* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Reference：
[1] Roczniki Chemii, 1934, vol. 14, p. 326,330[2] Chem. Zentralbl., 1935, vol. 106, # I, p. 70
2
[ 462-08-8 ]
[ 13534-97-9 ]
[ 39856-58-1 ]
[ 39856-57-0 ]
Reference：
[1] Synthesis, 2001, # 14, p. 2175 - 2179
[2] Synthesis, 2001, # 14, p. 2175 - 2179
3
[ 462-08-8 ]
[ 13534-97-9 ]
[ 39856-58-1 ]
[ 39856-57-0 ]
Reference：
[1] Synthesis, 2001, # 14, p. 2175 - 2179
[2] Synthesis, 2001, # 14, p. 2175 - 2179
4
[ 39856-57-0 ]
[ 2408-70-0 ]
Reference：
[1] Roczniki Chemii, 1934, vol. 14, p. 326,330[2] Chem. Zentralbl., 1935, vol. 106, # I, p. 70
5
[ 462-08-8 ]
[ 39856-57-0 ]
Yield
Reaction Conditions
Operation in experiment
92%
With N-Bromosuccinimide In water; dimethyl sulfoxide at 0 - 20℃;
Method F; Example F-1; 4-({6-Bromo-2-oxo-1-[2-(trifluoromethyl)benzyl]-2,3-dihydro-1 H-pyrido[2,3- b][1 ,4]thiazin-3-yl}methyl)benzoic Acid; Preparation of F-1-a 2,6-Dibromopyridin-3-amine; As suggested in Majumdar, K. C; Mondal, S. Regioselective synthesis of substituted pyrrolopyridines based on Pd(ll)-mediated cross coupling and base induced heteroannulation. Tet. Letters 2007, 48, 6951-6953, to a solution of 3-aminopyridine (4.75 g, 50.5 mmol) in DMSO (100 ml_) and water (2.5 ml_) at 0°C was added portionwise N-bromosuccinimide (18.9 g, 8.91 mmol). The mixture stirred for 24 hours at ambient temperature. A solid was formed, which was filtered off and dried on a glass frit. The solid was then dissolved in ethyl acetate and dried over sodium sulfate and filtered. Solvent was removed under vacuum to afford a reddish brown solid (11.7g, 92percent), which was used without further purification and displayed 1H NMR that matched previously reported (Parlow, J. J.; Kurumbail, R. G.; Stegeman, R. A.; Stevens, A. M.; Stallings, W. C; South, M. S. Design, Synthesis, and Crystal Structure of Selective 2-Pyridone Tissue Factor Vila Inhibitors. J. Med. Chem. 2003, 46, 4696-4701 ).
89%
With N-Bromosuccinimide; dimethyl sulfoxide In water at 0 - 20℃; for 24 h;
500ml round bottom flask, 3-aminopyridine (25.0g, 0.226mol), dimethyl sulfoxide(250ml), water (5ml) were placed in a 0 ° C N- bromosuccinimide (99.3g, 0.558mol)little by little the scored. The reaction solution was stirred at room temperature for 24 hours and recrystallizedacetonitrile was obtained [Intermediate 2-b]. (59g, 89percent)
34%
With N-Bromosuccinimide In tetrachloromethane at 0 - 20℃; for 16.3333 h; Inert atmosphere
Synthesis of 2, 6-dibromopyridin-3-amine [0310] To a stirred solution of pyridine-3 -amine (20.0 g, 0.21 mol) in CC14 (200 mL) under argon atmosphere was added N-bromo succinimide (82.87 g, 0.42 mol) portion wise at 0 °C for 20 min. The reaction was warmed to RT and stirred for 16 h. After consumption of the starting materials (monitored by TLC), the reaction was concentrated in vacuo to afford the crude material purified by silica gel column chromatography using 5-8percent EtOAc:hexanes to afford 2, 6-dibromopyridin-3 -amine (18 g, 34percent) as a brown solid. 1H-NMR (CDC13, 400 MHz): δ 7.24 (d, 1H), 6.92 (d, 1H), 4.15 (bs, 2H); TLC: 30percent EtOAc:hexane (R 0.35).
