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
Stage #1: With 2,2,6,6-tetramethyl-piperidine; n-butyllithium In tetrahydrofuran; hexanes at -78℃; for 2 h; Stage #2: With iodine In tetrahydrofuran; hexanes for 0.5 h;
2,2, 6,6-tetramethylpiperidine (17 ML, 14 g, 0.1 mol) and 2-chloropyridine (9.5 mL, 11.5 g, 0.1 mol) were consecutively added at-78°C to n-butyllithium 1.6 M in hexanes (62.5 mL, 0.1 mol) in 150 mL of tetrahydrofuran. After 2h AT-78°C, the mixture was treated with a solution of iodine (25.5 g, 0.1 mol) in THF (50 ML) and stirred for 30 min before being partitioned between water (100 mL) and diethyl ether (3 x 50 mL). The combined organic layers were washed with a saturated aqueous solution of sodium thiosulfate (2 x 50 mL), dried over magnesium sulfate, filtered and concentrated under vacuum to afford a crude solid which was purified by flash chromatography (heptane/ethyl acetate 90/10). Yield: 72percent (17.3 g), yellow SOLID. IH NMR (CDC13) : 8 8.38 (dd, J = 4.6/1. 7 Hz, 1H), 8.16 (dd, J = 8. 0/1. 6 Hz, 1H), 6.96 (dd, J = 8.0/4. 6 Hz, 1H). 13C NMR (CDC13) : 8 154.5, 148.9, 148 : 8, 123.2, 94.9. MS (EI) M/Z 240 (M+1).
Reference：
[1] European Journal of Organic Chemistry, 2001, # 7, p. 1371 - 1376
[2] Bioorganic and Medicinal Chemistry Letters, 2006, vol. 16, # 5, p. 1397 - 1401
[3] Patent: WO2004/52880, 2004, A1, . Location in patent: Page 29-30
[4] Tetrahedron Letters, 1994, vol. 35, # 35, p. 6489 - 6492
[5] Organic letters, 2002, vol. 4, # 13, p. 2201 - 2203
[6] Angewandte Chemie - International Edition, 2018, vol. 57, # 33, p. 10748 - 10751[7] Angew. Chem., 2018, vol. 130, # 33, p. 10908 - 10911,4
[8] Chemistry - A European Journal, 2009, vol. 15, # 39, p. 10280 - 10290
[9] Journal of Organometallic Chemistry, 1991, vol. 406, # 1+2, p. 49 - 56
[10] Tetrahedron, 1993, vol. 49, # 1, p. 49 - 64
11
[ 6298-19-7 ]
[ 78607-36-0 ]
Reference：
[1] Journal of Organic Chemistry, 2004, vol. 69, # 22, p. 7752 - 7754
[2] Synthesis, 2007, # 1, p. 81 - 84
[3] Tetrahedron Letters, 2009, vol. 50, # 52, p. 7263 - 7267
[4] Chemical & Pharmaceutical Bulletin, 1985, vol. 33, # 11, p. 4764 - 4768
Reference：
[1] Chemistry - A European Journal, 2011, vol. 17, # 47, p. 13284 - 13297
15
[ 2942-59-8 ]
[ 78607-36-0 ]
Reference：
[1] Advanced Synthesis and Catalysis, 2011, vol. 353, # 8, p. 1359 - 1366
16
[ 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
17
[ 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
18
[ 78607-36-0 ]
[ 113975-22-7 ]
Yield
Reaction Conditions
Operation in experiment
65%
With cesium fluoride In dimethyl sulfoxide at 130℃; for 4 h;
General procedure: To a solution of 2,3-dichloropyridine(1.00 g, 6.76 mmol) in DMSO (33.8 ml) was added CsF (2.053 g, 13.51mmol) at room temperature. The mixture was stirred at 110 °C under air for 20h. The mixture was quenched with water at room temperature and extracted withEtOAc. The organic layer was separated, washed with water and brine, dried overNa2SO4 and concentrated in vacuo. The residue waspurified by column chromatography (silica gel, eluted with EtOAc in hexane) togive 3-chloro-2-fluoropyridine (0.639 g, 4.86 mmol, 71.9 percent) as colorlessoil. Thecompound 3B'-8B' were prepared in amanner similar to that described for 2B'.
