* 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.
Into a 250-mL round-bottom flask, was placed a solution of 2-bromopyridine-4- carboxylic acid (10 g, 49.50 mmol, 1.00 equiv) in methanol (100 mL), and sulfuric acid (98percent, 5 mL). The resulting solution was stirred overnight at 70 oC then concentrated under vacuum. The residue was dissolved in 200 mL of EtOAc and washed with 3x150 mL of saturated sodium bicarbonate. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. This resulted in 10 g (94percent) of methyl 2-bromopyridine-4- carboxylate as colorless oil.
77%
at 80℃; for 1 h;
A solution of 2-bromoisonicotinic acid (5.00 g, 24.8 mmol) in MeOH (50 mL) was treated with sulfuric acid (0.50 mL, 9.4 mmol) and the reaction mixture was stirred at 80 C for 1 hour. The mixture was returned to room temperature and stirred for a further 96 hours before heating to 80 C and stirring for 24 hours. The reaction mixture was cooled to room temperature, and the volatiles were removed in vacuo. An aqueous NaOH solution (2 M, -50 mL) was added to the residue and the aqueous was extracted with EtOAc (3 * 50 mL). The organic layers were combined, washed with brine, dried (MgS04) and the solvent removed in vacuo to give the title compound as a yellow oil (4.14 g, 77percent). LCMS-B: rt 3.55 min; m/z 216 [Μ+Η for /9Br. 218 [M+H]+ for 81 Br; 1H NMR (400 MHz, CDCb) δ 8.52 (dd, J = 5.0, 0.8 Hz, 1 H), 8.04 (t, J = 1.2 Hz. 1 H), 7.80 (dd, J = 5.0, 1.4 Hz, 1 H), 3.96 (s, 3H).
75%
With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃; Cooling with ice
To an ice cooled solution of 2-bromoisonicotinic acid (73 g, 0.361 mol) in dichloromethane (500 mL) and methanol (35 g, 1.08 mol) was added 1-ethyl-3-[3-(dimethylamino)propyl]carbodiimide hydrochloride (67 g, 0.434 mol) by portions. The mixture was stirred at ambient temperature overnight. Then 120 g silica gel was added and the solvent evaporated. The residue was purified by flash chromatography, eluting with 5percent ethyl acetate in petroleum ether to afford 58 g (75percent) of methyl 2-bromoisonicotinate as a white solid.
75%
With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃;
To an ice cooled solution of 2-bromoisonicotinic acid (73 g, 0.361 mol) in dichloromethane (500 mL) and methanol (35 g, 1.08mol) was added 1-ethyl-3-[3-(dimethylamino)propyl]carbodiimide hydrochloride (67g, 0.434mol) by portions. The mixture was stirred at ambient temperature overnight. Then 120g silica gel was added and the solvent evaporated. The residue was purified by flashchromatography, eluting with 5percent ethyl acetate in petroleum ether to afford 58 g (75percent) of methyl 2-bromoisonicotinate as a white solid.
Stage #1: With potassium phosphate In acetone at 20℃; for 0.5 h; Stage #2: for 2 h; Reflux
A mixture of 2-bromoisonicotinic acid, 2, (0.200 g, 0.99 mmol) in acetone and K3PO4 (0.290 g, 1.09 mmol) was stirred for 30 min at room temperature. When the time was over CH3I (0,155 g, 1.09 mmol) was added and the mixture refluxed for 2 h. Finally the mixture was cooled and left over ice, and the product extracted with CHCl3. The organic phase was dried with Na2SO4, and purified by silica gel chromatography with CHCl3 as mobile phase. The contents of the organic phase were removed in vacuo to obtain methyl 2-bromoisonicotinate with 82percent yield. FT-IR (KBr) ν = 3089 (str. C-H sp3), 2955 (str. C-H sp2), 1722 (str. C=O), 1588 (str. C=C aromatic), 1546 (str. C=N), 670 (str. C-Br) cm-1. 1H NMR (400 MHz, CDCl3, ppm) δ 8.36 (d, J = 5.1 Hz, 1H), 7.85 (s, 1H), 7.65 (d, J = 5.0 Hz, 1H), 3.82 (s, 3H).
80%
With caesium carbonate In N,N-dimethyl-formamide at 20℃; for 15 h;
2-Bromo isonicotinic acid (20.2 g, 100 mmol) was dissolved in DMF (500 mE) at ambient temperature. Cs2CO3 (32.6 g, 100 mmol) was added in one portion, followed by Mel (6.3 mE, 100 mmol). The mixture was stirred at ambient temperature for 15 h, followed by the addition of water (500 mE). The mixture was extracted with EtOAc (500 mE). The organic layer was washed with water (500 mE), brine (500 mE) and then dried over Na2SO4. The organic layer was then filtrated and concentrated to give compound DD as a white solid in 80percent yield (17.4 g, 80.5 mmol). EC-MS: [M+H] 217.0 (C7H5BrNO2+H, calc: 216.1). Compound DD was used directly without further purification.
Reference：
[1] Journal of the American Chemical Society, 1953, vol. 75, p. 1933,1934
[2] Journal of Medicinal Chemistry, 1997, vol. 40, # 18, p. 2866 - 2875
[3] Patent: US2004/102472, 2004, A1, . Location in patent: Page 35
4
[ 66572-56-3 ]
[ 98-80-6 ]
[ 55240-51-2 ]
Yield
Reaction Conditions
Operation in experiment
57%
Stage #1: With tetrakis(triphenylphosphine) palladium(0) In 1,2-dimethoxyethane for 0.25 h; Inert atmosphere Stage #2: With potassium carbonate In 1,2-dimethoxyethane at 95℃; for 18 h; Inert atmosphere
2-bromoisonicotinic acid (0.210 g, 1.040 mmol) was dissolved in degassed DME (Volume: 8 ml) under nitrogen. Tetrakis(triphenylphosphine)palladium(0) (0.060 g, 0.052 mmol) was added, the resulting reaction mixture was stirred for 15 min. Then aqueous potassium carbonate (4.16 ml, 8.32 mmol) and phenylboronic acid (0.171 g, 1.403 mmol) were added subsequently. The resulting RM was refluxed at 95° C. for 18 h and then cooled to rt. After filtration over celite the reaction mixture was acidified to pH 3-4 and the white precipitate was filtered off and washed with water This resulted in a white powder after recrystallization from 2-methoxyethanol. Yield: 0.106 g, 57percent. 1H NMR (400 MHz, DMSO-d6): δ 7.44-7.60 (m, 3H), 7.71-7.86 (dd, J=4.9, 1.5 Hz, 1H), 8.05-8.19 (m, 2H), 8.23-8.35 (t, J=1.2 Hz, 1H), 8.79-8.93 (dd, J=5.1, 0.8 Hz, 1H), 13.56-13.97 (s, 1H). UPLC I (ESI) Rt 1.37 min, m/z 200.5 [M+H]+ (92percent).
47%
With potassium carbonate In waterReflux
To a flask containing 237 mg (1.18 mmol) of 2-bromopyridine-4-carboxylic acid, 213 mg ( 1.75 mmol) of phenylboronic acid, and 26 mg (0.12 mmol) of Pd(OAc)2 was added a large excess of K2CO3 (1627 mg, 1 1.79 mmol) in 20 mL H20. The solution was refluxed overnight to produce a dark black suspension that was filtered to yield a dark black filtrate, which was then acidified to a pH of 4 using 2M HC1 to precipitate 1 10 mg of a white solid (yield = 47percent). NMR (DMSO-d6): δ 7.50 (m, 3H), 7.77 (dd, 1H, J = 5 Hz, \\l = lHz), 8.12 (d, 2H, J = 5 Hz), 8.28 (s, 1H), 8.85 (d, 1H, 3 J = 5 Hz), 13.85 (vbr, 1H)
To a stirred solution of 29.0 g (69 mmol) 2-bromo-4-methylpyridine in 150 mL concentrated sulfuric acid was added portionwise 67.9 g (231 mmol) potassium dichromate. The reaction mixture was cooled with an ice bath so that the temperature stayed between 20-50° C. After the addition was complete, stirring was continued at room temperature for a further 2 hours. The reaction mixture was then poured slowly onto 2 L ice-water and the mixture stirred for 1 hour at room temperature. The resulting crystals were collected by filtration, washed with water until the washings were colorless, and dried in vacuo to afford 30.0 g (88percent) of 2-bromoisonicotinic acid.
88%
at 20℃; for 3 h;
Acid Preparation 13: 2-(1H-pyrazol-3-yl)isonicotinic acid To a stirred solution of 29.0 g (69 mmol) 2-bromo-4-methylpyridine in 150 mL concentrated sulfuric acid was added portionwise 67.9 g (231 mmol) potassium dichromate. The reaction mixture was cooled with an ice bath so that thetemperature stayed between 20-50 °C. After the addition was complete, stirring was continued at room temperature for a further 2 hours. The reaction mixture was then poured slowly onto 2 L ice-water and the mixture stirred for 1 hour at room temperature. The resulting crystals were collected by filtration, washed with water until the washings were colorless, and dried in vacuo to afford 30.0 g (88percent) of 2-bromoisonicotinic acid.
47%
Stage #1: With potassium permanganate In pyridine; water at 95℃; for 96 h; Stage #2: With hydrogenchloride In water
To a mixture of 2-bromo-4-picoline (300 g, 1.74 mol) in pyridine/water (1 L each) at 95° C. was added KMnO4 (200 g) dissolved in water (IL). Further, added KMnO4 (2 Kg) in portions (app. 20 mg each time) over a period of 4 days. The reaction mixture was cooled to RT and filtered off the solid MnO2. The filtrate was evaporated completely under reduce pressure and acidified with 6N HCl. The solid product obtained was filtered, washed with water and dried to give 2-bromoisonicotinic acid (166 g, 47percent).
36%
With potassium permanganate In water at 110℃; for 5 h;
A mixture of 2-bromo-4-methylpiridine, 1, (9.27 g, 54 mmol) in 490 mL of water, and of KMnO4 (16 g, 11 mmol) in 250 mL of water were stirred for 5 h at 110 °C. The resulting mixture was filtered and the filtrate was reduced to 1/3 and acidified with HCl until pH 3. The white precipitated obtained was filtered and dried, Yield: 36percent of 2-bromoisonicotinic acid. FT-IR (KBr) ν, 3100-2350 (stretching O-H), 1710 (str. C=O), 1597 (str. C=C), 1546 (str. C=N), 1285 (str. C-O), 667 (str. C-Br) cm-1. 1H NMR (400 MHz, DMSO-d6, ppm) δ, 8.58 (dd, J = 5.0, 0.8 Hz), 7.95 (dd, J = 1.4, 0.8 Hz), 7.84 (dd, J = 5.0, 1.4 Hz).
34%
Stage #1: for 5 h; Heating / reflux Stage #2: With hydrogenchloride In water
Example 20; Synthesis of 2-bromoisonicotinic acid; [0119] 2-Bromo-4-methylpyridine (10 g, 0.058 moles) and potassium permanganate (18.3 g, 0.115 moles) was combined in water (500 ml). The mixture was refluxed for five hours, filtered through celite and reduced in volume to-400 ml. The dark brown solution was acidified with hydrochloric acid (10percent) to pH-3. The resulting white precipitate was filtered and rinsed with ethyl ether. 2-Bromoisonicotinic acid was isolated in 34 percent yield. 1H NMR (DMSO-d6) 7.8 (1H, d), 7.85 (1H, s), 8.5 (1H, d).
20.3%
With potassium permanganate In waterReflux
To 1.84 g ( 1 1.6 mmol) of KMn04 in 10 mL of H20 was added 0.65 mL (5.8 mmol) of 2-bromo-4-methylpyridine via syringe. The solution was refluxed for 1 hr, after which 1.25 equivalents ( 1.15 g; 7.25 mmol) of KMn04 was added. After an additional 2 hr reflux, 1.25 equivalents of KMn04 was added and stirred overnight to produce a dark solution containing a black suspension. After filtration through celite, the clear aqueous layer was washed with 3 x 20 mL of ethyl acetate. The aqueous layer was brought to a pH of 4 using 1M HC1 to precipitate out 237 mg of a white solid (yield = 20.3percent). ESI-MS: m/z, 199.7 (calcd for M+ 199.9) NMR (DMSO-d6): δ 7.84 (dd, 1H, J = 5 Hz, \\l = lHz), 7.96 (s, 1H), 8.59 (d, 1H, J = 5 Hz), 14.02 (vbr, 1H).
88%
With potassium dichromate In sulfuric acid
a 2-Bromo-Isonicotinic Acid To a stirred solution of 29.0 g (1(69 mmol) 2-bromo-4-methylpyridine in 150 ml concentrated sulfuric acid was added portionwise 67.9 g (231 mmol) potassium dichromate and the reaction mixture was cooled with an ice bath so that the temperature stayed between 20-50° C. After the addition was complete, stirring was continued at room temperature for a further 2 h. The reaction mixture was then poured slowly onto 2 l ice-water and the mixture stirred for 1 hour at room temperature. The resulting crystals were collected by filtration, washed with water until the washings were colourless, and dried in vacuo to afford 30.0 g (88percent) 2-bromo-isonicotinic acid as a white crystalline solid. EI-MS m/e (percent): 203 (M{81Br}+, 100), 201 (M{79Br}+, 93).