34%
With N-Bromosuccinimide In tetrachloromethane at 20℃; for 16 h; Inert atmosphere
To a stirred solution of pyridin-3-amine (20.0 g, 0.21 mol) in CCl4 (200 mL) under an argon atmosphere was added N-bromosuccinimide (82.87 g, 0.42 mol) portion wise at 0 °C for 20 min. The reaction mixture was warmed to room temperature and stirred for 16 h. After consumption of the starting material (monitored by TLC), the volatile components were evaporated in vacuo. The crude material was purified by silica gel column chromatography using 5-8percent EtOAc:hexanes to afford 2, 6-dibromopyridin-3-amine (18 g, 34percent) as a brown solid. 1H-NMR (CDCl3, 400 MHz): δ 7.24 (d, 1H), 6.92 (d, 1H), 4.15 (br s, 2H); TLC: 30percent EtOAc:hexane (Rf: 0.35).
34%
With N-Bromosuccinimide In tetrachloromethane at 0 - 20℃; for 16.3333 h; Inert atmosphere
Synthesis of 2, 6-dibromopyridin-3-amine (0972) To a stirred solution of pyridin-3-amine (20.0 g, 0.21 mol) in CCl4 (200 mL) under an argon atmosphere was added N-bromosuccinimide (82.87 g, 0.42 mol) portion wise at 0° C. for 20 min. The reaction mixture was warmed to room temperature and stirred for 16 h. After consumption of the starting material (monitored by TLC), the volatile components were evaporated in vacuo. The crude material was purified by silica gel column chromatography using 5-8percent EtOAc:hexanes to afford 2, 6-dibromopyridin-3-amine (18 g, 34percent) as a brown solid. 1H-NMR (CDCl3, 400 MHz): δ 7.24 (d, 1H), 6.92 (d, 1H), 4.15 (br s, 2H); TLC: 30percent EtOAc:hexane (Rf: 0.35).
Reference：
[1] Tetrahedron Letters, 2007, vol. 48, # 39, p. 6951 - 6953
[2] Synthesis, 2001, # 14, p. 2175 - 2179
[3] Patent: WO2010/116270, 2010, A1, . Location in patent: Page/Page column 50-51
[4] Patent: KR2015/52989, 2015, A, . Location in patent: Paragraph 0357-0362
[5] Chemistry - A European Journal, 2010, vol. 16, # 47, p. 14083 - 14093
[6] Chemistry - A European Journal, 2008, vol. 14, # 8, p. 2322 - 2339
[7] Patent: WO2015/66697, 2015, A1, . Location in patent: Paragraph 0310
[8] Patent: WO2015/109109, 2015, A1, . Location in patent: Paragraph 0702
[9] Patent: US2017/44182, 2017, A1, . Location in patent: Paragraph 0972
[10] Roczniki Chemii, 1934, vol. 14, p. 326,330[11] Chem. Zentralbl., 1935, vol. 106, # I, p. 70
[12] Chemische Berichte, 1936, vol. 69, p. 2593,2604
[13] Patent: WO2010/111483, 2010, A1, . Location in patent: Page/Page column 67
6
[ 55304-80-8 ]
[ 39856-57-0 ]
Reference：
[1] Journal of Organic Chemistry, 2011, vol. 76, # 23, p. 9841 - 9844
[2] Journal of Medicinal Chemistry, 2003, vol. 46, # 22, p. 4696 - 4701
[3] Tetrahedron, 2003, vol. 59, # 39, p. 7695 - 7701
7
[ 462-08-8 ]
[ 13534-97-9 ]
[ 39856-58-1 ]
[ 39856-57-0 ]
Reference：
[1] Synthesis, 2001, # 14, p. 2175 - 2179
[2] Synthesis, 2001, # 14, p. 2175 - 2179
8
[ 1657-32-5 ]
[ 39856-57-0 ]
[ 84539-49-1 ]
[ 84539-43-5 ]
[ 84539-44-6 ]
Reference：
[1] Journal of Organic Chemistry, 1983, vol. 48, # 7, p. 1064 - 1069
9
[ 626-05-1 ]
[ 39856-57-0 ]
Reference：
[1] Journal of Medicinal Chemistry, 2003, vol. 46, # 22, p. 4696 - 4701
10
[ 98-92-0 ]
[ 462-08-8 ]
[ 39856-57-0 ]
Reference：
