* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
With lithium diisopropyl amide In tetrahydrofuran at -78℃; for 3 h;
A solution of 2-chloro-3-iodopyridine (12 g, 50 mmol) in 20 ML of THF was slowly added to a cold (-78°C) lithium diisopropylamide solution (prepared by the addition of n- butyllithium 1.6 M (31.25 ML, 50 mmol) in hexanes to a solution of diisopropylamine (7 mL, 50 mmol) in THF (100 mL). After 3h, water (20 mL) was added to the mixture, which was extracted with ether (2 x 100 mL). The organic layers were dried over magnesium sulfate, filtered and concentrated under vacuum (20°C) to afford a brown solid, which was purified by filtration over silica (ethyl acetate/heptane 8/2). Yield: 95percent (11.4 g), pale yellow NEEDLES. IH NMR (CDC13) : 8 8.07 (d, J = 5.3 Hz, 1H), 7.76 (d, J = 1.1 Hz, 1H), 7.59 (dd, J = 5. 0/1. 1 Hz, 1H). 13C NMR (CDC13) : 8 151.7, 149.6, 133. 0,131. 5,106. 6. MS (EI) m/z 240 (M+1).
80%
With n-butyllithium; diisopropylamine In tetrahydrofuran at -78 - -15℃; for 1.33333 h;
To a THF solution (40 ml) of Diisopropyl amine (4.46 ml, 1.5 eqv) was added BuLi (1.88 M, 1.5 eqv) at -15° C. and the resulting reaction mixture was allowed to stir at same temperature for 20 minutes. It was then cooled to -78° C. and 2-chloro-3-iodopyridine (5 g, 20.92 mmol) in THF (10 ml) was added dropwise at the same temperature and allowed to stir for 1 hr at -78° C. Reaction was quenched with water (10 ml), stirred at ambient temperature for 15 minutes and extracted with ethyl acetate. Organic layer was washed successively with brine and finally dried over sodium sulfate. Evaporation of organic layer under reduced pressure gave the crude product which was immediately used in the next step without any further purification. Yield: 80percent (Crude)
75%
Stage #1: With n-butyllithium; diisopropylamine In tetrahydrofuran at -78 - -5℃; for 2 h; Stage #2: With water In tetrahydrofuran for 0.25 h;
Preparation of amine unit A4 1. A solution of diisopropylamine (12.7 g) in THF (160 ml) was cooled to -15° C., and n-BuLi (83 ml) was added dropwise over a period of 20 min at -10° C. After stirring for 20 min at -5° C., the reaction mixture was cooled to -78° C., and 2-chloro-3-iodo-pyridine (20 g) dissolved in THF (40 ml) was added dropwise over a period of 20 min. The reaction mixture was stirred for 1 h at -78° C. After addition of water (40 ml), stirring was carried out for 15 min. The organic phase was separated off and dried over Na2SO4. After filtration, the solvent was removed in vacuo and the residue was purified by flash chromatography (silica, 5percent ethyl acetate/n-hexane). Yield: 15 g (75percent)
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2006, vol. 16, # 5, p. 1397 - 1401
[2] Patent: WO2004/52880, 2004, A1, . Location in patent: Page 30
[3] Patent: US2009/186899, 2009, A1, . Location in patent: Page/Page column 45-46
[4] European Journal of Organic Chemistry, 2001, # 7, p. 1371 - 1376
[5] Patent: US2008/249128, 2008, A1, . Location in patent: Page/Page column 46
[6] Journal of Organic Chemistry, 1993, vol. 58, # 27, p. 7832 - 7838
[7] Patent: WO2009/90055, 2009, A1, . Location in patent: Page/Page column 133; 134
[8] Patent: US2009/264400, 2009, A1, . Location in patent: Page/Page column 64
3
[ 14432-12-3 ]
[ 153034-86-7 ]
Yield
Reaction Conditions
Operation in experiment
63%
Stage #1: With hydrogenchloride In water at 0℃; Stage #2: With sodium nitrite In water at -10℃; for 0.666667 h;
To a ice-cooled solution of 4-amino-2-chloro-pyridine (8.09g, 63 mmol, 1eq) in water [(150ML)] was added concentrated 98percent HCl whilst maintaining the reaction at [0°C A] solution of sodium nitrite (5.65g, [82MMOL,] 1.3eq) in water [(50ML)] was added slowly [AT-10°C.] The mixture was stirred at-10°C [FOR 40 MIN] and a solution of potassium iodide (12.55g, 75. [6MMOL,] 1.2eq) in water [(50ML)] was added. The resulting mixture was stirred at [0°C] overnight. After treatment with [NAOH] 35percent, and extraction with ethyl acetate, the organic phases were combined and dried over [NA2SO4.] The solvent was removed under reduced pressure and the residue was purified by chromatography on silica gel (eluent : CH2CI2 then [CH2CL2/CH30H] 99/1) to give the title compound as an orange solid (9.5g, 63percent) ;'H NMR (300 MHz, CDCl3) [6] : 7.99 (d, [1H),] 7.68 (s, 1H), 7.52 (d, 1H) ; (GC-MS) m/z: 239.
63%
Stage #1: With hydrogenchloride; sodium nitrite In water at -10℃; for 0.666667 h; Stage #2: With potassium iodide In water at 0℃;
To a solution of 4-amino-2-chloro-pyridine (8.09g, 63 mmol, [1EQ)] in water [(150ML)] cooled to [0°C] was added concentrated 98percent HCI. A solution of sodium nitrite (5.65g, [82MMOL,] 1.3eq) in water (50mL) was added slowly at-10°C and the mixture was stirred at this temperature for 40 min. A solution of potassium iodide [(12.] 55g, 75. [6MMOL,] 1.2eq) in water (50mL) was added and the resulting mixture was stirred at [0°C] overnight. After treatment with NaOH (35percent) and extraction with ethyl acetate, the organic phases were combined and dried over [NA2SO4.] The solvent was removed under reduced pressure and the residue was purified by chromatography on silica gel (eluent : CH2CI2 then [CH2CI2/CH30H] 99: 1) to give the title compound as an orange solid (9.5g, 63percent) [; 1H] NMR (300 MHz, [CD13)] [8] ppm: 7.99 (1H, d), 7.68 (1H, s), 7.52 (1H, d); (GC-MS) m/z: 239.
34%
With copper(l) iodide; tert.-butylnitrite In acetonitrile at 0 - 20℃; for 16 h;
General procedure: To a mixture of copper source (1.2 eq., CuBr2 for 4b, CuCl2 for 4c, CuI for 4d)in acetonitrile (0.4M) was slowly added tBuONO (1.5 eq.). The mixture was stirred for15 min and then cooled to 0°C. A solution of 2-chloro-4-aminopyridine 3 (1.0 eq.) inacetonitrile (0.5M) was slowly added. The mixture was stirred for 1h at 0°C and thenallowed to warm to r.t. for 16h. After concentration in vacuo, aq. 15percent ammonia solution (1.3 mL/mmol) was added, and the aqueous layer was extracted withdichloromethane (10 mL/mmol; 3x). The combined organic layers were washed withbrine, dried (Na2SO4), filtered and carefully concentrated under reduced pressure(CAUTION: volatile products) to give the crude 4b-d, which was used in the next stepwithout purification.
Reference：
[1] Patent: WO2004/13125, 2004, A1, . Location in patent: Page 18
[2] Patent: WO2004/13135, 2004, A1, . Location in patent: Page 42-43
[3] Synlett, 2016, vol. 27, # 1, p. 67 - 69
[4] Roczniki Chemii, 1955, vol. 29, p. 1019,1025[5] Chem.Abstr., 1956, p. 12045
Reference：
[1] Chemistry - A European Journal, 2011, vol. 17, # 47, p. 13284 - 13297
8
[ 109-09-1 ]
[ 153034-86-7 ]
[ 116195-81-4 ]
[ 78607-36-0 ]
[ 258506-66-0 ]
Reference：
[1] Chemistry - A European Journal, 2011, vol. 17, # 47, p. 13284 - 13297
9
[ 109-09-1 ]
[ 153034-86-7 ]
[ 1353056-33-3 ]
[ 1353056-34-4 ]
[ 78607-36-0 ]
Reference：
[1] Chemistry - A European Journal, 2011, vol. 17, # 47, p. 13284 - 13297
10
[ 2402-95-1 ]
[ 153034-86-7 ]
Reference：
[1] Roczniki Chemii, 1955, vol. 29, p. 1019,1025[2] Chem.Abstr., 1956, p. 12045
11
[ 14432-16-7 ]
[ 153034-86-7 ]
Reference：
[1] Roczniki Chemii, 1955, vol. 29, p. 1019,1025[2] Chem.Abstr., 1956, p. 12045
12
[ 153034-86-7 ]
[ 700811-29-6 ]
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2006, vol. 16, # 13, p. 3454 - 3458
[2] Patent: US2013/165464, 2013, A1, . Location in patent: Paragraph 0887
13
[ 153034-86-7 ]
[ 73027-79-9 ]
Reference：
[1] European Journal of Organic Chemistry, 2001, # 7, p. 1371 - 1376
14
[ 153034-86-7 ]
[ 141-52-6 ]
[ 52311-50-9 ]
Yield
Reaction Conditions
Operation in experiment
5 g
Reflux
6.01.22.01 2-chloro-4-ethoxy-pyridine 33 ml sodium ethoxide was added to 19.2 g 2-chloro-4-iodopyridine in 150 mL ethanol. The reaction was refluxed overnight. Then water was added and extracted with tert-butyl- methylether. The organic layer was evaporated and the residue cleanded by chromatography on silica gel (petrolether/EtOAC:9/l) to yield 5 g of the desired compound. Rf: 0.3 (petrolether/EtOAC:4/l), (M+H)+: 158
5 g
Reflux
6.01.22.01 2-chloro-4-ethoxy-pyridine 33 ml sodium ethoxide was added to 19.2 g 2-chloro-4-iodopyridine in 150 mL ethanol. The reaction was refluxed overnight. Then water was added and extracted with tert-butyl-methylether. The organic layer was evaporated and the residue cleanded by chromatography on silica gel (petrolether/EtOAC:9/1) to yield 5 g of the desired compound. Rf: 0.3 (petrolether/EtOAC:4/1), (M+H)+: 158
Reference：
[1] Chinese Journal of Chemistry, 2016, vol. 34, # 5, p. 481 - 484
23
[ 153034-86-7 ]
[ 1692-15-5 ]
[ 53344-73-3 ]
Reference：
[1] Journal of the American Chemical Society, 2015, vol. 137, # 8, p. 2852 - 2855
24
[ 153034-86-7 ]
[ 109-94-4 ]
[ 153034-90-3 ]
Yield
Reaction Conditions
Operation in experiment
54%
Stage #1: With lithium diisopropyl amide In tetrahydrofuran at -78℃; for 3 h; Stage #2: at -78℃; for 1.5 h;
A mixture of 2-chloro-3-iodopyridine(5.0g, 21mmol) in dry THF (30 mL) was slowly added to a cold (-78°C) solution oflithiumdiisopropylamide(15 mL, 30mmol) in dry THF (50 mL). The resulting mixture was stirred for 3h at this temperature.Ethylformate(4.0g, 54mmol) wasthenadded.Stirring continued for 1.5 h at the same temperature.Water (10 mL) was added to quench the reaction, and then theresultingmixture was warmed toroom temperature.2 MHCl(50 mL) was added and then the THF was removed under reduced pressure.The aqueous residue was extracted withethyl acetate(2 x 50 mL).The combined organic extracts were washed with brine, dried over Na2SO4andconcentrated under reduced pressure.The residuewas purified on silica gel(diethyl ether/petroleum ether1:4)to give the desired product as a yellow solid(3.0 g, 54percent yield).HNMR(500 MHz, CDCl3):δ10.22(s, 1H), 8.09(d, J =5.0Hz, 1H), 7.95(d,J =5.0Hz, 1H).
