* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
With bromine; sodium hydrogencarbonate In tetrachloromethane
A. 2-Chloro-5-bromopyridine A suspension of 2 g (12 mmol) of 2-chloro-5-pyridine-carboxylic acid, 4.12 g (19 mmol) of HgO (red) and 1 ml (19 mmol) of bromine in CCl4 was irradiated (flood lamp) under reflux for 2.5 h. The mixture was cooled to room temperature, 30 ml of sat. sodium bicarbonate solution was added, and the mixture was stirred vigorously for 15 min. The biphasic orange suspension was filtered through celite, the organic layer was washed with brine and dried over sodium sulfate. The filtrate was concentrated in vacuo to afford 1.1 g (45.8percent) of 2-chloro-5-bromopyridine, as a white solid, m.p. 67°-69° C.
Reference：
[1] Chinese Journal of Chemistry, 2012, vol. 30, # 1, p. 127 - 132
5
[ 5326-23-8 ]
[ 66572-55-2 ]
Reference：
[1] Patent: US4642308, 1987, A,
6
[ 67-56-1 ]
[ 5326-23-8 ]
[ 66572-55-2 ]
Reference：
[1] Helvetica Chimica Acta, 1991, vol. 74, # 2, p. 407 - 416
[2] Molecular Crystals and Liquid Crystals (1969-1991), 1985, vol. 126, p. 259 - 268
7
[ 5326-23-8 ]
[ 124-41-4 ]
[ 66572-55-2 ]
Reference：
[1] Monatshefte fuer Chemie, 1907, vol. 28, p. 38
8
[ 5326-23-8 ]
[ 133081-24-0 ]
Yield
Reaction Conditions
Operation in experiment
96%
at 100℃; for 4 h; Inert atmosphere
6-Chloronicotinic acid (0.30 g; 1.9 mmol) was added to a64percent hydrazine monohydrate solution (2 mL, 26 mmol) andplaced at 100°C for 4h. Thereafter, the reaction mixtureturned brown and was concentrated to dryness. The residuewas dissolved in water and pH adjusted to 5.5 with concentratedHCl. A precipitate was formed, filtered and washedwith ethanol, then ether to give a yellow solid (0.346 g,96percent). Mp = 292-293°C. IR (ATR, cm-1) 3210; 3058; 3039;1696; 1636; 1613; 1536-1444; 1170; 757; 736. 1H NMR(DMSO-d6) 8.63 (s, 1H); 8.07 (d, 1H, J= 9 Hz); 6.94 (d,1H, J = 9 Hz). 13C NMR (DMSO-d6) 167.2; 159.61;140.9; 119.9; 110.6. HRMS (ESI+) [M]+: 153.0531 observed,153.0538 Calcd for C6H7N3O2.
91%
With hydrazine hydrate In ethanolReflux
Example 72: 3-oxo-2,3-dihydro-[l,2,4]triazolo[4,3-a]pyridine-6-carbonyl chloride; [0235] To a solution of 6-chloronicotinic acid (20 g, 127 mmol) in 200 mL of EtOH was added hydrazine hydrate (14.8 mL, 317 mmol). The mixture was refluxed overnight, then cooled to room temperature to give a solid, which was collected by filtration, washed with petroleum ether/EA (2: 1) to give 18 g of 6-hydrazinylnicotinic acid as a yellow solid (Yield: 91percent). 1HNMR (DMSO, 400MHz) δ: 8.52 (s, IH), 7.88 (dd, J = 2.0 Hz, 8.8 Hz, IH), 6.63 (d, J = 8.8Hz, IH).[0236] To a suspension of 6-hydrazinylnicotinic acid (18 g, 117 mmol) in 100 mL of dry THF was added dry pyridine (23 g, 293 mmol), then the mixture was stirred at room temperature for 15 min, then bis(trichloromethyl)carbonate (80 g, 270 mmol) was added slowly. The reaction mixture was stirred overnight at room temperature, then MeOH was added and continued stirring for 15 hours to give a solid. The solid was collected by filtration and washed with petroleum ether/EA (1: 1) to give 20 g of dimethyl 3-oxo-[l,2,4]triazolo[4,3- a]pyridine-2,6(3H)-dicarboxylate. 1HNMR (CDCl3, 400MHz) δ: 3.95 (s, 3H), 4.13 (s, IH), 7.13 (dd, J = 1.6 Hz, 10 Hz, IH), 7.71 (dd, J = 1.6 Hz, 10 Hz, IH), 8.55 (t, J = 2 Hz, IH). [0237] To a solution of dimethyl 3-oxo-[l,2,4]triazolo[4,3-a]pyridine-2,6(3H)-dicarboxylate (10 g, 40 mmol ) in 60 mL of THF and 10 mL of H2O was added LiOH-H2O (4.8 g, 114 mmol), and then the reaction mixture was stirred at room temperature for 6 hours and then was concentrated in vacuo to remove THF, and then 1 mL of aq. HCl solution was added to adjust pH=2 to give a solid which was collected to give 1 Ig of compound 3-oxo-2,3-dihydro- [1 ,2,4]triazolo[4,3-a]pyridine-6-carboxylic acid which was used without the further purification. 1HNMR (DMSO, 400MHz) δ: 7.23 (d, J = IO Hz, IH), 7.48 (dd, J = 1.6 Hz, 10Hz, IH), 8.25 (s, IH), 9.13 (s, IH), 12.89 (s, IH).[0238] To a solution of 3-oxo-2,3-dihydro-[l,2,4]triazolo[4,3-a]pyridine-6-carboxylic acid (3 g, 16.8 mmol) in 60 mL of dry DCM was added oxalyl chloride (8.8 g, 74 mmol) and 1 mL ofDMF. The reaction mixture was stirred for 6 hrs at room temperature and concentrated to give[0239] 3 g of the title compound as a gray solid which was used without the further purification.
87%
With hydrazine In water at 95 - 100℃; for 4 h;
A mixture of 6-chloronicotinic acid (10.0 g, 63.4 mmol), hydrazine (20 mL), and water (20 mL) was refluxed at 95-100 °C for 4 h. The mixture was concentrated under vacuum and the residue was dissolved in 40 mL water. The resulting solution was acidified with 1N HCl to reach a pH 5-5.5. The solution was kept in a refrigerator overnight. The precipitated solid was collected by filtration, washed with cold water (10 mL x 2) and ether (10 mL x 2). The solid was dried to give 8.5 g (87percent) of the title compound. ES-MS: Observed [MH]+ 154.1.
85%
Stage #1: With hydrazine hydrate In ethanol for 72 h; Reflux Stage #2: With acetic acid In water for 0.25 h;
General procedure: A 0.5M solution of 2-chloropyridine-5-carboxylic acid (15 mmol) was treated with hydrazine hydrate (150 mmol, added at once) and heated at reflux for 72 h. The suspension was concentrated to dryness. The residue was dissolved in water and acidified (pH = 3) with acetic acid. The precipitate of 2-hydrazinopyridine-5-carboxylic acid that formed in 15 min was filtered off, washed with water and air-dried. It was dissolved in the respective aliphatic carboxylic acid and the solution (0.5M) was heated at reflux for 48 h. Upon cooling to room temperature, the volatiles were removed in vacuo and the residue was triturated with 1M aqueous sodium bicarbonate. The precipitate thus formed was filtered off, washed with water and air dried. The resulting 1,2,4-triazolo[4,3-a]pyridine 12 was dissolved in methanol (0.25M and was hydrogenated over Pd(OH)2 catalyst (0.1 equiv.) at 100 atm and 100 °C over 24 hours. The mixture was filtered while still hot and concentrated in vacuo. The residue was crystallized from isopropyl alcohol to provide analytically pure carboxylic acids 11a-d.
77%
With hydrazine hydrate In water
Synthesis of 6-hydrazinopyridine-3-carboxylic acid 6-Chloronicotinic acid (8.0 g) was added to 85percent hydrazine hydrate (35 ml). The reaction mixture was placed in a 100° C. oil bath for 4 hours. The homogeneous reaction mixture was concentrated to dryness to give a white solid. The solid was dissolved in water and on acidification to pH 5.5 with concentrated hydrochloric acid a precipitate formed. The precipitate was isolated by filtration and the solid was washed with 95percent ethanol and ether to give 6.0 g of a pale brown solid; yield 77percent m.p. 292°-293° C.; Analysis: Calculated for C6 H7 N3 O2; C 47.06; H 4.61; N 27.44; Found: C 46.83; H 4.38; N 27.27. 1 H NMR- δ: 6.69(d,J=8.8 Hz,1H),7.84(dd,J=2.4,8.8 Hz,1H), 8.51(d,J=2.4 Hz,1H)
57.7%
With hydrazine hydrate In 1,4-dioxane at 90℃;
Preparation 6 6-hydrazinylnicotinic acid [0147] A suspension of 6-chloronicotinic acid (30.0 g, 189 mmol) in 1,4-dioxane (29.0 mL) was treated with hydrazine hydrate (134 mL, 1.51 mol) and heated to 90°C overnight. The mixture was cooled to ambient temperature and then in ice for 30 min. Precipitate formation was induced by etching the side of the flask and the precipitate was filtered and re-suspended in EtOH (500 mL) with vigorous stirring. The resulting suspension was filtered. The precipitate was dissolved in water (300 mL) and HC1 (6N) was added until pH = 1. The pH was then adjusted to 5 with NaOH (50percent, aq.) and the resulting suspension was stirred for lh. The solids were collected by filtration and dried in vacuum to give the title compound (16.65 g, 57.7 percent yield) as an off-white solid. XH NMR (400 MHz, DMSO-i/6) δ ppm 6.70 (d, 1 H) 7.86 (dd, J=8.97, 2.15 Hz, 1 H) 8.32 (br. s., 1 H) 8.52 (d, J=1.77 Hz, 1 H). MS m/z [M+H]+ 154.
40%
With hydrazine hydrate In ethanol for 48 h; Reflux
Synthesis of 6-hydrazinylnicotinic acid To a solution of 6-chloronicotinic acid (5g, 32 mmol)) in EtOll (50 mL) was added hydrazine hydrate (3.7 mL, 80 mmol). The mixture was heated to reflux with stirring for 48 hrs. The mixture was allowed to cooled to r.t. to give a gray precipitatewhich was collected by filtration and then washed with EtCH and petroleum ether/EtOAc (2:1) to give 2 g solid (40percent)
Reference：
[1] Letters in Organic Chemistry, 2014, vol. 11, # 3, p. 208 - 214
[2] Patent: WO2010/96722, 2010, A1, . Location in patent: Page/Page column 54-55
[3] Polish Journal of Chemistry, 2004, vol. 78, # 7, p. 951 - 959
[4] Patent: WO2017/177144, 2017, A1, . Location in patent: Page/Page column 33; 39
[5] Pharmazie, 2006, vol. 61, # 4, p. 269 - 273
[6] Tetrahedron Letters, 2016, vol. 57, # 9, p. 1056 - 1059
[7] Patent: US5206370, 1993, A,
[8] Journal of Labelled Compounds and Radiopharmaceuticals, 2001, vol. 44, p. S66 - S68
[9] Journal of the American Chemical Society, 2012, vol. 134, # 28, p. 11392 - 11395
[10] Patent: WO2014/160810, 2014, A1, . Location in patent: Paragraph 0146; 0147
[11] Patent: WO2013/67597, 2013, A1, . Location in patent: Page/Page column 90; 91
[12] Journal of Labelled Compounds and Radiopharmaceuticals, 1997, vol. 40, p. 455 - 457
[13] Bioorganic and Medicinal Chemistry Letters, 2007, vol. 17, # 12, p. 3440 - 3444
[14] Chemische Berichte, 1903, vol. 36, p. 1114
[15] Patent: US5659041, 1997, A,
[16] Patent: WO2010/19899, 2010, A1, . Location in patent: Page/Page column 156
[17] Patent: US2010/305085, 2010, A1, . Location in patent: Page/Page column 16
[18] Bioorganic Chemistry, 2011, vol. 39, # 4, p. 138 - 142
[19] Chemical Communications, 2013, vol. 49, # 47, p. 5366 - 5368
[20] RSC Advances, 2015, vol. 5, # 113, p. 93374 - 93385
[21] Molecules, 2016, vol. 21, # 6,
[22] Chemical Biology and Drug Design, 2017, vol. 89, # 5, p. 755 - 761
[23] Journal of Labelled Compounds and Radiopharmaceuticals, 2017, vol. 60, # 9, p. 431 - 438
[24] Journal of Labelled Compounds and Radiopharmaceuticals, 2018, vol. 61, # 2, p. 68 - 76
[25] Inorganic Chemistry, 2017, vol. 56, # 16, p. 9725 - 9741
9
[ 5326-23-8 ]
[ 133081-24-0 ]
[ 731005-24-6 ]
Reference：
[1] Chemische Berichte, 1903, vol. 36, p. 1114
10
[ 5326-23-8 ]
[ 98-80-6 ]
[ 29051-44-3 ]
Reference：
[1] Journal of Medicinal Chemistry, 2010, vol. 53, # 16, p. 6129 - 6152
[2] Tetrahedron Letters, 2004, vol. 45, # 29, p. 5661 - 5663
11
[ 5326-23-8 ]
[ 1802-30-8 ]
Yield
Reaction Conditions
Operation in experiment
84%
With hydrogenchloride; sodium hydroxide In methanol; water
Example 2 25 g of 6-chloronicotinic acid and 14 g of sodium hydroxide are dissolved in a mixture of 100 ml of water and 80 ml of methanol. Following the addition of 5 g of palladium (10percent by weight on activated carbon) as catalyst, the mixture is stirred for 24 h at 80-85° C. at 0.1 MPa. The catalyst is then filtered off. Following acidification to pH 1 using hydrochloric acid, the product, 2,2'-bipyridyl-5,5'-dicarboxylic acid, precipitates out as a white solid. This gives 16.3 g (84percent yield).
