N-(5-fluoropyridin-2-yl)-3-(trifluoromethyl)-1 , 2, 4-thiadiazol-5-amine (3) as a yellow solid (900mg, 38%). LCMS (ES): Found 265.1 [M+H]+
38%
Example T (0377) 4-(((5-Fluoropyridin-2-yl)(3-(trifluoromethyl)-1 ,2,4-thiadiazol-5- yl)amino)methyl)-N-hydroxybenzamide (0378) (0379) T 5-Fluoropyridin-2-amine (1 ) (1.0g, 8.9mmol), 5-chloro-3-(trifluoromethyl)-1 ,2,4- thiadiazole (2) (1.68g, 8.9mmol), Xantphos (0.52g, 0.89mmol), and Cs2C03 (4.35g, 13.3mmol) were combined in dry 1 ,4-dioxane (15ml_). The reaction mixture was degassed with N2(g) and placed under vacuum for 10min. Pd2(dba)3 (0.41 g, 0.44mmol) was then added and the resulting reaction mixture was heated at 90C for 30h. It was then poured onto demineralised water (200ml_) and extracted with EtOAc (3 x 100ml_). The organic phases were combined, dried over Na2S04, filtered and subsequently concentrated in vacuo. The resulting residue was purified by flash chromatography with EtOAc/Hexane (3:7) to provide N-(5-fluoropyridin-2-yl)-3- (trifluoromethyl)-l , 2, 4-thiadiazol-5-amine (3) as a yellow solid (900mg, 38%). (0380) LCMS (ES): Found 265.1 [M+H]+.
3-Cyano-4-fluorobenzene-1-sulfonyl chloride (25 g, 114 mmol) was added to a solution of 5-fluoropyridin-2-amine (16.85 g, 150 mmol) and pyridine (23.7 g, 300 mmol) in dichloromethane (500 mL) at room temperature. The resulting mixture was stirred at room temperature for 3 hours. After evaporating the solvent the solid was stirred in diluted aqueous hydrochloric acid (2N, 400 mL) for 16 hours. The reaction mixture was filtered, washed with water (200 mL) and dried under high vacuum to afford the title compound as an orange solid (30.9 g, 98%). 1H NMR (400 MHz, DMSO-d6): delta ppm 7.09 (dd, 1H), 7.65-7.77 (m, 2H), 8.18 (d, 1H), 8.22-8.29 (m, 1H), 8.44 (dd, 1H)), 10.82 (br s, 1H). MS m/z 296 [M+H]+
(6-fluoro-1H-imidazo[1,2-a]pyridin-3-yl)(phenyl)methanone[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
83%
With iron(III) chloride; In toluene; at 60℃; for 18h;
General procedure: A mixture of 2-aminopyridine (0.2 mmol), 3-phenylpropiolaldehyde (0.2 mmol) and ferric chloride (5 mol%) in toluene (1 mL) was placed in a test tube (10 mL) equipped with a magnetic stirring bar. The mixture was stirred at 60 C for 18 h. After the reaction was finished, water (5 mL) was added and the solution was extracted with ethyl acetate (3×5 mL), the combined extract was dried with anhydrous MgSO4. Solvent was removed, and the residue was separated by column chromatography to give the pure sample.
N-(5-fluoropyridin-2-yl)morpholine-4-carboxamidine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
85%
Stage #1: 2-amino-5-fluoropyridine With sodium t-butanolate In dimethyl sulfoxide at 20℃; for 0.25h; Inert atmosphere;
Stage #2: N-cyanomorpholine In dimethyl sulfoxide at 20 - 50℃; Inert atmosphere;
To a solution of 5-fluoropyridin-2-amine (1.00 g, 8.92 mmol) andpyridine (0.86 mL, 10.7 mmol) in THF (30.0 mL) was added phenylcarbonochloridate (1.54 mL, 9.81 mmol) at 0 C. The mixture was stirred at room temperature for 1 h. The reaction was quenched by theaddition of water, and the mixture was stirred for 1 h. The precipitatewas then collected by filtration to yield phenyl (5-fluoropyridin-2-yl)carbamate as a colorless solid (2.05 g, 99% yield).
67%
With pyridine; In dichloromethane; at 20℃; for 0.5h;Inert atmosphere;
To a solution of phenyl carbonochloridate (1.397 g, 8.92 mmol), and Pyridine (0.721 mL, 8.92 mmol) in dichloromethane (DCM) (40 mL) stirred under nitrogen at room temp was added 5-fluoropyridin-2-amine (1.0 g, 8.92 mmol). The reaction mixture was stirred at RT for 30 min. The reaction mixture was quenched with saturated sodium bicarbonate solution. Separated organic layer and the aqueous layer extracted with DCM (20 ml). Combined organic layer washed with water followed by brine solution and dried out with sodium sulfate, filtered and concentrated under vacuum to give the desired product (1.4 g, 5.94 mmol, 67%), LCMS (m/z) 233.2 (M+H)+.