52%
Stage #1: With lithium diisopropyl amide In tetrahydrofuran at -78℃; for 3 h; Inert atmosphere; Schlenk technique Stage #2: at -78℃; for 1.5 h; Inert atmosphere; Schlenk technique
According to the literature,17 a dry, argon-flushed Schlenk flask equipped with a magnetic stirring bar and a septum was charged with a solution of LDA (18.0 mmol, 1.0 M in THF) and cooled to –78 °C. 2-Chloro-3-iodopyridine (3.1 g, 13.0 mmol) was added dropwise tothe cooled solution. The resulting mixture was stirred for 3 h at –78 °C. Ethyl formate (2.5 g, 34.0 mmol) was then added and stirred for 1.5 hat –78 °C. The resulting solution was quenched with sat. aq NH4Cl (80 mL), extracted with EtOAc (3 × 120 mL), and the combined organic phases were dried (anhyd MgSO4). After filtration, the solvents were evaporated in vacuo. The crude product was purified by flash column chromatography on silica gel (i-hexane/EtOAc, 9:1 to 8:2 +Et3N 2percent) yielding 2-chloro-4-iodonicotinaldehyde as a yellow solid(1.8 g, 52percent). 1H NMR (400 MHz, CDCl3): δ = 10.19 (s, 1 H), 8.07 (d, J = 5.1 Hz, 1 H),7.94 (d, J = 5.1 Hz, 1 H).
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2017, vol. 27, # 18, p. 4370 - 4376
[2] Synthesis (Germany), 2018, vol. 50, # 1, p. 155 - 169
[3] Organic Letters, 2018, vol. 20, # 2, p. 345 - 348
25
[ 153034-86-7 ]
[ 124-38-9 ]
[ 74-88-4 ]
[ 185041-05-8 ]
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2016, vol. 26, # 24, p. 5947 - 5950
26
[ 153034-86-7 ]
[ 185041-05-8 ]
Reference：
[1] Patent: WO2014/160185, 2014, A2,
27
[ 109-09-1 ]
[ 153034-86-7 ]
[ 78607-36-0 ]
[ 258506-66-0 ]
Reference：
[1] Chemistry - A European Journal, 2011, vol. 17, # 47, p. 13284 - 13297
28
[ 109-09-1 ]
[ 153034-86-7 ]
[ 116195-81-4 ]
[ 78607-36-0 ]
[ 258506-66-0 ]
Reference：
[1] Chemistry - A European Journal, 2011, vol. 17, # 47, p. 13284 - 13297
29
[ 153034-86-7 ]
[ 343781-36-2 ]
Reference：
[1] European Journal of Organic Chemistry, 2001, # 7, p. 1371 - 1376
30
[ 153034-86-7 ]
[ 343781-49-7 ]
Reference：
[1] European Journal of Organic Chemistry, 2001, # 7, p. 1371 - 1376
31
[ 153034-86-7 ]
[ 262423-77-8 ]
Reference：
[1] European Journal of Organic Chemistry, 2001, # 7, p. 1371 - 1376
[2] European Journal of Organic Chemistry, 2001, # 7, p. 1371 - 1376
32
[ 153034-86-7 ]
[ 871836-51-0 ]
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2017, vol. 27, # 18, p. 4370 - 4376
33
[ 153034-86-7 ]
[ 945717-09-9 ]
Reference：
[1] Journal of Medicinal Chemistry, 2012, vol. 55, # 11, p. 5270 - 5290
[2] Chemical Communications, 2013, vol. 49, # 20, p. 2037 - 2039
[3] Patent: WO2017/117708, 2017, A1,
34
[ 153034-86-7 ]
[ 858839-90-4 ]
Yield
Reaction Conditions
Operation in experiment
83%
at 150℃; for 72 h; Sealed tube
General procedure: To 4b/c/d (prepared above) and sodium acetate (2.0 eq.) in acetic acid (1.0M)was heated at 150°C in a sealed tube for 72h. The mixture was cooled to r.t. andconcentrated under reduced pressure. The residue was partitioned between ethylacetate (3 mL/mmol) and cold water (3mL/mmol). The aqueous layer was extractedwith ethyl acetate (3mL/mmol; 4x). The combined organic layers were successivelywashed with sat. NaHCO3 (1 mL/mmol), brine, dried (Na2SO4), filtered andconcentrated under reduced pressure. The crude material was purified by flashchromatography on silica gel to give products 1b/c/d, and details of individualcompounds are provided below.
38%
Stage #1: at 105℃; for 21 h; Stage #2: With sodium carbonate In water
A mixture of 2-chloro-4-iodopyridine (4.943 g, 20.6 mmol) and formic acid(88percent, 10 mL) was stirred at 105° C. for 21 h. The excess of formic acid was removed in vacuo, and the mixture was quenched with 2 M aq Na2CO3, extracted with 0H2Cl2, dried over Na2SO4. After the solvent was removed under reduced pressure, the residue was purified by chromatography on silica gel eluted with CH2Cl2/MeOH to afford 1.716 g (38percent) of 4-iodopyridin-2(1H)-one as a solid. LC-MS Method 1 tR=0.82 min, m/z=222 (MH+); 1H NMR (400 MHz, (0D3)2SO) δ 7.14 (d, J=6.5 Hz, 1H), 6.87 (s, 1H), 6.49 (d, J=7.0 Hz, 1H).
22%
With sodium acetate In acetic acid at 100℃; for 12 h;
Step i: 4-iodopyridin-2(lH)-one To 25 mL round bottom flask, were added 2-chloro-4-iodopyridine (1 g, 0.0042 mol) and acetic acid (10 mL). To the same flask, sodium acetate (1.7 g, 0.0209 mol) was added. The reaction mixture was maintained at 100 °C for 12 h. The reaction mixture was cooled to RT and poured into ice cold water. The aqueous layer partitioned with ethyl acetate. The organic layer was separated. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and evaporated under reduced pressure to obtain the title compound [0.34 g, 22 percent].H NMR (DMSO-de, 300 MHz): δ 11.80 (s, 1H), 7.15 (d, 1H), 6.87 (d, 1H), 6.50 (dd, 1H); LC-MS: 221.9 [M+H]+.
With lithium diisopropyl amide; In tetrahydrofuran; at -78℃; for 3h;
A solution of <strong>[78607-36-0]2-chloro-3-iodopyridine</strong> (12 g, 50 mmol) in 20 ML of THF was slowly added to a cold (-78C) lithium diisopropylamide solution (prepared by the addition of n- butyllithium 1.6 M (31.25 ML, 50 mmol) in hexanes to a solution of diisopropylamine (7 mL, 50 mmol) in THF (100 mL). After 3h, water (20 mL) was added to the mixture, which was extracted with ether (2 x 100 mL). The organic layers were dried over magnesium sulfate, filtered and concentrated under vacuum (20C) to afford a brown solid, which was purified by filtration over silica (ethyl acetate/heptane 8/2). Yield: 95% (11.4 g), pale yellow NEEDLES. IH NMR (CDC13) : 8 8.07 (d, J = 5.3 Hz, 1H), 7.76 (d, J = 1.1 Hz, 1H), 7.59 (dd, J = 5. 0/1. 1 Hz, 1H). 13C NMR (CDC13) : 8 151.7, 149.6, 133. 0,131. 5,106. 6. MS (EI) m/z 240 (M+1).