[1] Archiv der Pharmazie (Weinheim, Germany), 1902, vol. 240, p. 358
11
[ 462-08-8 ]
[ 67-56-1 ]
[ 7726-95-6 ]
[ 39856-57-0 ]
Reference：
[1] Roczniki Chemii, 1934, vol. 14, p. 326,330[2] Chem. Zentralbl., 1935, vol. 106, # I, p. 70
12
[ 462-08-8 ]
[ 7732-18-5 ]
[ 10035-10-6 ]
[ 7722-84-1 ]
[ 39856-57-0 ]
Reference：
[1] Chemische Berichte, 1936, vol. 69, p. 2593,2604
13
[ 39856-57-0 ]
[ 124-41-4 ]
[ 89466-18-2 ]
Yield
Reaction Conditions
Operation in experiment
78.3%
for 3 h; Reflux
Sodium methoxide (176.2 g, 3.26 mol) was added in portions to a sol. of 3-amino-2,6- dibromopyridine (100 g, 939 mmol) in 1,4-dioxane (1 1) and the r.m. was stirred under reflux for 3 h. After cooling, the r.m. was poured onto a sat. aq. NH4C1 aq. sol (1 1). Additional NH4CI (150 g) and H20 (1 1) were added and the r.m. was stirred at r.t. for 30 min. Et20 (2 1) was added and the r.m. was stirred for 30 min. The layers were separated and the aq. layer was diluted with H20 (1.5 1) and further extracted with Et20 (6 x 0.5 1). The combined o.l. were treated with brine (2 x 0.5 1), dried (MgS04) and cone, under reduced pressure to give a black residue. The residue was purified by flash chromatography over silicagel (glas filter, eluent DCM). The product fractions were combined and cone, under reduced pressure to afford an orange-brownish solid residue. Yield: 67.2 g of intermediate 24 (78.3 percent).
42%
for 8 h; Reflux; Inert atmosphere
Synthesis of 6-bromo-2-methoxypyridin-3-amine [0311] To a stirred solution of 2, 6-dibromopyridin-3 -amine (38 g, 0.15 mol) in 1, 4- dioxane (400 mL) under argon atmosphere was added sodium methoxide (70.55 g, 1.30 mol) and stirred at reflux for 8 h. After consumption of the starting materials (monitored by TLC), the reaction was quenched with ice cold water (200 mL) and extracted with EtOAc (3 x 200 mL). The combined organic extracts were washed with cold water (2 x 100 mL), dried over sodium sulfate and concentrated in vacuo. The crude material was purified through silica gel column chromatography using 10percent EtOAc:hexanes to afford 6-bromo-2-methoxypyridin-3- amine (13 g, 42percent) as an off-white solid. 1H-NMR (CDC13, 400 MHz): δ 6.87 (d, 1H), 6.76 (d, 1H), 4.01 (s, 3H), 3.75 (bs, 2H); TLC: 20percent EtOAc:hexane (R/. 0.5).
42%
at 20℃; for 8 h; Inert atmosphere; Reflux
To a stirred solution of 2, 6-dibromopyridin-3-amine (38 g, 0.188 mol) in 1, 4- dioxane (400 mL) under an argon atmosphere was added sodium methoxide (70.55 g, 1.30 mol) at room temperature. The reaction mixture was stirred at reflux for 8 h. After consumption of the starting material (monitored by TLC), the reaction mixture was quenched with ice cold water (200 mL) and extracted with EtOAc (3 x 200 mL). The combined organic extracts were washed with cold water (2 x 100 mL), dried over sodium sulfate and concentrated in vacuo. The crude material was purified by column chromatography using 10percent EtOAc:hexanes to afford 6-bromo-2-methoxypyridin-3-amine (13 g, 42percent) as a brown solid. 1H-NMR (CDCl3, 400 MHz): δ 6.87 (d, 1H), 6.76 (d, 1H), 4.01 (s, 3H), 3.75 (br s, 2H); TLC: 20percent EtOAc:hexane (Rf: 0.5).