81%
With hydrogenchloride; sodium hydroxide In water; ethylene glycol
Example 1 25 g of 6-chloronicotinic acid and 14 g of sodium hydroxide are dissolved in a mixture of 100 ml of water and 80 ml of ethylene glycol. Following the addition of 0.56 g of palladium (30percent by weight on activated carbon; corresponds to an addition of 168 mg of pure palladium) as catalyst, the mixture is stirred for 5 h at 80-85° C. at 0.1 MPa. The catalyst is then filtered off. Following acidification to pH 1 using hydrochloric acid, the product, 2,2'-bipyridyl-5,5'-dicarboxylic acid, precipitates out as a white solid. This gives 15.7 g (81percent yield).
79%
With hydrogenchloride; sodium hydroxide In methanol; water
Example 3 25 g of 6-chloronicotinic acid and 14 g of sodium hydroxide are dissolved in a mixture of 100 ml of water and 80 ml of methanol. Following the addition of 10 g of palladium (5percent by weight on activated carbon) as catalyst, the mixture is stirred for 30 h at 80-85° C. at 0.1 MPa. The catalyst is then filtered off. Following acidification to pH 1 using hydrochloric acid, the product, 2,2'-bipyridyl-5,5'-dicarboxylic acid, precipitates out as a white solid. This gives 15.3 g (79percent yield).
Reference：
[1] Journal of Organic Chemistry, 2006, vol. 71, # 5, p. 2000 - 2008
[2] Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 14, p. 4713 - 4718
13
[ 110-91-8 ]
[ 5326-23-8 ]
[ 64614-49-9 ]
Reference：
[1] Patent: US2009/105209, 2009, A1, . Location in patent: Page/Page column 58
[2] Patent: WO2009/77334, 2009, A1, . Location in patent: Page/Page column 88
[3] Journal of Medicinal Chemistry, 2015, vol. 58, # 1, p. 512 - 516
14
[ 5326-23-8 ]
[ 23100-12-1 ]
Reference：
[1] Tetrahedron, 2002, vol. 58, # 37, p. 7381 - 7389
[2] Journal of the Chemical Society, Chemical Communications, 1994, # 15, p. 1775 - 1776
[3] Bioorganic and Medicinal Chemistry Letters, 2006, vol. 16, # 7, p. 2013 - 2016
[4] Organic Letters, 2001, vol. 3, # 19, p. 3009 - 3012
[5] Chemical and Pharmaceutical Bulletin, 2000, vol. 48, # 5, p. 694 - 707
[6] Synthesis, 1998, # 9, p. 1335 - 1338
[7] Journal of Organic Chemistry, 1998, vol. 63, # 3, p. 760 - 768
[8] Journal of Organic Chemistry, 1993, vol. 58, # 21, p. 5600 - 5602
[9] Patent: WO2014/167084, 2014, A1,
15
[ 105827-78-9 ]
[ 616-45-5 ]
[ 5326-23-8 ]
[ 6271-78-9 ]
[ 23100-12-1 ]
[ 463-04-7 ]
[ 625-74-1 ]
[ 120868-66-8 ]
Reference：
[1] Chinese Journal of Chemistry, 2012, vol. 30, # 1, p. 127 - 132
16
[ 5326-23-8 ]
[ 58584-63-7 ]
Reference：
[1] Journal of Labelled Compounds and Radiopharmaceuticals, 2007, vol. 50, # 5-6, p. 613 - 615
17
[ 5326-23-8 ]
[ 21543-49-7 ]
Yield
Reaction Conditions
Operation in experiment
75%
With BH3 In tetrahydrofuran; ethyl acetate
9-Chloro-5-{3-[2-(6-chloropyridin-3-yl)-2-hydroxyethylamino]cyclohexyl}-3-methyl-5H-isoxazolo[4,3-c]quinolin4one To a stirred solution of 6-chloronicotinic acid (900 mg, 5.7 mmol) in THF (7 mL) was added BH3 (16 mL, 17.1 mmol, 1M in THF) under N2 atmosphere. The reaction mixture was stirred for 5 h. It was quenched with methanol (5 mL) and then concentrated. The crude was dissolved in EtOAc (30 mL), washed with 1N NaOH (15 mL*3), brine, dried and concentrated. Yield: 615 mg (75percent) of 6-chloro-pyridin-3-yl-methanol.
0.55 g
With lithium aluminium tetrahydride In tetrahydrofuran at 0 - 30℃; for 3 h; Inert atmosphere
To a solution of methyl 6-chloronicotinate (1.08 g, 0.009 mole) in THF (30 mL) at 0 °C under N2, was added lithium aluminum hydride (1 M in THF, 7.5 mL, 0.0075 mole) drop wise. Reaction mixture was warmed to RT and stirred for 3 hours. The reaction mixture was cooled to 0 °C, diluted with ethyl acetate and treated with water (2 mL). The mixture was filtered through celite bed and concentrated under vacuum to obtain the crude compound which was further purified by flash chromatography using ethyl acetate: n-hexane (40: 60) to afford 2-chloro-5-hydroxymethylpyridine. Yield: 0.55 g; lH - NMR (CDC13, 400 MHz) δ ppm: 2.09 (bs, 1H), 4.72 (s, 2H), 7.31 - 7.34 (d, J = 8.1 Hz, 1H), 7.68 - 7.71 (dd, J = 2.2, 8.4 Hz, 1H), 8.36 (s, 1H); Mass (m/z): 144.1, 146.0 (M+H)+.
Reference：
[1] Journal of Labelled Compounds and Radiopharmaceuticals, 1999, vol. 42, # SUPPL. 1, p. S99-S101
[2] Journal of Organic Chemistry, 1999, vol. 64, # 23, p. 8576 - 8581
[3] Synthesis, 1998, # 9, p. 1335 - 1338
[4] Journal of Organic Chemistry, 1993, vol. 58, # 21, p. 5600 - 5602
[5] Journal of Organic Chemistry, 1998, vol. 63, # 3, p. 760 - 768
[6] Bioorganic and Medicinal Chemistry Letters, 2006, vol. 16, # 7, p. 2013 - 2016
[7] Organic Letters, 2001, vol. 3, # 19, p. 3009 - 3012
[8] Chemical and Pharmaceutical Bulletin, 2000, vol. 48, # 5, p. 694 - 707
[9] Journal of medicinal chemistry, 1998, vol. 41, # 26, p. 5265 - 5271
[10] Synlett, 1999, # 3, p. 342 - 344
[11] Patent: US2003/100576, 2003, A1,
[12] Patent: US4332944, 1982, A,
[13] Patent: WO2013/82661, 2013, A1, . Location in patent: Page/Page column 28
[14] Journal of the American Chemical Society, 2013, vol. 135, # 43, p. 16120 - 16132
[15] Patent: WO2014/167084, 2014, A1, . Location in patent: Page/Page column 79; 80
[16] Patent: WO2018/42362, 2018, A1, . Location in patent: Page/Page column 40
18
[ 5326-23-8 ]
[ 70258-18-3 ]
Reference：
[1] Patent: US5225423, 1993, A,
[2] Patent: WO2013/82661, 2013, A1,
[3] Journal of the American Chemical Society, 2013, vol. 135, # 43, p. 16120 - 16132
19
[ 5326-23-8 ]
[ 182924-36-3 ]
Reference：
[1] Patent: WO2018/42362, 2018, A1,
20
[ 5326-23-8 ]
[ 101990-45-8 ]
Reference：
[1] Synlett, 1999, # 3, p. 342 - 344
21
[ 5326-23-8 ]
[ 64-17-5 ]
[ 49608-01-7 ]
Reference：
[1] Patent: EP1180514, 2002, A1, . Location in patent: Example 113
[2] Tetrahedron, 2002, vol. 58, # 22, p. 4429 - 4438
[3] Journal of Medicinal Chemistry, 1993, vol. 36, # 18, p. 2676 - 2688
[4] Patent: US6344463, 2002, B1, . Location in patent: Page column 17
22
[ 5326-23-8 ]
[ 78-39-7 ]
[ 49608-01-7 ]
Reference：
[1] Patent: US5659042, 1997, A,
23
[ 5326-23-8 ]
[ 49608-01-7 ]
Reference：
[1] Patent: US5250548, 1993, A,
24
[ 5326-23-8 ]
[ 97455-61-3 ]
Reference：
[1] Molecular Crystals and Liquid Crystals (1969-1991), 1985, vol. 126, p. 259 - 268
25
[ 5326-23-8 ]
[ 79-37-8 ]
[ 136592-00-2 ]
Yield
Reaction Conditions
Operation in experiment
97%
Stage #1: for 2.5 h; Stage #2: With diazomethyl-trimethyl-silane In dichloromethane; N,N-dimethyl-formamide for 2 h;
Example 34 ((2S,5S)-2-{5-[4-(5-{2-[(S)-1-((8)-2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-pyridin-2-yl)-phenyl]-1H-imidazol-2-yl}-4-oxo-1,2,4,5,6,7-hexahydro-azepino[3,2,1-hi]indol-5-yl)-carbamic acid methyl ester A suspension of 6-chloronicotinic acid (1.58 g, 10.0 mmol) in methylene chloride (50 ml) and DMF (4 drops) was treated with oxalyl chloride (1.53 g, 12.0 mmol). Stir the reaction mixture for 2.5 h and add trimethylsilyldiazomethane (25 ml, 2.0M solution, 50.1 mmol). Stir the reaction for 2 h and pass HCl gas through the mixture for 10 min. The reaction mixture was washed with a saturated sodium bicarbonate solution, a saturated sodium chloride solution and dried over magnesium sulfate, filtered and concentrated to afford, 2-chloro-1-(6-chloropyridin-3-yl)ethanone as a light brown solid, (1.85 g, 97percent): ESI-LRMS m/e calcd for C7H5Cl2NO [M+] 190, found 191 [M+H']
Reference：
[1] Journal of Antibiotics, 1995, vol. 48, # 11, p. 1336 - 1344
27
[ 5326-23-8 ]
[ 171178-47-5 ]
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2001, vol. 11, # 11, p. 1401 - 1405
28
[ 5326-23-8 ]
[ 58483-95-7 ]
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2001, vol. 11, # 11, p. 1401 - 1405
29
[ 5326-23-8 ]
[ 75-65-0 ]
[ 171178-45-3 ]
Yield
Reaction Conditions
Operation in experiment
62 g
for 2.5 h; Inert atmosphere; Reflux
N-5[N-tert-Butoxycarbonyl)amino]-2-chloropyridine (0581) A stirred solution of 6-chloronicotinic acid (47.3 g), diphenylphosphoryl azide (89.6 g) and triethylamine (46 ml) in t-butanol (240 ml) were heated under reflux under nitrogen for 2.5 hours. The solution was cooled and concentrated in vacuo. The syrupy residue was poured into 3 liters of a rapidly stirred solution of 0.33N aqueous sodium carbonate. The precipitate was stirred for one hour and filtered. The solid was washed with water and dried in vacuo at 70° C. to give the title compound (62 g) as a pale brown solid; m.p. 144-146° C.; δH [2H6]-DMSO 8.25 (1H, d), 7.95 (1H, bd), 7.25 (1H, d), 6.65 (1H, bs), 1.51 (9H, s); m/z (M+1)+ 229.