80%
With n-butyllithium; diisopropylamine; In tetrahydrofuran; at -78 - -15℃; for 1.33333h;
To a THF solution (40 ml) of Diisopropyl amine (4.46 ml, 1.5 eqv) was added BuLi (1.88 M, 1.5 eqv) at -15 C. and the resulting reaction mixture was allowed to stir at same temperature for 20 minutes. It was then cooled to -78 C. and <strong>[78607-36-0]2-chloro-3-iodopyridine</strong> (5 g, 20.92 mmol) in THF (10 ml) was added dropwise at the same temperature and allowed to stir for 1 hr at -78 C. Reaction was quenched with water (10 ml), stirred at ambient temperature for 15 minutes and extracted with ethyl acetate. Organic layer was washed successively with brine and finally dried over sodium sulfate. Evaporation of organic layer under reduced pressure gave the crude product which was immediately used in the next step without any further purification. Yield: 80% (Crude)
75%
Preparation of amine unit A4 1. A solution of diisopropylamine (12.7 g) in THF (160 ml) was cooled to -15 C., and n-BuLi (83 ml) was added dropwise over a period of 20 min at -10 C. After stirring for 20 min at -5 C., the reaction mixture was cooled to -78 C., and <strong>[78607-36-0]2-chloro-3-iodo-pyridine</strong> (20 g) dissolved in THF (40 ml) was added dropwise over a period of 20 min. The reaction mixture was stirred for 1 h at -78 C. After addition of water (40 ml), stirring was carried out for 15 min. The organic phase was separated off and dried over Na2SO4. After filtration, the solvent was removed in vacuo and the residue was purified by flash chromatography (silica, 5% ethyl acetate/n-hexane). Yield: 15 g (75%)
Preparation of amine building block A46 tert-Butyl 2- (pyridin-4-ylmethyl) -5, 6-dihydroimidazo [1,2- a]pyrazine-7 (8H) -carboxylateProcedure for step- 1 : <n="135"/>To a THF solution (40 ml) of Diisopropyl amine (4.46 ml, 1.5 eqv) was added BuLi ( 1.88 M, 1.5 eqv) at -15C and the resulting reaction mixture was allowed to stir at same temperature for 20 minutes. It was then cooled to -78C and <strong>[78607-36-0]2-chloro-3-iodopyridine</strong> (5g, 20.92 mmol) in THF (10 ml) was added dropwise at the same temperature and allowed to stir for 1 hr at -780C. Reaction was quenched with water ( 10 ml), stirred at ambient temperature for 15 minutes and extracted with ethyl acetate. Organic layer was washed successively with brine and finally dried over sodium sulfate. Evaporation of organic layer under reduced pressure gave the crude product which was immediately used in the next step without any further purification. Yield : 80% (Crude)
With lithium diisopropyl amide; In tetrahydrofuran; at -78℃;
Synthesis of the Amine Unit AM-08: 4-[4-(2-Pyrrolidin-1-yl-ethoxy)-piperidin-4-yl]-pyridine dihydrochloride (AM-08) Stage-1: n-Butyllithium (31.38 mmol) was added to a cold (-15 C.) solution of diisopropylamine (31.38 mmol) in THF (50 ml) and the mixture was stirred at this temperature for 30 min. It was then cooled to -78 C., <strong>[78607-36-0]2-chloro-3-iodopyridine</strong> (5 g, 20.9 mmol) in THF (10 ml) was added dropwise and the reaction mixture obtained was stirred at this temperature for a further hour (TLC control). The reaction was quenched with water (10 ml), the mixture was diluted with ethyl acetate and the organic phase was washed successively with water and sat. NaCl solution. Finally, this was dried over Na2SO4 and concentrated under reduced pressure to obtain the crude product, which was employed directly in the next stage. Yield: quantitative (crude)
With hydrazine hydrate; In ethanol; at 20℃;Reflux;
Step 1: 2-chloro-4-hydrazinopyridine To a solution of 2-chloro-4-iodopyridine (2.00 g, 8.35 mmol) in EtOH (38 mL) was added hydrazine hydrate (8 mL). The reaction mixture was allowed to stir at reflux overnight. After being allowed to cool to rt, the reaction mixture was poured into aqueous NaOH (1M, 100 mL) and was extracted several times with EtOAc. The organic solutions were combined, dried over Na2SO4, filtered and concentrated to give 2-chloro-4-hydrazinopyridine (1.16 g, 97%) which was used without purification in the next step. LCMS (AA): m/z=144 (M+H).
With copper(l) iodide; N,N,N,N,-tetramethylethylenediamine;tetrakis(triphenylphosphine) palladium(0); In tetrahydrofuran; at 60℃; for 4h;
To a solution of intermediate 1 (1.85g, 7. [74MMOL)] in dry THF (40m L) were added under nitrogen, TMEDA (20mL) and intermediate 3 (1. [1EQ, 1G,] 8. 51mmol). The resulting mixture was degassed with nitrogen for 10 min, then tetrakis [(TRIPHENLYPHOSPHINE) PALLADIUM (0)] (0. [464MOL,] 537mg) and copper iodide (0.928 mmol, 177mg) were added. The resulting mixture was heated at [60C] for 4h. The mixture was poured into a saturated solution of NH4CI and extracted with EtOAc. The organic phase was dried over [NA2SO4] and filtered. Solvent was removed under reduced pressure. The residue was purified by chromatography on silica gel [(CH2CI2/ETOAC] 90: 10) to afford the title compound as a beige solid (1. 54g, 86.4%) ; ['H] NMR (300 MHz, [CDCL3) No. ]: 8. 29 (d, 1H), 7.52 (t, 1H), 7.39 (s, 1H), 7.34-7. 24 (m, 2H), 7.10 (d, 1 H), 2.50 (s, 3H).
86.4%
With N,N,N,N,-tetramethylethylenediamine;copper(l) iodide; tetrakis(triphenylphosphine) palladium(0); In tetrahydrofuran; at 60℃; for 4h;
To a solution of intermediate 1 (1.85g, 7. [74MMOL)] in dry THF [(40ML)] were added under nitrogen TMEDA (20mL) and intermediate 3 (1. 1eq, 1g, 8. 51mmol). The resulting mixture was degassed with nitrogen for ten mins, tetrakis (triphenlyphosphine) palladium (0) (0.537g, 0. [464MOL)] and copper iodide (0. [177G,] 0.928 [MMOL)] were added and the mixture was heated at [60C] for 4hours. The mixture was poured into a saturated solution of NH4CI and extracted with EtOAc. The organic phase was dried over Na2SO4 and filtered. The solvent was removed under reduced pressure and the residue was purified by chromatography on silica gel (CH2CI2/EtOAc 90: 10) to afford the title compound as a beige solid (1.54g, 86.4%) [;'H] NMR (300 MHz, [CDCI3)] [8] ppm: 8.29 (d, 1H), 7.52 (t, 1H), 7.39 (s, 1H), 7.34-7. 24 (m, 2H), 7.10 (d, 1H), 2.50 (s, 3H).
With triethylamine; triphenylphosphine In tetrahydrofuran at 20℃;
B.1 Example B; 2-Chloro-4-(2-methyl-1H-imidazol-4-ylethynyl)-pyridine; Step 1: 2-Chloro-4-trimethylsilanylethynyl-pyridine
2-Chloro-4-iodo-pyridine (10.0 g, 41.8 mmol) was dissolved in 200 mL dry THF and 17.5 mL triethyl amine. This mixture was evacuated and backfilled with argon several times to remove oxygen from the solution. Triphenylphosphine (329 mg, 1.25 mmol) and bis(triphenylphosphine)palladium(II)chloride (1.47 g, 2.09 mmol) were added and the reaction mixture was stirred at room temperature for 1 h. Copper(I)iodide (239 mg, 1.25 mmol) and trimethylsilylacetylen (6.28 g, 6.39 mmol) were added. The reaction mixture was stirred at room temperature overnight. The solvent was evaporated. The residue was taken up in 500 mL water and extracted three times with ethyl acetate (500 mL each). The combined organic extracts were dried with magnesium sulfate, filtered and evaporated. The crude product was purified by chromatography on silica gel (cyclohexane/ethyl acetate 80:20). The desired product was obtained as a light brown semi solid (10 g, >100%). This material was used without any further purification for the next step.
100%
With copper(l) iodide; triphenylphosphine In tetrahydrofuran; triethylamine at 20℃;
A.1
Step 1: 2-CHLORO-4-TRIMETHYLSILANYLETHYNYL-PYRIDINE 2-Chloro-4-iodo-pyridine (10.0 g, 41.8 mmol) was dissolved in 200 mL of dry THF and 17.5 mL of triethyl amine. This mixture was evacuated and backfilled with argon several times to remove oxygen from the solution. Triphenylphosphine (329 mg, 1.25 mmol) and bis (triphenylphosphine) palladium (II) chloride (1.47 g, 2.09 mmol) were added and the reaction mixture was stirred at room temperature for lh. Copper (I) iodide (239 mg, 1.25 mmol) and trimethylsilylacetylene (6.28 g, 6.39 mmol) were added. The reaction mixture was stirred at room temperature overnight. The solvent was evaporated. The residue was taken up in 500 mL of water and extracted three times with ethyl acetate (500 mL each). The combined organic extracts were dried with magnesium sulfate, filtered and evaporated. The crude product was purified by chromatography on silica gel (cyclohexane/ethyl acetate 80: 20). The desired product was obtained as a light brown semi solid (10 g, >100%). This material was used without any further purification for the next step.
98%
With bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide; triethylamine; triphenylphosphine In tetrahydrofuran at 20℃; for 13h; Inert atmosphere;
69.2%
With bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide; triethylamine at 70℃; for 4h; Inert atmosphere;
2 Procedure for preparation of 2chioro4ethyny1pyridine:
To a solution of 5(3.3g, 13.78 mmol) and 2(1.49g. 15.i6mmol) in Et3N was added CuT (0.26g,138mmol) and Pd(PPh3)2C12 (0.48g. 0.69mmol). The resulting mixture was protected with N2 atmosphere, and then was heated at 70°C for 4 hours. The reaction mixture was filtered, and concentrated in vacuo. The residue was purified by flash chromatography to give product 6(2.Og, yield: 69.2 %).
68%
Stage #1: 2-chloro-4-iodopyridine With triethylamine In acetonitrile at 20℃; for 0.25h;
Stage #2: trimethylsilylacetylene In acetonitrile at 0℃; for 2h;
1.2.A.1
Method 2: Sonogashira route A Step 1 : 2-Chloro-4-trimethylsilanylethvnyl-pyridineTo the degassed mixture of triethylamine (50ml_) and acetonitrile (25ml_) was added 2- Chloro 4-iodopyridine (10g, 41.8mmol), bis(triphenylphosphine) palladium(ll)chloride (0.575g, 2mol%) and copper iodide (0.077g, 1 mol%) sequentially. The mixture was stirred at room temperature for 15min and then cooled to 0 °C. To the cold solution was added dropwise trimethylsilylacetylene(4.8g, 49.0mmol) in acetonitrile (25ml_) and it was stirred for 2 hrs. Reaction was monitored by TLC. Acetonitrile and triethylamine was removed under vacuo, and the residue was purified by column chromatography using alumina with mixture of ethyl acetate and hexane solvent system to yield silylated product (6g, 68%).