Reference：
[1] Patent: US2011/111046, 2011, A1, . Location in patent: Page/Page column 17; 18
[2] Patent: WO2011/58473, 2011, A1, . Location in patent: Page/Page column 36; 37
[3] Chemical and Pharmaceutical Bulletin, 1990, vol. 38, # 9, p. 2446 - 2458
[4] Patent: US2008/51397, 2008, A1, . Location in patent: Page/Page column 9; 24
[5] Polyhedron, 2016, vol. 118, p. 159 - 170
[6] Journal of Heterocyclic Chemistry, 1995, vol. 32, # 2, p. 665 - 669
[7] Patent: WO2005/84439, 2005, A1, . Location in patent: Page/Page column 37
[8] Tetrahedron, 2002, vol. 58, # 22, p. 4429 - 4438
[9] Patent: WO2011/32269, 2011, A1, . Location in patent: Page/Page column 33-34
[10] Synthesis, 2003, # 4, p. 551 - 554
[11] Patent: US2005/54654, 2005, A1, . Location in patent: Page/Page column 36
[12] Patent: US2003/134854, 2003, A1,
[13] Patent: WO2006/21801, 2006, A1, . Location in patent: Page/Page column 45
[14] Journal of Labelled Compounds and Radiopharmaceuticals, 2001, vol. 44, p. S451 - S454
6
[ 4926-28-7 ]
[ 1333-82-0 ]
[ 66572-56-3 ]
Reference：
[1] Patent: US4912101, 1990, A,
7
[ 695-34-1 ]
[ 66572-56-3 ]
Reference：
[1] Tetrahedron, 2002, vol. 58, # 22, p. 4429 - 4438
[2] Chemical and Pharmaceutical Bulletin, 1990, vol. 38, # 9, p. 2446 - 2458
[3] Journal of Labelled Compounds and Radiopharmaceuticals, 2001, vol. 44, p. S451 - S454
[4] Patent: US2008/51397, 2008, A1,
8
[ 6313-54-8 ]
[ 66572-56-3 ]
Reference：
[1] Journal of Porphyrins and Phthalocyanines, 2015, vol. 19, # 1-3, p. 344 - 351
9
[ 66572-56-3 ]
[ 89978-52-9 ]
Reference：
[1] Patent: US6251925, 2001, B1,
10
[ 64-17-5 ]
[ 66572-56-3 ]
[ 89978-52-9 ]
Reference：
[1] Inorganic Chemistry, 2017, vol. 56, # 16, p. 9903 - 9912
[2] Tetrahedron, 2002, vol. 58, # 22, p. 4429 - 4438
[3] Journal of Medicinal Chemistry, 1990, vol. 33, # 6, p. 1667 - 1675
Reference：
[1] Chemical and Pharmaceutical Bulletin, 1990, vol. 38, # 9, p. 2446 - 2458
13
[ 66572-56-3 ]
[ 118289-16-0 ]
Yield
Reaction Conditions
Operation in experiment
75.21%
With boron trifluoride diethyl etherate In tetrahydrofuran at 0 - 20℃; for 3 h;
To a solution of 215.1 (2g, 9.9mmol, l .Oeq) in tetrahydrofuran (30mL) at 0°C, boron trifluoride etherate (4.18g, 29.7mmol, 3.0eq) was added dropwise. Reaction mixture was stirred at room temperature for 3h. After completion of reaction, reaction mixture was transferred in ice-water and product was extracted with ethyl acetate. Organic layer was combined, washed with brine solution, dried over sodium sulphate and concentrated under reduced pressure to obtain 1.1 (1.4g, 75.21percent). MS(ES): m/z 189.65 [M]+
Reference：
[1] Patent: WO2018/71794, 2018, A1, . Location in patent: Paragraph 00983; 00984
[2] Chemical and Pharmaceutical Bulletin, 1990, vol. 38, # 9, p. 2446 - 2458
[3] Journal of Medicinal Chemistry, 1997, vol. 40, # 18, p. 2866 - 2875
[4] Patent: US2005/54654, 2005, A1, . Location in patent: Page/Page column 36
[5] Patent: EP2098517, 2009, A1, . Location in patent: Page/Page column 32
In tetrahydrofuran; diethyl ether; at 20℃; for 1h;
To a solution of 2-bromoisonicotinic acid (Chem. Pharm. Bull., 38:2446(1990)) (2.0 g) in tetrahydrofuran (100 ml) was added excess ethereal diazomethane and the resulting mixture was stirred at room temperature for 1 hour. The mixture was evaporated and the product chromatographed on silica gel eluting with a 1:3 mixture of ethyl acetate and hexane to afford the Methyl 2-bromoisonicotinate ester as a colorless liquid.
With potassium dichromate; sulfuric acid; at 20 - 50℃; for 2h;
To a stirred solution of 29.0 g (69 mmol) 2-bromo-4-methylpyridine in 150 mL concentrated sulfuric acid was added portionwise 67.9 g (231 mmol) potassium dichromate. The reaction mixture was cooled with an ice bath so that the temperature stayed between 20-50 C. After the addition was complete, stirring was continued at room temperature for a further 2 hours. The reaction mixture was then poured slowly onto 2 L ice-water and the mixture stirred for 1 hour at room temperature. The resulting crystals were collected by filtration, washed with water until the washings were colorless, and dried in vacuo to afford 30.0 g (88%) of 2-bromoisonicotinic acid.
88%
With potassium dichromate; sulfuric acid; at 20℃; for 3h;
Acid Preparation 13: 2-(1H-pyrazol-3-yl)isonicotinic acid To a stirred solution of 29.0 g (69 mmol) 2-bromo-4-methylpyridine in 150 mL concentrated sulfuric acid was added portionwise 67.9 g (231 mmol) potassium dichromate. The reaction mixture was cooled with an ice bath so that thetemperature stayed between 20-50 C. After the addition was complete, stirring was continued at room temperature for a further 2 hours. The reaction mixture was then poured slowly onto 2 L ice-water and the mixture stirred for 1 hour at room temperature. The resulting crystals were collected by filtration, washed with water until the washings were colorless, and dried in vacuo to afford 30.0 g (88%) of 2-bromoisonicotinic acid.
47%
To a mixture of 2-bromo-4-picoline (300 g, 1.74 mol) in pyridine/water (1 L each) at 95 C. was added KMnO4 (200 g) dissolved in water (IL). Further, added KMnO4 (2 Kg) in portions (app. 20 mg each time) over a period of 4 days. The reaction mixture was cooled to RT and filtered off the solid MnO2. The filtrate was evaporated completely under reduce pressure and acidified with 6N HCl. The solid product obtained was filtered, washed with water and dried to give 2-bromoisonicotinic acid (166 g, 47%).
36%
With potassium permanganate; In water; at 110℃; for 5h;
A mixture of 2-bromo-4-methylpiridine, 1, (9.27 g, 54 mmol) in 490 mL of water, and of KMnO4 (16 g, 11 mmol) in 250 mL of water were stirred for 5 h at 110 C. The resulting mixture was filtered and the filtrate was reduced to 1/3 and acidified with HCl until pH 3. The white precipitated obtained was filtered and dried, Yield: 36% of 2-bromoisonicotinic acid. FT-IR (KBr) nu, 3100-2350 (stretching O-H), 1710 (str. C=O), 1597 (str. C=C), 1546 (str. C=N), 1285 (str. C-O), 667 (str. C-Br) cm-1. 1H NMR (400 MHz, DMSO-d6, ppm) delta, 8.58 (dd, J = 5.0, 0.8 Hz), 7.95 (dd, J = 1.4, 0.8 Hz), 7.84 (dd, J = 5.0, 1.4 Hz).
34%
Example 20; Synthesis of 2-bromoisonicotinic acid; [0119] 2-Bromo-4-methylpyridine (10 g, 0.058 moles) and potassium permanganate (18.3 g, 0.115 moles) was combined in water (500 ml). The mixture was refluxed for five hours, filtered through celite and reduced in volume to-400 ml. The dark brown solution was acidified with hydrochloric acid (10%) to pH-3. The resulting white precipitate was filtered and rinsed with ethyl ether. 2-Bromoisonicotinic acid was isolated in 34 % yield. 1H NMR (DMSO-d6) 7.8 (1H, d), 7.85 (1H, s), 8.5 (1H, d).
20.3%
With potassium permanganate; In water;Reflux;
To 1.84 g ( 1 1.6 mmol) of KMn04 in 10 mL of H20 was added 0.65 mL (5.8 mmol) of 2-bromo-4-methylpyridine via syringe. The solution was refluxed for 1 hr, after which 1.25 equivalents ( 1.15 g; 7.25 mmol) of KMn04 was added. After an additional 2 hr reflux, 1.25 equivalents of KMn04 was added and stirred overnight to produce a dark solution containing a black suspension. After filtration through celite, the clear aqueous layer was washed with 3 x 20 mL of ethyl acetate. The aqueous layer was brought to a pH of 4 using 1M HC1 to precipitate out 237 mg of a white solid (yield = 20.3%). ESI-MS: m/z, 199.7 (calcd for M+ 199.9) NMR (DMSO-d6): delta 7.84 (dd, 1H, J = 5 Hz, l = lHz), 7.96 (s, 1H), 8.59 (d, 1H, J = 5 Hz), 14.02 (vbr, 1H).
b) Production of 2-Bromo-isonicotinic Acid 160 g (0.93 mol) of 2-bromo-4-methyl-pyridine is added in drops to 152 g (0.96 mol) of potassium permanganate in 41 of water. Then, it is stirred under reflux for one hour before 152 g (0.96 mol) of potassium permanganate is added once more. After two additional hours of stirring under reflux, it is suctioned off in a hot state over Celite and washed with water. The aqueous phase is shaken out three times with dichloromethane. The aqueous phase is concentrated by evaporation to one-half its original volume, and the pH is set at 2 with concentrated hydrochloric acid. The precipitated solid is suctioned off and dried at 70 C. in a vacuum. 56.5 g of white solid product accumulates.
30.0 g (88%)
With potassium dichromate; In sulfuric acid;
a 2-Bromo-Isonicotinic Acid To a stirred solution of 29.0 g (1(69 mmol) 2-bromo-4-methylpyridine in 150 ml concentrated sulfuric acid was added portionwise 67.9 g (231 mmol) potassium dichromate and the reaction mixture was cooled with an ice bath so that the temperature stayed between 20-50 C. After the addition was complete, stirring was continued at room temperature for a further 2 h. The reaction mixture was then poured slowly onto 2 l ice-water and the mixture stirred for 1 hour at room temperature. The resulting crystals were collected by filtration, washed with water until the washings were colourless, and dried in vacuo to afford 30.0 g (88%) 2-bromo-isonicotinic acid as a white crystalline solid. EI-MS m/e (%): 203 (M{81Br}+, 100), 201 (M{79Br}+, 93).
With potassium permanganate; In water; for 2h;Heating / reflux;
To 2-bromo-4-methyl-pyridine in water was added 1 equivalent of potassium permanganate. The solution was heated up at reflux for 2 hours. The reaction was followed and potassium permanganate was added until no starting material remained. After cooling down, the solution was filtered and the solution was acidified until pH=3. The precipitate was filtered and dried.
With boron trifluoride diethyl etherate; In tetrahydrofuran; at 0 - 20℃; for 3h;
To a solution of 215.1 (2g, 9.9mmol, l .Oeq) in tetrahydrofuran (30mL) at 0C, boron trifluoride etherate (4.18g, 29.7mmol, 3.0eq) was added dropwise. Reaction mixture was stirred at room temperature for 3h. After completion of reaction, reaction mixture was transferred in ice-water and product was extracted with ethyl acetate. Organic layer was combined, washed with brine solution, dried over sodium sulphate and concentrated under reduced pressure to obtain 1.1 (1.4g, 75.21%). MS(ES): m/z 189.65 [M]+
Production of 2-Bromo-4-hydroxymethyl-pyridine 30.2 ml (295 mmol) of triethylamine is added to 56.5 g (280 mmol) of <strong>[66572-56-3]2-bromo-isonicotinic acid</strong> in 1.2 1 of THF. Then, it is cooled to -10 C. and mixed drop by drop with 38.2 ml (295 mmol) of isobutyl chloroformate. After stirring has been continued for one hour at -10 C., it is cooled to -70 C. and mixed drop by drop with 590 ml (590 mmol) of LiAlH4 solution (1 M in THF). After stirring is continued for one hour at -70 C., it is allowed to reach -40 C. 600 ml of 50% acetic acid is added. It is stirred overnight at room temperature. The insoluble components are suctioned off, and the filtrate is concentrated by evaporation. The residue is purified on silica gel with hexane and hexane/ethyl acetate 1:1. 28.0 g of white solidifying oil accumulates.
1) Production of (2-bromopyridin-4-yl)methanol To a solution of <strong>[66572-56-3]2-bromoisonicotinic acid</strong> (678 mg) in tetrahydrofuran (30 ml), 8.4 ml of borane-tetrahydrofuran complex (1.17M tetrahydrofuran solution) was added, and the reaction solution was stirred overnight at room temperature. To the reaction solution was added 7.9 ml of 1N aqueous sodium hydroxide, and the mixture was stirred for 2 hours. The reaction solution was diluted with a saturated aqueous sodium chloride solution, extracted with diethyl ether, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue obtained was purified by silica gel column chromatography (eluent: chloroform/(chloroform/methanol (9:1)) (100:0-0:100)) to afford the title compound as a white crystal.
A mixture of <strong>[66572-56-3]2-bromoisonicotinic acid</strong> (40 g, 0.198 mol) and piperidine (200 mL) was refluxed at 105 C. for 24 h under N2 atmosphere. The excess piperidine was distilled under vacuum and crude residue was diluted with water (500 mL) and extracted with chloroform (3×250 mL), washed with brine and dried. The solvent was removed under vacuum to give 2-Piperidin-1-yl-isonicotinic acid (35 g, 85%) as a solid.
Example 21; Synthesis of 2-Bromo-4- . pyridine; [0120] 2-Bromoisonicotinic acid (2.02 g, 0. 010 moles), such as that prepared in Example 23, was dissolved in methylene chloride (20 ml) carbonyldiimidazole (1.8 g, 0.011 moles) was added and the reaction mixture stirred at room temperature for two hours. N, O-Dimethylhydroxylamine hydrochloride (1. 5 g, 0.015 moles) was added in one portion. After stirring overnight the reaction was quenched with 0. 1N NaOH (10 ml), added water and dichloromethane. Separated the layers and extracted the aqueous with dichloromethane (50 ml). The combined organic portion was washed with brine, dried over magnesium sulfate, filtered and stripped to give 2.4 g (98 % yield) of 2-bromo-4- (N- methyl-N-methoxycarboxamide) pyridine. 1H NMR (CDCl3) 3.42 (3H, s), 3.58 (3H, s), 7.15 (1H, d), 7.77 (1H, s), 8.57 (1H, d).