Reference：
[1] Journal of Organic Chemistry, 1993, vol. 58, # 27, p. 7832 - 7838
20
[ 78607-36-0 ]
[ 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;
Example 1 :N-(2-(2,6-Dichlorophenyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)cyclopropanecarboxamideStep 1 :2-Chloro-4-iodonicotinaldehydeA mixture of 2-chloro-3-iodopyridine (5.0 g, 21 mmol) in dry THF (30 mL) was slowly added to a cold (-78 °C) solution of lithium diisopropylamide (15 mL, 30 mmol) in dry THF (50 mL). The resulting mixture was stirred for 3 h at this temperature. Ethyl formate (4.0 g, 54 mmol) was then added. Stirring was continued for 1.5 h at the same temperature. Water (10 mL) was added to quench the reaction, and then the resulting mixture was warmed to room temperature. 2M HC1 (50 mL) was added and then the THF was removed under reduced pressure. The aqueous residue was extracted with ethyl acetate (2 x 50 mL). The combined organic extracts were washed with brine, dried over Na2S04 and concentrated under reduced pressure. The residue was purified on silica gel (diethyl ether: petroleum ether = 1 : 4) to give the desired product 2-chloro- 4-iodonicotinaldehyde as a yellow solid (3.0 g, 54percent yield). NMR (500 MHz, CDC13): δ 10.22 (s, 1H), 8.09 (d, J = 5.0 Hz, 1H), 7.95 (d, J = 5.0 Hz, 1H).
Reference：
[1] Synthetic Communications, 1996, vol. 26, # 23, p. 4421 - 4436
[2] Journal of Organic Chemistry, 1993, vol. 58, # 27, p. 7832 - 7838
[3] Journal of Heterocyclic Chemistry, 2001, vol. 38, # 5, p. 1039 - 1044
[4] Patent: WO2012/66061, 2012, A1, . Location in patent: Page/Page column 76-77
With tetrakis(triphenylphosphine) palladium(0); potassium carbonate In 1,4-dioxane at 120℃; for 4 h;
To a mixture of 2-chloro-3-iodopyridine (2.39 g, 9.98 mmol), cyclopropylboronic acid (860 mg, 10 mmol) and potassium carbonate (4.14 g, 30.0 mmol) in 1 ,4-dioxane (50 mL) was added tetrakis(triphenylphosphine)palladium(0) (1 .16 g, 1 .00 mmol). The reaction mixture was stirred at 120 °C for 4 hours, then diluted with ethyl acetate (50 mL) and filtered. The filtrate was concentrated and the residue was purified by silica gel chromatography (Gradient: 10percent to 30percent ethyl acetate in petroleum ether) to afford the product as a colorless oil. Yield: 1 g, 6 mmol, 60percent. 1 H NMR (400 MHz, CDCl3) δ 8.20 (dd, J=4.7, 1.8 Hz, 1 H), 7.24-7.28 (m, 1 H), 7.14 (br dd, J=7.6, 4.8 Hz, 1 H), 2.12-2.21 (m, 1 H), 1.04-1.11 (m, 2H), 0.67-0.72 (m, 2H).
2,2, 6,6-tetramethylpiperidine (17 ML, 14 g, 0.1 mol) and 2-chloropyridine (9.5 mL, 11.5 g, 0.1 mol) were consecutively added at-78C to n-butyllithium 1.6 M in hexanes (62.5 mL, 0.1 mol) in 150 mL of tetrahydrofuran. After 2h AT-78C, the mixture was treated with a solution of iodine (25.5 g, 0.1 mol) in THF (50 ML) and stirred for 30 min before being partitioned between water (100 mL) and diethyl ether (3 x 50 mL). The combined organic layers were washed with a saturated aqueous solution of sodium thiosulfate (2 x 50 mL), dried over magnesium sulfate, filtered and concentrated under vacuum to afford a crude solid which was purified by flash chromatography (heptane/ethyl acetate 90/10). Yield: 72% (17.3 g), yellow SOLID. IH NMR (CDC13) : 8 8.38 (dd, J = 4.6/1. 7 Hz, 1H), 8.16 (dd, J = 8. 0/1. 6 Hz, 1H), 6.96 (dd, J = 8.0/4. 6 Hz, 1H). 13C NMR (CDC13) : 8 154.5, 148.9, 148 : 8, 123.2, 94.9. MS (EI) M/Z 240 (M+1).