67%
With pyridine; In dichloromethane; at 20℃; for 0.5h;Inert atmosphere;
To a solution of phenyl carbonochloridate (1.397 g, 8.92 mmol), and Pyridine (0.721 mL, 8.92 mmol) in dichloromethane (DCM) (40 mL) stirred under nitrogen at room temp was added 5-fluoropyridin-2-amine (1.0 g, 8.92 mmol). The reaction mixture was stirred at RT for 30 min. The reaction mixture was quenched with saturated sodium bicarbonate solution. Separated organic layer and the aqueous layer extracted with DCM (20 ml). Combined organic layer washed with water followed by brine solution and dried out with sodium sulfate, filtered and concentrated under vacuum to give the desired product (1.4 g, 5.94 mmol, 67%), LCMS (m/z) 233.2 (M+H)+.
Multi-step reaction with 4 steps
1: 1.5 h / 230 °C
2: trichlorophosphate; N-ethyl-N,N-diisopropylamine / 15 h / 110 °C
3: tetrakis(triphenylphosphine) palladium(0); potassium carbonate / water; acetonitrile / 6 h / 100 °C / Inert atmosphere
4: N-ethyl-N,N-diisopropylamine / dimethyl sulfoxide / 48 h / 130 °C / Sealed tube
Multi-step reaction with 4 steps
1: 1.5 h / 230 °C
2: trichlorophosphate; N-ethyl-N,N-diisopropylamine / 15 h / 110 °C
3: tetrakis(triphenylphosphine) palladium(0); potassium carbonate / acetonitrile / 6 h / 100 °C
4: N-ethyl-N,N-diisopropylamine / dimethyl sulfoxide / 48 h / 130 °C / Sealed tube
Multi-step reaction with 4 steps
1: 1.5 h / 230 °C
2: trichlorophosphate; N-ethyl-N,N-diisopropylamine / 15 h / 110 °C
3: tetrakis(triphenylphosphine) palladium(0); potassium carbonate / acetonitrile; water / 6 h / 100 °C / Inert atmosphere
4: N-ethyl-N,N-diisopropylamine / dimethyl sulfoxide / 48 h / 130 °C / Sealed tube
Multi-step reaction with 4 steps
1: 1.5 h / 230 °C / Inert atmosphere
2: trichlorophosphate; N-ethyl-N,N-diisopropylamine / 15 h / 110 °C / Inert atmosphere
3: tetrakis(triphenylphosphine) palladium(0); potassium carbonate / water; acetonitrile / 6 h / 100 °C / Inert atmosphere
4: N-ethyl-N,N-diisopropylamine / dimethyl sulfoxide / 48 h / 130 °C / Inert atmosphere
Multi-step reaction with 4 steps
1: 1.5 h / 230 °C
2: N-ethyl-N,N-diisopropylamine; trichlorophosphate / 15 h / 110 °C
3: tetrakis(triphenylphosphine) palladium(0); potassium carbonate / acetonitrile; water / 6 h / 100 °C
4: N-ethyl-N,N-diisopropylamine / dimethyl sulfoxide / 48 h / 130 °C / Sealed tube
5-fluoro-N-(4-nitropyridin-3-yl)pyridin-2-amine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
30.6%
NaH (60% dispersion in mineral oil, 1.08g, 27.lmmol) was added portionwise to a solution of 2-amino-5-fluoropyridine (3.04g, 27.lmmol) in THF (6OmL) and the resultant mixture was stirred for 30mm. A solution of <strong>[13505-01-6]3-fluoro-4-nitropyridine</strong> (3.50g, 24.6mmol) in THF (lOmL) was added and the resultant mixture wasstirred for 16h. The reaction mixture was partitioned between EtOAc (4OmL) and water (4OmL) and the organic phase was washed with brine (4OmL), dried (MgSO4) and solvents were evaporated in vacuo. The residue was purified by column chromatography to give the title compound (1 .76g, 30.6%) as a red solid. LCMS (ESj: 235.0 [M+H]. HPLC: Rt 5.51mm, 100% purity.
The solution of (S)-5-(tert-butoxycarbonyl)-5-azaspiro[2.4]heptane-6-carboxylicacid (2.41 g, 10.0 mmol) and NMI (1.81 g, 22.0 mmol) in DMF (25 mL), cooled to 0 C, was added by MsCl (1.15 g,10.0 mmol) dropwise, and keptstirring for 15 min. Then 5-fluoropyridin-2-amine (1.12 g, 10.0 mmol) wasadded. The reaction was monitored by TLC. After completion, the mixture wasdiluted by EA, washed by 10% citric acid, and extracted by EA (2x50 mL). Thecombined organic layers were washed by saturated Na2CO3solution and brine. Concentration under reduced pressure gave the crude.