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2001, vol. 11, # 11, p. 1401 - 1405
31
[ 5326-23-8 ]
[ 133081-26-2 ]
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2007, vol. 17, # 12, p. 3440 - 3444
[2] Journal of Labelled Compounds and Radiopharmaceuticals, 1997, vol. 40, p. 455 - 457
[3] Letters in Organic Chemistry, 2014, vol. 11, # 3, p. 208 - 214
[4] RSC Advances, 2015, vol. 5, # 113, p. 93374 - 93385
[5] Journal of Labelled Compounds and Radiopharmaceuticals, 2017, vol. 60, # 9, p. 431 - 438
32
[ 5326-23-8 ]
[ 124-40-3 ]
[ 54864-83-4 ]
Yield
Reaction Conditions
Operation in experiment
75%
With 4-methyl-morpholine; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In tetrahydrofuran at 20℃; Inert atmosphere
Scheme 32 : Synthesis of 6-Chloro-N, V-dimethylnicotinamide [198 ] Compound [197 ] (3.0 g, 19.0 mmol) was dissolved in THF ( 100 ml) in a clean oven-dried two necked RB flask (250ml) and degassed with nitrogen. To this clear solution, EDC.HCl (4.02 g, 20.9 mmol) was added, followed by NMM (2.3 ml, 20.9 mmol). The reaction mixture was stirred and heated at RT for 10 min, under nitrogen atmosphere. Me2NH ( 13.06 ml, 2N, 2S.5 mmol) was added dropwise and reaction mixture was stirred RT for 16 hrs. The reaction was monitored by TLC. The reaction mixture was quenched with aq. NaHC( „ extracted with ethyl acetate (3 x 100ml). The organic extracts were combined, washed with brine and dried using Na2S04. The organic layer was evaporated to crude which was purified by column chromatography ( 100-200 mesh, 2 percent MeOH/DCM) to yield compound [198 ] (2.62 g, 75percent) as white solid. ESTMS: 185 (M++ l )
72%
With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In tetrahydrofuran at 20℃; for 15 h;
(1) 6-Chloro-N,N-dimethylnicotinamide To a solution of commercially available 6-chloronicotinic acid (1.58 g, 10.0 mmol) in THF(40 mL) were added triethylamine (2.09 mL, 15.0 mmol), 50percent dimethylamine (1.26 mL, 14.0 mmol), and 1-ethyl-3-[3-(N,N-dimethylamino)propyl]-carbodiimide hydrochloride (2.26 g, 11.0 mmol), and the mixture was stirred at room temperature for 15 hours. Chloroform was added to the reaction mixture. The organic layer was washed with water and saturated aqueous sodium hydrogencarbonate solution, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (chloroform) to obtain 6-chloro-N,N-dimethylnicotinamide (1.33 g, 7.20 mmol).yield: 72percent
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2007, vol. 17, # 12, p. 3440 - 3444
[2] Journal of Labelled Compounds and Radiopharmaceuticals, 1997, vol. 40, p. 455 - 457
[3] Bioorganic Chemistry, 2011, vol. 39, # 4, p. 138 - 142
[4] Patent: WO2013/67597, 2013, A1,
[5] Letters in Organic Chemistry, 2014, vol. 11, # 3, p. 208 - 214
[6] RSC Advances, 2015, vol. 5, # 113, p. 93374 - 93385
[7] Journal of Labelled Compounds and Radiopharmaceuticals, 2017, vol. 60, # 9, p. 431 - 438
[8] Patent: WO2017/177144, 2017, A1,
34
[ 5326-23-8 ]
[ 24424-99-5 ]
[ 115309-57-4 ]
Yield
Reaction Conditions
Operation in experiment
94%
Stage #1: With dmap In tetrahydrofuran for 3 h; Reflux Stage #2: for 3 h; Reflux
A solution of 6-chloronicotinic acid (31.6 g, 200 mmol) and 4-dimethylaminopyridine (2.4 g, 20 mmol) in THF (250 mE) was refluxed for 3 hours. Then di-tert-butyl dicarbonate (65.0 g, 300 mmol) was added dropwise. After addition, the reaction mixture was refluxed for 3 hours. Upon reaction completion, the reaction mixture was cooled to room temperature. The solvent was removed and the residue was purified by column chromatography on silica gel (ethyl acetate/petroleum ether=0.-1/10) to give tert-butyl 6-chloronicotinate (40 g, 94percent yield) as a white solid. EC-MS (Agilent ECMS 1200-6120, Column:Waters X-l3ridge C18 (50 mmx4.6 mmx3.5 pm); Column Temperature: 40° C.; Flow Rate: 2.0 mE/mm; Mobile Phase:from 95percent [water+10 mM NH4HCO3] and 5percent [CH3CN] to 0percent [water+10 mM NH4HCO3] and 100percent [CH3CN] in 1.6 mm, then under this condition for 1.4 mm, finally changed to 95percent [water+10 mM NH4HCO3] and 5percent [CH3CN] in 0.1mm and under this condition for 0.7 mm). Purity is 100percent,Rt=1.984 mm; MS Calcd.: 213.06; MS Found: 214.2[M+H]. ‘H NMR (400 MHz, DMSO-d5) ö 1.56 (9H, s),7.67 (1H, d, J=8.4 Hz), 8.26 (1H, dd, J=8.0, 2.4 Hz), 8.86(1H, d, J=2.4 Hz). Chemical Formula: C,QH,2C1N02, MolecularWeight: 213.66. Total H count from HNMR data: 12.
Reference：
[1] Journal of Heterocyclic Chemistry, 2012, vol. 49, # 2, p. 442 - 445
[2] Patent: US2018/215731, 2018, A1, . Location in patent: Paragraph 0897; 0909; 0910; 0911; 0912; 0913; 0914
[3] Patent: WO2006/65908, 2006, A1, . Location in patent: Page/Page column 67; 68
[4] Organic Process Research and Development, 2011, vol. 15, # 1, p. 64 - 72
35
[ 5326-23-8 ]
[ 115309-57-4 ]
Reference：
[1] Patent: US6239152, 2001, B1,
[2] Organic Process Research and Development, 2010, vol. 14, # 4, p. 936 - 938
36
[ 5326-23-8 ]
[ 36805-97-7 ]
[ 115309-57-4 ]
Reference：
[1] Journal of Organic Chemistry, 2006, vol. 71, # 5, p. 2000 - 2008
[2] Patent: US2011/301148, 2011, A1, . Location in patent: Page/Page column 12
37
[ 5326-23-8 ]
[ 75-65-0 ]
[ 115309-57-4 ]
[ 313350-11-7 ]
Yield
Reaction Conditions
Operation in experiment
70.3%
Stage #1: for 3 h; Heating / reflux Stage #2: With triethylamine In dichloromethaneHeating / reflux Stage #3: With sodium hydrogencarbonate In dichloromethane; water
A mixture of 6-chloronicotinic acid (12.0 g, 76 mmol) and thionyl chloride (65 mL) was heated at reflux for 3.0 h. The excess thionyl chloride was removed under reduced pressure, and the residual liquid was diluted with dichloromethane (20 mL) and then added to a solution of tert-butyl alcohol (71 mL, 760 mmol) in dichloromethane (40 mL). To the mixture was added triethylamine (31.7 mL, 760 EPO <DP n="68"/>mmol) and N,N-dimethylpyridine (0.5 g, 4.0 mmol), and the reaction mixture was stirred overnight (14 h) at reflux under nitrogen. The solution was diluted with dichloromethane (200 mL), washed with a saturated aqueous solution of sodium bicarbonate (3 x 100 mL), washed with water (3 x 100 mL), and dried over anhydrous sodium sulfate. Concentration under reduced pressure provided Preparation 3 (11.4 g, 70.3percent) as a yellow solid. The product had an analytical HPLC retention time = 3.18 min. (Column: YMC ODS 4.6 x 50 mm (4 min.); Solvent A = 10percent MeOH, 90percent H2O, 0.2percent H3PO4; Solvent B = 90percent MeOH, 10percent H2O, 0.2percent H3PO4) and a LCMS M+1 = 214. The purity of the product was about 96percent. The major impurity was the iso- propyl 6-chloronicotinate with an analytical HPLC retention time = 2.88 min. and a LOMS M+1 = 200.
General procedure: To 6-chloronicotinic acid 19a (10 g) in methylene chloride(100 ml) solution, N,N’-diisopropyl-O-tert-butylisourea (50 g) wasadded and the mixture was stirred under heating and reflux for16 h. The insoluble compound was filtered out, and the filtratewas concentrated. The residue was purified by silica gel column chromatography (chloroform/ethyl acetate = 6/1) to obtain the compound 20a (11.66 g). To the compound 20a (6.0 g) in dimethylacetoamide (30 ml) solution, tris(dibenzylideneacetone)dipalladium (0.51 g), zinc cyanide (0.22 g), diphenylphosphinoferrocene (0.62 g), and zinc powder (1.98 g) were added and the mixture was stirred under argon atmosphere at 120 °C for 3 h. The reaction solution was filtered by sellite, which was then washed with ethyl acetate. Then, the filtrate was washed with distilled water and saturated saline, then the organic layer was dried over with anhydrous sodium sulfate and concentrated. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate= 5/1) to obtain the compound 21a (3.59 g). To copper(I) iodide(0.93 g) in tetrahydrofuran (50 ml) suspension, ethylmagnesium bromide (0.86 M tetrahydrofuran solution)(12.5 ml) was added dropwise under cooling at 0 °C, the mixture was stirred at 0 °C for 30 min, then the compound 21a (1.0 g) obtained above in tetrahydrofuran (10 ml) solution was added atthe 20 °C. After stirring for 30 min at that temperature, 28percent ammonia solution in water and ethyl acetate were added to the mixture and the solution separated. The aqueous layer was extracted with ethyl acetate, while the combined organic layer was washed with saturated saline, then was dried over with anhydrous sodium sulfate and concentrated. The obtained residue was purifiedby silica gel column chromatography (hexane/ethyl acetate= 8/1) to obtained the compound 22a (0.47 g). To the compound 22a (200 mg) in tetrahydrofuran (1 ml) solution, (-)-B-chlorodiisopinocampheylborane (65percent hexane solution) (0.92 ml) was added dropwise under cooling at 20 °C, then the mixture was stirred at that temperature for 18 h. Then, ether and distilled water were added to the reaction mixture, and the solution was separated. The organic layer was extracted with distilled water and 1 M hydrogen chloride. Then, the combined aqueous layer was neutralized by sodium hydrogen carbonate, and extracted with ethyl acetate. Organic layer was washed with saturated saline, then was dried over with anhydrous sodium sulfate and concentrated to obtained the title compound (150 mg, 84percent ee). The optical purity was determined using CHIRALCEL AD-H(Daicel Chemical Industries) (movement phase: hexane/ethanol= 98/2, 1.0 ml/min).
Reference：
[1] Bioorganic and Medicinal Chemistry, 2013, vol. 21, # 14, p. 4233 - 4249
Reference：
[1] Journal of Organic Chemistry, 2006, vol. 71, # 5, p. 2000 - 2008
[2] Organic Process Research and Development, 2006, vol. 10, # 6, p. 1157 - 1166
41
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[ 342417-04-3 ]
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[1] Journal of Organic Chemistry, 2006, vol. 71, # 5, p. 2000 - 2008
[2] Organic Process Research and Development, 2006, vol. 10, # 6, p. 1157 - 1166
42
[ 5326-23-8 ]
[ 342417-01-0 ]
Reference：
[1] Journal of Organic Chemistry, 2006, vol. 71, # 5, p. 2000 - 2008
[2] Journal of Organic Chemistry, 2006, vol. 71, # 5, p. 2000 - 2008
[3] Organic Process Research and Development, 2006, vol. 10, # 6, p. 1157 - 1166
[4] Patent: US9403772, 2016, B2,
[5] Patent: JP2015/17121, 2015, A,
[6] Patent: US8426450, 2013, B1,
Reference：
[1] Journal of Labelled Compounds and Radiopharmaceuticals, 2007, vol. 50, # 5-6, p. 613 - 615
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[ 381233-78-9 ]
Reference：
[1] Patent: CN104356056, 2017, B,
46
[ 5326-23-8 ]
[ 3612-20-2 ]
[ 1017598-71-8 ]
Yield
Reaction Conditions
Operation in experiment
66%
Stage #1: With 2,2,6,6-tetramethyl-piperidine; n-butyllithium In tetrahydrofuran; hexane at -78℃; for 3 h; Stage #2: at -78℃; for 2 h;
The synthesis of the intermediate I-11.1 is described in EP2072519 A1, p. 36. At −78° C., a hexane solution (94 mL, 150.81 mmol) of 1.6 M n-butyllithium is added dropwise to a THF solution (110 mL) of 2,2,6,6-tetramethylpiperidine (16.14 g, 113.10 mmol) and obtained solution is stirred for 1 hour. Afterwards a THF solution (50 mL) of 6-chloronicotinic acid (6.0 g, 37.70 mmol) is added dropwise over 1 hour and the reaction mixture is stirred for 2 hours. A THF solution (50 mL) of 1-benzyl-4-piperidone (21.6 g, 113.10 mmol) is added dropwise at −78° C. After stirred for 2 hours, water (70 mL) is added, and the reaction mixture is warmed to room temperature. The aqueous layer is separated, and the organic layer is extracted with aqueous 1 N sodium hydroxide solution (2×75 mL). The obtained aqueous layer is extracted with diethyl ether (100 mL), and the aqueous layer is acidified (pH-1) by adding concentrated hydrochloric acid. After stirring for 1 hour, the precipitate is filtered off, washed with water, and dissolved in ethyl acetate. The organic layer is washed with aqueous saturated sodium hydrogen carbonate solution, dried over Na2SO4 and concentrated in vacuo. The residue is washed with diethyl ether. Yield 66percent, m/z 329 [M+H]+, rt 0.72 min, LC-MS Method Z012_S04.