42%
for 8 h; Inert atmosphere; Reflux
Synthesis of 6-bromo-2-methoxypyridin-3-amine To a stirred solution of 2, 6-dibromopyridin-3-amine (38 g, 0.188 mol) in 1,4-dioxane (400 mL) under an argon atmosphere was added sodium methoxide (70.55 g, 1.30 mol) at room temperature. The reaction mixture was stirred at reflux for 8 h. After consumption of the starting material (monitored by TLC), the reaction mixture was quenched with ice cold water (200 mL) and extracted with EtOAc (3*200 mL). The combined organic extracts were washed with cold water (2*100 mL), dried over sodium sulfate and concentrated in vacuo. The crude material was purified by column chromatography using 10percent EtOAc:hexanes to afford 6-bromo-2-methoxypyridin-3-amine (13 g, 42percent) as a brown solid. 1H-NMR (CDCl3, 400 MHz): δ 6.87 (d, 1H), 6.76 (d, 1H), 4.01 (s, 3H), 3.75 (br s, 2H); TLC: 20percent EtOAc:hexane (Rf: 0.5).
Reference：
[1] Journal of Medicinal Chemistry, 2003, vol. 46, # 22, p. 4696 - 4701
[2] Tetrahedron, 2003, vol. 59, # 39, p. 7695 - 7701
[3] Patent: WO2011/86098, 2011, A1, . Location in patent: Page/Page column 68; 69
[4] Journal of Medicinal Chemistry, 2012, vol. 55, # 21, p. 9089 - 9106,18
[5] Patent: WO2015/66697, 2015, A1, . Location in patent: Paragraph 0311
[6] Patent: WO2015/109109, 2015, A1, . Location in patent: Paragraph 0703
[7] Patent: US2017/44182, 2017, A1, . Location in patent: Paragraph 0973
Reference：
[1] Organic Preparations and Procedures International, 1998, vol. 30, # 6, p. 709 - 713
16
[ 39856-57-0 ]
[ 13250-46-9 ]
[ 1112982-76-9 ]
Yield
Reaction Conditions
Operation in experiment
100%
at 65 - 70℃; for 2.5 h;
Example 146 (Method N); N-(5-(3-(4-methoxyphenylsulfonamido)phenyl)thiazolo[5,4-b]pyridin-2-yl)acetamide; Step 1. N-(5-bromothiazolor5,4-blpyridin-2-yl)acetamide; 2,6-dibromopyridin-3-amine (4.235 g, 16.8 mmol) was dissolved in acetone and acetyl isothiocyanate(1.85 ml, 21.0 mmol) was added. The flask was fit with a reflux condensor and placed in a preheated oil bath (65 - 70° C) and stirred under nitrogen for 2.5 hours. Then, the reaction was cooled to room temperature, poured into water, and filtered. The solid was washed with water, saturated sodium bicarbonate, and water again, and then collected and dried under high vacuum to afford N-(5- bromothiazolo[5,4-b]pyridin-2-yl)acetamide (5.54 g, Yield > 100percent).MS (ESI pos. ion) m/z: 272 (MH+, 79Br), 274 (MH+, 81Br). Calculated exact mass for C8H6BrN3OS 271 (79Br), 273 (81Br).
With N-Bromosuccinimide; In water; dimethyl sulfoxide; at 0 - 20℃;
Method F; Example F-1; 4-({6-Bromo-2-oxo-1-[2-(trifluoromethyl)benzyl]-2,3-dihydro-1 H-pyrido[2,3- b][1 ,4]thiazin-3-yl}methyl)benzoic Acid; Preparation of F-1-a 2,6-Dibromopyridin-3-amine; As suggested in Majumdar, K. C; Mondal, S. Regioselective synthesis of substituted pyrrolopyridines based on Pd(ll)-mediated cross coupling and base induced heteroannulation. Tet. Letters 2007, 48, 6951-6953, to a solution of 3-aminopyridine (4.75 g, 50.5 mmol) in DMSO (100 ml_) and water (2.5 ml_) at 0C was added portionwise N-bromosuccinimide (18.9 g, 8.91 mmol). The mixture stirred for 24 hours at ambient temperature. A solid was formed, which was filtered off and dried on a glass frit. The solid was then dissolved in ethyl acetate and dried over sodium sulfate and filtered. Solvent was removed under vacuum to afford a reddish brown solid (11.7g, 92%), which was used without further purification and displayed 1H NMR that matched previously reported (Parlow, J. J.; Kurumbail, R. G.; Stegeman, R. A.; Stevens, A. M.; Stallings, W. C; South, M. S. Design, Synthesis, and Crystal Structure of Selective 2-Pyridone Tissue Factor Vila Inhibitors. J. Med. Chem. 2003, 46, 4696-4701 ).