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 2,4,6-Triisopropylbenzenesulfonyl azide; lithium diisopropyl amide; In tetrahydrofuran; at -78℃; for 1h;Inert atmosphere;
Example 5. Synthesis of Compound 5.[0134] Synthesis of 3-azido-2-chloro-4-iodopyridine. <strong>[78607-36-0]2-chloro-3-iodopyridine</strong> (8 g, 33 mmol) was added to 300 mL THF under inert environment and the reaction mixture was cooled to -78 C. Lithium diisopropylamide (2M solution in THF, 17 ml, 33 mmol) was added dropwise to the reaction mixture and after complete addition, THF solution stirred at - 78 C for 1 h. A solution of 2,4,6-triisopropylbenzenesulfonyl azide (15.5 g, 50 mmol) in 50 mL THF was then slowly added to the reaction mixture and was stirred for another 1 h at -78 C. Reaction flask was then slowly warmed up to room temperature. Reaction mixture was quenched with 10 mL saturated NH4C1 solution. Most of the organic solvent was evaporated under vacuum. Crude product was partitioned between brine and ethyl acetate. Organic layer was isolated, dried over anhd. Na2S04 and later purified by silica gel column chromatography using 2-10% ethylacetate/hexanes as eluent. 3-azido-2-chloro-4- iodopyridine (25 mmol, 7 g, 75% yield) was isolated as a light yellow color crystalline solid.
Example 1 :N-(2-(2,6-Dichlorophenyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)cyclopropanecarboxamideStep 1 :2-Chloro-4-iodonicotinaldehydeA mixture of 2-chloro-3-iodopyridine (5.0 g, 21 mmol) in dry THF (30 mL) was slowly added to a cold (-78 C) solution of lithium diisopropylamide (15 mL, 30 mmol) in dry THF (50 mL). The resulting mixture was stirred for 3 h at this temperature. Ethyl formate (4.0 g, 54 mmol) was then added. Stirring was continued for 1.5 h at the same temperature. Water (10 mL) was added to quench the reaction, and then the resulting mixture was warmed to room temperature. 2M HC1 (50 mL) was added and then the THF was removed under reduced pressure. The aqueous residue was extracted with ethyl acetate (2 x 50 mL). The combined organic extracts were washed with brine, dried over Na2S04 and concentrated under reduced pressure. The residue was purified on silica gel (diethyl ether: petroleum ether = 1 : 4) to give the desired product 2-chloro- 4-iodonicotinaldehyde as a yellow solid (3.0 g, 54% yield). NMR (500 MHz, CDC13): delta 10.22 (s, 1H), 8.09 (d, J = 5.0 Hz, 1H), 7.95 (d, J = 5.0 Hz, 1H).
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 48h;Inert atmosphere;
A suspension of <strong>[78607-36-0]2-chloro-3-iodopyridine</strong> (1) (1.07g, 4.46mmol), morpholine (0.43ml_, 4.90mmol), Cs2C03 (2.90gmg, 8.92mmol) and Xantphos (260mg, 0.4mmol) in 1 ,4-dioxane (50mL) was purged with Ar(g) for 0.5h. Pd2(dba)3 (204mg, 0.22mmol) was added and the reaction mixture was heated up to 90C for 2d. Once cooled down to rt, it was poured into a mixture of H20 (50ml_) and brine (50ml_), then extracted with EtOAc (3 x 50ml_). The combined organics were washed with brine (50ml_), dried over MgS04, filtered and concentrated in vacuo. Purification by silica gel column chromatography with hexane/EtOAc (1 :0-7:3) yielded (2) as a solid (628mg, 71 %).