General procedure: To an acid, DMF was added, then 2.1 equivalents of N-methylimidazole was added under ice bath, and then 1 equivalent of MsCl was slowly added. After stirring for 15 min, 1 equivalent of Boc-protected amine was added to the mixture.The reaction was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with EA, and washed with 10% citric acid; and the aqueous phase was extracted twice with 50 mL of EA. The combined organic phase was washed successively with saturated sodium bicarbonate and saturated sodium chloride. The organic phase was concentrated to gibe the product
With sodium hydrogencarbonate; In toluene; for 12h;Reflux;
General procedure: A mixture of appropriately substituted pyridin-2-amine (10 mmol), 2-bromoacetophenone (10 mmol), and sodium bicarbonate (15 mmol) in anhydrous toluene (25 mL) was stirred for 12 h under reflux. After removal of toluene under vacuum, dichloromethane was added to the residue and any insoluble was removed by filtration. The crude products were crystallized from methanol or purified by silica gel chromatography using hexane/ethylacetate, 7:3 (v/v) as eluent.
With sodium hydrogencarbonate; at 20℃; for 6h;
General procedure: Method A1a: To an ethanol solution containing 2-bromoacetophenones (1.0 equiv) and 2-aminopyridines (1.25 equiv) was added NaHCO3 (1.56 equiv). The reaction mixture was stirred at room temperature for 6 hours. After completion of the reaction, the resulting mixture was diluted with water and extract with ether. The combined organic layer was washed with brine, dried with anhydrous MgSO4, concentrated under vacuum to give the crude product, which was purified by silica gel column with petroleum ether/EtOAc as the eluent to give the analytical pure 2-arylimidazo[1,2-a]pyridine (1a-1r).
2-(2,4-difluorophenyl)-6-fluoroimidazo[1,2-a]pyridine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
81%
With sodium hydrogencarbonate In toluene for 12h; Reflux;
General procedure for the synthesis of 2-phenylimidazo[1,2-a]pyridine derivatives (2-13, 37-45)
General procedure: A mixture of appropriately substituted pyridin-2-amine (10 mmol), 2-bromoacetophenone (10 mmol), and sodium bicarbonate (15 mmol) in anhydrous toluene (25 mL) was stirred for 12 h under reflux. After removal of toluene under vacuum, dichloromethane was added to the residue and any insoluble was removed by filtration. The crude products were crystallized from methanol or purified by silica gel chromatography using hexane/ethylacetate, 7:3 (v/v) as eluent.
2-(3,4-difluorophenyl)-6-fluoro-imidazo[1,2-a]pyridine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
81%
With sodium hydrogencarbonate In toluene for 12h; Reflux;
General procedure for the synthesis of 2-phenylimidazo[1,2-a]pyridine derivatives (2-13, 37-45)
General procedure: A mixture of appropriately substituted pyridin-2-amine (10 mmol), 2-bromoacetophenone (10 mmol), and sodium bicarbonate (15 mmol) in anhydrous toluene (25 mL) was stirred for 12 h under reflux. After removal of toluene under vacuum, dichloromethane was added to the residue and any insoluble was removed by filtration. The crude products were crystallized from methanol or purified by silica gel chromatography using hexane/ethylacetate, 7:3 (v/v) as eluent.
2-[3,5-bis(trifluoromethyl)phenyl]-6-fluoro-imidazo[1,2-a]pyridine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
82%
With sodium hydrogencarbonate; In toluene; for 12h;Reflux;
General procedure: A mixture of appropriately substituted pyridin-2-amine (10 mmol), 2-bromoacetophenone (10 mmol), and sodium bicarbonate (15 mmol) in anhydrous toluene (25 mL) was stirred for 12 h under reflux. After removal of toluene under vacuum, dichloromethane was added to the residue and any insoluble was removed by filtration. The crude products were crystallized from methanol or purified by silica gel chromatography using hexane/ethylacetate, 7:3 (v/v) as eluent.
7-fluoro-2-phenyl-4H-pyrido[1,2-a]pyrimidin-4-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
82%
In ethylene glycol at 100℃; for 4h; Green chemistry;
General procedure for the synthesis of 4H-pyrido[1,2-a]pyrimidin-4-ones and 2-phenyl-4H-pyrido[1,2-a]pyrimidin-4-one
General procedure: A mixture of ethylacetoacetate or ethyl 3-phenylpropionate (1.5 mmol, 0.15 mL), 2-amino heterocycle (1 mmol, 0.10 mL) in ethylene glycol (1.5 ml) in a round bottom flask (RBF) was stirred for 4 to 6 h at 100 °C, and the reaction was monitored by TLC (ethanol/n-hexane, 4:6) (as shown in Table 1). After completion of the reaction, the reaction mixture was allowed to cool to room temperature, and the precipitates were filtered. The obtained crude products were purified by column chromatography using an ethyl acetate/n-hexane, (4:6) to give products 3 and 5 in high yield. Out of 17 compounds the majority are known except for 5i.
77%
With silver trifluoromethane sulfate In chlorobenzene at 120℃; for 24h; regioselective reaction;
C. General procedure for the synthesis of 4H-pyrido[1,2-a]pyrimidin-4-ones
General procedure: A mixture of 2-aminopyridine (0.1mmol), alkynoate (0.1mmol) and AgSO3CF3 (30mol%) in chlorobenzene (0.8mL) was stirred at 120°C for 24h. After the reaction was finished, water (5mL) was added and the solution was extracted with ethyl acetate (3×5mL), the combined extract was dried with anhydrous MgSO4. Solvent was removed, and the residue was separated by column chromatography to give the pure sample.