89%
With N-Bromosuccinimide; dimethyl sulfoxide; In water; at 0 - 20℃; for 24h;
500ml round bottom flask, 3-aminopyridine (25.0g, 0.226mol), dimethyl sulfoxide(250ml), water (5ml) were placed in a 0 C N- bromosuccinimide (99.3g, 0.558mol)little by little the scored. The reaction solution was stirred at room temperature for 24 hours and recrystallizedacetonitrile was obtained [Intermediate 2-b]. (59g, 89%)
34%
With N-Bromosuccinimide; In tetrachloromethane; at 0 - 20℃; for 16.3333h;Inert atmosphere;
Synthesis of 2, 6-dibromopyridin-3-amine [0310] To a stirred solution of pyridine-3 -amine (20.0 g, 0.21 mol) in CC14 (200 mL) under argon atmosphere was added N-bromo succinimide (82.87 g, 0.42 mol) portion wise at 0 C for 20 min. The reaction was warmed to RT and stirred for 16 h. After consumption of the starting materials (monitored by TLC), the reaction was concentrated in vacuo to afford the crude material purified by silica gel column chromatography using 5-8% EtOAc:hexanes to afford 2, 6-dibromopyridin-3 -amine (18 g, 34%) as a brown solid. 1H-NMR (CDC13, 400 MHz): delta 7.24 (d, 1H), 6.92 (d, 1H), 4.15 (bs, 2H); TLC: 30% EtOAc:hexane (R 0.35).
34%
With N-Bromosuccinimide; In tetrachloromethane; at 20℃; for 16h;Inert atmosphere;
To a stirred solution of pyridin-3-amine (20.0 g, 0.21 mol) in CCl4 (200 mL) under an argon atmosphere was added N-bromosuccinimide (82.87 g, 0.42 mol) portion wise at 0 C for 20 min. The reaction mixture was warmed to room temperature and stirred for 16 h. After consumption of the starting material (monitored by TLC), the volatile components were evaporated in vacuo. The crude material was purified by silica gel column chromatography using 5-8% EtOAc:hexanes to afford 2, 6-dibromopyridin-3-amine (18 g, 34%) as a brown solid. 1H-NMR (CDCl3, 400 MHz): delta 7.24 (d, 1H), 6.92 (d, 1H), 4.15 (br s, 2H); TLC: 30% EtOAc:hexane (Rf: 0.35).
34%
With N-Bromosuccinimide; In tetrachloromethane; at 0 - 20℃; for 16.3333h;Inert atmosphere;
Synthesis of 2, 6-dibromopyridin-3-amine (0972) To a stirred solution of pyridin-3-amine (20.0 g, 0.21 mol) in CCl4 (200 mL) under an argon atmosphere was added N-bromosuccinimide (82.87 g, 0.42 mol) portion wise at 0 C. for 20 min. The reaction mixture was warmed to room temperature and stirred for 16 h. After consumption of the starting material (monitored by TLC), the volatile components were evaporated in vacuo. The crude material was purified by silica gel column chromatography using 5-8% EtOAc:hexanes to afford 2, 6-dibromopyridin-3-amine (18 g, 34%) as a brown solid. 1H-NMR (CDCl3, 400 MHz): delta 7.24 (d, 1H), 6.92 (d, 1H), 4.15 (br s, 2H); TLC: 30% EtOAc:hexane (Rf: 0.35).
With N-Bromosuccinimide; In water; dimethyl sulfoxide; at 0 - 20℃;
NBS (14.9 g, 84 mmol) was added portion wise to a solution of compound 3- aminopyridine (14.9 g, 84 mmol) in DMSO (80 mL) and water (20 mL) at OC, and the reaction was stirred at RT for 3 hours. The mixture was poured into ice-water (250 mL) and stirred for 30 minutes. The precipitate was collected and dried to yield a solid (7.0 g). MS (ESI) m/e (M+HH): 250. 1H NMR (DMSO): delta 7.28 (d, J=7.6 Hz, 1H), 7.03 (d, J=7.6 Hz, 1H), 5.69 (s, 2H).