With potassium hydroxide In dimethyl sulfoxide at 70 - 80℃; for 22h;
Preparation of synthetic compounds
General procedure: 6-Chloronicotinic acid (0.5 g, 3.2 mmol), potassiumhydroxide powder (1 g, 17.8 mmol) and 1 ml of one of thefollowing alcohol (ethanol, butanol, hexanol or octanol)were added to DMSO (12 ml) at room temperature. Thereaction mixture was heated at 70-80 °C for 22 h, thencooled to room temperature and poured over 100 ml ofwater and crushed ice. An aqueous solution of HCl (2 M)was added to acidify the solution to pH = 2. The resultingprecipitate was collected by filtration, washed with waterand dried under vacuum. Structures of the products wereconfirmed by NMR, MS and IR as follows.
In isopropyl alcohol at 180℃; for 0.666667h; microwave irradiation;
at 180℃; im Rohr;
In water
35.a a
a 6-dimethylaminonicotinic acid 6-Chloronicotinic acid (0.5 g, 3.17 mmol) and dimethyl amine 10 ml, 40% in water) were heated in a sealed pressure vessel at 130° C. for 6 h. The solvent was then removed and the residue was taken up in water and the pH was adjusted to 4-5. Extraction with dichloromethane yielded the pure intermediate depicted above (0.1 g, 20%). 1H NMR (CDCl3): 8.87 (dd, 1H), 8.04 (dd, 1H), 6.49 (dd, 1H), 3.18 (s, 6H).
In tetrahydrofuran at 150℃; for 0.75h; Microwave irradiation;
20.1
To a solution of 82a (1.0 g, 6.34 mmol) and THF (15 mL) was added Me2NH (6.35 mL, 12.69 mmol; 2.0 M solution in THF) and the mixture was stirred in a microwave and heated to 150° C. for 45 min. The solvent was evaporated to afford 1.0 g of 82b which was used in the next step.
With potassium iodide; ethylenediamine; In pyridine; Triethylene glycol dimethyl ether; water;
EXAMPLE 43 Preparation of 2-isopropyl-11-oxo-11H-pyrido[2,1-b]quinazoline-8-carboxylic acid A suspension of 6.0 g. of <strong>[68701-22-4]5-isopropylanthranilic acid</strong>, 5.4 g. of 6-chloronicotinic acid and 0.05 g. of potassium iodide in 10 ml. of triglyme was heated overnight (bath temperature 150) under a stream of argon. On cooling, the mixture was triturated with ethanol and water and filtered to give 5.89 g. of crude product, mp 280-287. This material was dissolved in hot pyridine and treated with ethylenediamine to give the corresponding salt which was collected by filtration. This salt was dissolved in water and the pure acid was precipitated with dilute acetic acid. Recrystallization from dimethylformamide-acetic acid-water gave 2.5 g. (26.6%) of 2-isopropyl-11-oxo-11H-pyrido[2,1-b]quinazoline-8-carboxylic acid, mp 314-316.
With hydrazine hydrate; at 100℃; for 4h;Inert atmosphere;
6-Chloronicotinic acid (0.30 g; 1.9 mmol) was added to a64% hydrazine monohydrate solution (2 mL, 26 mmol) andplaced at 100C for 4h. Thereafter, the reaction mixtureturned brown and was concentrated to dryness. The residuewas dissolved in water and pH adjusted to 5.5 with concentratedHCl. A precipitate was formed, filtered and washedwith ethanol, then ether to give a yellow solid (0.346 g,96%). Mp = 292-293C. IR (ATR, cm-1) 3210; 3058; 3039;1696; 1636; 1613; 1536-1444; 1170; 757; 736. 1H NMR(DMSO-d6) 8.63 (s, 1H); 8.07 (d, 1H, J= 9 Hz); 6.94 (d,1H, J = 9 Hz). 13C NMR (DMSO-d6) 167.2; 159.61;140.9; 119.9; 110.6. HRMS (ESI+) [M]+: 153.0531 observed,153.0538 Calcd for C6H7N3O2.
91%
With hydrazine hydrate; In ethanol;Reflux;
Example 72: 3-oxo-2,3-dihydro-[l,2,4]triazolo[4,3-a]pyridine-6-carbonyl chloride; [0235] To a solution of 6-chloronicotinic acid (20 g, 127 mmol) in 200 mL of EtOH was added hydrazine hydrate (14.8 mL, 317 mmol). The mixture was refluxed overnight, then cooled to room temperature to give a solid, which was collected by filtration, washed with petroleum ether/EA (2: 1) to give 18 g of 6-hydrazinylnicotinic acid as a yellow solid (Yield: 91%). 1HNMR (DMSO, 400MHz) delta: 8.52 (s, IH), 7.88 (dd, J = 2.0 Hz, 8.8 Hz, IH), 6.63 (d, J = 8.8Hz, IH).[0236] To a suspension of 6-hydrazinylnicotinic acid (18 g, 117 mmol) in 100 mL of dry THF was added dry pyridine (23 g, 293 mmol), then the mixture was stirred at room temperature for 15 min, then bis(trichloromethyl)carbonate (80 g, 270 mmol) was added slowly. The reaction mixture was stirred overnight at room temperature, then MeOH was added and continued stirring for 15 hours to give a solid. The solid was collected by filtration and washed with petroleum ether/EA (1: 1) to give 20 g of dimethyl 3-oxo-[l,2,4]triazolo[4,3- a]pyridine-2,6(3H)-dicarboxylate. 1HNMR (CDCl3, 400MHz) delta: 3.95 (s, 3H), 4.13 (s, IH), 7.13 (dd, J = 1.6 Hz, 10 Hz, IH), 7.71 (dd, J = 1.6 Hz, 10 Hz, IH), 8.55 (t, J = 2 Hz, IH). [0237] To a solution of dimethyl 3-oxo-[l,2,4]triazolo[4,3-a]pyridine-2,6(3H)-dicarboxylate (10 g, 40 mmol ) in 60 mL of THF and 10 mL of H2O was added LiOH-H2O (4.8 g, 114 mmol), and then the reaction mixture was stirred at room temperature for 6 hours and then was concentrated in vacuo to remove THF, and then 1 mL of aq. HCl solution was added to adjust pH=2 to give a solid which was collected to give 1 Ig of compound 3-oxo-2,3-dihydro- [1 ,2,4]triazolo[4,3-a]pyridine-6-carboxylic acid which was used without the further purification. 1HNMR (DMSO, 400MHz) delta: 7.23 (d, J = IO Hz, IH), 7.48 (dd, J = 1.6 Hz, 10Hz, IH), 8.25 (s, IH), 9.13 (s, IH), 12.89 (s, IH).[0238] To a solution of 3-oxo-2,3-dihydro-[l,2,4]triazolo[4,3-a]pyridine-6-carboxylic acid (3 g, 16.8 mmol) in 60 mL of dry DCM was added oxalyl chloride (8.8 g, 74 mmol) and 1 mL ofDMF. The reaction mixture was stirred for 6 hrs at room temperature and concentrated to give[0239] 3 g of the title compound as a gray solid which was used without the further purification.
87%
With hydrazine; In water; at 95 - 100℃; for 4h;
A mixture of 6-chloronicotinic acid (10.0 g, 63.4 mmol), hydrazine (20 mL), and water (20 mL) was refluxed at 95-100 C for 4 h. The mixture was concentrated under vacuum and the residue was dissolved in 40 mL water. The resulting solution was acidified with 1N HCl to reach a pH 5-5.5. The solution was kept in a refrigerator overnight. The precipitated solid was collected by filtration, washed with cold water (10 mL x 2) and ether (10 mL x 2). The solid was dried to give 8.5 g (87%) of the title compound. ES-MS: Observed [MH]+ 154.1.
85%
General procedure: A 0.5M solution of 2-chloropyridine-5-carboxylic acid (15 mmol) was treated with hydrazine hydrate (150 mmol, added at once) and heated at reflux for 72 h. The suspension was concentrated to dryness. The residue was dissolved in water and acidified (pH = 3) with acetic acid. The precipitate of 2-hydrazinopyridine-5-carboxylic acid that formed in 15 min was filtered off, washed with water and air-dried. It was dissolved in the respective aliphatic carboxylic acid and the solution (0.5M) was heated at reflux for 48 h. Upon cooling to room temperature, the volatiles were removed in vacuo and the residue was triturated with 1M aqueous sodium bicarbonate. The precipitate thus formed was filtered off, washed with water and air dried. The resulting 1,2,4-triazolo[4,3-a]pyridine 12 was dissolved in methanol (0.25M and was hydrogenated over Pd(OH)2 catalyst (0.1 equiv.) at 100 atm and 100 C over 24 hours. The mixture was filtered while still hot and concentrated in vacuo. The residue was crystallized from isopropyl alcohol to provide analytically pure carboxylic acids 11a-d.
77%
With hydrazine hydrate; In water;
Synthesis of 6-hydrazinopyridine-3-carboxylic acid 6-Chloronicotinic acid (8.0 g) was added to 85% hydrazine hydrate (35 ml). The reaction mixture was placed in a 100 C. oil bath for 4 hours. The homogeneous reaction mixture was concentrated to dryness to give a white solid. The solid was dissolved in water and on acidification to pH 5.5 with concentrated hydrochloric acid a precipitate formed. The precipitate was isolated by filtration and the solid was washed with 95% ethanol and ether to give 6.0 g of a pale brown solid; yield 77% m.p. 292-293 C.; Analysis: Calculated for C6 H7 N3 O2; C 47.06; H 4.61; N 27.44; Found: C 46.83; H 4.38; N 27.27. 1 H NMR- delta: 6.69(d,J=8.8 Hz,1H),7.84(dd,J=2.4,8.8 Hz,1H), 8.51(d,J=2.4 Hz,1H)
57.7%
With hydrazine hydrate; In 1,4-dioxane; at 90℃;
Preparation 6 6-hydrazinylnicotinic acid [0147] A suspension of 6-chloronicotinic acid (30.0 g, 189 mmol) in 1,4-dioxane (29.0 mL) was treated with hydrazine hydrate (134 mL, 1.51 mol) and heated to 90C overnight. The mixture was cooled to ambient temperature and then in ice for 30 min. Precipitate formation was induced by etching the side of the flask and the precipitate was filtered and re-suspended in EtOH (500 mL) with vigorous stirring. The resulting suspension was filtered. The precipitate was dissolved in water (300 mL) and HC1 (6N) was added until pH = 1. The pH was then adjusted to 5 with NaOH (50%, aq.) and the resulting suspension was stirred for lh. The solids were collected by filtration and dried in vacuum to give the title compound (16.65 g, 57.7 % yield) as an off-white solid. XH NMR (400 MHz, DMSO-i/6) delta ppm 6.70 (d, 1 H) 7.86 (dd, J=8.97, 2.15 Hz, 1 H) 8.32 (br. s., 1 H) 8.52 (d, J=1.77 Hz, 1 H). MS m/z [M+H]+ 154.
40%
With hydrazine hydrate; In ethanol; for 48h;Reflux;
Synthesis of 6-hydrazinylnicotinic acid To a solution of 6-chloronicotinic acid (5g, 32 mmol)) in EtOll (50 mL) was added hydrazine hydrate (3.7 mL, 80 mmol). The mixture was heated to reflux with stirring for 48 hrs. The mixture was allowed to cooled to r.t. to give a gray precipitatewhich was collected by filtration and then washed with EtCH and petroleum ether/EtOAc (2:1) to give 2 g solid (40%)
With hydrazine hydrate; In ethanol;
A solution of (3.00 g, 19 mmoles) 6-chloronicotinic acid and (4.62 mL, 95 mmoles) hydrazine monohydrate in (15 mL) ethanol was refiuxed under argon for 18 hours. Upon cooling to room temperature a white solid product, 6-hydrazino nicotinic acid, formed. This was filtered and washed with ethanol then dissolved in water, acidified to pH 7.0 with acetic acid causing a white precipitate. This was filtered, washed with water, and dried in vacuo over KOH, (1.87 g, 64% yield)
With hydrazine; In methanol; at 140℃; for 2h;
6-chloronicotinic acid (1.6 g ) in MeOH (1OmL) was treated with NH2NH2 (2 g) at 140 0C for 2h. After cooling to -20 0C, the solid was filtered to give 560mg of compound 33B. Compound 33B was treated with isothiocyanatobenzene (141 mg) in 1 ,2-dichlorobenzene (5 mL) at 100 0C for 10 min, and then 180 0C for Ih. The product was purified by LCMS to give 3-mercapto- [l,2,4]triazolo[4,3-a]pyridine-6-carboxylic acid (450mg). ESI-MS:m/z 196.1 (M+H)+.