88.5%
To a solution of <strong>[66572-56-3]2-bromoisonicotinic acid</strong> (20 g, 100 mmol) in dichloromethane (200 mL) was added N-ethyl-N-isopropylpropan-2-amine (38.7 g, 300 mmol) and 2-(3H- [l,2,3]triazolo[4,5-b]pyridin-3-yl)-l,l,3,3-tetramethyluronium hexafluorophosphate(V) (76 g, 200 mmol). The reaction was stirred for 30 min at room temperature before addition of Nu,Omicron- dimethylhydroxylamine hydrochloride (19 g, 200 mmol). The mixture was stirred at room temperature for 18 hr. The solution was then partitioned between dichloromethane and water, the organic layer was separated, dried over magnesium sulfate, and concentrated. The crude residue was purified by silica gel chromatography (petroleum ether: ethyl acetate= 3: 1) to give 2-bromo-N-methoxy-N-methylisonicotinamide as a brown oil (21.6 g, 88.5 %).
86%
Preparation of Example 4 (S)-N-((S)-Cyclohexyl-2-{(S)-2-{2-[2,3-dihydro-indol-1-yl)-pyridin-4-yl]-pyrrolidin-1-yl}-pyrrolidin-1-yl)-2-oxo-ethyl)-2-methylamino-propionamide 2-Bromo-N-methoxy-N-methyl-isonicotinamide (1)To a solution of 2-bromo-pyridine-4-carboxylic acid (11.83 g, 58.56 mmol) in DMSO (100 mL) are added HOBt (9.49 g, 70.30 mmol) and HBTU (26.70 g, 70.30 mmol). The mixture is stirred at room temperature for 20 min, then N,O-dimethylhydroxylamine HCl (6.28 g, 64.41 mmol) and diisopropylethylamine (22.72 g, 175.68 mmol) are added to the mixture. After stirring at room temperature for 3 h, the reaction mixture is diluted with water and extracted with EtOAc. The combined organic layers are washed with water, sat. NaHCO3, brine, dried over Na2SO4, filtered and concentrated down. The crude product is purified by flash chromatography on silica gel (EtOAc/Hexane: 10%40%) to give 2-Bromo-N-methoxy-N-methyl-isonicotinamide (12.4 g, 86%) as a white solid. M/Z=245.0
85%
With N-ethyl-N,N-diisopropylamine; HATU; In dichloromethane; at 20℃; for 3h;Inert atmosphere;
To a solution of 2-Bromopyridine-4-carboxylic acid (CAS no. 66572-56-3, 6.1 g, 30 mmol, 1.0 eq) in dichloromethane (100 mL) were added Nu,Omicron-dimethylhydroxylamine hydrochloride (CAS No. 6638-79-5, 3.5 g, 36 mmol, 1.2 eq), HATU (17.0 g, 45 mmol, 1.5 eq) and DIEA (12.4 mL, 75 mmol, 2.5 eq). The mixture was stirred at room temperature for 16 h under N2 atmosphere. The mixture was diluted with dichloromethane (200 mL) and washed with water (80 mL x 3). The organic layer was dried over anhydrous sodium sulfate, filtrated and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE/EA = 2/1) to give 2-bromo-N-methoxy-N- methylisonicotinamide (6.3 g, Y: 85%) as colorless oil. ESI-MS (M+l)+: 247.0, 245.0.
75%
With benzotriazol-1-ol; N-(3-dimethylaminopropyl)-N-ethylcarbodiimide; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 0 - 20℃; for 1h;Product distribution / selectivity;
Example 25 (method 2)To <strong>[66572-56-3]2-bromoisonicotinic acid</strong>, (25.2 g, 124 mmol), HOBt (20.2 g, 149 mmol) and 0,N- dimethyl-hydroxylamine hydrochloride (14.6 g, 149 mmol) in DMF (150 ml.) at O0C, was added diisopropylethyalamine (26.0 ml_, 149 mmol). EDC (28.6 g, 149 mmol) was then added and the mixture stirred at room temperature for 1 hour. The mixture was then poured into ice cold water (500 ml.) and the resulting solution extracted with EtOAc (3 x 150 ml_). The combined organic fraction was were washed with water (2 x 200 ml_), 0.5 M HCI (200 ml_), sat. NaHCO3 solution, brine (200 ml.) and then dried (MgSO4). The solvent was evaporated in vacuo to give 2-bromo-Lambda/-methoxy-Lambda/-methyl- isonicotinamide (23 g, 75%)
70%
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In dichloromethane; at 20℃; for 16h;
Example 1-88 4-(2-Bromo-4-pyridinyl)-7V-(3-methylphenyl)-l,3-thiazol-2-amine (154). [0360] 2-Bromo-7V-methyl-7V-(methyloxy)-4-pyridinecarboxamide (151). Et3N(14.9 mL, 107 mmol) was added to a stirred suspension of 2-bromo-4- pyridinecarboxylic acid (5.40 g, 26.7 mmol), EDCI (5.64 g, 29.4 mmol), HOBT (3.97 g, 29.4 mmol) and MeNHOMe-HCl (3.91 g, 40.0 mmol) in dry DCM (100 mL), and the mixture was stirred at 20 0C for 16 h. The resulting solution was diluted with DCM (200 mL) and washed with water (2 x 50 mL), washed with brine (50 mL), dried and the solvent evaporated. The residue was purified by column chromatography, eluting with 50% EtO Ac/pet, ether, to give amide 151 (4.56 g, 70%) as an oil: 1H NMR (CDCl3) delta 8.45 (d, J= 5.0 Hz, 1 H, H-6), 7.72 (br s, 1 H, H-3), 7.48 (dd, J= 5.0, 1.3 Hz, 1 H, H-5), 3.56 (s, 3 H, OCH3), 3.67 (s, 3 H, NCH3); MS m/z 245.3/247.3 (MH+, 100%).
59.64%
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In dichloromethane; at 20℃; for 3h;
To a suspension of <strong>[66572-56-3]2-bromo-4-pyridinecarboxylic acid</strong> (23.5g, [116MMOL)] in [CH2CI2] (600mL) were added under nitrogen HOBT (17.3g, [128MOL),] [EDCI] (24.5g, [128MOL),] [TRIETHYLAMINE (46. 85G, 464MMOL)] and N, O-dimethylhydroxylamine hydrochloride [(17.] 02g, 175mmol. The reaction mixture was stirred at room temperature for 3h and then partitioned between water and [CH2CI2.] The organic phase was dried over [NA2SO4,] filtered and evaporated under reduced pressure to afford the title compound as [A] white [SOLID (17G,] 59.64 %); [APCI MS] m/z 246 (MH+).
59.64%
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In dichloromethane; at 20℃; for 3h;
To a suspension of <strong>[66572-56-3]2-bromo-4-pyridinecarboxylic acid</strong> (23.5g, 116mmol) in [CH2CI2] (600mL) were added under nitrogen HOBT (17.3g, [128MOL),] EDCI (24. [5G,] [128MOL),] triethylamine (46.85g, [464MOL)] and N, O-dimethylhydroxylamine hydrochloride (17.02g, [175MMOL).] The reaction mixture was stirred at room temperature for 3 hours and then partitioned between water and CH2CI2. The organic phase was dried over [NA2SO4,] filtered and evaporated under reduced pressure to afford the title compound as a white solid (17g, 59.64 %); [[APCI] MS] m/z 246 [(MH+).]
57%
To a solution of <strong>[66572-56-3]2-bromoisonicotinic acid</strong> (40.4 g, 0.2 mol) in 200 mL of dry DMF was added CDI (32.4 g, 0.2 mol) in portions. After stirring for 30 min under N2 atmosphere Nu,Omicron-methylhydroxylamine hydrochloride (19.5 g, 0.2 mol) was added and the mixture was stirred at room temperature overnight under N2 atmosphere. The mixture was diluted with water and extracted with EtOAc. The combined organic phase was washed with water and brine, dried over Na2S04, filtered and concentrated in vacuo to afford a crude residue, which was purified by flash chromatography on silica gel to give compound 2-bromo-N-methoxy-N-methylisonicotinamide (28 g, yield 57%). 1HNMR (400MHz, DMSO-d6): delta= 8.50 (d, / = 4.8 Hz, 1 H), 7.79 (s, 1 H), 7.59 (d, / = 4.8 Hz, 1 H), 3.56 (s, 3 H), 3.27 (s, 3 H). MS (ESI): M/Z (M/M+2 = 1/1) 244.7/246.7.
57%
With 1,1'-carbonyldiimidazole; In N,N-dimethyl-formamide;
(a) 2-bromo-N-methoxy-N-methylisonicotinamide To a solution of <strong>[66572-56-3]2-bromoisonicotinic acid</strong> (40.4 g, 0.2 mol) in 200 mL of dry DMF was added CDI (32.4 g, 0.2 mol) in portions. After stirring for 30 min under N2 atmosphere N,O-methylhydroxylamine hydrochloride (19.5 g, 0.2 mol) was added and the mixture was stirred at room temperature overnight under N2 atmosphere. The mixture was diluted with water and extracted with EtOAc. The combined organic phase was washed with water and brine, dried over Na2SO4, filtered and concentrated in vacuo to afford a crude residue, which was purified by flash chromatography on silica gel to give compound 2-bromo-N-methoxy-N-methylisonicotinamide (28 g, yield 57%). 1HNMR (400 MHz, DMSO-d6): delta=8.50 (d, J=4.8 Hz, 1H), 7.79 (s, 1H), 7.59 (d, J=4.8 Hz, 1H), 3.56 (s, 3H), 3.27 (s, 3H). MS (ESI): M/Z (M/M+2=1/1) 244.7/246.7.
57%
To a solution of <strong>[66572-56-3]2-bromoisonicotinic acid</strong> (40.4 g, 0.2 mol) in 200 mL of dry DMF was added CDI (32.4 g, 0.2 mol) in portions. After stirring for 30 min under N2 atmosphere Nu,Omicron-methylhydroxylamine hydrochloride (19.5 g, 0.2 mol) was added and the mixture was stirred at room temperature overnight under N2 atmosphere. The mixture was diluted with water and extracted with EtOAc. The combined organic phase was washed with water and brine, dried over Na2S04, filtered and concentrated in vacuo to afford a crude residue, which was purified by flash chromatography on silica gel to give compound 2-bromo-N-methoxy-N-methylisonicotinamide (28 g, yield 57%). 1HNMR (400MHz, DMSO-d6): delta= 8.50 (d, J = 4.8 Hz, 1 H), 7.79 (s, 1 H), 7.59 (d, J = 4.8 Hz, 1 H), 3.56 (s, 3 H), 3.27 (s, 3 H). MS (ESI): M/Z (M/M+2 = 1/1) 244.7/246.7
With pyridine; N-(3-dimethylaminopropyl)-N-ethylcarbodiimide; In tetrahydrofuran; at 20℃; for 40h;
6.6 2-Bromo-N-methoxy-N-methylisonicotinamideIn a round-bottomed flask, 2.0 g of <strong>[66572-56-3]2-bromoisonicotinic acid</strong>, 1.1 g of N,O-dimethylhydroxylamine hydrochloride, 3.8 g of 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide and 3.2 ml of pyridine are placed in 50 ml of tetrahydrofuran. The mixture is stirred at ambient temperature for 40 h. The mixture is concentrated, and the residue is taken up in 50 ml of ethyl acetate and 50 ml of water. The organic phase is washed with 50 ml of a 1N solution of sodium hydroxide and 50 ml of a saturated solution of sodium chloride, dried over magnesium sulphate and then concentrated under reduced pressure. 2.0 g of compound are obtained.1H NMR (CDCl3, delta in ppm): 3.3 (s, 3H); 3.5 (s, 3H); 7.4 (d, 1H); 7.65 (s, 1H); 8.4 (d, 1H). M+H=245.
With 1-hydroxybenzotriazol-hydrate; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In dichloromethane; at 20℃; for 3h;
To a suspension of <strong>[66572-56-3]2-bromo-4-pyridinecarboxylic acid</strong> (23.5g, [116MMOL)] in [CH2CI2] (600mL) were added under nitrogen HOBT [(17.] 3g, [128MOL),] [EDCI] (24.5g, [128MMOL),] triethylamine (46.85g, [464MMOL)] and N, [O-DIMETHYLHYDROXYLAMINE] hydrochloride (17.02g, [175MMOL).] The reaction mixture was stirred at room temperature for 3h and then partitioned between water and [CHSCTS.] The organic phase was dried over [NA2SO4,] filtered and evaporated under reduced pressure to afford the title compound as a white solid [(17G,] 59 %); [[APCI] MS] m/z 246 (MH+).
2-bromoisonicotinic acid (0.210 g, 1.040 mmol) was dissolved in degassed DME (Volume: 8 ml) under nitrogen. Tetrakis(triphenylphosphine)palladium(0) (0.060 g, 0.052 mmol) was added, the resulting reaction mixture was stirred for 15 min. Then aqueous potassium carbonate (4.16 ml, 8.32 mmol) and phenylboronic acid (0.171 g, 1.403 mmol) were added subsequently. The resulting RM was refluxed at 95 C. for 18 h and then cooled to rt. After filtration over celite the reaction mixture was acidified to pH 3-4 and the white precipitate was filtered off and washed with water This resulted in a white powder after recrystallization from 2-methoxyethanol. Yield: 0.106 g, 57%. 1H NMR (400 MHz, DMSO-d6): delta 7.44-7.60 (m, 3H), 7.71-7.86 (dd, J=4.9, 1.5 Hz, 1H), 8.05-8.19 (m, 2H), 8.23-8.35 (t, J=1.2 Hz, 1H), 8.79-8.93 (dd, J=5.1, 0.8 Hz, 1H), 13.56-13.97 (s, 1H). UPLC I (ESI) Rt 1.37 min, m/z 200.5 [M+H]+ (92%).