7-fluoro-2-(m-tolyl)-4H-pyrido[1,2-a]pyrimidin-4-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
95%
With silver trifluoromethane sulfate; In chlorobenzene; at 120℃; for 24h;
General procedure: A mixture of 2-aminopyridine (0.1mmol), alkynoate (0.1mmol) and AgSO3CF3 (30mol%) in chlorobenzene (0.8mL) was stirred at 120C for 24h. After the reaction was finished, water (5mL) was added and the solution was extracted with ethyl acetate (3×5mL), the combined extract was dried with anhydrous MgSO4. Solvent was removed, and the residue was separated by column chromatography to give the pure sample.
3-(2-methoxyphenoxy)-2-(4-methoxyphenyl)-6-fluoroimidazo[1,2-a]pyridine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
66%
With copper(l) iodide; oxygen; In 1,2-dichloro-ethane; at 100℃; for 24h;
Take a clean 8mL sealed micro-reaction bottle, add a small magnet, dry, add2-amino-5-fluoropyridine (67.3 mg, 0.6 mmol)2- (2-methoxyphenoxy) -1- (4-methoxy) acetophenone (54.5 mg, 0.2 mmol)Cuprous iodide (0.01 mmol),1,2-dichloroethane (1.0 mL),After heating at 100 C for 24 hours in air,The reaction solution was isolated by direct column chromatography to give the title product (48.0 mg, yield 66%).
7-fluoro-3-methyl-2H-pyrido[1,2-a]pyrimidin-2-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
77%
With 1,1,1,3',3',3'-hexafluoro-propanol Reflux;
With N-heterocyclic carbene palladium(II) complex supported on fibrous nanosilica In trifluoroacetic acid for 1h; Reflux; Green chemistry; chemoselective reaction;
2.7 General procedure for synthesis of pyridopyrimidinones
General procedure: A mixture of 2-aminopyridine derivative (1.0mmol) and Baylis-Hillman adducts (1.0mmol), and KCC-1/Pd-NHC-Py NPs (1mg) was stirred heating under reflux in TFA (3mL) for 1h. The catalyst was separated by filtration. Evaporation of the solvent of the filtrate under reduced pressure gave the crude products. The pure products were isolated by chromatography on silica gel eluted with petroleum ether:EtOAc (3:1).
5-fluoro-2-(2-(4-isopropylphenyl)-5-methyl-1H-pyrrol-1-yl)pyridine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
75%
With toluene-4-sulfonic acid; In ethanol; at 160℃; under 7757.43 Torr; for 0.5h;Sealed tube; Microwave irradiation;
General procedure: The proper 1,4-pentanedione 48 (2.28 mmol) and the suitableamine (2.28 mmol) were dissolved in ethanol (2 ml) in a sealedglass tube equipped with a stirring bar in the presence of p-toluenesulfonicacid (30 mg, 0.17 mmol). The tube was heated in thecavity of the microwave reactor for 30 min (150W, internal temperature160 C, and internal pressure 150 psi). At the end, thereaction mixture was cooled down and concentrated. The crudematerial was purified by chromatography on aluminum oxide(activity II-III, according to Brockmann) with cyclohexane to givethe expected pyrroles 49a-n? as solids in satisfactory yields.
(rac)-1-(3'-chloro-2,5'-difluoro-5-methoxy-[1,1'-biphenyl]-4-yl)-5,6,7,8-tetrahydro-1,6-naphthyridin-2(1H)-one[ No CAS ]
[ 21717-96-4 ]
(rac)-1-(3'-chloro-2,5'-difluoro-5-methoxy-[1,1'-biphenyl]-4-yl)-N-(5-fluoropyridin-2-yl)-2-oxo-1,2,7,8-tetrahydro-1,6-naphthyridine-6(5H)-sulfonamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
94%
A 5-mL vial was charged with imidazole (85 mg, 1.24 mmol) and 5-fluoropyridin-2-amine (Acros Organics, 44.5 mg, 0.40 mmol) then purged with nitrogen. CH2C12 (1.24 mL) was introduced and the reaction mixture was cooled to -78 C in a dry ice-acetone bath. Sulfuryl chloride (32.2 |xL, 0.40 mmol) was added dropwise via syringe to the reaction mixture. Following addition, the cold bath was removed and the resultant mixture was allowed to warm to ambient temperature. After 30 minutes, (^"cj-lW-chloro^,'-difluoro-5-methoxy-[l,r-biphenyl]-4-yl)-5,6,7,8-tetrahydro-l,6-naphthyridin-2(lH)-one (See Example 4, step 2, 100 mg, 0.25 mmol) was introduced in a single portion followed by CH2C12 (1.0 mL). The vial was sealed with a PTFE lined cap and the reaction mixture was warmed to 80 C. After 30 min, the reaction mixture was cooled to ambient the resultant brown temperature mixture was cooled to ambient temperature and and diluted with an aqueous solution of citric acid (1.0 M, 5 mL), brine (5 mL), and EtOAc (15 mL). The layerswere separated and the aqueous layer was extracted with EtOAc (3x5 mL). The combined organic layers were dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure and purified by reverse phase HPLC in 2 separate injections (XBridge Prep Shield RP18 19 x 100 mm Mobile phase: 0.1% TFA in water/acetonitrile Flow rate: 40 ml/min Inj: 1500 uL Gradient: 12 min 25-80%). The fractions containing product were frozen and lyophilized to afford (rac)-1-(3'-chloro-2,5'-difluoro-5-methoxy-[1,1'-biphenyl]-4-yl)-N-(5-fluoropyridin-2-yl)-2-oxo-1,2,7,8-tetrahydro-1,6-naphthyridine-6(5H)-sulfonamide(134 mg, 0.23 mmol, 94 % yield) as a tan solid.