Stage #1: 2-chloro-4-iodopyridine With triethylamine In tetrahydrofuran at 20℃; for 1h;
Stage #2: trimethylsilylacetylene In tetrahydrofuran at 20℃; for 12h;
48.1
Example 48: Synthesis of {4-[2-(4-Fluoro-2-methyl-phenyl)-ethyl]-pyridin-2-yl}-urea Step 1: Synthesis of 2-Chloro-4-trimethylsilanylethynyl-pyridine 2-Chloro-4-iodo-pyridine (10 g, 42 mmol), palladium bis(triphenylphosphine) dichloride (2.93 g, 4.18 mmol) and triphenylphosphine (1.09 g, 4.17 mmol) are dissolved in de-gased dry THF (10 mL) and triethylamine (42 mL, 301 mmol). The resulting mixture is stirred for 1 hr at room temperature. Then Copper (I) iodide (2.3 g, 12 mmol) and ethynyl-trimethyl-silane (7.1 mL, 50 mmol) are added. The reaction mixture is stirred for 12 hrs at room temperature. The solvents are removed and the residue is diluted with water (100 mL). The mixtue is extracted with EtOAc (3 x 250 mL) and the organic layers are combined, washed with brine, dried over anhydrous Na2S04 and concentrated to give the crude product. Purification by silica flash column chromatography using 0.5 % EtOAc in hexanes affords 4.6 g of the desired product.
With bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide; triethylamine In 1,4-dioxane at 45℃; for 5h; Inert atmosphere;
516 mg
Stage #1: 2-chloro-4-iodopyridine With bis-triphenylphosphine-palladium(II) chloride; triethylamine; triphenylphosphine In tetrahydrofuran for 1h;
Stage #2: trimethylsilylacetylene With copper(l) iodide In tetrahydrofuran
24a Intermediate 24a: 2-chloro-4-((trimethylsilyl)ethynyl)pyridine
A solution 0.835 mL of triethylamine in 10 mL of THF was degassed and treated with 16 mg of Ph3P, 70 mg of (Ph3P)2PdCl2, and 479 mg of 2-chloro-4-iodopyridine. The solution was stirred 1 h then treated with 236 mg of TMSC≡CH and 11.4 mg of CuI. After stirring overnight the solvent was evaporated and the residue was dissolved in dichloromethane. The solution was washed with water and then with brine. The solution was dried (Na2SO4) and then the solvent was evaporated at reduced pressure. The residue was chromatographed on silica gel eluting with a gradient of 0% to 20% ethyl acetate in hexanes to give 516 mg of product. MS (ESI, m/z) 210.1 [M+H]+.
With potassium carbonate;dichloro[di-tert-butyl(chloro)phosphine]palladium(II) dimer; In methanol; for 3.00833h;
Example 1; 4-Aminomethyl-cyclohexanecarboxylic acid [2-phenyl-1-(4-phenyl-pyridin-2-yl)- ethyl] -amide, bistrifluoroacetic acid salt; [00335] lA. 2-Chloro-4-phenylpyridine: A flask was charged with 2-chloro- 4-iodo pyridine (2.5g, 10.4 mmol), phenylboronic acid (1.33 g, 10.96 mmol) , K2C03 (4.54 g, 32.88 mmol), PXPd2 (0.186 g, 0.261 mmol), and methanol (34.8 mL). Argon was blown through flask for 30 sec. The dark brown suspension was stirred for 3 h and then filtered, washing with methanol. The filtrate was concentrated to give 2.15 g as a brown solid. Column chromatography (120g silica gel column; gradient elution; 0-35% ethyl acetate/hexane) afforded lA (1.79 g, 90%) as a yellow solid. iH-NMR (400 MHz, CDCI3) 8: 8.43 (d, J = 5.3 Hz, 1H), 7.61 (dd, J = 8.2, 1.5 Hz, 2H), 7.54 (d, J = 2.2 Hz, 1H), 7.52-7.47 (m, 3H), 7.43 (dd, J = 5.1, 1.5 Hz, 1H). ¹3C-NMR (125 MHz, CDC13) No.: 152.2, 151.5, 149.9, 136.8, 129.6,129.2, 127.0, 122.0,120.4. MS 190.0 (M+H) + and 192.0 (M+2+H)+.
84%
With potassium carbonate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In tetrahydrofuran; water; for 2h;Inert atmosphere; Reflux;
To a mixture of 1 (57.36 g, 0.24 mol) in THF/H2O (400 mL/100 mL) were added phenylboric acid (24.2 g, 0.2 mol) and K2CO3 (82.8 g, 0.6 mol). PdCl2(dppf) (2 g) was then added after being charged with N2 three times. The resulting mixture was refluxed for 2 hrs, cooled, and partitioned between a.q. NH4C1 and EtOAc. The aqueous layer was washed with EtOAc. The combined organic layers were washed with water, brine and dried over Na2 S O4. The solvent was removed in vacuo and the residue was purified by silica gel column (PE:EA=10: 1) to afford 32 g of 2 (yield 84%).
82%
With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In 1,2-dimethoxyethane; water;Inert atmosphere; Reflux;
A mixture of 2-chloro-4-iodopyridine (20.0 g, 82 mmol), phenylboronicacid (10.2 g, 82 mmol), Pd(Ph3P)4 (2.84 g 2.46 mmol), sodium carbonate (26.0 g, 246 mmol), DME (600 mL) andwater (150 mL) was degassed with nitrogen and then refluxed overnight. The reaction was concentrated and the extractedwith ethyl acetate. The ethyl acetate layer was dried on Na2SO4 and then vacuum distilled to give 2-chloro-4-phenylpyridine(2.79 g, 12.7 mmol, 82 % yield).
51%
With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In water; toluene; for 12h;Inert atmosphere; Reflux;
To a 1 L three-necked flask were added 2-chloro-4-iodopyridine (50 g, 208.8 mmol), phenyl boronic acid (28 g, 229.7 mmol), Pd(PPh3)4 (12 g, 10.4 mmol), potassium carbonate (86 g, 626 mmol), toluene (500 mL) and water (200 mL), and then the resulting reaction mixture was heated to reflux for 12 h under N2 protection. Then the reaction solution was cooled to room temperature, separated, the organic phase was collected, the water phase was extracted with EA for several times, and the organic phase was combined, dried with MgSO4 and evaporated to dryness, purified via silica gel column chromatography, eluting with EA:PE=1:50 (v:v), to afford intermediate 1 (20 g, 51% yield) as a white solid.
With sodium carbonate In water; toluene at 90℃; for 20h;
7.c
(c) 7-(2-Chloropyridin-4-yl)quinoline. To a solution of 4-iodo-2-chloro pyridine (0.300 g, 1.25 mmol, Alfa Aesar) and (t-4)-tetrakis(triphenylphosphine)-palladium (0.145 g, 0.125 mmol, Strem Chemicals) in toluene (4 mL) in a 150-mL round-bottomed flask under N2 was added 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline (0.352 g, 1.38 mmol) followed by Na2CO3 (0.159 g, 1.50 mmol, Mallinckrodt) in 1 mL of water. The reaction mixture was stirred at 90° C. for 20 h. The reaction was allowed to cool to room temperature and partitioned between EtOAc (10 mL) and saturated NaCl (10 mL). The aqueous layer was back extracted with EtOAc (3×10 mL) and the combined EtOAc layers were dried over Na2SO4, filtered, and concentrated. The crude material was purified by normal phase column chromatography (gradient: 5%-50% EtOAc/Hexanes) to yield 7-(2-chloropyridin-4-yl)quinoline as a yellow solid [MS (ESI, pos. ion) m/z: 241 (M+1)].
With triethylamine;bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide; In tetrahydrofuran; at 20℃;
l-Bromo-3-ethynylbenzene (3.76 g, 20.77 mmol), palladium(II) dicMorobis(triphenylphosphine) (73 mg, 0.10 mmol) and copper(I) iodide (0.020 g, 0.10 mmol) were dissolved in anhydrous tetrahydrofuran (15 mL) and triethylamine (10 mL). 2- Chloro-4-iodorhoyridine (4.97 g, 20.77 mmol) dissolved in anhydrous tetrahydrofuran (5 mL) was added. The reaction was stirred at room temperature over night under an atmosphere of nitrogen. The reaction was quenched with hydrochloric acid (2M aq.) and extracted with dichloromethane twice. The aquous phase was then made basic using NaOH (15% aq.) and extracted with dichloromethane twice. The combined organic phases were concentrated in vacuo and the product was purified by column chromatography using a gradient eluent (0 to 30% ethyl acetate in heptane) to give 5.38 g (89% yield) of the title compound: MS (ESI) m/z 294 [M+l]+
Stage #1: 2-chloro-4-iodopyridine With n-butyllithium In tetrahydrofuran for 0.833333h;
Stage #2: benzyl 4-oxo-1-piperidinecarboxylate In tetrahydrofuran at -78℃; for 1.25h;
Stage #3: With ammonium chloride In tetrahydrofuran; water at 0℃;
2
2. n-BuLi (2.5 M, 20 ml) was added dropwise over a period of 30 min to a solution of stage 2 (10 g) in THF (500 ml), and the mixture was stirred for 20 min. N-Cbz-4-piperidone (8.8 g) in THF (20 ml) was added drowpise at -78° C. over a period of 15 min, and the reaction mixture was stirred for 1 h. After warming to 0° C., aqueous saturated NH4Cl solution (250 ml) was added, and the organic phase was separated off and extracted with ethyl acetate (2×200 ml). The combined organic phases were dried over Na2SO4. After filtration, the solvent was removed in vacuo and the residue was purified by flash chromatography (silica, gradient 10-40%, ethyl acetate/n-hexane). Yield: 7.5 g (52%)
With copper(l) iodide; caesium carbonate In N,N-dimethyl-formamide at 150℃; for 0.666667h; Microwave irradiation;
A mixture of CuT (0.1 14 g), 2-chloro-4-iodo pyridine (0.718 g), 3-hydroxy pyridine (0.289 g), Cs2CO3 and DMF (12 mL) was heated in a microwave to 150° C. for 40 mins. After cooling the mixture was diluted with water and EtOAc. The phases were separated, and the aqueous phase was extracted with EtOAc. The combined organic portions were dried (MgSO4) and concentrated in vacuo. Purification by FCC eluting with 0-100% EtOAc in iso-hexane afforded the title compound as a solid; (0.478 g, 77%);
77%
With copper(l) iodide; caesium carbonate In N,N-dimethyl-formamide at 150℃; for 0.666667h; Microwave irradiation; Inert atmosphere;
With 1,10-Phenanthroline; caesium carbonate In toluene at 105℃; for 18h; Inert atmosphere;
9.a
A suspension of (2,4-difluorophenyl)methanol (4.86 g, 33.7 mmol), 2-chloro-4-iodopyridine (7.35 g, 30.7 mmol), Cs2CO3 (14.3 g, 43.8 mmol), CuI (5.83 g, 30.7 mmol) and 1,10-phenanthroline (1.11 g, 6.14 mmol) in toluene (20 mL) was degassed by bubbling N2 through the suspension for 15 min. The suspension was put under N2, and heated at 105° C. for 18 h. The suspension was cooled, EtOAc (50 mL) was added, and the resulting suspension was passed through a plug of SiO2. The resulting solution was concentrated under reduced pressure. Flash chromatography on silica gel (hexanes/(1:1 EtOAc/hexanes), 100:0 to 0:100) afforded a white solid. A suspension of the white solid and NH4OAc (8.21 g, 107 mmol) in 1:1 HCO2H/H2O (40 mL) was heated at reflux with stirring for 4 d. The solution was cooled and concentrated under reduced pressure. The resulting residue was made basic with saturated NaHCO3 solution, and the resulting suspension was filtered. The solid was washed with H2O and dried under reduced pressure to afford 3.16 g (44%) of the title compound as a white solid: 1H NMR (300 MHz, DMSO-d6) δ 11.14 (br s, 1H), 7.62 (br dd, J=15.3, 8.7 Hz, 1H), 7.33 (ddd, J=10.5, 10.5, 2.4 Hz, 1H), 7.25 (d, J=7.2 Hz, 1H), 7.12 (ddd, J=8.4, 8.4, 1.8 Hz, 1H), 5.91-5.82 (m, 2H), 5.06 (s, 2H).