64%
With caesium carbonate;palladium diacetate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; In toluene; at 120℃; for 16h;Inert atmosphere;
A 2-dram vial equipped with a stirbar was charged with Pd(OAc)2 (0.234 g, 1.044 mmol) and rac-BINAP (0.683 g, 1.096 mmol) as solids. Toluene (4 mL) was added via syringe, and the mixture was stirred for 10 min while being degassed with argon, and until a uniform tan suspension resulted. A 100-mL round-bottom flask was charged with <strong>[78607-36-0]2-chloro-3-iodopyridine</strong> (1.25 g, 5.22 mmol) and Cs2C03 (7.14 g, 21.93 mmol). Toluene (34.8 mL) was added followed by morpholine (0.542 ml, 6.26 mmol). This solution was degassed for 1 min under argon, and then the catalyst ligand suspension was added via pasteur pipette. A reflux condenser was attached to the flask, and the reaction mixture was refiuxed at 120 C for 16 h. The reaction mixture was concentrated in vacuo, and then diluted with CH2C12 (150 mL). The organics were washed with 2x 100 mL brine, dried over Na2S04, filtered, and concentrated in vacuo. The material was purified by gradient elution on silica gel (5 to 75% [5% MeOH/EtOAc] in hexanes) to afford the title compound as light yellow solid (700 mg, 64%).
With tetrabutyl-ammonium chloride; sodium hydrogencarbonate;palladium diacetate; In DMF (N,N-dimethyl-formamide); at 50℃; for 5h;
To a mixture of 2-chloro-5-iodopyridine (6.76 g, 28.2 mmol) in 50 mL N,N-dimethylformamide was added 1-buten-3-ol (24.4 mL, 282.3 mmol), palladium acetate (0.64 g, 2.82 mmol), tetrabutylammonium chloride (0.79 g, 2.82 mmol), and sodium bicarbonate (5.94 g, 70.6 mmol). The resulting mixture was stirred at 50 C. for 5 hr, and then quenched with water (20 mL). Subsequently, the mixture was diluted with 20 mL of ethyl acetate and filtered through a pack of celite. The organic layer was separated from the filtrate, and the aqueous layer was further extracted with ethyl acetate. The organics were combined, washed with saturated NaCl solution, and dried over magnesium sulfate. Chromatography (on silica, ethyl acetate/hexane) afforded the desired 4-(6-chloropyridin-3-yl)butan-2-one intermediate in the form of a yellow oil (4.01 g, 77% yield). MS MH+ for C9H10ClNO: calc. 184, found 184.
With cesium fluoride; In DMF (N,N-dimethyl-formamide); at 20 - 75℃; for 72h;
Example 15: (2SUR (S)-R (3-IODOPYRIDIN-2-YL) thio] (phenyl methyl] morpholine fumarate 0 N f t N X t N f s I -' I N C Ph O J Ph Ph N N I H Fumarate salt i) To (S)-PHENYL [(2S)-4-(PHENYLMETHYL) morpholin-2-yl] methanethiol (6) (0.50 g, 1.67 mmole) and 2-CHLORO-3-IODOPYRIDINE (0.48 g, 2.00 mmole) in degassed DMF (3 ml) is added cesium fluoride (0.38 g, 2.50 mmole) at room temperature and under nitrogen. The mixture is heated at between 55-75C for 3 days. The organic layer is then loaded directly onto a 35 g ISCO column (SI02) and columned using automated flash chromatography (0-30% EtOAc in cyclohexane over 30 minutes) to give a pale yellow crystalline solid (0.55 g). The solid is taken up in DCM: MeOH (1: 1) and loaded onto an SC10-2 column (10 g) preconditioned with MeOH. The column is washed with MeOH to remove 2-CHLORO-3-IODOPYRIDINE, then more basic material is eluted with 2 N NH3/METHANOL. The ammonia solution is concentrated in vacuo to give (2S)-2-[(5)-[(3-IODOPYRIDIN-2-YL) thio] (phenyl) methyl]-4- (phenylmethyl) morpholine as a pale yellow solid (0.19 g, 23%). LCMS 6 min gradient method, Rt = 3.8 min, (M+H+) = 503