With hydrazine hydrate; In ethanol; for 16h;Reflux;
.0 g (31.7 mmol) 6-chloronicotinic acid and 30.9 ml (31.8 g, 634.7 mmol) hydrazine hydrate are initially introduced into 10 ml ethanol and the mixture is stirred at the boiling point at a bath temperature of 100 C. for 16 h. The solvent and excess hydrazine hydrate are distilled off on a rotary evaporator, the residue is taken up in water, 1.8 g (31.7 mmol) potassium hydroxide are then added and the mixture is stirred for 15 min. The solvent is removed completely on a rotary evaporator, the residue is dried in vacuo and 7.5 g of crude product, which is reacted further as such, are obtained.LC-MS (Method 1): Rt=0.48 min; MS (ESIpos): m/z=154 [M+H]+;1H-NMR (400 MHz, DMSO-d6): delta=8.49 (d, 1H), 7.89 (br. s, 1H), 7.84 (dd, 1H), 6.63 (d, 1H), 5.37 (br. s, 2H).
With hydrazine hydrate; at 100℃; for 6h;
6-Chloronicotinic acid (5 g; 31.7 mmol) was added to 80% hydrazine hydrate (22 mL; 584.6 mmol)and the resulting solution was heated at 100 C for 6 h. Then the reaction mixture was concentrated todryness to afford a white solid. The solid was dissolved in water (50 mL). The pH was adjusted to 5.5by addition of concentrated hydrochloric acid, and a yellow precipitate was formed. The precipitatewas collected by filtration, washed with 95% ethanol and ether and dried under high vacuum to afford3.6 g of 6-hydrazinopyridine-3-carboxylic acid in a yield of 75%.
With hydrazine hydrate; at 100℃;
Hydrazine hydrate (8 ml_) was added to 6-chloronicotinic acid (3.0 g, 19.1 mmol). The reaction mixture was heated to 100 C and stirred 16 h. The volatiles were removed under reduced pressure and ethanol (50 ml_) was added. The resulting precipitate was filtered and collected to give 6-hydrazinylnicotinic acid (2.8 g, crude) as a white solid. Used directly in the next step without further purification. LCMS (ESI) m/z: 1 54.1 [M+H]+.
With diphenyl phosphoryl azide; triethylamine; for 2.5h;Heating / reflux;
N-5-[N-tert-Butoxycarbonyl)amino]-2-chloropyridine A stirred solution of 6-chloronicotinic acid (47.3 g), diphenylphosphoryl azide (89.6 g) and triethylamine (46 ml) in t-butanol (240 ml) were heated under reflux under nitrogen for 2.5 hours. The solution was cooled and concentrated in vacuo. The syrupy residue was poured into 3 litres of a rapidly stirred solution of 0.33N aqueous sodium carbonate. The precipitate was stirred for one hour and filtered. The solid was washed with water and dried in vacuo at 70 C. to give the title compound (62 g) as a pale brown solid; m.p. 144-146 C.; deltaH [2H6]-DMSO 8.25(1H, d), 7.95 (1H, bd), 7.25 (1H, d), 6.65(1H, bs), 1.51 (9H, s); m/z (M+1)+ 229.
With diphenyl phosphoryl azide; triethylamine; In tert-butyl alcohol; for 2.5h;Heating / reflux;
A stirred solution of 6-chloronicotinic acid (47.3 g), diphenylphosphoryl azide (89.6 g) and triethylamine (46 ml) in t-butanol (240 ml) were heated under reflux under nitrogen for 2.5 hours. The solution was cooled and concentrated in vacuo. The syrupy residue was poured into 3 litres of a rapidly stirred solution of 0.33N aqueous sodium carbonate. The precipitate was stirred for one hour and filtered. The solid was washed with water and dried in vacuo at 70 C. to give the title compound (62 g) as a pale brown solid; m.p. 144-146 C.;deltaH [2H6]-DMSO 8.25 (1H, d), 7.95 (1H, bd), 7.25 (1H, d), 6.65 (1H, bs), 1.51 (9H, s); m/z (M+1)+229.
62 g
With diphenyl phosphoryl azide; triethylamine; for 2.5h;Inert atmosphere; Reflux;
N-5[N-tert-Butoxycarbonyl)amino]-2-chloropyridine (0581) A stirred solution of 6-chloronicotinic acid (47.3 g), diphenylphosphoryl azide (89.6 g) and triethylamine (46 ml) in t-butanol (240 ml) were heated under reflux under nitrogen for 2.5 hours. The solution was cooled and concentrated in vacuo. The syrupy residue was poured into 3 liters of a rapidly stirred solution of 0.33N aqueous sodium carbonate. The precipitate was stirred for one hour and filtered. The solid was washed with water and dried in vacuo at 70 C. to give the title compound (62 g) as a pale brown solid; m.p. 144-146 C.; deltaH [2H6]-DMSO 8.25 (1H, d), 7.95 (1H, bd), 7.25 (1H, d), 6.65 (1H, bs), 1.51 (9H, s); m/z (M+1)+ 229.
To a suspension of 1 g (6.35 mmol) of 6-chloropyridine-3-carboxylic acid in 10 mL of refluxing toluene are added dropwise 7.6 mL (31.75 mmol) of 1,1-di-tert-butoxy-N,N-dimethylmethanamine, and the reaction medium is then refluxed for 30 minutes. After cooling to room temperature, the reaction medium is taken up in 200 mL of EtOAc, washed successively with water (2*100 mL), with saturated NaHCO3 solution (100 mL) and brine (100 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. 1.16 g of tert-butyl 6-chloropyridine-3-carboxylate are obtained in the form of a yellow oil, which is used without further purification in the following step.Yield=86%1H NMR, d6-DMSO, 400 MHz, delta (ppm): 8.8 (s, 1H); 8.2 (d, 1H); 7.3 (d, 1H); 1.5 (s, 9H).
With dmap; bis-(2-oxo-3-oxazolidinyl)phosphoryl chloride; triethylamine; In dichloromethane; at 20℃; for 12h;
To a solution of 6-chloronicotinic acid (1.5 eq) and triethylamine (2.0 eq) in CH2Cl2 (5 mL) was added BopCl (2.0 eq). After 15 min, <strong>[616238-78-9]7-amino-benzo[b]thiophene-2-carboxylic acid methyl ester</strong> (87 mg) in CH2Cl2 and 4-dimethylaminopyridine (DMAP) (1.0 eq) were added to the reaction solution above. The reaction was stirred at room temperature 12 h. The reaction was then diluted with EtOAc, and washed with NaHCO3 solution and brine. The organics were dried over MgSO4, filtered and concentrated to give a crude material which was purified by flash chromatography on silica gel (20%-50% EtOAc/hexane) to provide 100 mg (68%) of the desired 7-[(6-chloro-pyridine-3-carbonyl)-amino]-benzo[b]thiophene-2-carboxylic acid methyl ester as a light yellow solid. To a solution of 6-chloronicotinic acid (1.5 eq) and triethylamine (2.0 eq) in CH2Cl2 (5 mL) was added BopCl (2.0 eq). After 15 min, <strong>[616238-78-9]7-amino-benzo[b]thiophene-2-carboxylic acid methyl ester</strong> (87 mg) in CH2Cl2 and 4-dimethylaminopyridine (DMAP) (1.0 eq) were added to the reaction solution above. The reaction was stirred at room temperature 12 h. The reaction was then diluted with EtOAc, and washed with NaHCO3 solution and brine. The organics were dried over MgSO4, filtered and concentrated to give a crude material which was purified by flash chromatography on silica gel (20%-50% EtOAc/hexane) to provide 100 mg (68%) of the desired 7-[(6-chloro-pyridine-3-carbonyl)-amino]-benzo[b]thiophene-2-carboxylic acid methyl ester as a light yellow solid.
To a cooled (0 ° C.) solution of 7 6-chloronicotinic acid 6 (200 mg, 1.29 mmol) in 8 CH2Cl2 (5 mL), 2 drops of 9 DMF and 10 oxalyl Chloride (0.13 mL, 1.52 mmol) was added drop wise. The reaction mixture was stirred at room temperature for 16 h and the volatiles were removed under reduced pressure. The residue was cooled to 0° C. and dissolved in CH2Cl2 (5 mL), 11 methanol (1 mL) and heated to 40° C. (monitored by TLC). After 15 min, the solvents were removed under vacuo, diluted with ether. The organic layer was washed with water and brine solution. The organic extracts were dried over anhydrous Na2SO4 and concentrated under reduced pressure, to afford 12 methyl 6-chloronicotinate 7 (200 mg, 91percent) as off-white solid. 1H NMR (400 MHz, CDCl3): delta 9.00 (s, 1H), 8.26 (d, J=8.4 Hz, 1H), 7.43 (d, J=8.4 Hz, 1H), 3.96 (s, 3H).
With hydrogenchloride; for 5h;Heating / reflux;
6-Chloronicotinic acid (2,0 g) was dissolved in methanol and concentrated hydrochloric acid (3,0 ml) was added. The reaction mixture was refluxed for 5 hours and methanol was removed in vacuum. Ethyl acetate was added and the resulting solution was washed with saturated sodium bicarbonate solution, water and brine NMR (400 MHZ,) 8 : 8.92 (d, 1H, J 2.1 Hz), 8.32 (dd, 1H, J 8.4, 2.1 Hz), 7.70 (d, 1H, J 8.4 Hz), 3.90 (s, 3H).
1. 6-Chloronicotinic acid, methyl ester. To a solution of 6-chloronicotinic acid (20.0 g, 0.127 mol) in CH2Cl2(250 mL) was added oxalyl chloride (123.3 mL, 0.15 mol) with 1-5 drops of DMF. The solution was stirred 18 h and concentrated in vacuo. The residue was dissolved in CH2Cl2 (100 mL) and cooled in an ice bath. To this was added MeOH (20 mL) and the solution was stirred for 15 min while maintaining a temp below 40° C. The solvent was removed in vacuo, and the residue was dissolved in Et2O, washed with H2O and brine, dried with Na2SO4, and filtered through SiO2. The solvent was removed in vacuo to yield 6-chloronicotinic acid, methyl ester (21 g) as an off-white solid: 1H-NMR (300 MHz, CDCl3) delta 9.02 (d, J=13.8 Hz, 1H), 8.51-8.06 (m, 1H), 7.76-7.30 (m, 1H), 4.01 (s, 3H); EIMS m/z 171 ([M]+), which was used in Step 2 without further purification.
With diazomethyl-trimethyl-silane; In toluene; at 20℃; for 0.5h;
To a solution of 6-chloronicotinic acid (0.78 g, 5.00 mmol) in toluene (50 mL) and CH3OH (10 mL) was slowly added a solution of trimethylsilyldiazomethane (2.75 mL, 2.0 M in ether). After stirring at room temperature for 30 min, AcOH (0.5 mL) was added, and the solution was concentrated to dryness to yield crude 6-chloronicotinic acid methyl ester. The crude ester was dissolved in CH3CN (50 mL) and phenol (1.10 g, 11.0 mmol), Cs2C03 (0.98 g), and K2C03 (0.74 g) were then added. The mixture was refluxed overnight. The reaction showed incomplete conversion, so the solvent was replaced with DMF (10 mL), K2C03 (0.91 g) and phenol (0.64 g) were added, and the mixture was refluxed for 1 h. The mixture was poured into ice and extracted with Et20 (3 chi 25 mL). The combined organic layers were washed with aqueous Na2C03 and brine, dried (Na2S04), and concentrated to yield crude 20.
With sulfuric acid; at 65℃;Reflux;
A solution of 6-chloronicotinic acid (0.785 g,0.005 mol) in anhydrous methanol was added dropwise 98percent sulfuric acid. The mixture was gradually heated to reflux at 65°C. The solvent was evaporated in vacuum.The mixture was neutralized to pH=8 with saturated sodium bicarbonate solution and then extracted with ethyl acetate, dried by sodium sulfate. The mixture was filtered and the filtrate was concentrated in vacuum to give compound 11 as a pale yellow solid.
A solution of 6-chloronicotinic acid (31.6 g, 200 mmol) and 4-dimethylaminopyridine (2.4 g, 20 mmol) in THF (250 mE) was refluxed for 3 hours. Then di-tert-butyl dicarbonate (65.0 g, 300 mmol) was added dropwise. After addition, the reaction mixture was refluxed for 3 hours. Upon reaction completion, the reaction mixture was cooled to room temperature. The solvent was removed and the residue was purified by column chromatography on silica gel (ethyl acetate/petroleum ether=0.-1/10) to give tert-butyl 6-chloronicotinate (40 g, 94% yield) as a white solid. EC-MS (Agilent ECMS 1200-6120, Column:Waters X-l3ridge C18 (50 mmx4.6 mmx3.5 pm); Column Temperature: 40 C.; Flow Rate: 2.0 mE/mm; Mobile Phase:from 95% [water+10 mM NH4HCO3] and 5% [CH3CN] to 0% [water+10 mM NH4HCO3] and 100% [CH3CN] in 1.6 mm, then under this condition for 1.4 mm, finally changed to 95% [water+10 mM NH4HCO3] and 5% [CH3CN] in 0.1mm and under this condition for 0.7 mm). Purity is 100%,Rt=1.984 mm; MS Calcd.: 213.06; MS Found: 214.2[M+H]. ?H NMR (400 MHz, DMSO-d5) oe 1.56 (9H, s),7.67 (1H, d, J=8.4 Hz), 8.26 (1H, dd, J=8.0, 2.4 Hz), 8.86(1H, d, J=2.4 Hz). Chemical Formula: C,QH,2C1N02, MolecularWeight: 213.66. Total H count from HNMR data: 12.