With copper(l) iodide; 1,10-Phenanthroline; caesium carbonate In toluene at 105℃; for 18h; Inert atmosphere;
16.a
A suspension of (2,4-difluorophenyl)methanol (4.86 g, 33.7 mmol), 2-chloro-4-iodopyridine (7.35 g, 30.7 mmol), Cs2CO3 (14.3 g, 43.8 mmol), CuI (5.83 g, 30.7 mmol) and 1,10-phenanthroline (1.11 g, 6.14 mmol) in toluene (20 mL) was degassed by bubbling N2 through the suspension for 15 min. The suspension was put under N2, and heated at 105° C. for 18 h. The suspension was cooled, EtOAc (50 mL) was added, and the resulting suspension was passed through a plug of SiO2. The resulting solution was concentrated under reduced pressure. Flash chromatography on silica gel (hexanes/(1:1 EtOAc/hexanes), 100:0 to 0:100) afforded a white solid. A suspension of the white solid and NH4OAc (8.21 g, 107 mmol) in 1:1 HCO2H/H2O (40 mL) was heated at reflux with stirring for 4 d. The solution was cooled and concentrated under reduced pressure. The resulting residue was made basic with saturated NaHCO3 solution, and the resulting suspension was filtered. The solid was washed with H2O and dried under reduced pressure to afford 3.16 g (44%) of the title compound as a white solid: 1H NMR (300 MHz, DMSO-d6) δ 11.14 (br s, 1H), 7.62 (br dd, J=15.3, 8.7 Hz, 1H), 7.33 (ddd, J=10.5, 10.5, 2.4 Hz, 1H), 7.25 (d, J=7.2 Hz, 1H), 7.12 (ddd, J=8.4, 8.4, 1.8 Hz, 1H), 5.91-5.82 (m, 2H), 5.06 (s, 2H).
A suspension of <strong>[56456-49-6](4-chloro-2-fluorophenyl)methanol</strong> (3.24 g, 20.1 mmol), 2-chloro-4-iodopyridine (4.40 g, 18.3 mmol), Cs2CO3 (7.76 g, 23.8 mmol), CuI (3.48 g, 18.7 mmol) and 1,10-phenanthroline (659 mg, 3.66 mmol) in toluene (20 mL) was degassed by bubbling N2 through the suspension for 15 min. The suspension was put under N2 and heated at 105 C. for 18 h. The suspension was cooled, 9:0.9:0.1 CH2Cl2/MeOH/NH4OH (10 mL) was added, and the resulting suspension was passed through a plug of SiO2. The resulting solution was concentrated under reduced pressure. Flash chromatography on silica gel (hexanes/(1:1 EtOAc/hexanes), 100:0 to 0:100) afforded a white solid. A suspension of the white solid and NH4OAc (2.66 g, 34.6 mmol) in 1:1 HCO2H/H2O (20 mL) was heated at reflux with stirring for 4 d. The solution was cooled and concentrated under reduced pressure. The resulting residue was made basic with saturated NaHCO3 solution, and the resulting suspension was filtered. The solid was washed with H2O and CH2Cl2, and dried under reduced pressure to afford 1.28 g (28%) of the title compound as a white solid: 1H NMR (300 MHz, DMSO-d6) delta 11.14 (br s, 1H), 7.59 (dd, J=8.1, 8.1 Hz, 1H), 7.52 (dd, J=10.2, 1.8 Hz, 1H), 7.36 (dd, J=8.1, 1.8 Hz, 1H), 7.25 (d, J=7.2 Hz, 1H), 5.89 (d, J=7.2, 2.4 Hz, 1H), 5.83 (d, J=2.4 Hz, 1H), 5.06 (s, 2H).
28%
a) 4-(4-Chloro-2-fluorobenzyloxy)pyridin-2(1H)-one A suspension of <strong>[56456-49-6](4-chloro-2-fluorophenyl)methanol</strong> (3.24 g, 20.1 mmol), 2-chloro-4-iodopyridine (4.40 g, 18.3 mmol), Cs2CO3 (7.76 g, 23.8 mmol), CuI (3.48 g, 18.7 mmol) and 1,10-phenanthroline (659 mg, 3.66 mmol) in toluene (20 mL) was degassed by bubbling N2 through the suspension for 15 min. The suspension was put under N2 and heated at 105 C. for 18 h. The suspension was cooled, 9:0.9:0.1 CH2Cl2/MeOH/NH4OH (10 mL) was added, and the resulting suspension was passed through a plug of SiO2. The resulting solution was concentrated under reduced pressure. Flash chromatography on silica gel (hexanes/(1:1 EtOAc/hexanes), 100:0 to 0:100) afforded a white solid. A suspension of the white solid and NH4OAc (2.66 g, 34.6 mmol) in 1:1 HCO2H/H2O (20 mL) was heated at reflux with stirring for 4 d. The solution was cooled and concentrated under reduced pressure. The resulting residue was made basic with saturated NaHCO3 solution, and the resulting suspension was filtered. The solid was washed with H2O and CH2Cl2, and dried under reduced pressure to afford 1.28 g (28%) of the title compound as a white solid: 1H NMR (300 MHz, DMSO-d6) delta 11.14 (br s, 1H), 7.59 (dd, J=8.1, 8.1 Hz, 1H), 7.52 (dd, J=10.2, 1.8 Hz, 1H), 7.36 (dd, J=8.1, 1.8 Hz, 1H), 7.25 (d, J=7.2 Hz, 1H), 5.89 (d, J=7.2, 2.4 Hz, 1H), 5.83 (d, J=2.4 Hz, 1H), 5.06 (s, 2H).
With copper(l) iodide; 1,10-Phenanthroline; caesium carbonate; In toluene; at 105℃; for 16h;Inert atmosphere;
(6-Methylpyridin-3-yl)methanol (3.25 g, 26.4 mmol), 2-chloro-4-iodopyridine (5.7 g, 24 mmol), cesium carbonate (10.1 g, 31.2 mmol), CuI (0.90 g, 4.8 mmol) and 1,10-phenanthroline (0.86 g, 4.8 mmol) were stirred in toluene (15 mL) and degassed with a nitrogen stream for 10 minutes. The mixture was heated to 105 C. for 16 h, allowed cool and filtered through a silica plug eluting with ethyl acetate. The filtrate was concentrated, and the residue was purified by column chromatography (80 g ISCO column eluting with ethyl acetate/hexanes; gradient 100% hexanes to 100% ethyl acetate) to provide the title compound (4.2 g, 75%) as a white solid: 1H NMR (300 MHz, CDCl3) delta 8.54 (d, J=2.0 Hz, 1H), 8.21 (d, J=5.7 Hz, 1H), 7.65-7.62 (dd, J=7.9, 2.2 Hz, 1H), 7.21 (d, J=7.9 Hz, 1H), 6.91 (d, J=2.2 Hz, 1H), 6.83-6.80 (dd, J=5.8, 2.2 Hz, 1H), 5.08 (s, 2H), 2.59 (s, 3H).
75%
With 1,10-Phenanthroline; caesium carbonate;copper(l) iodide; In toluene; at 105℃; for 16h;
a) 2-Chloro-4-((6-methylpyridin-3-yl)methoxy)pyridine (6-Methylpyridin-3-yl)methanol (3.25 g, 26.4 mmol), 2-chloro-4-iodopyridine (5.7 g, 24 mmol), cesium carbonate (10.1 g, 31.2 mmol), CuI (0.90 g, 4.8 mmol) and 1,10-phenanthroline (0.86 g, 4.8 mmol) were stirred in toluene (15 mL) and degassed with a nitrogen stream for 10 minutes. The mixture was heated to 105 C. for 16 h, allowed cool and filtered through a silica plug eluding with ethyl acetate. The filtrate was concentrated, and the residue was purified by column chromatography (80 g ISCO column column eluding with ethyl acetate/hexanes; gradient 100% hexanes to 100% ethyl acetate) to provide the title compound (4.2 g, 75%) as a white solid: 1H NMR (300 MHz, CDCl3) delta 8.54 (d, J=2.0 Hz, 1H), 8.21 (d, J=5.7 Hz, 1H), 7.65-7.62 (dd, J=7.9, 2.2 Hz, 1H), 7.21 (d, J=7.9 Hz, 1H), 6.91 (d, J=2.2 Hz, 1H), 6.83-6.80 (dd, J=5.8, 2.2 Hz, 1H), 5.08 (s, 2H), 2.59 (s, 3H).