23%
With cesium fluoride; In DMF (N,N-dimethyl-formamide); at 20 - 75℃; for 72h;
To ( -PHENYL [(2S)-4-(PHENYLMETHYL) morpholin-2-yl] methanethiol (6) (0.50 g, 1.67 mmole) and <strong>[78607-36-0]2-chloro-3-iodopyridine</strong> (0. 48 g, 2.00 mmole) in degassed DMF (3 ml) is added cesium fluoride (0.38 g, 2.50 mmole) at room temperature and under nitrogen. The mixture is heated at between 55-75C for 3 days. The organic layer is then loaded directly onto a 35 g ISCO column (SI02) and columned using automated flash chromatography (0 - 30% EtOAc in cyclohexane over 30 minutes) to give a pale yellow crystalline solid (0.55 g). The solid is taken up in DCM: MeOH (1: 1) and loaded onto an SC10-2 column (10 g) preconditioned with MeOH. The column is washed with MeOH to remove 2- CHLORO-3-IODOPYRIDINE, then more basic material is eluted with 2 N NH3/METHANOL. The ammonia solution is concentrated in vacuo to give (2S-2- [ (- [ (3-IODOPYRIDIN-2- yl) thio] (phenyl) methyl]-4- (phenylmethyl) morpholine as a pale yellow solid (0.19 g, 23%). LCMS 6 min gradient method, Rt = 3.8 min, (M+H+) = 503
23%
With cesium fluoride; In DMF (N,N-dimethyl-formamide); at 20 - 75℃; for 72h;
To (phenyl [(2S)-4-(phenylmethyl) morpholin-2-yl] methanethiol (6) (0.50 g, 1.67 mmole) and <strong>[78607-36-0]2-chloro-3-iodopyridine</strong> (0.48 g, 2.00 mmole) in degassed DMF (3 ml) is added cesium fluoride (0.38 g, 2.50 mmole) at room temperature and under nitrogen. The mixture is heated at between 55-75C for 3 days. The organic layer is then loaded directly onto a 35 g ISCO column (SiO2) and columned using automated flash chromatography (0 - 30% EtOAc in cyclohexane over 30 minutes) to give a pale yellow crystalline solid (0.55 g). The solid is taken up in DCM: MeOH (1: 1) and loaded onto an SC10-2 column (10 g) preconditioned with MeOH. The column is washed with MeOH to remove 2- chloro-3-iodopyridine, then more basic material is eluted with 2 N NH3/methanol. The ammonia solution is concentrated in vacuo to give (2S)-2-[(S)-[(3-iodopyridin-2- yl) thio] (phenyl) methyl]-4- (phenylmethyl) morpholine as a pale yellow solid (0.19 g, 23%). LCMS 6 min gradient method, Rt = 3.8 min, (M+H+) = 503
With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In 1,4-dioxane; at 120.0℃; for 4.0h;
To a mixture of 2-chloro-3-iodopyridine (2.39 g, 9.98 mmol), cyclopropylboronic acid (860 mg, 10 mmol) and potassium carbonate (4.14 g, 30.0 mmol) in 1 ,4-dioxane (50 mL) was added tetrakis(triphenylphosphine)palladium(0) (1 .16 g, 1 .00 mmol). The reaction mixture was stirred at 120 C for 4 hours, then diluted with ethyl acetate (50 mL) and filtered. The filtrate was concentrated and the residue was purified by silica gel chromatography (Gradient: 10% to 30% ethyl acetate in petroleum ether) to afford the product as a colorless oil. Yield: 1 g, 6 mmol, 60%. 1 H NMR (400 MHz, CDCl3) delta 8.20 (dd, J=4.7, 1.8 Hz, 1 H), 7.24-7.28 (m, 1 H), 7.14 (br dd, J=7.6, 4.8 Hz, 1 H), 2.12-2.21 (m, 1 H), 1.04-1.11 (m, 2H), 0.67-0.72 (m, 2H).