With dmap; In tetrahydrofuran; at 62.5℃; for 5.6h;Product distribution / selectivity;
A 3 -necked flask was charged with 6-chloronicotinic acid (53.0 g, 336 mmol), 4-(dimethylamino)-pyridine (3.03 g, 24.6 mmol), and tetrahydrofuran (350 mL). The contents of the flask was heated to 62.5C and a solution of di-tert-bntyl dicarbonate (200.2 g, 917 mmol) in tetrahydrofuran (240 mL) was slowly added over a period of 4.6h. The contents of the flask were maintained at 62.5C for approximately Ih and then cooled to 210C. A portion of the solution (219mL), which contained tert-butyl 6-chloronicotinate (16.4 g, 76.8 mmol), was mixed with 1 N EPO <DP n="70"/>NaOH (150 mL) and methyl tert-butyl ether (150 mL) at 21C. To this mixture was charged 4-[(5S, 9i?)-3-(3,5-Dichlorophenyl)-l-methyl-2,4-dioxo-l,3,7- triazaspiro[4.4]non-9-yl]-benzonitrile semi (+)-DTTA salt (37.4 mmol, 61.5 mmol). After mixing for 10 minutes, a phase split was performed, the aqueous layer was discarded and the organic layer was distilled under atmospheric pressure. After 220 mL of distillate was collected, 220 mL of methyl tert-butyl ether was charged back and the distillation was resumed. After an additional 250 mL of distillate was collected, 100 mL of ft-methyl-2-pyrrolidinone was charged and the distillation was continued until the pot temperature rose to 90C. Diisopropylethyl amine (27 mL, 155 mmol) was then charged and the mixture was heated at 1100C for approximately 17h. A portion of the crude reaction mixture (48 mL) was transferred into a separate funnel and was extracted twice with 3.4:1 heptanexyclohexane (31 mL). The top layers were discarded and the bottom layer was extracted three times with a mixture of methyl tert-butyl ether (36mL) and H2O (24 mL). The bottom aqueous layers were discarded. To the top layer was added methyl tert-butyl ether (40 mL) and was filtered back to a distillation flask. After most of methyl tert-butyl ether was distilled off, the mixture was diluted to a total volume of 169 mL with 1 : 1 methyl tert-butyl ether: isopropyl alcohol. /?-Toluenesulfonic acid (0.358 g) was then added to this solution and was dissolved upon gently heating. The solution was then cooled and stirred until crystals appeared. A second charge of />-toluenesulfonic acid (0.424 g) was added and the slurry was further stirred at 210C for 30 minutes before it was filtered and washed twice with 25 mL of 1:1 methyl tert-butyl ether: isopropyl alcohol. The product (3.34 g, 86 % yield) was isolated as white crystals and was dried in a vacuum oven at 4O0C. EPO <DP n="71"/>
With dmap; In tetrahydrofuran; at 70℃; for 1h;Large scale;
Compound 1 (330 g, 2.09 mol) and 4-dimethylaminopyridine (25.6 g, 209 mmol) were dissolved in tetrahydrofuran.After heating to 70 C, Boc anhydride (480 g, 2.20 mol) dissolved in tetrahydrofuran was slowly added dropwise to the reaction solution.After reacting at 70 C for 1 hour, TLC (petroleum ether / ethyl acetate volume ratio = 2 / 1) showed completion of the reaction.The reaction system was spun dry and then dissolved in ethyl acetate (3000 mL) and water (3000 mL).The pH was adjusted to 3 with 2 mol of hydrochloric acid in an ice bath, and then extracted with ethyl acetate (1000 mL * 2).The organic phase was washed with brine (1000 mL), then dried and concentrated to give crude Compound 2 (1.3 kg).
Production Example 28 6-(4-Fluorophenyl)nicotinic acid Operations similar to those of Production Example 14 were conducted using 6-chloronicotinic acid and 4-fluorophenylboronic acid, to provide the title compound as white solid. 1H-NMR(400MHz,DMSO-d6,deltappm):7.30-7.37(2H,m), 8.03(1H,d,J=8.0Hz),8.16-8.22(2H,m),8.26(1H,d,J=8.0Hz), 9.07(1H,s) ESI-MS Found:m/z 218[M+H]+
With 4-methyl-morpholine; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In tetrahydrofuran; at 20℃;Inert atmosphere;
Scheme 32 : Synthesis of 6-Chloro-N, V-dimethylnicotinamide [198 ] Compound [197 ] (3.0 g, 19.0 mmol) was dissolved in THF ( 100 ml) in a clean oven-dried two necked RB flask (250ml) and degassed with nitrogen. To this clear solution, EDC.HCl (4.02 g, 20.9 mmol) was added, followed by NMM (2.3 ml, 20.9 mmol). The reaction mixture was stirred and heated at RT for 10 min, under nitrogen atmosphere. Me2NH ( 13.06 ml, 2N, 2S.5 mmol) was added dropwise and reaction mixture was stirred RT for 16 hrs. The reaction was monitored by TLC. The reaction mixture was quenched with aq. NaHC( ? extracted with ethyl acetate (3 x 100ml). The organic extracts were combined, washed with brine and dried using Na2S04. The organic layer was evaporated to crude which was purified by column chromatography ( 100-200 mesh, 2 % MeOH/DCM) to yield compound [198 ] (2.62 g, 75%) as white solid. ESTMS: 185 (M++ l )
72%
With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In tetrahydrofuran; at 20℃; for 15h;
(1) 6-Chloro-N,N-dimethylnicotinamide To a solution of commercially available 6-chloronicotinic acid (1.58 g, 10.0 mmol) in THF(40 mL) were added triethylamine (2.09 mL, 15.0 mmol), 50% dimethylamine (1.26 mL, 14.0 mmol), and 1-ethyl-3-[3-(N,N-dimethylamino)propyl]-carbodiimide hydrochloride (2.26 g, 11.0 mmol), and the mixture was stirred at room temperature for 15 hours. Chloroform was added to the reaction mixture. The organic layer was washed with water and saturated aqueous sodium hydrogencarbonate solution, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (chloroform) to obtain 6-chloro-N,N-dimethylnicotinamide (1.33 g, 7.20 mmol).yield: 72%
6-chloro-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-nicotinamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
3.03 g (99%)
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;
a 6-Chloro-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-nicotinamide To a stirred solution of 1.89 g (7.54 mmol) 6-chloro-nicotinic acid in 20 ml THF were added 2.87 g (7.54 mmol) HATU and 1.28 ml (7.54 mmol) N-ethyldiisopropylamine and stirring continued at room temperature for 30 minutes. A solution of 2.00 g (7.54 mmol) <strong>[383865-57-4]4-methoxy-7-morpholin-4-yl-benzothiazol-2-ylamine</strong> in 20 ml dioxane and 4 ml DMF was then added and stirring continued at room temperature for 16 h. The reaction mixture was then poured into 350 ml water and the mixture stirred for 30 min. The resulting crystals were collected by filtration, washed with methanol and then with ether, and dried in vacuo to afford 3.03 g (99%) 6-chloro-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-nicotinamide as a yellow crystalline solid. ES-MS m/e (%): 429 (M{37Cl}+Na+, 15), 427 (M{35Cl}+Na+, 38).
Example 46 N-t-Butyl-6-chloro-3-pyridinecarboxamide The title compound was prepared by the same method as that described in Example 26, using 6-chloronicotinic acid and t-butylamine. 1H-NMR(270 MHz, CDCl3) 8.67 (d, J=2.6 Hz, 1H), 8.03 (dd, J=8.3, 2.6 Hz, 1H), 7.39 (dd, J=8.3, 0.7 Hz, 1H), 5.88 (br, 1H), 1.48 (s, 9H)
With hydrogenchloride; In water; N,N-dimethyl-formamide;
to a stirred suspension of sodium hydride (60%, 0.63 g) in DMF (10 ml) at 0 C. was added portionwise over 10 min 6-chloronicotinic acid (1.0 g). The mixture was stirred for 30 min then a solution of <strong>[446-51-5]2-fluorobenzyl alcohol</strong> (0.84 g) in DMF (5 ml) was added dropwise over 10 min. The mixture was warmed to room temperature, stirred for 1 h then heated to 100 C. and stirred for a further 18 h then cooled to room temperature. To the mixture were added dropwise water (10 ml) and hydrochloric acid (2M, 10 ml). The emerging precipitate was washed with water and dried to give the product as an off-white solid (1.34 g); 1H-NMR (400 MHz, CDCl3) deltaH 8.75 (1H, dd, J 2.5, 1 Hz), 8.17 (1H, dd, J 8.5, 2.5 Hz), 7.56 (1H, dt, J 7.5, 1.5 Hz), 7.43 (1H, m), 7.27 (1H, dd, J 8.5, 1 Hz), 7.22 (1H, dd, J 7.5, 1 Hz), 6.97 (1H, dd, J 8.5, 1 Hz) and 5.48 (2H, s); [XTERRA; methanol-10 mM aqueous NH4OAc (50:50); 2 mL/min; 220 nm] 98%, 0.80 min. 2-(2-Fluorobenzyloxy)-5-pyridylmethanol:
With hydrogenchloride; sodium hydroxide;palladium; In methanol; water;
Example 2 25 g of 6-chloronicotinic acid and 14 g of sodium hydroxide are dissolved in a mixture of 100 ml of water and 80 ml of methanol. Following the addition of 5 g of palladium (10% by weight on activated carbon) as catalyst, the mixture is stirred for 24 h at 80-85 C. at 0.1 MPa. The catalyst is then filtered off. Following acidification to pH 1 using hydrochloric acid, the product, 2,2'-bipyridyl-5,5'-dicarboxylic acid, precipitates out as a white solid. This gives 16.3 g (84% yield).
81%
With hydrogenchloride; sodium hydroxide;palladium; In water; ethylene glycol;
Example 1 25 g of 6-chloronicotinic acid and 14 g of sodium hydroxide are dissolved in a mixture of 100 ml of water and 80 ml of ethylene glycol. Following the addition of 0.56 g of palladium (30% by weight on activated carbon; corresponds to an addition of 168 mg of pure palladium) as catalyst, the mixture is stirred for 5 h at 80-85 C. at 0.1 MPa. The catalyst is then filtered off. Following acidification to pH 1 using hydrochloric acid, the product, 2,2'-bipyridyl-5,5'-dicarboxylic acid, precipitates out as a white solid. This gives 15.7 g (81% yield).
79%
With hydrogenchloride; sodium hydroxide;palladium; In methanol; water;
Example 3 25 g of 6-chloronicotinic acid and 14 g of sodium hydroxide are dissolved in a mixture of 100 ml of water and 80 ml of methanol. Following the addition of 10 g of palladium (5% by weight on activated carbon) as catalyst, the mixture is stirred for 30 h at 80-85 C. at 0.1 MPa. The catalyst is then filtered off. Following acidification to pH 1 using hydrochloric acid, the product, 2,2'-bipyridyl-5,5'-dicarboxylic acid, precipitates out as a white solid. This gives 15.3 g (79% yield).
6-iodonicotinic acid Sodium iodide (20.59 g, 137.40 mmol) was cooled to -78 C. under argon and then hydriodic acid (97.13 g, 759.34 mmol) was added. The cooling bath was removed and the suspension was stirred for 5 minutes. To this mixture was added 6-chloronicotinic acid (22.09 g, 140.20 mmol) and the resulting mixture was slowly warmed to ambient temperature with stirring. The mixture was heated to reflux at 125 C. for 24 hours, cooled to ambient temperature and poured into acetone (500 ml) at 0 C. The yellow solid was collected by filtration and washed with 200 ml of 1N aqueous NaHSO3 solution. Recrystallization from methanol (crystals were washed with ethyl ether) afforded the title compound as white crystals: mp 177-179 C. ›lit. mp 187-192, Newkome et al. "Reductive Dehalogenation of Electron-Poor Heterocycles: Nicotinic Acid Derivatives" J. Org. Chem. 51: 953-954 (1986). 1H NMR (DMSO-d6): δ 8.81 (1H, dd, J=0.8, 2.4 Hz), 8.01 (1H, dd, J=0.8, 8.2 Hz), 7.91 (1H, dd, J=2.4, 8.2 Hz).