With sulfuric acid; chloroacetic acid; In water; at 120℃;
In a high-pressure reaction vessel, 2,3-dichloro-5-fluoropyridine 85g (0.5 mol) was added to 200 mL of ammonia water, and the temperature was set at 180 C., and the reaction under high pressure was performed for 24 h. The reaction of the starting material was complete by TLC, and the solvent was swirled to obtain 2- Chloro-5-fluoro-3-aminopyridine 65g;Place 2-chloro-5-fluoro-3-aminopyridine 65 g (0.45 mol) in a 900 mL round-bottomed flask in acetonitrile, and add 450 mL of water buffer solution (0.6 M K2CO3-4×10-4 M EDTA disodium salt). 350 mL (3 mol) of acetonitrile and 290 mL (3 mol) of a 30% H2O2 aqueous solution, and the reaction mixture was stirred at room temperature for 1 hour and extracted with ethyl acetate (3 x 300 mL). The organic layers were combined and dried over anhydrous Na2SO4. The solvent was removed to give a sufficiently pure product, 2-chloro-5-fluoro-3-nitropyridine, 65 g;To a solution of 65 g (0.35 mol) of 2-chloro-5-fluoro-3-nitropyridine in DMSO/H2O (mass ratio 9:1, 3500 mL) was added L-proline 230 g (2 mol), Na2CO3 210 g (2 mol), NaN3 230 g (3.5 mol), sodium ascorbate 350 g (1.75 mol) and CuSO4.5H2O 500 g (2 mol); the mixture was stirred in an oil bath at 70C for 24 hours, and then the mixture was poured into 5000 mL of ice water to give a solid product. Filter and crystallize to obtain 47g of <strong>[212268-12-7]2-amino-5-fluoro-3-nitropyridine</strong>; add <strong>[212268-12-7]2-amino-5-fluoro-3-nitropyridine</strong> to the aqueous solution of sulfuric acid, add a certain amount of chloroacetic acid, and heat to 120C. After TLC monitored the reaction of the raw materials, the reaction mixture was extracted with methylene chloride. The pH of the organic phase was adjusted to 7-8 with a saturated sodium carbonate solution, and the organic phase was concentrated to obtain 2-amino-5-fluoro-pyridine.
With hydrogen; In ethanol; at 120 - 130℃; under 11251.1 - 18751.9 Torr;Autoclave;
Add 2000 mL of anhydrous ethanol to the autoclave, 160 g (1 mol) of 2-amino-5-fluoro-3-nitropyridine, and 16 g of Raney nickel to seal the lid of the kettle; replace the gas inside the reactor with nitrogen for several times, and then Hydrogen is replaced several times, each time passes 1.0Mpa; after the end of the replacement, hydrogen is passed to 1.5Mpa, stirring is started, the temperature is increased to 120-130C, hydrogen consumption is started, when it is reduced to 0.5Mpa, hydrogen is added to 2.5Mpa,And maintain 2.0 ~ 2.5Mpa, the reaction for some time confirmed that no longer consume hydrogen, the sampling control, when the remaining raw material is less than 1% when the reaction is over, cooling to 30 C, filter out the catalyst,The filtrate was distilled off and the product was evaporated under reduced pressure to give 2-amino-5-fluoro-3-nitropiperidine (150 g).The yield was 92%.
With triethylamine; In dichloromethane; at 20℃;Cooling with ice;
Step A: <strong>[21717-96-4]2-Amino-5-fluoropyridine</strong> (2.5 g, 22.3 mmol) and triethylamine (2.71 g, 26.8 mmol) Dissolved in dichloromethane (25 mL), then propionyl chloride (2.17 g, 23.5 mmol) was added dropwise in an ice water bath. The resulting mixture was naturally warmed to room temperature and stirring was continued overnight. Water (40 mL) was added and extracted with dichloromethane (40 mL×3). The combined organic layers were washed with brine (30 mL) The solvent was evaporated under reduced pressure, and the product was purified by column chromatography (200-300 mesh silica gel, ethyl acetate: petroleum ether = 1:5). N-(5-fluoropyridin-2-yl)propanamide (24) (3.04g). The yield was 81.1%.