With tris-(dibenzylideneacetone)dipalladium(0); 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; sodium t-butanolate; In toluene; at 110℃; for 18h;
A mixture of 2-chloro-3-iodopyridine (400 mg , 1.67 mmol ), 2-methylpiperazine (200 mg, 2.0 mmol), sodium tert-butoxide (224 mg, 2.3 mmol), 9,9-dimethyl-4,5-bis(diphenyl- phosphino)Xanthen (48 mg, 0.08 mmol) and tris(dibenzylideneacetone) palladium (38 mg, 0.04 mmol) in toluene (6 mL) was heated at 110C for 18 hours. The mixture was poured out into water, extracted with EtOAc, the mixture was filtered through a short pad of Celite, the organic layer was separated, washed with water and brine, dried (MgS04), evaporated till dryness and the residue was carried out by flash chromatography over silica gel (grace, 40 g,CH2Cl2/MeOH/NH4OH 95/5/0.5) The pure fractions were collected and evaporated to dryness to afford 155 mg (44%) of intermediate (8).
Synthesis of 2'-chloro-3-fluoro-2,3'-bipyridine A solution of isopropylmagnesium chloride in THF (2.0 M, 20.05 ml, 40.1 mmol) was dissolved in THF (25 ml) and cooled in ice/water bath, before <strong>[40273-45-8]2-bromo-3-fluoropyridine</strong> (3.72 ml, 36.8 mmol) was slowly added via syringe. The resulting solution in stirred at room temperature for 1 hour, then a zinc(II) chloride solution in THF (0.5 M, 80 ml, 40.1 mmol) was added via syringe and stirred at room temperature overnight, forming a nearly colorless, heterogeneous mixture. Separately, a flask containing 2-chloro-3-iodopyridine (8 g, 33.4 mmol) and Pd(PPh3)4 (1.930 g, 1.671 mmol) was degassed, then THF (100 ml) was added and the resulting solution was warmed to near reflux. The zinc chloride suspension was added via cannula to the 2-chloro-3iodopyridine solution and the resulting yellow mixture was stirred at reflux over the weekend, cooled to room temperature, and then filtered through celite. Solvent removal from the filtrates was followed by partitioning between EtOAc and basic water. The aqueous layer was extracted with EtOAc three times, the combined organics were washed with brine, dried, and the solvent as removed. After coating on celite, the product was eluted on a 200 g silica column using 10-25% EtOAc in DCM, collecting pale yellow Rf?0.45 fractions, yielding a pale yellow solid, 5.29 g (76%).
With caesium carbonate; In dimethyl sulfoxide; at 120℃; for 23h;
Step 1 2-chloro-3-iodopyridine (III-2) (1.00 g, 4.18 mmol) and compound (II-1) (819 mg, 5.20 mmol) were dissolved in DMSO (8.4 mL), cesium carbonate (1.91 g, 5.85 mmol) was added, and the mixture was stirred at 120°C for 23 hr. The reaction mixture was cooled, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and filtered. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate) to give compound (IV-2) (yield 964 mg, 63percent) as a colorless oil.
63%
With caesium carbonate; In dimethyl sulfoxide; at 120℃; for 23h;
2-Chloro-3-iodopyridine (III-2) (1.00 g, 4.18 mmol) and compound (II-1) (819 mg, 5.20 mmol) were dissolved in DMSO (8.4 mL)Cesium carbonate (1.91 g, 5.85 mmol) was added,Followed by stirring at 120 ° C. for 23 hours. The reaction solution was cooled,Water was added and extracted with ethyl acetate.The organic layer was washed successively with water and saturated brine,After drying with anhydrous sodium sulfate, filtration was carried out.After distilling off the solvent under reduced pressure,The residue was purified by silica gel column chromatography (n-hexane: ethyl acetate)Compound (IV-2)(Yield 964 mg, yield 63percent)As a colorless oil.
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