47%
With potassium carbonate;palladium diacetate; In water;Reflux;
To a flask containing 237 mg (1.18 mmol) of 2-bromopyridine-4-carboxylic acid, 213 mg ( 1.75 mmol) of phenylboronic acid, and 26 mg (0.12 mmol) of Pd(OAc)2 was added a large excess of K2CO3 (1627 mg, 1 1.79 mmol) in 20 mL H20. The solution was refluxed overnight to produce a dark black suspension that was filtered to yield a dark black filtrate, which was then acidified to a pH of 4 using 2M HC1 to precipitate 1 10 mg of a white solid (yield = 47%). NMR (DMSO-d6): delta 7.50 (m, 3H), 7.77 (dd, 1H, J = 5 Hz, l = lHz), 8.12 (d, 2H, J = 5 Hz), 8.28 (s, 1H), 8.85 (d, 1H, 3 J = 5 Hz), 13.85 (vbr, 1H)
A mixture of 2-bromo-4-pyridinecarboxylic acid (1.1 g, 5.45 mmol), phenylboronic acid (1.3 g, 10.9 mmol), 2.0 M potassium phosphate (aq) (8.2 mL, 16.34 mmol), and DMF (10 mL) in a 20 mL microwave tube was degassed under vacuum/Ar. A catalytic amount of tetrakis(triphenylphosphine)palladium(0) was added to the tube, the mixture was degassed again, the tube was sealed, and the reaction was heated at 150 C. in the microwave for 30 min. The reaction mixture was filtered, the filtrate was concentrated in-vacuo, and the residue was dissolved in water (10 mL). The mixture was acidified to pH=6 with the addition of 1.0 N HCl, and the resulting precipitate was collected by filtration, rinsed with two portions of ice-cold water, and air dried to yield 575 mg of 2-phenylisonicotinic acid as an off-white solid. MS (ES+)=200 (M+H+).
Preparation H1: Synthesis of lithium 2-phenylisonicotinate, N-oxide Preparation H1, Step 1: A mixture of 2-bromo-4-pyridinecarboxylic acid (1.1 g, 5.45 mmol), phenylboronic acid (1.3 g, 10.9 mmol), 2.0 M potassium phosphate (aq) (8.2 mL, 16.34 mmol), and DMF (10 mL) in a 20 mL microwave tube was degassed under vacuum/Ar. A catalytic amount of tetrakis(triphenylphosphine)palladium(0) was added to the tube, the mixture was degassed again, the tube was sealed, and the reaction was heated at 150 C. in the microwave for 30 min. The reaction mixture was filtered, the filtrate was concentrated in-vacuo, and the residue was dissolved in water (10 mL). The mixture was acidified to pH=6 with the addition of 1.0 N HCl, and the resulting precipitate was collected by filtration, rinsed with two portions of ice-cold water, and air dried to yield 575 mg of 2-phenylisonicotinic acid as an off-white solid. MS (ES+)=200 (M+H+).
With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In 1,2-dimethoxyethane; water; at 95℃; for 18h;Inert atmosphere;
Stepl : 2-phenylisonicotinic acid 2-bromoisonicotinic acid (0.210 g, 1 .040 mmol) was dissolved in degassed DME (Volume: 8 ml) under nitrogen. Tetrakis(triphenylphosphine)palladium(0) (0.060 g, 0.052 mmol) was added, the resulting reaction mixture was stirred for 15min.Then aqueous potassium carbonate (4.16 ml, 8.32 mmol) and phenylboronic acid (0.171 g, 1 .403 mmol) were added subsequently. The resulting RM was refluxed at 95 C for 18h and then cooled to rt. After filtration over celite the reaction mixture was acidified to pH 3-4 and the white precipitate was filtered off and washed with water. This resulted in a white powder after recrystallization from 2-methoxyethanol. Yield: 0.1 06 g, 57%. 1 H NMR (400 MHz, DMSO-c): delta 7.44 - 7.60 (m, 3H), 7.71 - 7.86 (dd, J = 4.9, 1 .5 Hz, 1 H), 8.05 - 8.19 (m, 2H), 8.23 - 8.35 (t, J = 1 .2 Hz, 1 H), 8.79 - 8.93 (dd, J = 5.1 , 0.8 Hz, 1 H), 13.56 - 13.97 (s, 1 H). UPLC I (ESI) Rt 1 .37 min, m/z 200.5 [M+H]+ (92%). - -
2-Bromoisonicotinic acid (2.02 g, 10 mmol) was dissolved in DMF (80 mL) under argon. Pd(PPh3)4 (0.6 g, 0.52 mmol) was added, and the reaction mixture was stirred at room temperature for 15 min. Na2CO3 (aq. 2N, 40 mL) was then added, followed by the addition of phenylboronic acid (1.67 g, 13.7 mmol). The reaction mixture was heated at 95C (18 h), cooled to room temperature and filtered through <n="76"/>a celite pad. Water (80 mL) was added, and the mixture was acidified with HCl (2 N) to pH = 4. The precipitate was collected via filtration and rinsed with water (2 x 7 mL). The crude product was recrystallized from 2-methoxylethanol to give 2- phenylisonicotinic acid as a grey solid (1.2 g). 1HNMR (DMSO-d6, 400 MHz): delta 7.51 (m, 3H), 7.78 (d, J=4.8 Hz, 1H), 8.13 (t, J=1.6 Hz, 2H), 8.29 (s, 1H), 8.85 (d, j=4.8 Hz, 1H), 13.73 (bs, 1H).
With potassium carbonate;tetrakis(triphenylphosphine) palladium(0); In water; acetonitrile; at 80℃; for 24h;
Compound KLL was prepared from [2, 3'] bipyridinyl-4-carboxylic acid methyl ester [pre- pared by the following procedure: A mixture of pyridine-3-boronic acid (0.7 g, 5.7 mmol), <strong>[66572-56-3]2-bromo-isonicotinic acid</strong> (1.15 g, 5.7 mmol) and K2CO3 (0.63 g, 4.6 mmol) in CH3CN (120 ML)/H20 (10 mL) was degassed and Pd (PPh3) 4 (0.13 g, 0.11 mmol) was added. The mixture was stirred for 24 h at 80C in an atmosphere of nitrogen and then concentrated in vacuum to a volume of ca. 10 ml. The pH was set to 6 by addition of 3N HC1 and the solution was then evaporated in vacuum to dryness. The residue was stirred in IN HCL-MEOH (23 ml) for 65 h at 50C. The crude product was purified by chroma- tography (silica gel, AcOEt/cyclohexane 1 : 1) to give the methyl ester as light yellow oil (0. 37 g). ] (044 g, 2.1 mmol) by treatment with lithium tert-butyl acetate according to general procedure K (method b).
With potassium carbonate;tetrakis(triphenylphosphine) palladium(0); In water; acetonitrile; at 80℃; for 70h;
Compound K12 was prepared from 2-METHYL-[2, 4] BIPYRIDINYL-4-CARBOXYLIC acid methyl ester [prepared by the following procedure: A cooled solution OF 4-BROMO-2-METHYL- pyridine (2.75 g) in ET20 (26 ml) was added AT-78C over to a solution of 1.6 M butyl lithium/hexane (12 ml) in ET20 (50 ml). The solution was stirred for 20 min AT-78C. Triisopropylborate (4.8 ml, 20.8 mmol) was added and the mixture was allowed to warm up to RT over 1 hour and subsequently stirred for 18 h. H20 (13 ml) was added and the layers were separated. The organic layer was extracted with 0.5N NAOH (25 ML) and the combined aqueous layers were acidified to pH 6 with 2N HCl and then extracted with AcOEt (200 ML). The organic extract was dried and evaporated in vacuum and the residue was triturated with ET20 to give pyridine-2-methyl-4-boronic acid (0.36 g). A mixture of this material (0.36 g, 2.6 mmol), <strong>[66572-56-3]2-bromo-isonicotinic acid</strong> (0.53 g, 2.6 mmol) and K2CO3 (0.29 g, 2.1 mmol) in CH3CN (9 ML)/H20 (4.5 ml) was degassed and Pd (PPh3) 4 (0.12 g, 0.1 mmol) was added. The mixture was stirred for 70 h at 80C in an atmosphere of nitrogen and then concentrated in vacuum to a volume of ca. 5 ml. The pH was set to 6 by addition OF 3N HCL and the solution was then evaporated to dryness in vacuum. The residue was stirred in IN HCL-MEOH (30 ml) for 20 h at 50 C. The crude product was purified by chromatography (silica gel, AcOEt/cyclohexane 1 : 1) to give the methyl ester as light yellow oil (0.22 g). ] (0.16 g, 0.71 mmol) by treatment with lithium tert-butyl acetate according to general procedure K (method b).
A solution of <strong>[66572-56-3]2-bromo-isonicotinic acid</strong> (Lancaster, 70 mg, 0.34 mmol) in thionyl chloride (1.2 mL) was heated at reflux temperature for 1.5 h. The mixture was concentrated and the crude product of 2-bromoisonicotinoyl chloride was used directly in the next step without further purification.
With oxalyl dichloride; N,N-dimethyl-formamide; In dichloromethane; at 0 - 20℃; for 3h;
General procedure: To a solution of 3-iodo-4-methylbenzoic acid 5-1 (262mg, 1.0mmol) in dry DCM (10mL) at 0C was added oxalyl chloride (0.13mL, 1.5mmol) and 3 drops of dry DMF. The resulting reaction mixture was stirred at room temperature for 3h, and then the solvent was removed under reduced pressure. The crude product was used directly for the next step without further purification.
With benzotriazol-1-ol; O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃;
2-Bromopyridine-4-carboxylic acid (1.00 g, 4.96 mmol), 1-hydroxybenzotriazole hydrate (0.85 g, 5.56 mmol), O-benzotriazol-l-yl-N,N,iV',iV'-tetramethyluronium tetrafluoroborate (1.81 g, 5.64 mmol), (N,iV-dimethylamino)pyridine (20 mg), N,N- diisopropylethylamine (3.5 mL, 2.59 g, 20 mmol), and morpholine (0.87 ml, 0.87 g, 10 mmol) in dimethylformamide (15 ml) were stirred at room temperature overnight. The solution was evaporated and the residue was partitioned between chloroform and water. The organic extract was dried over MgSO4, filtered, and evaporated. The residue was purified by flash chromatography on silica using a gradient of 0-100% ethyl acetate and hexane to give the sub-title compound as an oil; m/z 271, 273 (MH+).
With hydrogenchloride; potassium carbonate;Pd(PPh3)4; In HCl-MeOH; cyclohexane; water; acetonitrile;
Example K57 3-[2,3']Bipyridinyl-4-yl-3-oxo-propionic acid tert-butyl ester The title compound was prepared from [2,3']bipyridinyl-4-carboxylic acid methyl ester [prepared by the following procedure: A mixture of pyridine-3-boronic acid (0.7 g, 5.7 mmol), <strong>[66572-56-3]2-bromo-isonicotinic acid</strong> (1.15 g, 5.7 mmol) and K2CO3 (0.63 g, 4.6 mmol) in CH3CN (120 mL)/H2O (10 mL) was degassed and Pd(PPh3)4 (0.13 g, 0.11 mmol) was added. The mixture was stirred for 24 h at 80 C. in an atmosphere of nitrogen and then concentrated in vacuum to a volume of about 10 ml. The pH was set to 6 by addition of 3N HCl and the solution was then evaporated in vacuum to dryness. The residue was stirred in 1N HCl-MeOH (23 ml) for 65 h at 50 C. The crude product was purified by chromatography (silica gel, AcOEt/cyclohexane 1:1) to give the methyl ester as light yellow oil (0.37 g).] (044 g, 2.1 mmol) by treatment with lithium tert-butyl acetate according to general procedure K (method b).
With hydrogenchloride; potassium carbonate;Pd(PPh3)4; In HCl-MeOH; cyclohexane; water; acetonitrile;
Example K58 3-[2,4']Bipyridinyl-4-yl-3-oxo-propionic acid tert-butyl ester The title compound was prepared from [2,4']bipyridinyl-4-carboxylic acid methyl ester [prepared by the following procedure: A mixture of pyridine-4-boronic acid (0.7 g, 5.7 mmol), <strong>[66572-56-3]2-bromo-isonicotinic acid</strong> (1.15 g, 5.7 mmol) and K2CO3 (0.63 g, 4.6 mmol) in CH3CN (120 ml)/H2O (10 ml) was degassed and Pd(PPh3)4 (0.13 g, 0.11 mmol) was added. The mixture was stirred for 24 h at 80 C. in an atmosphere of nitrogen and then concentrated in vacuum to a volume of about 10 ml. The pH was set to 6 by addition of 3N HCl and the solution was then evaporated in vacuum to dryness. The residue was stirred in 1N HCl-MeOH (23 ml) for 65 h at 50 C. The crude product was purified by chromatography (silica gel, AcOEt/cyclohexane 1:1) to give the methyl ester as light yellow oil (0.37 g).] (0.21 g, 1.0 mmol) by treatment with lithium tert-butyl acetate according to general procedure K (method b).
With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In tetrahydrofuran; 1,4-dioxane; N,N-dimethyl-formamide;
b 2-Bromo-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-isonicotinamide To a stirred solution of 3.81 g (18.8 mmol) 2-bromo-isonicotinic acid in 50 ml THF were added 7.16 g (18.8 mmol) HATU and 3.21 ml (18.8 mmol) N-ethyldiisopropylamine and stirring continued at room temperature for 90 minutes. A solution of 5.00 g (18.8 mmol) <strong>[383865-57-4]4-methoxy-7-morpholin-4-yl-benzothiazol-2-ylamine</strong> in 50 ml dioxane and 10 ml DMF was then added and stirring continued at room temperature for 16 h. The reaction mixture was then poured into 300 ml 1 M hydrochloric acid and the mixture stirred for 20 min. The resulting crystals were collected by filtration, washed with water and then with ether, and dried in vacuo to afford 7.53 g (89%) 2-bromo-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-isonicotinamide as a yellow crystalline solid. ES-MS m/e (%): 473 (M{81Br}+Na+, 30), 471 (M{79Br}+Na+, 34).
With potassium carbonate;palladium tetrakis; In ISOPROPYLAMIDE; water; at 170℃; for 0.75h;
A solution of <strong>[66572-56-3]2-bromo-isonicotinic acid</strong>, 1.5 equivalents of vinylboronic acid dibutyl ester, 1.2 equivalents of potassium carbonate in DMA/water 9/1 was degassed for twenty minutes, then 0.06 equivalent of palladium tetrakis were added, the suspension degassed for a furtherthirty seconds and the suspension heated up in the microwave at 170C for twenty five minutes. The resulting suspension was filtered through a pad of silica gel and the filtrate concentrated.