81.1%
With triethylamine; In dichloromethane; at 20℃;Cooling with ice;
To a mixture of <strong>[21717-96-4]2-amino-5-fluoropyridine</strong> (2.5 g, 22.3 mmol) and triethylamine (2.71 g, 26.8 mmol) in anhydrous dichloromethane (25 mL) was added propionyl chloride (2.17 g, 23.5 mmol) dropwise in an ice-water bath. After addition, the reaction mixture was stirred at room temperature overnight, quenched with water (40 mL), and extracted with dichloromethane (40 mL*3). The combined organic layer was washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (eluted with ethyl acetate/petroleum ether = 1:5) to afford N-(5-fluoropyridine-2-yl)propionamide (15) (3.04 g) with 81.1% yield.
2-(2-cyanophenyl)-N-(5-fluoropyridin-2-yl)acetamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
60%
Stage #1: 2-amino-5-fluoropyridine With trimethylaluminum In toluene at 0 - 20℃; for 0.5h;
Stage #2: methyl 2-(2-cyanophenyl)acetate In toluene at 0 - 80℃; for 9h;
General procedure for synthesis of substituted 2-(2-cyanophenyl)-N-phenylacetamide 3(a-u) derivatives
General procedure: Trimethyl aluminium (1.5 mmol, 2.0 M in toluene) was added to a solution ofamine (2 mmol) in toluene (10 mL) at 0 °C and stirred at room temperature for 30 min. Compound 4 (1 mmol) was added at 0 °C and stirred at 80 °C for 9 h. Afterthe completion of the reaction (by TLC), the reaction mixture was quenched withwater (15 mL), stirred for 10 min, ltered through a pad of Celite, and the Celitebed washed with AcOEt (10 mL). The organic layer was separated from the ltrate,and the aqueous layer was extracted with AcOEt (2 9 15 mL). The combinedorganic layers were washed with 1 N HCl and brine solution, dried over anhydroussodium sulphate and concentrated in vaccuo. Crude product was puried by ashchromatography (Hexane/AcOEt 7:3 v/v) to afford 2-(2-cyanophenyl)-N-phenylac-etamide 3(a-u) derivatives.
4-chloro-8-fluoro-11H-pyrido[2,1-b]quinazolin-11-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
59%
With potassium tert-butylate; dimethyl sulfoxide; at 20.0℃; for 12.0h;Inert atmosphere;
General procedure: An oven-dried round bottomed flask (50 mL capacity) equipped with a magnetic stir bar was evacuated and purged with argon. 2-Aminopyridine (1 mmol, 1 euiv), 2-fluorobenzonitrile (1.2 mmol, 1.2 euiv), KtOBu (4 mmol, 4 euiv) and DMSO (5 mL) were added successivelyat room temperature and the reaction mixture was allowed to stir at room temperature for 12 h. Water (10 mL) was added to the reaction mixture and the organic layer was extracted with ethyl acetate (2×20 mL). The combined organic phases were washed with brine and dried over sodium sulfate. The solvent was removed and the residue was purified by column chromatography on silica gel using hexanes/ethyl acetate as an eluent.
3-((13S,15R)-4-fluoro-13-methyl-17-oxo-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthren-15-yl)propanoic acid[ No CAS ]
[ 21717-96-4 ]
3-((13S,15R)-4-fluoro-13-methyl-17-oxo-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthren-15-yl)-N-(5-fluoropyridin-2-yl)propanamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
99%
With pyridine; triphenylphosphine; In tetrahydrofuran; ethyl acetate; at 20℃; for 3h;Inert atmosphere;
To the solution of Acid SM-IX (500 mg, 1.45 mmol, 100 mol-%) in dry THF (10 ml) under nitrogen atmosphere was added <strong>[21717-96-4]2-amino-5-fluoropyridine</strong> (325 mg, 2.90 mmol, 200 mol-%) and pyridine (351 il, 4.36 mmol, 300 mol-%). T3P (50 w-% in EtOAc) (1.73 ml, 2.90 mmol, 200 mol-%) was added dropwise and the reaction mixture stirred at rt for three hours. Solvent was evaporated and residue dissolved in ethyl acetate (15 ml) and washed with 10 % NaHCO3 (30 ml). The water phase was extracted twice withethyl acetate (2 x 15 ml). The organic phases were combined and washed with 0.1 N HCI solution (3 x 30 ml), water (3 x 30 ml) and finally with brine (2 x 30 ml) and dried with sodium sulfate. The Example was used in the next step without further purification. The crude yield of compound 7 was 99 % (631 mg).1H NMR (200 MHz, DMSO-d6): 0.98 (5, 3 H), 1.24-2.46 (m, 16 H),2.59 - 3.03 (m, 2 H), 6.90 - 7.05 (m, 1 H), 7.06 - 7.22 (m, 2 H), 7.73 (td, 1 H),8.15 (dd, 1 H), 8.32 (d, 1 H), 10.63 (5, 1 H). MS m/z (TOF ESj: 439 (M+1)
2-bromo-N-(5-tert-butyl-1,2-oxazol-3-yl)-1,3-thiazole-4-carboxamide[ No CAS ]
[ 21717-96-4 ]
N-(5-tert-butyl-1,2-oxazol-3-yl)-2-[(5-fluoropyridin-2-yl)amino]-1,3-thiazole-4-carboxamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
88%