Stage #1: 2-chloro-4-iodopyridine; 2,4-difluorobenzyl alcohol With copper(l) iodide; 1,10-Phenanthroline; caesium carbonate In toluene at 105℃; for 18h; Inert atmosphere;
Stage #2: With formic acid; ammonium acetate In water for 96h; Reflux;
28.a
A suspension of (2,4-difluorophenyl)methanol (4.86 g, 33.7 mmol), 2-chloro-4-iodopyridine (7.35 g, 30.7 mmol), Cs2CO3 (14.3 g, 43.8 mmol), CuI (5.83 g, 30.7 mmol) and 1,10-phenanthroline (1.11 g, 6.14 mmol) in toluene (20 mL) was degassed by bubbling N2 through the suspension for 15 min. The suspension was put under N2, and heated at 105° C. for 18 h. The suspension was cooled, EtOAc (50 mL) was added, and the resulting suspension was passed through a plug of SiO2. The resulting solution was concentrated under reduced pressure. Flash chromatography on silica gel (hexanes/(1:1 EtOAc/hexanes), 100:0 to 0:100) afforded a white solid. A suspension of the white solid and NH4OAc (8.21 g, 107 mmol) in 1:1 HCO2H/H2O (40 mL) was heated at reflux with stirring for 4 d. The solution was cooled and concentrated under reduced pressure. The resulting residue was made basic with saturated NaHCO3 solution, and the resulting suspension was filtered. The solid was washed with H2O and dried under reduced pressure to afford 3.16 g (44%) of the title compound as a white solid: 1H NMR (300 MHz, DMSO-d6) δ 11.14 (br s, 1H), 7.62 (br dd, J=15.3, 8.7 Hz, 1H), 7.33 (ddd, J=10.5, 10.5, 2.4 Hz, 1H), 7.25 (d, J=7.2 Hz, 1H), 7.12 (ddd, J=8.4, 8.4, 1.8 Hz, 1H), 5.91-5.82 (m, 2H), 5.06 (s, 2H).
44%
With 1,10-Phenanthroline; caesium carbonate In toluene at 105℃; for 18h; Inert atmosphere;
52.a
A suspension of (2,4-difluorophenyl)methanol (4.86 g, 33.7 mmol), 2-chloro-4-iodopyridine (7.35 g, 30.7 mmol), Cs2CO3 (14.3 g, 43.8 mmol), CuI (5.83 g, 30.7 mmol) and 1,10-phenanthroline (1.11 g, 6.14 mmol) in toluene (20 mL) was degassed by bubbling N2 through the suspension for 15 min. The suspension was put under N2, and heated at 105° C. for 18 h. The suspension was cooled, EtOAc (50 mL) was added, and the resulting suspension was passed through a plug of SiO2. The resulting solution was concentrated under reduced pressure. Flash chromatography on silica gel (hexanes/(1:1 EtOAc/hexanes), 100:0 to 0:100) afforded a white solid. A suspension of the white solid and NH4OAc (8.21 g, 107 mmol) in 1:1 HCO2H/H2O (40 mL) was heated at reflux with stirring for 4 d. The solution was cooled and concentrated under reduced pressure. The resulting residue was made basic with saturated NaHCO3 solution, and the resulting suspension was filtered. The solid was washed with H2O and dried under reduced pressure to afford 3.16 g (44%) of the title compound as a white solid: 1H NMR (300 MHz, DMSO-d6) δ 11.14 (br s, 1H), 7.62 (br dd, J=15.3, 8.7 Hz, 1H), 7.33 (ddd, J=10.5, 10.5, 2.4 Hz, 1H), 7.25 (d, J=7.2 Hz, 1H), 7.12 (ddd, J=8.4, 8.4, 1.8 Hz, 1H), 5.91-5.82 (m, 2H), 5.06 (s, 2H).
With copper(l) iodide; 1,10-Phenanthroline; caesium carbonate; In toluene; at 105℃; for 16h;Inert atmosphere;
(3,5-Difluoropyridin-2-yl)methanol (4.15 g, 28.4 mmol), 2-chloro-4-iodopyridine (7.47 g, 31.2 mmol), cesium carbonate (12.0 g, 36.3 mmol), CuI (5.40 g, 28.4 mmol) and 1,10-phenanthroline (1.02 g, 5.60 mmol) were stirred in toluene (20 mL) and degassed with a nitrogen stream for 10 minutes. The mixture was heated to 105 C. for 16 h, allowed cool and filtered through a silica plug eluting with ethyl acetate. The filtrate was concentrated, and the residue was purified by column chromatography (80 g ISCO column eluting with ethyl acetate/hexanes; gradient 100% hexanes to 60% ethyl acetate) to provide the title compound (3.42 g, 47%) as a yellow oil: ESI MS m/z 257 [M+H]+.
47%
With 1,10-Phenanthroline; caesium carbonate;copper(l) iodide; In toluene; at 105℃; for 16h;
a) 2((2-Chloropyridin-4-yloxy)methyl)-3,5-difluoropyridine (3,5-Difluoropyridin-2-yl)methanol (4.15 g, 28.4 mmol), 2-chloro-4-iodopyridine (7.47 g, 31.2 mmol), cesium carbonate (12.0 g, 36.3 mmol), CuI (5.40 g, 28.4 mmol) and 1,10-phenanthroline (1.02 g, 5.60 mmol) were stirred in toluene (20 mL) and purged with a nitrogen stream for 10 minutes. The mixture was heated to 105 C. for 16 h, allowed cool and filtered through a silica plug eluding with ethyl acetate. The filtrate was concentrated, and the residue was purified by column chromatography (80 g ISCO column column eluding with ethyl acetate/hexanes; gradient 100% hexanes to 60% ethyl acetate) to yield the title compound (3.42 g, 47%) as a yellow oil; ESI MS m/z 257 [M+H]+.
With 1,10-Phenanthroline; caesium carbonate In toluene at 105℃;
100.a
a) 2-Chloro-4-(4-chlorobenzyloxy)pyridine A mixture of 2-chloro-4-iodopyridine (5.0 g, 21 mmol), 4-chlorobenzyl alcohol (3.3 g, 23 mmol), cesium carbonate (8.9 g, 27 mmol), CuI (4.0 g, 21 mmol) and phenanthronine (0.76 g, 4.2 mmol) in toluene (20.0 mL) was purged with nitrogen for 10 min. The reaction mixture was heated at 105° C. overnight and then cooled and diluted with EtOAc. The resulting solution was washed with brine, passed through a pad of celite and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography (hexanes/EtOAc 100% to 70%) to give the title compound (3.0 g, 56%): 1H NMR (500 MHz, CDCl3) δ 8.21 (d, J=6.0 Hz, 1H), 7.39 (d, J=8.5 Hz, 2H), 7.32 (d, J=8.5 Hz, 2H), 6.90 (d, J=2.0 Hz, 1H), 6.80 (dd, J=6.0, 2.0 Hz, 1H), 4.07 (s, 2H).
With 1,10-Phenanthroline; caesium carbonate;copper(l) iodide; In toluene; at 105℃; for 16.0h;Inert atmosphere;
a) 3,5-Dichloro-2-((2-chloropyridin-4-yloxy)methyl)pyridine <strong>[275383-87-4](3,5-Dichloropyridin-2-yl)methanol</strong> (2.00 g, 10.4 mmol), 2-chloro-4-iodopyridine (2.49 g, 10.4 mmol), cesium carbonate (4.41 g, 13.5 mmol), CuI (1.97 g, 10.4 mmol) and 1,10-phenanthroline (374 mg, 2.08 mmol) were stirred in toluene (20 mL) and degassed with a nitrogen stream for 10 minutes. The mixture was heated to 105° C. for 16 h, allowed to cool and filtered through a silica plug eluding with ethyl acetate. The filtrate was concentrated, and the resulting residue was purified by column chromatography (80 g ISCO column column eluding with ethyl acetate/hexanes; gradient 100percent hexanes to 40percent ethyl acetate) to provide the title compound (1.15 g, 38percent) as an orange solid: 1H NMR (300 MHz, CDCl3) delta 8.50 (d, J=2.1 Hz, 1H), 8.21 (d, J=5.8 Hz, 1H), 7.80 (d, J=2.1 Hz, 1H), 6.97 (d, J=2.2 Hz, 1H), 6.88-6.85 (dd, J=5.8, 2.2 Hz, 1H), 5.31 (s, 2H).
With sodium acetate; acetic acid; at 150℃; for 72.0h;Sealed tube;
General procedure: To 4b/c/d (prepared above) and sodium acetate (2.0 eq.) in acetic acid (1.0M)was heated at 150C in a sealed tube for 72h. The mixture was cooled to r.t. andconcentrated under reduced pressure. The residue was partitioned between ethylacetate (3 mL/mmol) and cold water (3mL/mmol). The aqueous layer was extractedwith ethyl acetate (3mL/mmol; 4x). The combined organic layers were successivelywashed with sat. NaHCO3 (1 mL/mmol), brine, dried (Na2SO4), filtered andconcentrated under reduced pressure. The crude material was purified by flashchromatography on silica gel to give products 1b/c/d, and details of individualcompounds are provided below.
38%
A mixture of 2-chloro-4-iodopyridine (4.943 g, 20.6 mmol) and formic acid(88%, 10 mL) was stirred at 105 C. for 21 h. The excess of formic acid was removed in vacuo, and the mixture was quenched with 2 M aq Na2CO3, extracted with 0H2Cl2, dried over Na2SO4. After the solvent was removed under reduced pressure, the residue was purified by chromatography on silica gel eluted with CH2Cl2/MeOH to afford 1.716 g (38%) of 4-iodopyridin-2(1H)-one as a solid. LC-MS Method 1 tR=0.82 min, m/z=222 (MH+); 1H NMR (400 MHz, (0D3)2SO) delta 7.14 (d, J=6.5 Hz, 1H), 6.87 (s, 1H), 6.49 (d, J=7.0 Hz, 1H).
22%
With sodium acetate; In acetic acid; at 100℃; for 12.0h;
Step i: 4-iodopyridin-2(lH)-one To 25 mL round bottom flask, were added 2-chloro-4-iodopyridine (1 g, 0.0042 mol) and acetic acid (10 mL). To the same flask, sodium acetate (1.7 g, 0.0209 mol) was added. The reaction mixture was maintained at 100 C for 12 h. The reaction mixture was cooled to RT and poured into ice cold water. The aqueous layer partitioned with ethyl acetate. The organic layer was separated. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and evaporated under reduced pressure to obtain the title compound [0.34 g, 22 %]. H NMR (DMSO-de, 300 MHz): delta 11.80 (s, 1H), 7.15 (d, 1H), 6.87 (d, 1H), 6.50 (dd, 1H); LC-MS: 221.9 [M+H]+.