With sodium iodide;
6-iodonicotinic acid Sodium iodide (20.59 g, 137.40 mmol) was cooled to -78 C. under argon and then hydriodic acid (97.13 g, 759.34 mmol) was added. The cooling bath was removed and the suspension was stirred for 5 minutes. To this mixture was added 6-chloronicotinic acid (22.09 g, 140.20 mmol) and the resulting mixture was slowly warmed to ambient temperature with stirring. The mixture was heated to reflux at 125 C. for 24 hours, cooled to ambient temperature and poured into acetone (500 ml) at 0 C. The yellow solid was collected by filtration and washed with 200 ml of 1N aqueous NaHSO3 solution. Recrystallization from methanol (crystals were washed with ethyl ether) afforded the title compound as white crystals: mp 177-179 C. ›lit. mp 187-192, Newkome et al. "Reductive Dehalogenation of Electron-Poor Heterocycles: Nicotinic Acid Derivatives" J. Org. Chem. 51: 953-954 (1986). 1H NMR (DMSO-d6): δ 8.81 (1H, dd, J=0.8, 2.4 Hz), 8.01 (1H, dd, J=0.8, 8.2 Hz), 7.91 (1H, dd, J=2.4, 8.2 Hz).
With hydrogen iodide;
6-Iodonicotinic acid (Compound B) To 27.97 g (186.6 mmol) of sodium iodide cooled to -78 C. was added 121.77 g (71.6 ml, 952.0 mmol) of hydriodic acid (in 57 wt % aqueous solution). The reaction mixture was allowed to warm slightly with stirring for 5 minutes and then 30.00 g (190.4 mmol) of 6-chloronicotinic acid was added. The resulting mixture was allowed to warm to room temperature with stirring and then heated at 120-125 C. in an oil bath for 42 hours. A dark brown layer formed above the yellow solid material. The reaction mixture was allowed to cool to room temperature and then poured into acetone (chilled to 0 C.). The resultant yellow solid was collected by filtration, washed with 200 ml of 1 N aqueous NaHSO3 solution, and dried in vacuum (3 mm Hg) to give the title compound as a pale yellow solid. PMR (DMSO-d6):d 7.90 (1H, dd, J=8.1, 2 Hz), 7.99 (1H, d, J=8.1 Hz), 8.80 (1H, d, J=2 Hz).
6-Iodonicotinic acid To 27.97 g (186.6 mmol) of sodium iodide cooled to -78 C. was added 121.77 g (71.6 ml, 952.0 mmol) of hydroiodic acid (57 wt %). The reaction mixture was allowed to warm slightly with stirring for 5 minutes, and then 30.00 g (190.4 mmol) of 6-chloronicotinic acid was added. The resulting mixture was allowed to warm to room temperature with stirring and then heated at 120-125 C. in an oil bath for 42 hours. A dark brown layer formed above the yellow solid material. The reaction mixture was allowed to cool to room temperature and then poured into acetone (chilled to 0 C.). The resultant yellow solid was collected by filtration, washed with 200 ml of 1N NaHSO3 solution, and dried in high vacuum (3 mmHg) to give the title compound as a pale yellow solid. PMR (DMSO-D6): δ 7.90 (1H, dd, J=8.1, 2 Hz), 7.99 (1H, d, J=8.1 Hz), 8.80 (1H, d, J=2.Hz).
To a suspension of 6-chloropyridine-3-carboxylic acid (4.15 g) in methanol (40 cc), 4 M methanolic sodium methylate solution (40 cc) is added. The mixture is heated under reflux for 60 hours. The solvent is distilled off under reduced pressure (4 kPa). The residue is taken up in distilled water (100 cc) and the mixture is acidified to pH 5 with hydrochloric acid in 11.9 M aqueous solution. The precipitate produced is separated by filtration, washed with distilled water (5*10 cc) and dried in the air. 6-Methoxypyridine-3-carboxylic acid (3.3 g) is produced, m.p. 180 C.
EXAMPLE 6 Hydrolysis step 5 g of 2-chloro-5-trichloromethyl pyridine was dissolved in 30 g of concentrated sulfuric acid, and the solution was heated to 110 C., whereupon hydrogen chloride gas was vigorously generated. The reaction was conducted at a temperature of from 110 to 120 C. for 2 hours. After the completion of the reaction, the reaction product was introduced into ice water, whereupon white crystals precipitated. The crystals were filtered, washed and dried to obtain 3.2 g of 6-chloronicotinic acid (yield: 94%, purity: 95%).
With thionyl chloride; In tetrahydrofuran; N,N-dimethyl-formamide;
t-Butyl 6-chloronicotinate Thionyl chloride (25 mL) was added to 6-chloronicotinic acid (5.00 g, 0.0317 mol) containing 1 drop of N,N-dimethylformamide, and the mixture heated under reflux for 2 h. The solution was evaporated under vacuum, and residue thoroughly dried under vacuum. The acid chloride thus obtained was dissolved in tetrahydrofuran (50 mL), and 1 M lithium t-butoxide in tetrahydrofuran (66.6 mL, 0.0666 mol) added dropwise at r.t. The mixture was stirred overnight, diluted with water (100 mL) and extracted with ethyl acetate. The extract was washed with sat. aqueous NaHCO3, brine and dried (MgSO4). Solvent was removed under vacuum to afford the pure ester as an off white solid. Yield 6.23 g (92%). 1H NMR. MS (m/z): 214 [M+H]+.
With potassium carbonate;tetrakis(triphenylphosphine) palladium(0); tetrabutylammomium bromide; In water; toluene; for 20h;Heating / reflux;Product distribution / selectivity;
3-Fluorophenylboronic acid (39.5 g, 0.282 mol), a solution of K2CO3 (150 g) in water (700 mL), [Bu4N]Br (3.5 g, 0.0107 mol), and Pd(PPh3)4 (12.4 g, 0.0107 mol) were added to a solution of 6-chloronicotinic acid (37.0 g, 0.235 mol) in toluene. The reaction mixture was stirred under reflux for 20 h. After cooling, the reaction mixture was filtered and acidified with 2 M HCl to pH 3. The formed precipitate was separated by filtration and dried to give 6-(3-fluorophenyl)nicotinic acid (49.9 g). 1H NMR (400 MHz, DMSO-d6) deltappm 7.29 (td, J=8.46, 2.42 Hz, 1 H) 7.50-7.56 (m, 1 H) 7.93 (dd, J=10.47, 2.15 Hz, 1 H) 7.97 (d, J=7.79 Hz, 1 H) 8.11 (d, J=8.06 Hz, 1 H) 8.30 (dd, J=8.32, 2.15 Hz, 1 H) 9.11 (d, J=1.88 Hz, 1 H), 13.48 (bs, 1 H).; Step A: 6-(3-Fluorophenyl)nicotinic acid; 3-Fluorophenylboronic acid (39.5 g, 0.282 mol), a solution of K2CO3 (150 g) in water (700 mL), [BU4N]Br (3.5 g, 0.0107 mol), and Pd(PPh3)4 (12.4 g, 0.0107 mol) were added to a solution of 6-chloronicotinic acid (37.0 g, 0.235 mol) in toluene. The reaction mixture was stirred under reflux for 20 h. After cooling, the reaction mixture was filtered and acidified with 2 M HCl to pH 3. The formed precipitate was separated by filtration and dried to give 6-(3-fluorophenyl)nicotinic acid (yield 97%, 49.9 g). 1H NMR (400 MHz, DMSO-d6) ppm 7.29 (td, J=8.46, 2.42 Hz, 1 H) 7.50-7.56 )m, 1 H) 7.93 (dd, J=10.47, 2.15 Hz, 1 H) 7.97 (d, J=7.79 Hz, 1 H) 8.11 (d, J=8.06 Hz, 1 H) 8.30 (dd, J=8.32, 2.15 Hz, 1 H) 9.11 (d, J=1.88 Hz, 1 H), 13.48 (bs, 1H).
With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In water; N,N-dimethyl-formamide; at 90℃;Product distribution / selectivity;
6-Chloronicotinic acid (25.4g, 161 mmol) and 3-fluorophenylboronic acid (33.9g, 242 mmol) were dissolved in dimethylformamide (300 mL) and the mixture degassed with nitrogen. Tetrakis(triphenylphosphine)palladium (0) (1.0 g, 0.87mmol) was added followed by a solution of sodium carbonate (34.0 g in 160 mL of water) drop wise. The reaction was heated overnight at 90 C. The reaction was cooled to room temperature and then water (200 mL) was added. The reaction mixture was filtered over celite and then the filtrate was washed with a mixture of ethyl acetate (50 mL) and heptane (50 mL). The phases were separated and the aqueous layer was acidified to pH 2 with 6M HCl. The yellow precipitate was filtered off and dried to give 6-(3-fluorophenyinicotinic acid) 27.9g. 1H NMR (400MHz, DMSO-d6) ppm 7.36 (dt, J=2.3, 8.3 Hz, 1 H) 7.79 (m, 1H) 8.01 (m, 2H) 8.18 (d, J=8.3 Hz, 1H) 8.36 (dd, J=2.3, 8.3 Hz, 1H) 9.16 (d, J=1.8 Hz, 1H).
Preparation 1 6-(3-Fluorophenyl)nicotinic acid3-Fluorophenylboronic acid (39.5 g, 0.282 mol), a solution of K2CO3 (150 g) in water (700 ml_), [Bu4N]Br (3.5 g, 0.0107 mol), and Pd(PPh3)4 (12.4 g, 0.0107 mol) were added to a solution of 6- chloronicotinic acid (37.0 g, 0.235 mol) in toluene. The reaction mixture was stirred under reflux for 20 hours. After cooling, the reaction mixture was filtered and acidified with 2 M HCI to pH 3. The resulting precipitate was separated by filtration and dried to give 6-(3-fluorophenyl)nicotinic acid (49.9 g).1H NMR (400 MHz, DMSOd6) delta ppm 7.29 (td, J=8.46, 2.42 Hz, 1 H) 7.50 - 7.56 (m, 1 H) 7.93 (dd, J=10.47, 2.15 Hz, 1 H) 7.97 (d, J=7.79 Hz, 1 H) 8.11 (d, J=8.06 Hz, 1 H) 8.30 (dd, J=8.32, 2.15 Hz, 1 H) 9.11 (d, J=1.88 Hz, 1 H), 13.48 (bs, 1 H).
To a suspension of 6-chloro-nicotinic acid (2.3 eq) and <strong>[68641-49-6]Bis(2-oxo-3-oxazolidinyl)phosphinic chloride</strong> (BOP-Cl) (4.0 eq) in CH2Cl2 (10 mL) was added triethylamine (4.0 eq). After 1 h, the reaction solution was almost clear and 7-amino-benzo[b]thiophene-2-carboxylic acid (5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-amide (98 mg) was added. The yellow reaction solution was stirred at room temperature 12 h. The reaction mixture was partitioned between EtOAc and water, and the organic layer then washed with brine. The organics were dried over MgSO4, filtered and concentrated to give N-(2-{5-tert-butyl-3-[(6-chloro-pyridine-3-carbonyl)-methanesulfonyl-amino]-2-methoxy-phenylcarbamoyl}-benzo[b]thiophen-7-yl)-6-chloro-nicotinamide as a white solid (125 mg, 78%). To the above chloronicotinamide intermediate (107 mg) in a sealed tube was added 4-methoxybenzylamine (700 muL). The reaction was purged with Ar (Argon) and then heated to 100 C. in the sealed tube. It became a clear yellow solution. After 4 h, the reaction was cooled to room temperature, diluted with EtOAc, washed with NH4Cl solution, water, and brine.
With triethylamine; In dichloromethane; at 0℃; for 2h;
To a solution of 6-chloronicotinic acid (25.0 g, 142 mmol) and DCM cooled to a 0 C. was added morpholine (13.6 g, 156 mmol) and TEA (28.7 g, 284 mmol). After stirring for 2 h at 0 C., the solution was washed with aqueous NaHCO3, dried (MgSO4), filtered and concentrated in vacuo to afford 29.5g (130 mmol) of 66: MS (ESI) 227.1 (M+H)+.