In (2S)-N-methyl-1-phenylpropan-2-amine hydrate; sulfuric acid
R.3 REFERENTIAL EXAMPLE 3 STR38
REFERENTIAL EXAMPLE 3 STR38 50 g of 2-bromo-4-methylpyridine was dissolved in 400 ml of conc. sulfuric acid, and under ice cooling, 87.2 g of chromic trioxide was added little by little. The mixture was stirred for 1 hour and put in ice water. The precipitated crystals were collected by filtration, and recrystallized from ethanol to give 48.8 g (yield 82%) of 2-bromo-4-pyridinecarboxylic acid having a melting point of 213.9° to 214.4° C.
2-Bromo4-pyridinecarboxylic acid ethyl ester To a suspension of 2-bromo4-pyridine carboxylic acid (prepared according to the method of Ashimori, Chem. Pharm. Bull. 38 (9) 2446-2458 (1990)) in 2:1 toluene: absolute ethanol (45 mL) was added sulfuric acid (0.75 mL). The mixture was heated at reflux for 16 h. The mixture was poured into saturated aqueous sodium bicarbonate and extracted with chloroform (3 times). The combined chloroform extracts were dried over magnesium sulfate, filtered and concentrated afforded the crude product as a yellow oil. Purification by silica gel chromatography eluding with 9:1 hexane:ethyl acetate to afford the title compound (900 mg) as a clear, colorless oil.
trans-(4-aminomethyl-cyclohexylmethyl)-carbamic acid tert-butyl ester[ No CAS ]
[ 66572-56-3 ]
tert-butyl [(trans-4-[(2-bromoisonicotinoyl)amino]methyl}cyclohexyl)methyl]carbamate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
96%
With O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃;
2-Bromo-isonicotinic acid (0.92 g, 4.5 mmol), TBTU (1.6 g, 5.0 mmol) and DIPEA (1.1 g, 8.3 mmol) were added to a solution of fers-butyl [tralphans-4-(aminomethyl)cyclohexyl]methyl}-carbamate (1.0 g, 4.1 mmol) in DMF (10 mL) and the reaction mixture was stirred at rt for 22 h. Water was added to give a precipitate which was filtered to give the title compound (1.7 g, 96%). 1H NMR (400 MHz, CDCl3) delta 8.48 (d, IH), 7.78 (s, IH), 7.55 (dd, IH), 6.21 (s, IH), 4.58 (s, IH), 3.31 (t, 2H), 2.97 (t, 2H), <n="233"/>1.87-1.76 (m, 4H), 1.62-1.49 (m, 2H), 1.44 (s, 9H), 1.08-0.88 (m, 4H); m/z 426.14 (M+H)+.
To a slurry of <strong>[66572-56-3]2-bromo-4-pyridinecarboxylic acid</strong> (1.2 g, 5.94 mmol), tetrakis(triphenylphosphine)palladium(0) (0.23 g, 0.198 mmol), ethylene glycol dimethyl ether (27 mL) and 2 N sodium carbonate (24 mL) was added [6- (methyloxy)-2-naphthalenyl]boronic acid (1 g, 4.95 mmol) and the reaction mixture was heated at 80 0C for 24 h. The reaction mixture was cooled to room temperature, then diluted with water, followed by ethyl acetate. The layers were separated and the aqueous layer was acidified to approximately pH 5 (litmus paper) with IN hydrochloric acid and extracted with ethyl acetate. The ethyl acetate layer was filtered to afford 0.02 g of 2-[6-(methyloxy)-2-naphthalenyl]-4-pyridinecarboxylic acid and the filtrate was washed with brine, dried over magnesium sulfate, filtered, and concentrated to afford 1.3 g of 2-[6-(methyloxy)-2-naphthalenyl]-4- pyridinecarboxylic acid. The materials were combined to afford a total of 1.32 g <n="149"/>(96%) of 2-[6-(methyloxy)-2-naphthalenyl]-4-pyridinecarboxylic acid with a small impurity present by 1H NMR. Thionyl chloride (0.57 mL, 7.80 mmol) was added slowly to a slurry of 2-[6-(methyloxy)-2-naphthalenyl]-4-pyridinecarboxylic acid (1.09 g, 3.90 mmol) in methanol (35 mL) and the reaction mixture was heated at 75 0C for 2 days. The reaction mixture was cooled to room temperature, then concentrated. The crude material was diluted with 5% sodium bicarbonate and ethyl acetate. The mixture was stirred for several minutes, then the layers were separated and the ethyl acetate layer was washed with brine, dried over magnesium sulfate, filtered, and concentrated. The crude material was purified by flash chromatography over silica using a hexanes:ethyl acetate gradient of 0 to 30% ethyl acetate to afford 0.597 g (52%) of methyl 2-[6-(methyloxy)-2-naphthalenyl]-4-pyridinecarboxylate. 1H NMR (400 MHz, DMSO-J6): delta 8.88 (d, J = 5 Hz, IH), 8.65 (s, IH), 8.43 (s, IH), 8.23 (dd, J = 9, 2 Hz, IH), 8.00 (d, J = 9 Hz, IH), 7.92 (d, J = 9 Hz, IH), 7.77 (d, J = 7 Hz, IH), 7.36 (d, J = 2 Hz, IH), 7.20 (dd, J = 9, 3 Hz, IH), 3.93 (s, 3H), 3.88 (s, 3H).
Into a 250-mL round-bottom flask, was placed a solution of 2-bromopyridine-4- carboxylic acid (10 g, 49.50 mmol, 1.00 equiv) in methanol (100 mL), and sulfuric acid (98%, 5 mL). The resulting solution was stirred overnight at 70 oC then concentrated under vacuum. The residue was dissolved in 200 mL of EtOAc and washed with 3x150 mL of saturated sodium bicarbonate. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. This resulted in 10 g (94%) of methyl 2-bromopyridine-4- carboxylate as colorless oil.
77%
With sulfuric acid; at 80℃; for 1h;
A solution of 2-bromoisonicotinic acid (5.00 g, 24.8 mmol) in MeOH (50 mL) was treated with sulfuric acid (0.50 mL, 9.4 mmol) and the reaction mixture was stirred at 80 C for 1 hour. The mixture was returned to room temperature and stirred for a further 96 hours before heating to 80 C and stirring for 24 hours. The reaction mixture was cooled to room temperature, and the volatiles were removed in vacuo. An aqueous NaOH solution (2 M, -50 mL) was added to the residue and the aqueous was extracted with EtOAc (3 * 50 mL). The organic layers were combined, washed with brine, dried (MgS04) and the solvent removed in vacuo to give the title compound as a yellow oil (4.14 g, 77%). LCMS-B: rt 3.55 min; m/z 216 [Mu+Eta for /9Br. 218 [M+H]+ for 81 Br; 1H NMR (400 MHz, CDCb) delta 8.52 (dd, J = 5.0, 0.8 Hz, 1 H), 8.04 (t, J = 1.2 Hz. 1 H), 7.80 (dd, J = 5.0, 1.4 Hz, 1 H), 3.96 (s, 3H).
75%
With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃;Cooling with ice;
To an ice cooled solution of 2-bromoisonicotinic acid (73 g, 0.361 mol) in dichloromethane (500 mL) and methanol (35 g, 1.08 mol) was added 1-ethyl-3-[3-(dimethylamino)propyl]carbodiimide hydrochloride (67 g, 0.434 mol) by portions. The mixture was stirred at ambient temperature overnight. Then 120 g silica gel was added and the solvent evaporated. The residue was purified by flash chromatography, eluting with 5% ethyl acetate in petroleum ether to afford 58 g (75%) of methyl 2-bromoisonicotinate as a white solid.
75%
With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃;
To an ice cooled solution of 2-bromoisonicotinic acid (73 g, 0.361 mol) in dichloromethane (500 mL) and methanol (35 g, 1.08mol) was added 1-ethyl-3-[3-(dimethylamino)propyl]carbodiimide hydrochloride (67g, 0.434mol) by portions. The mixture was stirred at ambient temperature overnight. Then 120g silica gel was added and the solvent evaporated. The residue was purified by flashchromatography, eluting with 5% ethyl acetate in petroleum ether to afford 58 g (75%) of methyl 2-bromoisonicotinate as a white solid.
2-bromo-N-[4-methoxy-7-(tetrahydro-pyran-4-yl)-benzooxazol-2-yl]-isonicotinamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
84%
To a stirred solution of 106 mg (0.52 mmol) <strong>[66572-56-3]2-bromo-isonicotinic acid</strong> in 5 ml THF were added 230 mg (0. 60 mmol) HATU and 0.10 ml (0.. 60 mmol) N- ethyldiisopropylamine and stirring continued at room temperature for 5 h. A solution of 100 mg (0.40 mmol) 4-METHOXY-7- (TETRAHYDRO-PYRAN-4-YL)-BENZOOXAZOL-2-YLAMINE in 5 ml dioxane and 1 ml DMF was then added and stirring continued at 40 C for 72 h. The reaction mixture was then poured into 100 ml water and extracted three times with ethyl acetate. The combined organic phases were dried over sodium sulfate and concentrated H . VNCTTO. Flash chromatography (dichoromethane then methanol/dichloromethane 20/80) followed by trituration in ether afforded 146 mg (84 %) 2-BROMO-N- [4-METHOXY- 7- (tetrahydro-pyran-4-yl)-benzooxazol-2-yl]-isonicotinamide as a white crystalline solid. ES-MS m/e (%): 434 (M {8LBR} +H+, 95), 432 (M{79Br}+H+, 100).
7-(4-fluoro-phenyl)-4-methoxy-benzooxazol-2-ylamine[ No CAS ]
[ 66572-56-3 ]
2-bromo-N-[7-(4-fluoro-phenyl)-4-methoxy-benzooxazol-2-yl]-isonicotinamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
68%
To a stirred solution of 203 mg (1. 00 mmol) <strong>[66572-56-3]2-bromo-isonicotinic acid</strong> in 5 ml THF were added 442 mg (1.16 mmol) HATU and 0.20 ml (1.16 mmol) N- ethyldiisopropylamine and stirring continued at room temperature for 5 h. A solution of 200 mg (0.77 mmol) 7- (4-fluoro-phenyl)-4-methoxy-benzooxazol-2-yl-amine in 5 ml dioxane and 1 ml DMF was then added and stirring continued at 40 C for 16 h. The reaction mixture was then poured into 100 ml water and extracted three times with ethyl acetate. The combined organic phases were dried over sodium sulfate and concentrated ILL VACICO. Trituration in ether/ethyl acetate (4/1) afforded 233 mg (68 %) 2-BROMO-N- [7- (4-fluoro-phenyl)-4-methoxy-benzooxazol-2-yl]-isonicotinamide as an off-white crystalline solid. ES-MS m/e (%): 444 (M{81Br}+H+, 90), 442 (M{79Br}+H+, 100).
To a stirred solution of 296 mg (1.46 mmol) <strong>[66572-56-3]2-bromo-isonicotinic acid</strong> in 10 ml THF were added 642 mg (1.69 mmol) HATU and 0.29 ml (1.69 mmol) N-ethyldiisopropylamine and stirring continued at room temperature for 1 h. 300 mg (1.13 mmol) (+/-)-7-[1,4]dioxan-2-yl-4-methoxy-benzothiazol-2-ylamine was then added and stirring continued at room temperature for 24 h. The reaction mixture was then poured into saturated aqueous sodium bicarbonate solution and extracted three times with ethyl acetate. The combined organic phases were dried over sodium sulfate and concentrated in vacuo. Trituration in ether afforded 370 mg (73%) (+/-)-2-bromo-N-(7-[1,4]dioxan-2-yl-4-methoxy-benzothiazol-2-yl)-isonicotinamide as a light yellow solid. ES-MS m/e (%):452 (M{81Br}+H+, 100), 450 (M{79Br}+H+, 95).
(+)-7-[1,4]dioxan-2-yl-4-methoxy-benzothiazol-2-ylamine[ No CAS ]
[ 66572-56-3 ]
(+)-2-bromo-N-(7-[1,4]dioxan-2-yl-4-methoxy-benzothiazol-2-yl)-isonicotinamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
99%
To a stirred solution of 789 mg (3.91 mmol) <strong>[66572-56-3]2-bromo-isonicotinic acid</strong> in 50 ml THF were added 1.71 g (4.51 mmol) HATU and 1.29 ml (7.51 mmol) N-ethyldiisopropylamine and stirring continued at room temperature for 2 h. 800 mg (3.00 mmol) (+)-7-[1,4]dioxan-2-yl-4-methoxy-benzothiazol-2-ylamine was then added and stirring continued at room temperature for 24 h. The reaction mixture was then poured into saturated aqueous sodium bicarbonate solution and extracted three times with ethyl acetate. The combined organic phases were dried over sodium sulfate and concentrated in vacuo. Flash chromatography (acetone) followed by trituration in ether afforded 1.35 g (99%) (+)-2-bromo-N-(7-[1,4]dioxan-2-yl-4-methoxy-benzothiazol-2-yl)-isonicotinamide as a light yellow solid. [alpha]D20=+12.9 (c=0.76, CHCl3), ES-MS m/e (%):452 (M{81Br}+H+, 95), 450 (M{79Br}+H+, 100).
2-bromo-N-(7-methoxy-4-morpholin-4-yl-thiazolo[5,4-c]pyridin-2-yl)-isonicotinamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
62%
a) 2-Bromo-N-(7-methoxy-4-morpholin-4-yl-thiazolo[5,4-c]pyridin-2-yl)-isonicotinamide To a stirred solution of 455 mg (2.25 mmol) <strong>[66572-56-3]2-bromo-isonicotinic acid</strong> in 8 ml THF were added 914 mg (2.40 mmol) HATU and 0.50 ml (4.51 mmol) N-methylmorpholine and stirring continued at 50 C. for 16 h. 200 mg (0.75 mmol) 7-methoxy-4-morpholin-4-yl-thiazolo[5,4-c]pyridin-2-ylamine was then added and stirring continued at 60 C. for 4 h. The reaction mixture was then concentrated in vacuo. Flash chromatography (methanol/dichloromethane) afforded 208 mg (62%) 2-bromo-N-(7-methoxy-4-morpholin-4-yl-thiazolo[5,4-c]pyridin-2-yl)-isonicotinamide as a yellow crystalline solid. ES-MS m/e (%): 452 (M{81Br}+H+, 95), 450 (M{79Br}+H+, 100).
With benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃;
Example 11a) N-{2-[4-(4-Benzyloxy-phenyl)-piperazin-1-yl]-2-oxo-ethyl}-2-bromo-isonicotinamideTo a solution of 202 mg (1 mmol) of <strong>[66572-56-3]2-bromo-4-pyridinecarboxylic acid</strong> (Alfa) and 398 mg(1.1 mmol) of 2-[4-(4-benzyloxyphenyl)-piperazin-1-yl]-2-oxoethyl-ammonium chloride (10b) in 20 mL DMF are added 624 mg (1.2 mmol) PyBOP and 0.61 ml. N-ethyl-N,N- diisopropylamine and the reaction mixture is stirred overnight at room temperature. After evaporation of the solvent the residue is chromatographed on silica gel using an ethyl ace- tate/ethanol gradient. The product containing fractions are collected and recrystallized from ethyl acetate.Yield: 165 mg (32.4 %).Elemental analysis: calcd.: C 58.95 H 4.95 Br 15.69 N 11.00 found: C 58.32 H 5.09 Br 15.11 N 10.73The compound has a purity >95% according to HPLC and is suitable as a precursor for the F-18 labelling.
With benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃;
To a solution of 1.01 g (5.01 mmol) of <strong>[66572-56-3]2-bromopyridine-4-carboxylic acid</strong> (Aldrich) and 2.0 g (5.51 mmol) of hydrochloride prepared above in 160 mL DMF were added 3.13 g (6.0 mmol) PyBOP and 2.75 mL N-ethyl-N,N-diisopropylamine and the reaction mixture was stirred overnight at room temperature. After evaporation of the solvent the residue was chroma- tographed on silica gel using an ethyl acetate/ethanol gradient and the appropriate fractions were combined and concentrated.Yield: 739 mg (27.7 %).MS (ESIpos): m/z = 510, 512 [M+H]+1H-NMR (400MHz, DMSO-d6): d [ppm]= 2.72 (s, 1 H), 2.88 (s, 1 H), 3.40 - 3.48 (m, 2H), 3.51 - 3.64 (m, 4H), 4.21 (d, 2H), 5.07 (s, 2H), 6.86 (d, 1 H), 7.25 - 7.48 (m, 6H), 7.81 (dd, 1 H), 7.95 (d, 1 H), 8.02 (s, 1 H), 8.56 (d, 1 H), 9.06 (s, 1 H).
With benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃;
) N-(2-{4-[5-(benzyloxy)pyridin-2-yl]piperazin-1 -yl}-2-oxoethyl)-2-bromopyridine-4- carboxamide8.0 g (18.76 mmol) of tert-butyl (2-{4-[5-(benzyloxy)pyridin-2-yl]piperazin-1-yl}-2-oxoethyl) carbamate (14c) were suspended in 160 mL 2N HCI in diethyl ether and stirred overnight at room temperature. The precipitate was filtered off and washed with ether and dried at 400C in vacuo.Yield: 7.4 g (quantitative). The product was used in the next step without further purification. MS (ESIpos): m/z = 327 [M+H]+ To a solution of 1.01 g (5.01 mmol) of <strong>[66572-56-3]2-bromopyridine-4-carboxylic acid</strong> (Aldrich) and 2.0 g (5.51 mmol) of hydrochloride prepared above in 160 mL DMF were added 3.13 g (6.0 mmol) PyBOP and 2.75 mL N-ethyl-N,N-diisopropylamine and the reaction mixture was stirred overnight at room temperature. After evaporation of the solvent the residue was chromatographed on silica gel using an ethyl acetate/ethanol gradient. Yield: 739 mg (27.7 %). MS (ESIpos): m/z = 510, 512 [M+H]+ 1H-NMR (400MHz, DMSOd6): delta [ppm]= 2.72 (s, 1 H), 2.88 (s, 1H), 3.40 - 3.48 (m, 2H), 3.51 - 3.64 (m, 4H), 4.21 (d, 2H), 5.07 (s, 2H), 6.86 (d, 1 H), 7.25 - 7.48 (m, 6H), 7.81 (dd, 1 H), 7.95 (d, 1 H), 8.02 (s, 1 H), 8.56 (d, 1 H), 9.06 (s, 1 H).
d) 2-{4-[4-(Benzyloxy)phenyl]piperazin-1-yl}-2-oxoethyl 2-bromopyridine-4-carboxylate To a solution of 185.7 mg (0.92 mmol) <strong>[66572-56-3]2-bromopyridine-4-carboxylic acid</strong> (Aldrich) in 25 mL THF and 0.2 mL triethyl amine (1.44 mmol) at -15C, 132.3 uL (1.01 mmol) isobutyl chloro- formate were added dropwise and the solution was maintained at this temperature for an- other 15 min. Then, 300 mg (0.92 mmol) of 1-[4-(4-Benzyloxy-phenyl)-piperazin-1-yl]-2- hydroxy-ethanone (15b) and 0.6 mL triethyl amine (4.3 mmol) in 24 mL THF/dichloromethane (1 :1) were added slowly to this cold solution, the temperature was kept below -100C for another 15 min and was then allowed to reach room temperature. After stirring overnight the solvent was evaporated and the residue was taken up in ethyl acetate. This solution was washed successively with aqueous sodium carbonate, water, 1 M aqueous HCI solution, saturated aqueous sodium chloride solution, finally dried over magnesium sulfate and then evaporated. This residue was chromatographed on silica gel using a hexane/ethyl acetate gradient. Yield: 145 mg (30.6 %).MS (ESIpos): m/z = 510, 512 [M+H]+ 1H-NMR (400MHz1 CHLOROFORM-d): delta [ppm]= 3.11 (d, 4H), 3.60 (br. s., 2H), 3.80 (br. s.,2H), 5.05 (d, 4H), 6.86 - 6.99 (m, 4H), 7.29 - 7.48 (m, 5H), 7.89 (dd, 1 H), 8.13 (s, 1 H), 8.56(d, 1 H).
With benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃;
d) 2-Bromo-N-{2-[4-(4-hydroxyphenyl)piperazin-1-yl]-2-oxoethyl}pyridine-4-carboxamide1.8 g (5.37 mmol) of tert-butyl {2-[4-(4-hydroxyphenyl)piperazin-1-yl]-2-oxoethyl}carbamate (16c) were suspended in 60 ml_ 2N HCI in diethyl ether and stirred overnight at room temperature. The precipitate was filtered off and washed with ether and dried at 400C in vacuo. Yield: 1.8 g (quantitative). The product was used in the next step without further purification.To a solution of 338 mg (1.67 mmol) of <strong>[66572-56-3]2-bromo-4-pyridinecarboxylic acid</strong> (Alfa) and 500 mg (1.84 mmol) of the hydrochloride prepared above in 60 mL DMF were added 1.045 g (2 mmol) PyBOP and 2.86 mL (16.73 mmol) of N-ethyl-N.N-diisopropylamine and the reaction mixture was stirred overnight at room temperature. After evaporation of the solvent the residue was chromatographed on silica gel using an ethyl acetate/ethanol gradient. The product containing fractions were collected and recrystallized from ethyl acetate. Yield: 284 mg (40.5 %). MS (ESIpos): m/z = 419, 421 [M+H]+ 1H-NMR (300MHz, METHANOL-d4): delta [ppm]= 1.49 (dt, 4H), 2.17 (dt, 4H), 2.76 (s, 2H), 5.11 5.22 (m, 2H), 5.29 - 5.40 (m, 2H), 6.23 (dd, 1 H), 6.43 - 6.50 (m, 1 H), 6.89 - 6.98 (m, 1H).
Example 42i S-Ethyl 2-bromopyridine-4-carbothioate Triethylamine (3.0 g, 29.7 mmol) was added to a suspension of <strong>[66572-56-3]2-bromo-isonicotinic acid</strong> (5.0 g, 24.8 mmol) in anhydrous dichloromethane (50 mL). The mixture was stirred at room temperature for 10 minutes, cooled to 0 C. and isobutyl chloroformate (3.6 g, 26.0 mmol) was added dropwise. The reaction mixture was then stirred at 0 C. for 30 minutes, ethanethiol (1.6 g, 25.99 mmol) was then added dropwise and the stirring was continued for an additional 2 h at 0 C. The reaction mixture was diluted with dichloromethane (100 mL) and water (100 mL). The organic layer was separated, washed with water, dried over is sodium sulfate and concentrated under reduced pressure. The residue was purified by flash column chromatography using 15% ethyl acetate in hexane to afford the title compound (5.0 g, 80%). 1H NMR (400 MHz, CDCl3) delta ppm 8.53 (d, 1H) 7.93 (s, 1H) 7.70 (dd, 1H) 3.12 (q, 2H) 1.37 (t, 3H); MS (ES+) m/z: 246, 248 [M+1]+
(E)-2-(4-Phenylphenyl)ethenylpyridine-4-carboxylic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
Example 148; (E)-2-(2-(biphenyl-4-yl)vinyl)-N-hydroxyisonicotinamide; A. (£)-2-(2-(biphenyl-4-yl)vinyl)isonicotinic acid; 7>;alpha/?5-2-(4-biphenyl)vinylboronic acid (0.224 g, 1.00 mmol) and 2- bromoisonicotinic acid (0.202 g, 1 mmol) were combined and degassed/flushed with N2. The 1,4-dioxane (4 mL) and a solution of sodium carbonate (0.286 g, 2.70 mmol) in water (1 mL) were added. The mixture was degassed/purged with N2 again. The Pd(PPh3)4 (0.058 g, 0.05 mmol) was added. The mixture was degassed/purged with N2. The reaction mixture was heated to 100 0C overnight. After cooling to RT, aq 1 N HCl was added until the pH was 4. The resultant solid was collected and washed with several portions of water and washed once with ether to yield the title compound. LC-MS: [M+l]+ 302.1 Mass: Calculated for C20Hi5NO2, 301.34
2-Bromo-2-pyridinecarboxylic acid (1.00 g, 5.0 mmol) was suspended in methylene chloride (15 mL) at 0 0C. Oxalyl chloride (754 mg, 5.0 mmol) was added slowly into the solution at 0 C, and the mixture was then stirred at room temperature for 2 h. The reaction mixture was cooled to 0 C, then triethylamine (1.21 g, 9.9 mmol), 4-dimethylaminopyridine (121 mg, 0.99 mmol) followed by pyrrolidine (528 mg, 7.43 mmol) were added slowly. During the addition, the temperature was between 0 to 5 C. The reaction mixture was allowed to warm to room temperature, and stirred for another 1 h. The reaction mixture was then diluted with methylene chloride, washed with aqueous sodium bicarbonate, dried over MgSO4, filtered, and evaporated. The residue was purified by flash chromatography using a gradient of ethyl acetate in hexane to give the sub-title compound as an oil, m/z 255, 257 (MH+).
With 1-hydroxy-7-aza-benzotriazole; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In N,N-dimethyl-formamide; at 20℃; for 2h;
To a solution of intermediate 3-9 (250 mg, 0.937 mmol) in DMF (3.7 mL) was added <strong>[66572-56-3]2-bromopyridine-4-carboxylic acid</strong> (284 mg, 1.41 mmol), EDC (359 mg, 1.88 mmol), HO At (255 mg, 1.88 mmol), and TEA (523 muL, 3.75 mmol) and the reaction was stirred at ambient temperature for 2 h. The reaction was diluted with EtOAc (30 mL), and the organic phase was washed with saturated NaHCO3 (2 x 30 mL), water (2 x 30 mL), and brine (2 x 30 niL). The combined organics were dried over magnesium sulfate, filtered, and concentrated. The crude mixture was purified via normal phase column chromatography (silica, 5% to 85% EtOAc in hexanes) to afford 6-1 as a white solid. MS m/z (M+H) 450.0322 found, 450.0327 required.
Intermediate HHTo a 50 mL flask containing 20 mL of DMF was added 1 mL of oxaiyl chloride slowly and stirred for 10 min at RT. 2-Bromo-sonicotinic acid (100mg) was added to 2 mL of the above solution and stirred for 5 min at RT. Aniline E (50 mg) was dissolved in pyridine (1 mL) and added to the above solution. The reaction was completed in 5 min at RT and quenched with 1 mL NH4OH. The solvent was then evaporated under vacuum and the residue dissolved in CH3CN and water and purified with prep HPLC (0% to 95% water/ CH3CN) to afford intermediate H (32mg, 43%).1H-NMR (DMSO, 300 MHz): delta 8.91 (s, 1 H)5 8.43 (d, J = 3.3 Hz, 1 H)1 7.74 (d, J = 7.5 Hz, 1 H), 7.64(d, J = 8.5 Hz, 1 H), 7.45 (d, J = 8.1 Hz1 1 H), 7.23 (s, 1 H)5 7.15 (d, J = 7.5 Hz, 2H), 7.12-7.04 (m, 2H), 6.68 (s, 1 H), 6.54 (d, J = 7.5 Hz, 1 H)1 5.22 (s, 1 H), 4.76 (d, J = 8.1 Hz, 1 H), 3.34-3.15 (m, 3H), 2.97-2.91 (m Hz, 1 H), 2.81 (s, 1 H), 0.91 - 0.84 (m, 2H)1 0.65 (m, 2H).LCMS m/z [M+H]+ C29H23BrN4O3S requires: 587.07. Found 587.45 HPLC Tr (min), purity %: 3.33, 98%
6-(2-bromo-pyridine-4-carbonyl)-4-methyl-3H-benzoxazol-2-one 2.20 mL (30.0 mmol) thionyl chloride and 0.390 mL (4.80 mmol) DMF were added to 2.00 g (9.90 mmol) <strong>[66572-56-3]2-bromopyridine-4-carboxylic acid</strong> in 30 mL DCM and refluxed for 2 h. The reaction mixture was evaporated to dryness and coevaporated twice with toluene. The residue was combined with 6.24 g (46.8 mmol) aluminium trichloride and 1.50 g (10.1 mmol) 4-methyl-3H-benzoxazol-2-one and the mixture obtained was stirred overnight at 110 C. and for 5 hours at 130 C. The mixture was decomposed with ice water and extracted twice with DCM. The organic phases were dried on magnesium sulphate, filtered and evaporated down i. vac. The residue was triturated with DIPE/MeOH and suction filtered. The product obtained is a mixture of the corresponding bromine and chlorine compound (40/60). Yield: 1.0 g (~30% of theoretical)
To a mixture of NaH (11.95 g, 300 mmol, 60% with oil) in anhydrous THF (667 mL) was added 2,2-dimethyl-l,3-dioxolan-4-yl (solketal) (39.65 g, 300 mmol) at 0 C. The mixture was stirred for 1 hour.<strong>[66572-56-3]2-bromoisonicotinic acid</strong> (47; 20.0 g, 100 mmol) was added and stirred under reflux for 1.5 h. Water (83 mL) was added and adjusted pH to 2-3. The mixture was extracted with EtOAc (83 mL x 4). The combined organic layers were washed with water (42 mL x 3), dried overNa2SC>4 and concentrated in vacuo to give 2-((2,2-dimethyl-l,3-dioxolan-4- yl)methoxy)isonicotinic acid (48; 1 3.0 g? 52%) as a white solid. M S (ES I) calcd for(m/z) 253.25.