With sodium acetate; In acetic acid; at 180℃; for 2.0h;microwave;
4-lodo-1 H-pyridin-2-one 17.1 g (208 mmol) sodium acetate are added to 10.0 g (41 .8 mmol) 2-chloro-4- iodopyridine in 100 mL acetic acid and the mixture is heated at 180C for 2 h in a microwave oven. DCM and water are added to the mixture. The organic layer is separated and washed with water, dried over sodium sulphate and the solvent is removed in vacuo. The crude product is triturated with TBME.C5H4INO (M = 221 .0 g/mol)ESI-MS: 222 [M+H]+ Rf (TLC): 0.3 (silicia gel; DCM:MeOH 9: 1 )
With sodium acetate; acetic acid; at 180℃; for 2.0h;Microwave irradiation;
Example XXIExample XXI.14-Iodo-1H-pyridin-2-one17.1 g (208 mmol) sodium acetate are added to 10.0 g (41.8 mmol) 2-chloro-4-iodopyridine in 100 mL acetic acid and the mixture is heated at 180 C. for 2 h in a microwave oven. DCM and water are added to the mixture. The organic layer is separated and washed with water, dried over sodium sulphate and the solvent is removed in vacuo. The crude product is triturated with TBME.C5H4INO (M=221.0 g/mol)ESI-MS: 222 [M+H]+Rf (TLC): 0.3 (silicia gel; DCM:MeOH 9:1)
With water; sodium acetate; acetic acid; at 180℃; for 2.0h;microwave irradiation;
Intermediate 1; 4-Iodo-1H-pyridin-2-one; To 10.0 g (41.8 mmol) 2-chloro-4-iodopyridine in 100 mL AcOH are added 17.1 g (208 mmol) NaOAc and the reaction mixture is heated at 180 C. for 2 h in a microwave oven. DCM and water are added to the reaction mixture and the layers are separated. The organic layer is washed with water, dried with Na2SO4 and the solvent is removed in vacuo. The crude product is triturated with TBME.C5H4INO (M=221.0 g/mol),ESI-MS: 222 [M+H]+ Rf (TLC): 0.3 (silica gel DCM/MeOH 9/1)
With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; at 90℃; for 3.5h;
Step 1 To a solution of 2-cyclopentenyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (681 mg, 3.51 mmol) and 2-chloro-4-iodopyridine (700 mg, 2.92 mmol) in 1,4-dioxane (12 mL) was added 2.0 M aqueous Na2CO3 (4.39 mL, 8.77 mmol) and tetrakis(triphenylphosphine)palladium(0) (67.6 mg, 0.059 mmol). The reaction mixture was heated at 90 C. for 3.5 h then cooled to room temperature, diluted with water and extracted with EtOAc (2*). The combined organics were dried over MgSO4 and concentrated. The residue was purified by silica gel chromatography (0% to 10% EtOAc/hexanes) to afford 450 mg (86%) of 2-chloro-4-cyclopent-1-enyl-pyridine as a white solid.
To a solution of of 2-chloro-4-iodopyridine (1.0 g, 4.18 mmol) in anhydrous THF (10 mL) was added n-BuLi (3.34 mL, 8.35 mmol) at -78 C. The mixture was stirred at -78 C for 20 mins. Then <strong>[6704-31-0]oxetan-3-one</strong> (361 mg, 5.01 mmol) was added at -78 C and the mixture was stirred at -78 C for 50 mins. The mixture was quenched with saturatedNH4Cl (10 mL) and extracted with ethyl acetate (100 mL><3). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated to afford the crude product, which was purified on silica gel chromatography (EA: PE = 5% ~ 40%) to afford3-(2-chloropyridin-4-yl)oxetan-3- ol(620 mg, yield 86%) as a yellow solid.(ESI): M/Z (M+l): 352 (Condition: 0- 60AB 3MIN; R.T.: 1.303).
86%
(a) 3-(2-chloropyridin-4-yl)oxetan-3-ol To a solution of 2-chloro-4-iodopyridine (1.0 g, 4.18 mmol) in anhydrous THF (10 mL) was added n-BuLi (3.34 mL, 8.35 mmol) at -78 C. The mixture was stirred at -78 C. for 20 mins. Then <strong>[6704-31-0]oxetan-3-one</strong> (361 mg, 5.01 mmol) was added at -78 to C. and the mixture was stirred at -78 C. for 50 mins. The mixture was quenched with saturated NR4Cl (10 mL) and extracted with ethyl acetate (100 mL*3). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated to afford the crude product, which was purified on silica gel chromatography (EA: PE=5%?40%) to afford 3-(2-chloropyridin-4-yl)oxetan-3-ol (620 mg, yield 86%) as a yellow solid. (ESI): M/Z (M+1): 352 (Condition: 0-60AB-3 MIN; R.T.:1.303).
86%
To a solution of of 2-chloro-4-iodopyridine (1.0 g, 4.18 mmol) in anhydrous THF (10 mL) was added n-BuLi (3.34 mL, 8.35 mmol) at -78 C. The mixture was stirred at -78 C for 20 mins. Then <strong>[6704-31-0]oxetan-3-one</strong> (361 mg, 5.01 mmol) was added at -78 C and the mixture was stirred at -78 C for 50 mins. The mixture was quenched with saturated H4CI (10 mL) and extracted with ethyl acetate (100 mLx3). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated to afford the crude product, which was purified on silica gel chromatography (EA: PE = 5% ~ 40%) to afford 3-(2-chloropyridin-4-yl)oxetan-3-ol (620 mg, yield 86%) as a yellow solid. (ESI): M/Z (M+l): 352 (Condition: 0-60AB_3MIN; R.T. : 1.303).
65.3%
2-Chloro-4-iodopyridine (19.04 mmol, 4.56 g) in THF (10 ml) was added dropwise to isopropylmagnesium chloride (21.90 mmol, 10.95 ml) (2M solution in THF) at -40C under N2-atmosphere. The reactionmixture was stirred at -40 C for 0.5 hr, followed by addition of <strong>[6704-31-0]oxetan-3-one</strong> (19.04 mmol, 1.372 g) in 5 ml THF. The reactionmixture was stirred 1.5 h at -40 C after which the temperature was allowed to come to 0 C and stirred 2h. The reactionmixture was added dropwise to brine (cooled with an icebath), extracted with EtOAc twice. The combined organic layers were dried (Na2SO4) filtered and concentrated. The residue was crystallized from EtOH (p.a.) to give 3-(2-chloropyridin-4-yl)oxetan-3-ol (2.31 g, 65.3%).
6.01.22.01 2-chloro-4-ethoxy-pyridine 33 ml sodium ethoxide was added to 19.2 g 2-chloro-4-iodopyridine in 150 mL ethanol. The reaction was refluxed overnight. Then water was added and extracted with tert-butyl- methylether. The organic layer was evaporated and the residue cleanded by chromatography on silica gel (petrolether/EtOAC:9/l) to yield 5 g of the desired compound. Rf: 0.3 (petrolether/EtOAC:4/l), (M+H)+: 158
5 g
In ethanol;Reflux;
6.01.22.01 2-chloro-4-ethoxy-pyridine 33 ml sodium ethoxide was added to 19.2 g 2-chloro-4-iodopyridine in 150 mL ethanol. The reaction was refluxed overnight. Then water was added and extracted with tert-butyl-methylether. The organic layer was evaporated and the residue cleanded by chromatography on silica gel (petrolether/EtOAC:9/1) to yield 5 g of the desired compound. Rf: 0.3 (petrolether/EtOAC:4/1), (M+H)+: 158
With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In ethanol; water; toluene; at 90℃;
(1 eq), n-BuLi (1.2 eq), THF, -78 C., 5 min; 12 (1.2 eq) in THF, -78 C. to RT, 1 h. Crude LCMS showed 42% of desired mass of compound 16. The crude was used as such for the next step where compound 17 (1 eq), 16 crude (1.2 eq), Pd(PPh3)4 (0.05 eq), Na2CO3 (3 eq), toluene/EtOH/H2O was heated to 90 C. Work up and purification provided the desired producted 18. The compound 18 under similar conditions were reacted with 19 to obtain the final product 20(6
1-((tert-butyl(dimethyl)silyl)oxy)-2-(2-chloro-4-pyridinyl)-2-propanol[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
62 g
In 1.0 L three necked round bottom flask, 2-chloro-4-iodopyridine (95g, 0.396 mol, Apollo Sci. UK) was dissolved in dry THF (500 mL) at rt under nitrogen atmosphere. The resulting solution was cooled to -78C and at this temperature n-BuLi (1.6M, 297 mL, 0.476 mol, Acros, India) was added dropwise over a period of 45 minutes under nitrogen atmosphere. The reaction mixture was stirred at same temperature for 30 minutes under nitrogen atmosphere. After 30 minutes, l-((tert-butyl(dimethyl)silyl)oxy)-2-propanone (89.5g, 0.476 mol, from Step 1) was added dropwise over a period of 20 minutes at the same temperature The reaction mixture was stirred under nitrogen atmosphere for 2 h. Upon completion of reaction, the mixture was diluted with saturated NH4C1 solution and EtOAc. The organic layer was separated, washed with water, brine and dried over anhydrous Na2S04. The solution was concentrated under reduced pressure and the residue obtained was purified by silica gel (60 to 120 mesh) column chromatography (eluent, 8% EtOAc-hexanes) to give of l-((tert-butyl(dimethyl)silyl)oxy)-2-(2-chloro-4-pyridinyl)-2-propanol (62 g) as a colorless liquid.