General procedure: According to literature: J. Med. Chem., 2006, 49, 6819-6832, the aryl bromide partner (1 eq.) and the nucleophile (4 eq.) were dissolved in THF (4.6 mL/mmol) under argon atmosphere. After degasing the solution with argon for 5 min, sodium hydride (60% in mineral oil, 8 eq.) was carefully added (portionswise). The resulting mixture was stirred at RT for 30 min and then further stirred at 67 - 70 overnight. In cases where the reaction was not completed, additional sodium hydride (60% in mineral oil, 8 eq.) was added and the mixture was further heated to 70 "C o vernight. After cooling, two different methods were used for work up:
6-fluoro-2-phenyl-3-(m-tolyloxy)imidazo[1,2-a]pyridine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
92%
With iodine; In 1,2-dichloro-ethane; at 100℃; for 0.5h;
General procedure: A dried glass reaction tube equipped with a magnetic stir bar was charged with 1 (106 mg, 0.5 mmol), 2 or 4 (141.2 mg, or 207 mg,1.5 mmol), I2 (254 mg, 1 mmol) in DCE (10 mL); stirred at 100 C for30 min. The solvent was evaporated under vacuum, and washed with saturated sodium thiosulfate solution, water, brine. The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated to give the crude product, which was purified through flash column chromatography (ethyl acetate in petroleum ether) to give the desired product.
3-(4-ethylphenoxy)-6-fluoro-2-phenylimidazo[1,2-a]pyridine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
90%
With iodine; In 1,2-dichloro-ethane; at 100℃; for 0.5h;
General procedure: A dried glass reaction tube equipped with a magnetic stir bar was charged with 1 (106 mg, 0.5 mmol), 2 or 4 (141.2 mg, or 207 mg,1.5 mmol), I2 (254 mg, 1 mmol) in DCE (10 mL); stirred at 100 C for30 min. The solvent was evaporated under vacuum, and washed with saturated sodium thiosulfate solution, water, brine. The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated to give the crude product, which was purified through flash column chromatography (ethyl acetate in petroleum ether) to give the desired product.
6-fluoro-3-(4-nitrophenoxy)-2-phenylimidazo[1,2-a]pyridine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
93%
With iodine; In 1,2-dichloro-ethane; at 100℃; for 0.5h;
General procedure: A dried glass reaction tube equipped with a magnetic stir bar was charged with 1 (106 mg, 0.5 mmol), 2 or 4 (141.2 mg, or 207 mg,1.5 mmol), I2 (254 mg, 1 mmol) in DCE (10 mL); stirred at 100 C for30 min. The solvent was evaporated under vacuum, and washed with saturated sodium thiosulfate solution, water, brine. The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated to give the crude product, which was purified through flash column chromatography (ethyl acetate in petroleum ether) to give the desired product.
General procedure: Synthesis of 3a is representative. To a solution of ethylbenzene (1a, 1 mmol, 107 mg) in ethylacetate:water (5:1, 6 mL) were added NBS (3.5 mmol, 628 mg) and AIBN (0.1 mmol, 16.5 mg) at roomtemperature, and the mixture was stirred at 65 C for 1.5 h. The mixture was concentrated to drynessand then dissolved in water (5 mL), followed by reaction with 2-aminopyridine (2a, 1.2 mmol, 114 mg)and sodium carbonate (5 mmol, 534 mg) for 2 h at 80 C. After completion of the reaction (as indicatedby TLC), the crude product was extracted with ethyl acetate (3 x 10 mL). The combined organic layerwas dried over anhydrous Na2SO4 and concentrated in vacuo. The crude product was purified bysilica gel column chromatography (PE/EA = 8/1-4/1, v/v) to give 3a (78% yield) as a white solid.
Stage #1: 1-(4-bromophenyl)cyclobutane-1-carboxylic acid With N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In N,N-dimethyl-formamide
Stage #2: 2-amino-5-fluoropyridine With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; for 4h;
68.1 Step 1: 1-(4-bromophenyl)-N-(5-fluoropyridin-2-yl)cyclobutane-1-carboxamide (I-140)
To a 100 mL vial was charged with a magnetic spin bar, 209 1-(4-bromophenyl)cyclobutanecarboxylic acid (1000.0 mg, 3.92 mmol) in 106 DMF (10.0 ml) was added with stirring 7 HATU (1789 mg, 4.70 mmol), and the mixture was stirred for a few minutes. 185 5-Fluoropyridin-2-amine (439 mg, 3.92 mmol), 9 DIEA (2.054 ml, 11.76 mmol) were added and the reaction mixture was stirred for 4 h at RT. The reaction was worked up as usual and the crude was purified by chromatography (Isco CombiFlash system, using 48 g 108 RediSep silica gel gold column, 10-100% 10 EtOAc/Hex as eluent) to afford compound 225 I-140. MS (ESI) [M+H]+: m/z 349.