7 g
With N-Bromosuccinimide; In water; dimethyl sulfoxide; at 0 - 25℃; for 3h;
NBS (14.9 g, 84 mmol) was added portion wise to a solution of compound 3-aminopyridine (14.9 g, 84 mmol) in DMSO (80 mL) and water (20 mL) at 0 C., and the reaction was stirred at RT for 3 hours. The mixture was poured into ice-water (250 mL) and stirred for 30 minutes. The precipitate was collected and dried to yield a solid (7.0 g). MS (ESI) m/e (M+H+): 250. 1H NMR (DMSO): delta 7.28 (d, J=7.6 Hz, 1H), 7.03 (d, J=7.6 Hz, 1H), 5.69 (s, 2H).
Preparation of F-1-b; 6-Bromo-1 H-pyrido[2,3-b][1 ,4]thiazin-2(3H)-one; Similar to that described in Dunn, A. D.; Norrie, R. The synthesis of pyrido[1 ,4]thiazinones. J. Prakt. Chem. 1990, 332, 444-452: 60% sodium hydride (8.33 g, 347 mmol) was taken up in tetrahydrofuran (1 L), and add methylthioglycolate (20 g, 190 mmol) was added. After stirring for 1 h, 2,6-dibromopyhdin-3-amine (40 g, 160 mmol) was added. The reaction mixture was heat to reflux for 18 hours, allowed to cool, and quenched by adding methanol (80 ml_). Solvent was removed under reduced pressure to afford a brown solid residue. The brown solid was washed with hot ethyl acetate (5 x 200 ml_) and filtered. The ethyl acetate mother liquor was concentrated to 15% of original volume. The solid was filtered, then washed with ethyl acetate to afford the titled product (9.Og, 22%). 1H NMR (400 MHz, DMSO-c/6) delta ppm 10.75 (br. s., 1 H) 7.41 (d, J=8.34 Hz, 1 H) 7.18 (d, J=8.34 Hz, 1 H) 3.69 (s, 3 H).
With tert.-butylnitrite; boron trifluoride diethyl etherate; In 1,2-dimethoxyethane; at -10 - -5℃; for 1h;
2,6-Dibromopyridine-3-diazonium Tetrafluoroborate (36); A 500-mL three-neck round-bottomed flask equipped with a magnetic stirrer, nitrogen inlet and addition funnel was purged with nitrogen and charged with <strong>[39856-57-0]2,6-dibromo-3-aminopyridine</strong> (25.0 g, 99.2 mmol) and 1,2-dimethoxyethane (70 mL), and the solution was cooled to -10 C. using an ice/acetone bath. A solution of boron trifluoride-diethyl etherate (21.1 g, 148 mmol) in 70 mL of 1,2-dimethoxyethane was added at such a rate at to maintain the internal reaction temperature below -5 C. After the addition was complete, a solution of tert-butyl nitrite (12.2 g, 118 mmol) in 70 mL of 1,2-dimethoxyethane was added dropwise maintaining the internal reaction temperature below -5 C. The reaction was stirred for a further 1 h at -10 C. After this time the reaction was filtered and the filter cake was washed with hexanes (3×75 mL) and dried at room temperature on air for 24 h, to afford a 98% yield (34.1 g) of 36 as a white solid: mp 130-131 C.; 1H NMR (300 MHz, DMSO-d6) delta7.72 (d, 1H, J=9.6 Hz), 5.66 (d, 1H, J=9.6 Hz).
With copper(l) iodide; triethylamine;bis-triphenylphosphine-palladium(II) chloride; In N,N-dimethyl-formamide; at 20℃;Inert atmosphere;
To a solution of <strong>[39856-57-0]3-amino-2,6-dibromopyridine</strong> (9.41 g, 37.5 mmol), 4- ethynylacetanilide (4.77 g, 30 mmol) and Pd(PPh3)2Cl2 (1.31 g, 1.9 mmol) in a mixture of 150 mL Of Et3N and 50 mL of DMF was added CuI (0.71 g, 0.4 mmol) under N2. The resulting mixture was stirred at RT overnight. The solvent was removed, and the residue was purified by chromatography (8.5 g). MS (ESI) m/e (MH-H+): 331. 1HNMR (DMSO): delta 7.59 (d, J=8.8 Hz, 2H), 7.54 (d, J=8.4 Hz, 2H), 7.21 (d, J=8.8 Hz, 2H), 7.07 (d, J=8.4 Hz, 2H), 2.12 (s, 3H).