With O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 22h;Inert atmosphere;
2-Bromo-isonico-tinic acid (0.92 g, 4.5 mmol), TBTU (1.6 g, 5.0 mmol) and DIPEA (1.1 g, 8.3 mmol) were added to a solution of 4 (1.0 g, 4.1 mmol) in DMF (10 mL) and the reaction mixture was stirred at rt for 22 h. Water was added to give a precipitate which was filtered to give the intermediate amide (1.7 g, 96%). The amide (62 mg, 0.15 mmol) was dissolved in CH3CN (3 mL) and treated with phenylboronic acid (32 mg, 0.26 mmol), Pd(OAc)2 (14 mg, 0.06 mmol), and a 1 M aqueous solution of NaHCO3 (1 mL). The reaction mixture was sealed, degassed with nitrogen for 15 min, and heated in a microwave reactor at 150 C for 10 min. The solvent was concentrated in vacuo to leave a residue. The residue was dissolved in CH2Cl2 and washed with a saturated aqueous solution of NaHCO3 and then dried using a phase separator. The solvent was concentrated in vacuo to leave a residue which was purified by flash chromatography, using EtOAc/heptane (2:1) + 1% Et3N as eluent, to give the title compound as a white solid (33 mg, 53%). 1H NMR (500 MHz, CDCl3) delta 8.80 (d, J = 5.0 Hz, 1H), 8.09-8.03 (m, 3H), 7.54-7.43 (m, 4H), 6.43-6.32 (m, 1H), 4.65-4.57 (m, 1H), 3.36 (t, J = 6.4 Hz, 2H), 2.99 (t, J = 6.2 Hz, 2H), 1.91-1.78 (m, 4H), 1.67-1.55 (m, 2H), 1.45 (s, 9H), 1.10-0.90 (m, 4H); HRMS (ESI) m/z calcd for C25H34N3O3 [M+H]+ 424.2600; found 424.2610.
General procedure: A mixture of 11 (100 mg, 0.24 mmol), an acid (0.72 mmol), EDCI (125 mg, 0.78 mmol), HOBt (88 mg, 0.78 mmol), TEA (0.167 mL, 1.2 mmol) and DMF (4 mL) was stirred at ambient temperature under N2 protection for 24 h, the reaction was monitored by TLC (CH2Cl2:MeOH = 5:1), upon the completion of the coupling reaction, MeOH (5 mL), and K2CO3 (199 mg, 1.44 mmol) were added to the mixture and stirred at ambient temperature overnight. The mixture was then filtered through celite. The filtrate was concentrated to remove DMF and methanol. The residue was partitioned between CH2Cl2 (50 mL) and H2O (50 mL). The organic layer was separated and washed with H2O (50 mL x 3), dried over anhydrous MgSO4, concentrated under reduced pressure. The residue was then purified by column chromatography (Silica Gel 15 g), eluented with CH2Cl2 (150 mL), CH2Cl2/MeOH (80:1, 160 mL), CH2Cl2/MeOH (60:1, 180 mL), CH2Cl2/MeOH (40:1, 160 mL),CH2Cl2/MeOH (20:1, 160 mL), CH2Cl2/MeOH (10:1, 200 mL) successively to afford the corresponding target compound as free base. Upon confirmation by 1H NMR and 13C NMR, the free base was then transformed into hydrochloride salt by soluting in MeOH (0.1 mL), adding HCl methanol solution (1.25 M, 0.3 mL) and stirred at ambient temperature for 30 min. Diethyl ether (10 mL) was then added and the precipitate formed was collected by filtration, dried in vacuum to give the target compound as hydrochloride salt.
With benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃;
To a solution of 1.01 g (5.01 mmol) of <strong>[66572-56-3]2-bromopyridine-4-carboxylic acid</strong> (Alfa) and 2.0 g (5.51 mmol) of hydrochloride prepared above in 160 mL DMF were added 3.13 g (6.0 mmol) PyBOP (Benzotriazol-l-yloxy)tripyrrolidinophosphonium hexafluorophosphate) and 2.75 mL (16 mmol) N-ethyl-N,N-diisopropylamine and the reaction mixture was stirred overnight at room temperature. After evaporation of the solvent the residue was taken up in dichloro- methane. This solution was washed with water and saturated aqueous sodium chloride solution, dried over sodium sulfate and then evaporated. This residue was chromatographed on silica gel using an ethyl acetate/ethanol gradient and the appropriate fractions were com- bined and concentrated.Yield: 1 .91 g (70.7 %).MS (ESIpos): m/z = 509, 51 1 [M+H]+ 1H-NMR (400MHz, DMSO-d6): delta [ppm]= 3.86 - 3.44 (m, 4H), 3.59 (m, 4H), 4.20 (m, 2H), 5.08 (s, 2H), 6.83 - 6.88 (m, 1 H), 7.32 - 7.44 (m, 6H), 7.82 - 7.84 (m, 1 H), 7.95 (s, 1 H), 8.02 - 8.03 (m, 1 H), 8.54 - 8.57 (m, 1 H), 9.02 - 9.07 (m, 1 H).
N-(5-amino-2-methylphenyl)thieno[2,3-b]pyrazine-6-carboxamide hydrochloride[ No CAS ]
[ 66572-56-3 ]
[ 1351238-26-0 ]
Yield
Reaction Conditions
Operation in experiment
44%
Step 5: synthesis of N-(5-(2-bromoisonicotinamido)-2-methylphenyl)thieno[2,3- b]pyrazine-6-carboxamide (30)A solution of <strong>[66572-56-3]2-bromoisonicotinic acid</strong> (160 mg, 0.792 mmol), HATU (331 mg, 0.871 mmol) and DIPEA (0.655 mL, 3.96 mmol) in DMF (8 mL) was stirred at rt for 10 min. N-(5-amino-2-methylphenyl)thieno[2,3-b]pyrazine-6-carboxamide hydrochloride 29 (248 mg, 0.871 mmol) was added and stirred at rt for 3 h. Quenched in 3% citric acid solution and the resulting precipitate was collected. Triturating with acetonitrile gave N-(5-(2-bromoisonicotinamido)-2-methylphenyl)thieno[2,3-b]pyrazine-6-carboxamide (30) (163 mg, 44%). (m/z) = 468 and 470 (M+H)+.
44%
Step 5: synthesis of N-(5-(2-bromoisonicotinamido)-2-methylphenyl)thieno[2,3-b]pyrazine-6-carboxamide (30) A solution of <strong>[66572-56-3]2-bromoisonicotinic acid</strong> (160 mg, 0.792 mmol), HATU (331 mg, 0.871 mmol) and DIPEA (0.655 mL, 3.96 mmol) in DMF (8 mL) was stirred at rt for 10 min. N-(5-amino-2-methylphenyl)thieno[2,3-b]pyrazine-6-carboxamide hydrochloride 29 (248 mg, 0.871 mmol) was added and stirred at rt for 3 h. Quenched in 3% citric acid solution and the resulting precipitate was collected. Triturating with acetonitrile gave N-(5-(2-bromoisonicotinamido)-2-methylphenyl)thieno[2,3-b]pyrazine-6-carboxamide (30) (163 mg, 44%). (m/z)=468 and 470 (M+H)+.
Stage #1: thiophen-2-yl magnesium bromide With titanium(IV) tetraethanolate In tetrahydrofuran at 20℃; for 0.5h; Inert atmosphere;
Stage #2: 2-bromoisonicotinic acid With tributylphosphine; cobalt(II) chloride In tetrahydrofuran at 20℃; Inert atmosphere; chemoselective reaction;
With copper(l) iodide; caesium carbonate; In dimethyl sulfoxide; at 125℃; for 18h;
To a solution of <strong>[66572-56-3]2-bromoisonicotinic acid</strong> (1.87 g, 9.26 mmol), 1H-imidazole (573mg, 8.42 mmol) and Cs2C03 (6.03 g, 18.5 mmol) in DMSO (18.6 mL), was added Cui (176mg, 0.926 mmol). The mixture was heated to 125C, stirred for 18 hours, cooled to room10 temperature, filtered and purified by preparative HPLC (1 0-90% acetonitrile in water) to givethe title compound as a light pink solid (1. 72 g, 98% ). MS 190 (MH+).
With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In dichloromethane; at 0 - 20℃; for 96h;
General procedure: [00160] To a solution of pyridine-2-carboxylic acid (148 mg, 1.2 mmol) and1,1-dioxo-1H-IA6-benzo[b]thiophen-6-ylamine (181 mg, 1.0 mmol) in 10 mL of DCM wasadded DIPEA (388 mg, 3.0 mmol). HBTU (570 mg, 1.5 mmol) was added at 0 C. Theresulting mixture was stirred at r. t. for 24 h and then was concentrated. The residue wasdissolved in DMF (10 mL). The solution was added to the stirring water (50 mL) dropwise. Ayellow solid was formed. The solid was filtered and washed with H20 (50 mL). 130 mg ofthe desired product was obtained as a yellow solid (45% yield). [00165] The general procedure was the same as HJC-3-20 by using 2-bromoisonicotinicacid as reactant. Obtained as a pale yellow solid (82% yield); 1H NMR (600MHz, DMSO-d6) o 10.96 (s, 1H), 8.63 (d, 1H, J = 4.8 Hz), 8.23 (s, 1H), 8.15 (s, 1H), 7.97-7.99 (m, 1H), 7.91 (d, 1H, J= 4.8 Hz), 7.61-7.63 (m, 2H), 6.33 (d, 1H, J = 7.2 Hz). 13C NMR(150 MHz, DMSO-d6) o 162.9, 151.3, 144.4, 141.8, 140.8, 137.1, 132.8, 130.5, 126.5, 126.5,125.9, 124.6, 121.6, 112.6.
A mixture of 2-bromoisonicotinic acid, 2, (0.200 g, 0.99 mmol) in acetone and K3PO4 (0.290 g, 1.09 mmol) was stirred for 30 min at room temperature. When the time was over CH3I (0,155 g, 1.09 mmol) was added and the mixture refluxed for 2 h. Finally the mixture was cooled and left over ice, and the product extracted with CHCl3. The organic phase was dried with Na2SO4, and purified by silica gel chromatography with CHCl3 as mobile phase. The contents of the organic phase were removed in vacuo to obtain methyl 2-bromoisonicotinate with 82% yield. FT-IR (KBr) nu = 3089 (str. C-H sp3), 2955 (str. C-H sp2), 1722 (str. C=O), 1588 (str. C=C aromatic), 1546 (str. C=N), 670 (str. C-Br) cm-1. 1H NMR (400 MHz, CDCl3, ppm) delta 8.36 (d, J = 5.1 Hz, 1H), 7.85 (s, 1H), 7.65 (d, J = 5.0 Hz, 1H), 3.82 (s, 3H).
80%
With caesium carbonate; In N,N-dimethyl-formamide; at 20℃; for 15h;
2-Bromo isonicotinic acid (20.2 g, 100 mmol) was dissolved in DMF (500 mE) at ambient temperature. Cs2CO3 (32.6 g, 100 mmol) was added in one portion, followed by Mel (6.3 mE, 100 mmol). The mixture was stirred at ambient temperature for 15 h, followed by the addition of water (500 mE). The mixture was extracted with EtOAc (500 mE). The organic layer was washed with water (500 mE), brine (500 mE) and then dried over Na2SO4. The organic layer was then filtrated and concentrated to give compound DD as a white solid in 80% yield (17.4 g, 80.5 mmol). EC-MS: [M+H] 217.0 (C7H5BrNO2+H, calc: 216.1). Compound DD was used directly without further purification.
With caesium carbonate; In N,N-dimethyl-formamide; at 20℃; for 15h;
2-Bromo isonicotinic acid (20.2 g, 100 mmol) was dissolved in DMF (500 mL) at ambient temperature. Cs2CO3 (32.6 g, 100 mmol) was added in one portion, followed by MeI (6.3 mL, 100 mmol). The mixture was stirred at ambient temperature for 15 h, followed by the addition of water (500 mL). The mixture was extracted with EtOAc (500 mL). The organic layer was washed with water (500 mL), brine (500 mL) and then dried over Na2SO4. The organic layer was then filtered and concentrated to give a white solid (18.3 g, 84.7 mmol). LC-MS: [M+H] 217.1 (C7H6BrNO2+H, calc: 216.1). The crude product was used directly without further purification.