With copper(l) iodide; fluorine; sodium hydroxide; In water; 1,2-dichloro-ethane; at 30 - 40℃; for 10h;Inert atmosphere;
Stirring, thermometer, reflux condenser and 20wt% sodium hydroxide aqueous exhaust absorberIn a 500 ml PTFE-lined three-necked flask, 120 g of 1,2-dichloroethane was added.15.8 g (0.2 mol) of 4-cyano-1-butyne, 0.5 g of cuprous chloride (0.005 mol),Under stirring, a nitrogen-diluted fluorine gas (concentration of fluorine gas of 2-5 wt%) is intermittently introduced at 30-35 C.A total of 8 grams of fluorine gas was added to the fluorine gas within 5 hours, and then the reaction was stirred at 35-40 C for 3 hours.At the same time, the addition reaction was completed by sampling, and then nitrogen gas was bubbled for 2 hours to replace residual fluorine gas and hydrogen fluoride.120 g of 17 wt% aqueous ammonia was added, and the reaction was stirred at 60-65 C for 5 hours.Cooled to 20 C, layered, and the aqueous layer was extracted three times with 1,2-dichloroethane, 20 g each time.The organic phases were combined and washed with 20 g of saturated brine and dried over 5 g of anhydrous sodium sulfate.The 1,2-dichloroethane was recovered by rotary distillation to obtain 16.9 g of a yellow powder crystal of 2-amino-5-fluoropyridine.The yield was 75.5%, and the gas phase purity was 99.4%.
4-bromo-6-acetamido-1H-indole-2-carboxylic acid ethyl ester[ No CAS ]
[ 21717-96-4 ]
4-((5-fluoropyridin-2-yl)amino)-6-acetylamino-1H-indole-2-carboxylic acid ethyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
75.6%
With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; XPhos; In 1,4-dioxane; at 90℃; for 1h;Microwave irradiation; Inert atmosphere;
4-Bromo-6-acetamino-1H-indole-2-carboxylic acid ethyl ester (150 mg, 0.46 mmol), Pd2 (dba) 3 (42 mg, 0.046 mmol), X-phos (44 mg, 0.092 mmol), Cs2CO3 (450 mg, 1.38 mmol) and 2-amino-5-methoxypyridine (172 mg, 1.38 mmol) were added to a microwave tube, dissolved in 1,4-dioxane (3 mL), and filled with argon. Protect, microwave reaction at 100 C for 60min, the raw materials disappear. Direct sample column chromatography (P / E = 3: 1 to 1: 1) gave 124 mg of a yellow solid with a yield of 75.6% and a melting point of 142-144 C.
75.6%
With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; XPhos; In 1,4-dioxane; at 100℃;Inert atmosphere; Microwave irradiation;
General procedure: Ethyl 4-bromo-1H-indole-2-carboxylate (1 eq), Pd2(dba)3 (0.1 eq), X-phos(0.2 eq), Cs2CO3 (3 eq) and aryl amine (3 eq) was added to a microwave tube,dissolved in 1,4-dioxane, and filled with argon gas. The microwave reaction wascarried out at 100 C for 0.5-1.5 h, and the starting material disappeared. The mixturewas cooled to room temperature and concentrated. Ethyl acetate was added todissolve the residue, and the mixture was washed with saturated brine and water, driedover anhydrous Na2SO4, and concentrated in vacuo. The crude product was purifiedby column chromatography to afford the target compound. Compounds 8m-8o, 8s,8a-3 ~ 8a-5, 8a-13, 8a-15 ~ 8a-17, 8o-1 ~ 8o-24 were prepared with method 3.
47.3%
With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; XPhos; In 1,4-dioxane; at 100℃; for 0.5h;Microwave irradiation; Inert atmosphere;
4-bromo-6-acetylamino-1H-indole-2-carboxylic acid ethyl ester (100 mg, 0.31 mmol), Pd2 (dba) 3 (28 mg, 0.031 mmol), X-phos (30 mg, 0.062 mmol), Cs2CO3 (301 mg, 0.92 mmol) and 3-amino-5,6-dimethoxypyridine (143 mg, 0.92 mmol) were added to a microwave tube, dissolved in 1,4-dioxane (2 mL), and charged Protected by argon, microwave reaction at 100 C for 30min, the raw materials disappeared. Direct sample column chromatography (P / E = 1: 1 10: 1) yielded 58 mg of off-white solid with a yield of 47.3% and melting point:> 250 C.
Chemistry
Pharmaceutical Intermediates
Inhibitors/Agonists
Material Science
For Research Only
110K+ Compounds
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