8.5 g
With bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide; triethylamine; In N,N-dimethyl-formamide; at 25℃;Inert atmosphere;
To a solution of <strong>[39856-57-0]3-amino-2,6-dibromopyridine</strong> (9.41 g, 37.5 mmol), 4-ethynylacetanilide (4.77 g, 30 mmol) and Pd(PPh3)2Cl2 (1.31 g, 1.9 mmol) in a mixture of 150 mL of Et3N and 50 mL of DMF was added CuI (0.71 g, 0.4 mmol) under N2. The resulting mixture was stirred at RT overnight. The solvent was removed, and the residue was purified by chromatography (8.5 g). MS (ESI) m/e (M+H+): 331. 1HNMR (DMSO): delta 7.59 (d, J=8.8 Hz, 2H), 7.54 (d, J=8.4 Hz, 2H), 7.21 (d, J=8.8 Hz, 2H), 7.07 (d, J=8.4 Hz, 2H), 2.12 (s, 3H).
Benzoyl chloride (1 .9 rnL, 16.7 mmol) was added to a solution of ammonium thiocyanate (1 .45 g, 19.1 mmol) in acetone (21 mL) and the mixture was refiuxed for 15 minutes. 3-Amino~2,6-dibromopyridine (3.0 g, 1 1 .9 mmol, Parlow, J. J.; South, . S. Tetrahedron 2003, 59, 7695 - 7702) in acetone (26 mL) was added to the mixture at 40 and refiuxing was continued for 1 .5 hours. The hot solution was poured over ice (100 mL) and the mixture was stirred for 5 minutes until a precipitate formed, which was collected by filtration and washed with 50% methanol in water (30 mL). To the precipitate was added a 5% sodium hydroxide solution (100 mL) and the suspension was stirred for 2 hours at 60. The mixture was ai lowed to cool down to room temperature over 17 hours while stirring and filtered. The filtrate was washed with diethyl ether then thoroughly extracted with ethyl acetate. The combined extracts were washed with brine, dried over sodium sulphate and evaporated under reduced pressure to yield 3.22 g (83%) 1-(2, 6-dibromopyridin-3-yl)thiourea:1 H NMR (300 MHz, DMSO-cfe) delta = 7.69 (d, 1 H), 8.01 (d, 1 H), 9.40 (s, 1 H) ppm.
With bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide; triethylamine; In N,N-dimethyl-formamide; at 100℃; for 8h;
To a mixture of <strong>[39856-57-0]3-amino-2,6-dibromopyridine</strong> (1.26 g, 5 mmol), CuI (95 mg, 0.1 equiv), PdCl2(PPh3)2 (175 mg, 0.05 equiv) in triethylamine (5 ml) and DMF (10 ml) was added (2-Chlorophenyl)acetylene (0.6 ml, 1 equiv) at room temperature. The mixture was then heated to 100 C. for 8 hours, cooled to room temperature and filtered through a pad of celite. The celite was washed with EtOAc. The filtrate was then washed with sat. LiCl solution and dried over MgSO4. The solvent was removed under reduced pressure and the remaining residue purified on silica gel by flash chromatography (EtOAc/hexane 10%-70%) to yield 6-Bromo-2-(2-chloro-phenylethynyl)-pyridin-3-ylamine (328 mg, 1.07 mmol) as a single isomer in form of a yellow solid.