With caesium carbonate; N,N-dimethyl-formamide; at 20℃;
2-bromo-4-carboxypyridine (40.0 g) was dissolved in ~200 mL anhydrous DMF; CsCO3 (1 eq.) was then added (caution vigorous CO2 evolution occurs); MeI (1 eq.) was then added and the reaction was stirred at RT overnight. Reaction was confirmed to be complete by LC/MS, then diluted with ~500 mL of ethyl acetate and transferred to a 1L separatory funnel and the remaining salts were dissolved in ~100 mL water and also transferred to the separatory funnel. The resulting aqueous layer was extracted with EtOAc (3 X 100 mL); the combined organic layers were washed with water (2x 100 mL); saturated sodium bicarbonate solution (2 x 100 mL); and brine (1 x 100 mL); the organic phase was then dried over MgSO4; filtered and concentrated to afford 39.0 g of Intermediate D as an off-white solid which was used in the next step without further purification. Synthesis of 2-cyano-4-carbomethoxypyridine (Intermediate E)
N-(3-(trifluoromethyl)benzyl)-2-bromoisonicotinamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
59%
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 25℃;
Into a 250-mL round bottom flask, was placed a solution of <strong>[66572-56-3]2-bromoisonicotinic acid</strong> (1.4 g, 6.93 mmol, 1.20 equiv) in dichloromethane (50 mL), EDC.HCl (1.64 g, 8.56 mmol, 1.50 equiv), 4-dimethylaminopyridine (1.04 g, 8.51 mmol, 1.50 equiv), and 3-(trifluoromethyl)benzylamine (1.0 g, 5.71 mmol, 1.00 equiv). The resulting solution was stirred overnight at 25 C. in an oil bath. The resulting solution was diluted with 100 mL of dichloromethane. The resulting mixture was washed with 2*50 mL of sat. NH4Cl, 2*50 mL of sat. Na2CO3, and 2*50 mL of brine. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column and eluted with ethyl acetate/petroleum ether (1:10-1:5). The product was obtained as 1.2 g (59%) of a white solid.
methyl 2-bromoisonicotinate hydrochloride[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
80%
With thionyl chloride; at -5 - 70℃;
Into a 500-mL round bottom flask, was placed a solution of <strong>[66572-56-3]2-bromoisonicotinic acid</strong> (10 g, 49.75 mmol, 1.00 equiv) in methanol (200 mL). This was followed by dropwise addition of thionyl chloride (24 g, 203.39 mmol, 4.09 equiv) with stirring at 0 C.-5 C. The resulting solution was stirred for 5 h at 70 C. in an oil bath. The resulting mixture was concentrated under vacuum, to yield 10 g (80%) of methyl 2-bromoisonicotinate hydrochloride as a white solid.
(S)-2-bromo-N-(1,2,3,4-tetrahydronaphthalen-1-yl)isonicotinamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
89%
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃; for 3h;
Into a 250-mL round-bottom flask, was placed a solution of <strong>[66572-56-3]2-bromoisonicotinic acid</strong> (10 g, 49.50 mmol, 1.10 equiv) in dichloromethane (60 mL), (S)-1,2,3,4-tetrahydronaphthalen-1-amine (6.6 g, 44.90 mmol, 1.00 equiv), EDC.HCl (12.9 g, 67.29 mmol, 1.50 equiv), 4-dimethylaminopyridine (8.3 g, 68.03 mmol, 1.50 equiv). The resulting solution was stirred for 3 h at room temperature. The resulting solution was diluted with 20 mL of water. The resulting solution was extracted with 2*20 ml of dichloromethane and the organic layers combined. The resulting mixture was washed with 1*10 mL of hydrogen chloride (10%) and 1*20 ml of water. The resulting mixture was washed with 1*20 mL of brine. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. This resulted in 13.2 g (89%) of (S)-2-bromo-N-(1,2,3,4-tetrahydronaphthalen-1-yl)isonicotinamide as a off-white solid.
tert-butyl 2-bromopyridine-4-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
61%
With dmap; In tetrahydrofuran; at 20℃; for 18h;
Boc20 (4.28 g, 19.6 mmol) in THF (40 ml) was added to an ice-cold solution of 5-bromonicotinic acid (3.6 g, 17.82 mmol) and DMAP (1.09 g, 8.91 mmol) in THF (70 ml). The reaction mixture was stirred and allowed to warm to room temperature over 1.5 h then concentrated in vacuo. The residue was dissolved in saturated NaHC03 (aq) and extracted with DCM (3 x 100 ml). The combined organic extracts were dried (Na2S04), filtered and evaporated in vacuo. Purification by flash column chromatography (eluting with a gradient of 0-10% EtOAc / heptane) afforded the title compound (3.79 g, 82%) as a coloirless oil which solidified over time. 1 H-NMR (CDCI3, 250 MHz): d[ppm]= 9.09 (m, 1 H), 8.83 (d, J = 2.2 Hz, 1 H), 8.38 (t, J = 2.2 Hz, 1 H), 1.63 (s, 9H) HPLCMS (Method M): [m/z]: 259.85 / 261.85 [M+H]+ In a similar fashion to general procedure 17, <strong>[66572-56-3]2-bromoisonicotinic acid</strong> (541 mg, 2.68 mmol), Bo 1 H-NMR (CDCI3, 250 MHz): d[ppm]= 8.51 (dd, J = 5.0, 0.6 Hz, 1 H), 8.02 - 7.95 (m, 1 H), 7.77 (dd, J = 5.0, 1.4 Hz, 1 H), 1.62 (s, 9H) HPLCMS (Method M): [m/z]: 259.85/261.85 [M+H]+
With dmap; In 1-methyl-pyrrolidin-2-one; at 25℃; for 16h;
To a 1 L three-necked flask was added <strong>[66572-56-3]2-bromoisonicotinic acid</strong> (48.1 g, 0.238 mol).NMP (120ml), start stirring,Additional di-tert-butyl dicarbonate (126 ml, 0.547 mol) was added.DMAP (5.82 g, 0.056 mol), reaction at 25 C for 16 h.1H NMR was monitored and the starting material was completely converted.Dissolve NaCl (25g) and KH2PO4 (25g) in 250ml of water.Dropped into the reaction flask, the temperature did not change significantly.After the addition was completed, 250 ml of methyl tert-butyl ether was added.Stir for 15 min and extract. Wash with 100 ml of water.After concentration under reduced pressure, a white solid was obtained.
7-methoxy-4-(tetrahydropyran-4-yl)-1H-benzoimidazol-2-ylamine[ No CAS ]
[ 66572-56-3 ]
2-bromo-N-[7-methoxy-4-(tetrahydropyran-4-yl)-1H-benzoimidazol-2-yl]isonicotinamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
100%
With 4-methyl-morpholine; benzotriazol-1-ol; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In N,N-dimethyl-formamide; at 20℃; for 72h;
7-Methoxy-4-(tetrahydro-pyran-4-yl)-1 H-benzoimidazol-2-ylamine, 95% (1.00 g, 3.84 mmol), <strong>[66572-56-3]2-bromopyridine-4-carboxylic acid</strong>, 97% (1 .01 g, 4.99 mmol) 1 - hydroxybenzotriazole hydrate (156 mg, 1.15 mmol) and [dimethylamino- ([1 ,2,3]triazolo[4,5-b]pyridin-3-yloxy)-methylene]-dimethyl-ammonium, hexafluoro phosphate (HATU, 1.90 g, 4.99 mmol) were dissolved in N,N-dimethylformamide (30 ml). Then 4-methylmorpholine (1 .27 ml, 1 1.5 mmol) was added at RT and the mixture stirred at RT for 3 days. The reaction mixture was evaporated to dryness, taken up in dichloromethane and stirred for 1 h. The precipitate formed was filtered off and discarded. The filtrate was evaporated to dryness and the residue was purified by column chromatography (dichloromethane/ethanol, gradient) to yield in 2.67 g (100%) of the title compound as a light yellow fine powder. HPLC/MS (purity) 62%. Rt 2.34 min (method A). [M+H]+ 201 .9, 203.9.
B-1 be (720.5 mg; 3.6 mmol) is dissolved in DCM (50.0 ml_). DIPEA (1.6 ml_, 9.7 mmol) and HATU (1357.6 mg, 3.6 mmol) are added. The reaction mixture is stirred at 20 C for 5 min, then A-1 b (750 mg, 3.2 mmol) is added and stirring is continued over a period of 18 h. The reaction mixture is evaporated to dryness, the remaining residue is dissolved in DMSO, filtered and purified by reverse phase chromatography (method: prep. HPLC1 ) yielding U-1a (yield: 61 % - 415 mg, 1.99 mmol; HPLC-MS: (M+H)+ = 416, tRet. = 0.9 min, method: VAB).
In N,N-dimethyl-formamide; at 120℃; for 18h;Inert atmosphere;
At 20 C,5.0 g of <strong>[66572-56-3]2-bromopyridine-4-carboxylic acid</strong> (24.9 mmol, 1.0 eq), 4.46 g of CuCN (49.8 mmol, 2.0 eq), 50 mL of DMF was added to a 100 mL single-mouth bottle, replaced with nitrogen three times, and heated in an oil bath at 120 C for 18 h. The heating was stopped, cooled to room temperature, and most of the DMF was removed by rotary evaporation, poured into water, extracted with EA 200 mL three times, and the organic phase was washed twice with 50 mL of water and 20 mL of saturated sodium chloride. The organic phase is dried and dried to give a crude product. 2.0g crude product as a white solid after recrystallization from methanol,Yield: 54.2%.
Stage #1: 2-bromoisonicotinic acid With 1,1'-carbonyldiimidazole In dichloromethane at 25℃; for 0.5h;
Stage #2: Ν,Ο-dimethylhydroxylamine hydrochloride In dichloromethane at 20℃;
Step 1: 2-Bromo-N-methoxy-N-methylisonicotinamide
A mixture of 2-bromopyridine-4-carboxylic acid (50 g, 247.52 mmol) and CDI (42.14 g, 259.9 mmol) in CH2Cl2 (500 mL) was stirred at 25° C. for 0.5 h. N-methoxymethanamine hydrochloride (48.29 g, 495.4 mmol) was added, and the mixture was stirred at rt overnight. The mixture was poured into ice H2O (1000 mL) and extracted with EtOAc (500 mL×2). The organic layer was washed with sat'd NaHCO3 (200 mL) and brine (300 mL), and then concentrated to give 2-bromo-N-methoxy-N-methyl-pyridine-4-carboxamide (60 g, crude) as a brown oil.
2-bromo-N-(1-imino-2-methylpropyl)isonicotinamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
34%
HATU (45.17 g, 118.81 mmol) was added to a mixture of 2-bromopyridine-4- carboxylic acid (20 g, 99.01 mmol), DIPEA (69 mL, 396.03 mmol), and DMF (150 mL) at rt. The mixture was stirred for 45 min, and then 2-methylpropanamidine hydrochloride (14.57 g, 118.8 mmol) was added. The mixture was stirred for 3 h, poured into H20 (2 L), and then extracted with EtOAc (500 mL c 3). The combined organic layers were dried over Na2S04, filtered, concentrated, and then purified by silica gel chromatography (petroleum ether/EtOAc = 1/1) to give 2-brom o-N-( 1 -i m i no-2-m ethyl propyl )i soni coti nam i de (9 g, 34%) as a white solid. LCMS: 270.0 [M+H]+
Stage #1: 2-bromoisonicotinic acid With triethylamine; HATU In N,N-dimethyl-formamide at 20 - 30℃; for 0.333333h;
Stage #2: N,N-dimethylhydroxylamine hydrochloride In N,N-dimethyl-formamide at 20 - 30℃;
2.1 The first step 2-bromo-N-methoxy-N-methylisonicotinamide 2b
2-Bromo-4-pyridinecarboxylic acid 2a (4.0g, 19.80mmol), HATU (11.28g, 29.67mmol) and triethylamine (6.0g, 59.29mmol) dissolved in N,N-dimethylformamide (80mL )in,Stir at room temperature for 20 minutes, add dimethylhydroxylamine hydrochloride (2.32 g, 23.78 mmol), react at room temperature overnight, and TLC monitors most of the raw material reaction. The reaction solution was diluted with water, extracted with ethyl acetate, combined the organic phases, washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography to obtain the title compound 2b as a pale yellow liquid (4.8g, yield 99%)
methyl 4-((2-bromoisonicotinamido)methyl)benzoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
40.6%
With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; for 1.5h; Inert atmosphere;
1 Example 1Synthesis of methyl 4-((2-bromoisonicotinamide)methyl)benzoate (3a)
In a 50mL two-necked flask was added compound 1a (1212.1mg, 6.0mmol), compound 2 (1451.9mg, 7.2mmol), HBTU (2502.9mg, 6.6mmol), dissolved with anhydrous DMF (8mL), nitrogen protection, and then added N , N-Diisopropylethylamine (1705.9mg, 13.2mmol), after the addition was completed, the reaction was stirred at room temperature for 1.5 hours, and then water and ethyl acetate were added to the reaction system for extraction, and the ethyl acetate layers were combined, and water and saturated salt were added. Washed with water, dried with anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the concentrate was separated and purified by silica gel column chromatography (petroleum ether: acetone = 5:1) to obtain compound 3a (850.4 mg), a white solid, the yield: 40.6%
Stage #1: 2-bromoisonicotinic acid With N-ethyl-N,N-diisopropylamine; HATU In N,N-dimethyl-formamide at 0℃; for 0.0833333h; Inert atmosphere;
Stage #2: (1r,4r)-4-(2-methoxyethoxy)cyclohexan-1-amine In N,N-dimethyl-formamide at 0 - 20℃; for 16h; Inert atmosphere;
21.1 Step 1: 2-bromo-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)isonicotinamide
To a stirred solution of 2-bromoisonicotinic acid (510 mg, 2.52 mmol) in DMF (5 mL) at 0 C was added HATU (1.43 g, 3.78 mmol) followed by DIPEA (1.16 mL, 6.30 mmol) under nitrogen atmosphere and stirred for 5 min. After 5 min, (1r,4r)-4-(2-methoxyethoxy)cyclohexan-1-amine (656 mg, 3.78 mmol) was added and stirred at RT for 16 h. Upon completion, the reaction mixture was quenched with ice-cold water (20 mL) and extracted with EtOAc (50 mL). The ethyl acetate layer was washed with water (2 x 25 mL), dried over anhydrous Na2SO4, filtered and concentrated under vacuum to give title compound. Yield: 48.2% (435 mg, yellow solid). 1H NMR (400 MHz, DMSO-d6): δ 8.59 (d, J = 7.60 Hz, 1H), 8.53 (d, J = 5.20 Hz, 1H), 7.99 (s, 1H), 7.78 (dd, J = 6.40, 1.2 Hz, 1H), 3.84-3.79 (m, 1H), 3.57-3.50 (m, 2H), 3.45-3.40 (m, 2H), 3.30-3.20 (m, 4H), 2.06-2.00 (m, 2H), 1.84-1.80 (m, 2H), 1.61-1.50 (m, 2H),1.30-1.20 (m, 2H), LCMS: (Method A) 357.0 [M+H], Rt.1.86 min.
Chemistry
Pharmaceutical Intermediates
Inhibitors/Agonists
Material Science
For Research Only
110K+ Compounds
Competitive Price
1-2 Day Shipping