General procedure: Synthesis of intermediates (4) (Scheme I, Step b) [0212] Alkenes 2a-i were synthesized as described above. Alkene 2j (Table 3) was synthesized in accordance with the literature method (WO2004/74291 A1, p. 67-68). Alkene 21 (Table 3) was synthesized in accordance with the literature method (US2006/106016 A1, p. 32) [0213] To a solution of alkene 2 (0.1 mol) in 80 ml of anhydrous THF 9-borabicyclo[3.3.1]nonane (0.1 mol, 200 ml, 0.5M solution in THF) under argon atmosphere. The resulting solution was stirred at ambient temperature for 24 h. Thereafter the corresponding halide 3 (0.12 mol), potassium carbonate (110.4g, 0.8 mol), water (80 ml), and Pd(PPh3)4 (5.5 g, 0.0067 mol) were added. The resulting reaction mixture was heated under reflux for 3 h, then cooled down to the room temperature and poured into the ice-cold water. The resulting mixture was extracted with ethyl acetate several times. The combined organic extracts were dried over anhydrous sodium sulfate and evaporated in vacuo. The residue was purified by a column chromatography on silica gel to give the corresponding key intermediates 4. The yields are specified in Table 3.
With copper(l) iodide; cesium fluoride In N,N-dimethyl-formamide at 120℃; for 48h; Sealed tube;
CuI-Catalyzed Couplings of Aryltriethoxysilanes with Aryl Iodidesand Bromides: General Procedure B (in the Absence of Ligand)
General procedure: In a glovebox, aryl iodide (1.0 mmol), CsF (228 mg, 1.5 mmol), and CuI (19.0 mg, 0.1 mmol) were weighed into a 4-dram borosilicate scintillation vial and dissolved in DMF (5 mL). Aryltriethoxysilane (1.0 mmol) was then added to the mixture, and the vial was tightly capped with a poly-seal cone-lined urea cap (Wheaton). The mixture was taken out of the glovebox and placed in an oil bath preheated to 120 °C with vigorous stirring. After 48 h, the mixture was cooled to r.t., diluted with EtOAc (15 mL), and washed with H2O (2× 5 mL). The aqueous fraction was back-extracted with EtOAc (3 ×5 mL). The combined organic fractions were dried (Na2SO4) and cotton-filtered, and the solvent was removed on a rotary evaporator. The product was purified by column chromatography (silica gel, hexanes, hexanes-Et2O, or hexanes-EtOAc).
With potassium phosphate; palladium diacetate; triphenylphosphine; In N,N-dimethyl-formamide; at 90℃; for 1h;Inert atmosphere; Schlenk technique;
General procedure: An oven dried Schlenk tube was purged with nitrogen and charged with 3-iodopyridine (0.875 mmol, 179.3 mg), BiPh3 (0.25 mmol, 110 mg), K3PO4 (1.5 mmol, 318 mg), Pd(OAc)2 (0.025 mmol, 5.6 mg), PPh3 (0.1 mmol, 26.2 mg) followed by dry DMF (3 mL) under nitrogen atmosphere. The reaction mixture was stirred in an oil bath at 90°C for 1h. It was brought to rt, treated with water (10mL), and extracted with ethyl acetate (2×20 mL). The organic extract was treated with brine, dried over anhydrous MgSO4, and concentrated using rotary evaporator under the reduced pressure. The crude was subjected to silica gel column chromatography (5percent EtOAc/Hexane) to obtain 3-phenylpyridine (1.1) as colorless oil (115 mg, 98percent).
tert-butyl 2'-chloro-5,6-dihydro-[3,4'-bipyridine]-1(2H)-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; caesium carbonate; In 1,4-dioxane; water; at 70℃; for 16h;Sealed tube; Inert atmosphere;
A deoxygenated mixture of tert-butyl 3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan- 2-yl)-5,6-dihydropyridine-l(2H)-carboxylate (110 mg, 0.356 mmol), 2-chloro-4-iodopyridine (102 mg, 0.427 mmol), 1 , l'-bis(di-tert-butylphosphino)ferrocene palladium dichloride (23.2 mg, 0.036 mmol), and cesium carbonate (232 mg, 0.711 mmol) in dioxane (1.62 mL) and water (0.162 mL) was heated at 70 °C in a sealed vessel for 16 h. The mixture was cooled to room termperature and partitioned between water and ethyl acetate (2x). The combined organic layers were washed with saturated aqueous sodium chloride, dried over sodium sulfate, and concentrated. The residue was purified by silica gel chromatography eluting with a gradient of hexanes:ethyl acetate - 95:5 to 35:65 to give the title compound. MS: mlz = 295.2 [M+l]+.
A mixture of 2-chloro-3-iodopyridine(5.0g, 21mmol) in dry THF (30 mL) was slowly added to a cold (-78C) solution oflithiumdiisopropylamide(15 mL, 30mmol) in dry THF (50 mL). The resulting mixture was stirred for 3h at this temperature.Ethylformate(4.0g, 54mmol) wasthenadded.Stirring continued for 1.5 h at the same temperature.Water (10 mL) was added to quench the reaction, and then theresultingmixture was warmed toroom temperature.2 MHCl(50 mL) was added and then the THF was removed under reduced pressure.The aqueous residue was extracted withethyl acetate(2 x 50 mL).The combined organic extracts were washed with brine, dried over Na2SO4andconcentrated under reduced pressure.The residuewas purified on silica gel(diethyl ether/petroleum ether1:4)to give the desired product as a yellow solid(3.0 g, 54% yield).HNMR(500 MHz, CDCl3):delta10.22(s, 1H), 8.09(d, J =5.0Hz, 1H), 7.95(d,J =5.0Hz, 1H).
52%
According to the literature,17 a dry, argon-flushed Schlenk flask equipped with a magnetic stirring bar and a septum was charged with a solution of LDA (18.0 mmol, 1.0 M in THF) and cooled to -78 C. 2-Chloro-3-iodopyridine (3.1 g, 13.0 mmol) was added dropwise tothe cooled solution. The resulting mixture was stirred for 3 h at -78 C. Ethyl formate (2.5 g, 34.0 mmol) was then added and stirred for 1.5 hat -78 C. The resulting solution was quenched with sat. aq NH4Cl (80 mL), extracted with EtOAc (3 × 120 mL), and the combined organic phases were dried (anhyd MgSO4). After filtration, the solvents were evaporated in vacuo. The crude product was purified by flash column chromatography on silica gel (i-hexane/EtOAc, 9:1 to 8:2 +Et3N 2%) yielding 2-chloro-4-iodonicotinaldehyde as a yellow solid(1.8 g, 52%). 1H NMR (400 MHz, CDCl3): delta = 10.19 (s, 1 H), 8.07 (d, J = 5.1 Hz, 1 H),7.94 (d, J = 5.1 Hz, 1 H).
1-(2-chloropyridin-4-yl)-3-methyl-1H-indazole[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
1.2 g
With potassium phosphate; copper(l) iodide; trans-N,N?-dimethyl-1,2-cyclohexane diamine; In toluene; at 80℃;Inert atmosphere;
Compound 98 (1.1 g, 8.3 mmol), 2-chloro-4-iodopyridine (4.0 g, 16.7 mmol), copper iodide (158 mg, 0.83 mmol),potassium phosphate (3.5 g, 16.7 mmol), trans-N,N?-dimethylcyclohexanediamine (237 mg, 1.67 mmol), and toluene(30 mL) were added to a 100 mL reaction flask under a nitrogen atmosphere, and the temperature was raised to 80 Cto react overnight. After the completion of reaction, the mixture was filtered. The filtrate was concentrated, and compound99 (1.2 g) was obtained by column chromatography. 1H NMR (400 MHz, CDCl3): delta 8.47 (d, J = 5.6 Hz, 1H), 7.90-7.85(m, 2H), 7.79-7.70 (m, 2H), 7.62 -7.53 (m, 1H), 7.35 (t, J = 7.5 Hz, 1H), 2.67 (s, 3H); MS (ESI) (m/z): [M+H]+ 244.1.
With 1,1,1,3',3',3'-hexafluoro-propanol; 2-chloro-6-hydroxybenzaldehyde; water; palladium diacetate; silver trifluoroacetate; 2-hydroxy-5-(trifluoromethyl)pyridine at 150℃; for 12h; Sealed tube;
tert-butyl (3-(2-chloropyridin-4-yl)-5-methylcyclohexyl)carbamate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
Multi-step reaction with 2 steps
1.1: palladium diacetate; 2-chloro-6-hydroxybenzaldehyde; 2-hydroxy-5-(trifluoromethyl)pyridine; 1,1,1,3',3',3'-hexafluoro-propanol; silver trifluoroacetate; water / 12 h / 150 °C / Sealed tube
2.1: hydrogenchloride / tetrahydrofuran / 1 h / 20 °C
2.2: 4 h / 20 °C
Pd2dba3 (356 mg, 0.39 mmol), Xantphos (375 mg, 0.65 mmol) and K3PO4 (4.40 g, 20.7 mmol) were added to a solution of 2-chloro-4-iodopyridine [153034-86-7] (1.55 g, 6.47 mmol) in anhydrous DMF (25 mL) in a sealed tube while N2 was bubbling. After 10 min, <strong>[2968-33-4]3,3,3-trifluoropropylamine hydrochloride</strong> [2968-33-4] (997 mg, 6.67 mmol) was added and the reaction mixture was stirred at room temperature for 10 min, and at 70 C for 20 h. The mixture was filtered over Celite and the filtrate was concentrated in vacuo. The crude mixture was purified by flash column chromatography (silica, heptane/EtOAc, gradient from 100:0 to 90:10) to afford 1-140 (1.06 g, 72%).
With copper(l) iodide; (S,S)-1,2-diaminocyclohexane; potassium carbonate In toluene at 110℃; for 16h;
17 Synthesis of compound 17.1
To a solution of 2-chloro-4-iodopyridine (1.0g, 4.18mmol, 1.0eq) and potassium carbonate (1.73g, 12.54mmol, 3.0eq) in toluene (15mL) was added 3-methyl-1H-pyrazole (1.0g, 12.54mmol, 3.0eq), trans-1,2-diaminocyclohexane (0.190g, 1.67mmol, 0.4eq) and copper(I) iodide(0.159g, 0.83mmol, 0.2eq). The reaction mixture was heated at 110°C for 16h. After completion of reaction, reaction mixture was transferred into ice cold water and product was extracted with ethyl acetate. Organic layer was combined, washed with brine solution, dried over sodium sulfate and concentrated under reduced pressure to obtain crude material. This was further purified by column chromatography eluting with 20% ethyl acetate in hexane to obtain 17.1. (0.320g, 39.57%), MS (ES): m/z 194.04 [M+H]+.
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