General procedure: In a microwave vial 1-chloro-3-fluoro-2-iodobenzene (1 g, 3.90 mmol) was dissolved in 9 ml N,N-dimethylformamide (dry) and triethylamine (4.5 ml, 32.4 mmol). Argon was bubbled through the solution for 10 minutes. Next the copper (I) iodide (0.030 mg, 0.156 mmol) and bis(triphenylphosphine)palladium (II) chloride (0.055 g, 0.078 mmol) were added, followed by trimethylsilylacetylene (1.665 ml, 11.70 mmol). The reaction was stirred at 80C for 30 minutes and it was partitioned between brine and heptane, organic layer was washed with brine, dried (Na2SO4), filtered and solvent evaporated in vacuo to afford the desired product (0.7 g, 79% yield) as a yellow oil. Obtained (34% yield) as a solid from <strong>[39856-57-0]2,6-dibromopyridin-3-amine</strong> (Preparation 14a) and ethynylcyclohexane following the experimental procedure as described in Preparation 5a, using thermal conditions instead of microwave irradiation and followed by flash chromatography purification (0% to 100%, hexane - ethyl acetate) and then reverse phase purification using SP1 Purification System. LRMS (m/z): 279, 280 (M+1)+
General procedure: In a microwave vial 1-chloro-3-fluoro-2-iodobenzene (1 g, 3.90 mmol) was dissolved in 9 ml N,N-dimethylformamide (dry) and triethylamine (4.5 ml, 32.4 mmol). Argon was bubbled through the solution for 10 minutes. Next the copper (I) iodide (0.030 mg, 0.156 mmol) and bis(triphenylphosphine)palladium (II) chloride (0.055 g, 0.078 mmol) were added, followed by trimethylsilylacetylene (1.665 ml, 11.70 mmol). The reaction was stirred at 80C for 30 minutes and it was partitioned between brine and heptane, organic layer was washed with brine, dried (Na2SO4), filtered and solvent evaporated in vacuo to afford the desired product (0.7 g, 79% yield) as a yellow oil. LRMS (m/z): 228 (M+1)+ .. Obtained (34% yield) as a solid from <strong>[39856-57-0]2,6-dibromopyridin-3-amine</strong> (Preparation 14a) and 2-ethynyl-1,3-difluorobenzene (Preparation 16b) following the experimental procedure as described in Preparation 5a, using thermal conditions instead of microwave irradiation and followed by flash chromatography using SP1 Purification System (0% to 100% hexane - diethyl ether). LRMS (m/z): 309, 311 (M+1)+.
General procedure: In a microwave vial 1-chloro-3-fluoro-2-iodobenzene (1 g, 3.90 mmol) was dissolved in 9 ml N,N-dimethylformamide (dry) and triethylamine (4.5 ml, 32.4 mmol). Argon was bubbled through the solution for 10 minutes. Next the copper (I) iodide (0.030 mg, 0.156 mmol) and bis(triphenylphosphine)palladium (II) chloride (0.055 g, 0.078 mmol) were added, followed by trimethylsilylacetylene (1.665 ml, 11.70 mmol). The reaction was stirred at 80C for 30 minutes and it was partitioned between brine and heptane, organic layer was washed with brine, dried (Na2SO4), filtered and solvent evaporated in vacuo to afford the desired product (0.7 g, 79% yield) as a yellow oil. LRMS (m/z): 228 (M+1)+ .Obtained (51% yield) as an oil from <strong>[39856-57-0]2,6-dibromopyridin-3-amine</strong> (Preparation 14a) and pent-1-yne following the experimental procedure as described in Preparation 5a, using thermal conditions instead of microwave irradiation and followed by flash chromatography purification (0-100%, hexane - diethyl ether) and then reverse phase chromatography using SP1 Purification System. LRMS (m/z): 239, 241 (M+1)+.
General procedure: In a microwave vial 1-chloro-3-fluoro-2-iodobenzene (1 g, 3.90 mmol) was dissolved in 9 ml N,N-dimethylformamide (dry) and triethylamine (4.5 ml, 32.4 mmol). Argon was bubbled through the solution for 10 minutes. Next the copper (I) iodide (0.030 mg, 0.156 mmol) and bis(triphenylphosphine)palladium (II) chloride (0.055 g, 0.078 mmol) were added, followed by trimethylsilylacetylene (1.665 ml, 11.70 mmol). The reaction was stirred at 80C for 30 minutes and it was partitioned between brine and heptane, organic layer was washed with brine, dried (Na2SO4), filtered and solvent evaporated in vacuo to afford the desired product (0.7 g, 79% yield) as a yellow oil. LRMS (m/z): 228 (M+1)+; Obtained (29% yield) from <strong>[39856-57-0]2,6-dibromopyridin-3-amine</strong> (Preparation 14a) and 1-chloro-2-ethynyl-3-fluorobenzene (Preparation 5) following the experimental procedure as described in Preparation 5a, using thermal conditions instead of microwave irradiation and followed by flash chromatography purification (0-100%, hexane - ethyl acetate). LRMS (m/z): 325, 327 (M+1)+.
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