Example 20.; To a solution of 6-chloro nicotinic acid (1.1 Ig, 7.04mmol) in CH2Cl2 at 00C was added EDCI (2.7Og, 14.08mmol) and HOBt and then the resulting mixture was stirred for 30 minutes at 00C. After that, morpholine (2.46ml, 28.17mmol) was added, the ice-bath removed and the reaction was done in 15 minutes. Water was added, the mixture was extracted with CH2Cl2, dried over MgSO4 and concentrated to afford 1.55 g of (6-Chloro- pyridin-3-yl)-morpholin-4-yl-methanone.
a) [2-(6-Chloro-pyridin-3-yl)-5,6-difluoro-benzoimidazol-1-yl]-cyclohexyl-acetic acid; To a solution of <strong>[1000698-88-3](2-amino-4,5-difluoro-phenyl)-carbamic acid tert-butyl ester</strong> (1.0 g, 4.1 mmol) in methanol (15 mL) were added cyclohexanecarbaldehyde (0.82 mL, 6.14 mmol, 1.5 equiv.), 6-chloro-nicotinic acid (0.665 g, 4.1 mmol, 1.0 equiv.) and isocyanomethyl-benzene (0.48 mL, 10.24 mmol, 1.0 equiv.) and stirred at rt for 16 h. A solution of 4 M HCl in dioxane (10 mL) was added and the reaction mixture stirred at rt for 3 h. The solution was concentrated by evaporation under reduced pressure, the pH adjusted to 9 by addition of a solution of 1 M NaHCO3 and the aqueous layer extracted with ethyl acetate. The combined organic phases were dried over MgSO4 and concentrated by evaporation under reduced pressure. The crude material was dissolved in a mixture of acetic anhydride (40 ml) and acetic acid (20 ml) and cooled to 0 C. Sodium nitrite (7.4 g, 107 mmol) were added in portions. After the addition the reaction was warmed to rt and stirred for 3 h. The solution was concentrated by evaporation under reduced pressure, the pH adjusted to 9 by addition of a solution of 1 M NaHCO3 and the aqueous layer extracted with ethyl acetate. The resulting brown oil was taken up in a mixture of THF:water (3:1, 20 mL) and a pre-prepared solution of LiOH (2.1 g, 48.7 mmol) in hydrogen peroxide (10 mL, 30% solution in water) was added drop wise. The mixture was stirred at rt for 30 min. The solution was concentrated by evaporation under reduced pressure, the pH adjusted to 4 by addition of acetic acid and the aqueous layer extracted with ethyl acetate. The intermediate was not further purified but used as crude material for further modification. MS (ES-): 404 (M-H).
trans-4-isocyano-cyclohexanecarboxylic acid methyl ester[ No CAS ]
[ 2043-61-0 ]
trans-4-{2-[2-(6-chloro-pyridin-3-yl)-5,6-difluoro-benzoimidazol-1-yl]-2-cyclohexyl-acetylamino}-cyclohexanecarboxylic acid methyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
Example 7 trans-4-{2-[2-(6-Chloro-pyridin-3-yl)-5,6-difluoro-benzoimidazol-1-yl]-2-cyclohexyl-acetylamino}-cyclohexanecarboxylic acid; To a solution of <strong>[1000698-88-3](2-amino-4,5-difluoro-phenyl)-carbamic acid tert-butyl ester</strong> (0.2 g, 0.82 mmol) in methanol (4 mL) were added cyclohexanecarbaldehyde (0.16 mL, 1.22 mmol, 1.5 equiv.), 6-chloro-nicotinic acid (0.13 g, 0.82 mmol, 1.0 equiv.) and trans-4-Isocyano-cyclohexanecarboxylic acid methyl ester (0.137 mg, 0.82 mmol, 1.0 equiv.) and stirred at rt for 16 h. A solution of 4 M HCl in dioxane (4 mL) was added and the reaction mixture stirred at rt for 3 h. The solution was concentrated by evaporation under reduced pressure, the pH adjusted to 9 by addition of a solution of 1 M NaHCO3 and the aqueous layer extracted with ethyl acetate. The combined organic phases were dried over MgSO4 and concentrated by evaporation under reduced pressure. The crude material was dissolved in methanol (15 ml) and NaOH (5 ml) and DMF (1 ml) were added and the mixture heated to 50 C. overnight. The pH was adjusted to 4. A light brown solid appeared which was further purified by preparative HPLC. MS (ES+): 532 (M+H).
With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In methanol; at 0 - 25℃;
Example 28: l-Propyl-8-[6-(3-trifluoromethyl-benzylamino)-pyridin-3-yl]-l,7- dihydro-purin-6-oneStep 1: N-(6-Amino-2,4-dioxo-3-propyl-l,2,3,4-tetrahydro-pyrimidin-5-yl)-6-chloro- nicotinamideA mixture of 5,6-diamino-3-propyl-lH-pyrimidine-2,4-dione (2.Og, ll.Ommol), 6-Chloro nicotinic acid (1.86g, ll.dmmol) in methanol (40ml) were cooled to 0 0C and added EDCLHCl (4.2g, 22mmol). The reaction mixture was stirred at 25 0C for 20 hours and the solvents were removed under reduced pressure. To this residue water (20ml) was added and the precipitate was filtered off, and washed sequentially with cold water (20ml) and methanol (5ml) to obtain N-(6-Amino-2,4-dioxo-3-propyl-l,2,3,4-tetrahydro- pyrimidin-5-yl)-6-chloro-nicotinarnide as an off white solid. (2.47g, 70%). 1HNMR^OOMHZ, DMSO d6): d 0.81 (t, J=7.6Hz, 3H); 1.45-1.51 (m, 2H); 3.64 (t, J=7.2Hz, 2H); 6.24 (s, 2H); 7.65 (d, J=8.4Hz, IH); 8.29 (dd, J=8.4Hz5 2.4Hz, IH); 8.90 (d, J=2Hz, IH); 9.17 (s, IH); 10.54 (s, IH)
70%
With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In methanol; at 0 - 25℃; for 20h;
Step 1: N-(6-Amino-2,4-dioxo-3-propyl-1,2,3,4-tetrahydro-pyrimidin-5-yl)-6-chloro-nicotinamide A mixture of <strong>[142665-13-2]5,6-diamino-3-propyl-1H-pyrimidine-2,4-dione</strong> (2.0 g, 11.0 mmol), 6-Chloro nicotinic acid (1.86 g, 11.8 mmol) in methanol (40 ml) were cooled to 0 C. and added EDCI.HCl (4.2 g, 22 mmol). The reaction mixture was stirred at 25 C. for 20 hours and the solvents were removed under reduced pressure. To this residue water (20 ml) was added and the precipitate was filtered off, and washed sequentially with cold water (20 ml) and methanol (5 ml) to obtain N-(6-Amino-2,4-dioxo-3-propyl-1,2,3,4-tetrahydro-pyrimidin-5-yl)-6-chloro-nicotinamide as an off white solid. (2.47 g, 70%). 1HNMR (400 MHz, DMSO d6): delta 0.81 (t, J=7.6 Hz, 3H); 1.45-1.51 (m, 2H); 3.64 (t, J=7.2 Hz, 2H); 6.24 (s, 2H); 7.65 (d, J=8.4 Hz, 1H); 8.29 (dd, J=8.4 Hz, 2.4 Hz, 1H); 8.90 (d, J=2 Hz, 1H); 9.17 (s, 1H); 10.54 (s, 1H)
With dicyclohexyl-carbodiimide; In 1,4-dioxane; at 20℃;
2,3,5,6-<strong>[769-39-1]tetrafluorophenol</strong> (Tfp) active ester of 2-trimethylammonium nicotinic acid was synthesised in three steps starting from 6-chloro nicotinic acid (Sigma-Aldrich). Esterification of 6-chloro nicotinic acid (3 g, 19 mmol) with 2,3,5,6-<strong>[769-39-1]tetrafluorophenol</strong> (3,25 mg, 19 mmol)) activated by dicyclohexyl carbodiimide (DCC) (3,96, 19 mmol) in 50 m L dioxane following crystallization from hexane gave the 6-chloro nicotine acid Tfp ester in 73 % yield. Generation of the trimethylammonium salt by treating the active 6-chloro nicotinic acid tfp-ester (1 g, 3,27 mmol) in a saturated solution of trimethylamine (continuous bubbling for two hours) in tetrahydrofuran (THF) (15 ml_), gave the trimethylammonium salt with chloride as counterion in 45% yield.Unreacted material could be filtered away since the salt precipitates out of the tetrahydrofuran solution. Generation of the triflate salt can be achieved in two ways; either treatment of the corresponding chloride salt with silver triflate in 1 .2 molar excess in acetonitrile or treatment with trimethylsilyl trifluoromethanesulfonate. The latter is the preferred choice as work-up is simpler and no preparative chromatography is needed. Both methods are almost quantitative. The synthesized precursor (9.2mg) was initially labelled with F by means of K222 (1 Omg) and KF (1 .1 mg) in acetonitrile (0.7ml). The reaction of 19F with the Tfp ester was studied using 1 H- NMR in acetonitrile-d6 at 27O to assay reaction kinetics and impurities formed.
A mixture of 6-chloronicotinic acid (12.0 g, 76 mmol) and thionyl chloride (65 mL) was heated at reflux for 3.0 h. The excess thionyl chloride was removed under reduced pressure, and the residual liquid was diluted with dichloromethane (20 mL) and then added to a solution of tert-butyl alcohol (71 mL, 760 mmol) in dichloromethane (40 mL). To the mixture was added triethylamine (31.7 mL, 760 EPO <DP n="68"/>mmol) and N,N-dimethylpyridine (0.5 g, 4.0 mmol), and the reaction mixture was stirred overnight (14 h) at reflux under nitrogen. The solution was diluted with dichloromethane (200 mL), washed with a saturated aqueous solution of sodium bicarbonate (3 x 100 mL), washed with water (3 x 100 mL), and dried over anhydrous sodium sulfate. Concentration under reduced pressure provided Preparation 3 (11.4 g, 70.3%) as a yellow solid. The product had an analytical HPLC retention time = 3.18 min. (Column: YMC ODS 4.6 x 50 mm (4 min.); Solvent A = 10% MeOH, 90% H2O, 0.2% H3PO4; Solvent B = 90% MeOH, 10% H2O, 0.2% H3PO4) and a LCMS M+1 = 214. The purity of the product was about 96%. The major impurity was the iso- propyl 6-chloronicotinate with an analytical HPLC retention time = 2.88 min. and a LOMS M+1 = 200.
A mixture of 5.0 g (31.7 mmol) of 6-chloronicotinic acid and 15.1 ml (79.4 mmol) of 3,4-dimethoxy-N-methylbenzylamine was heated at 150 C. overnight, while stirring. After cooling to RT, 300 ml of ethyl acetate and 600 ml of water were added. The solid formed was filtered off in the course of the phase separation and dried in vacuo. 7.38 g (77% of th.) of the title compound were obtained.1H-NMR (400 MHz, CDCl3, delta/ppm): 8.91 (d, 1H), 8.07-8.02 (dd, 1H), 6.81 (d, 1H), 6.78-6.73 (m, 2H), 6.52 (d, 1H), 4.82 (d, 2H), 3.86 (s, 3H), 3.82 (s, 3H), 3.12 (s, 3H).LC/MS (method I, ESIpos): Rt=0.74 min, m/z=303 [M+H]+.
77%
at 150℃;
Step 1: 6-[(3,4-Dimethoxybenzyl)(methyl)amino]nicotinic acid With stirring, a mixture of 5.0 g (31.7 mmol) of 6-chloronicotinic acid and 15.1 ml (79.4 mmol) of 3,4-dimethoxy-N-methylbenzylamine was heated at 150 C. overnight. After cooling to RT, 300 ml of ethyl acetate and 600 ml of water were added. The solid formed was removed during phase separation and dried under reduced pressure. This gave 7.38 g (77% of theory) of the title compound. 1H NMR (400 MHz, CDCl3, delta/ppm): 8.91 (d, 1H), 8.07-8.02 (dd, 1H), 6.81 (d, 1H), 6.78-6.73 (m, 2H), 6.52 (d, 1H), 4.82 (d, 2H), 3.86 (s, 3H), 3.82 (s, 3H), 3.12 (s, 3H). LC/MS (Method 5, ESIpos): Rt=0.74 min, m/z=303 [M+H]+.
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 70 - 80℃;
General procedure: The synthesis route of compounds 1-24 followed the general pathway outlined in Scheme 1. The substituted nicotinic acid (1 mmol) mixed with benzenesulfonamide (1 mmol) through by using 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC·HCl) (1.2 mmol) and 4-dimethylaminopyridine (DMAP) (1.2 mmol) in anhydrous CH2Cl2 for 6-8 h at 70-80 C. The reaction was monitored by TLC. The products are extracted with ethyl acetate. The extract is washed successively with 1 N HCl, water, 1 M NaHCO3, and water, dried over MgSO4, filtered and evaporated. The residue is purified by column chromatography using petroleum ether and ethyl acetate (1:1).
Example 34 ((2S,5S)-2-{5-[4-(5-{2-[(S)-1-((8)-2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-pyridin-2-yl)-phenyl]-1H-imidazol-2-yl}-4-oxo-1,2,4,5,6,7-hexahydro-azepino[3,2,1-hi]indol-5-yl)-carbamic acid methyl ester A suspension of 6-chloronicotinic acid (1.58 g, 10.0 mmol) in methylene chloride (50 ml) and DMF (4 drops) was treated with oxalyl chloride (1.53 g, 12.0 mmol). Stir the reaction mixture for 2.5 h and add trimethylsilyldiazomethane (25 ml, 2.0M solution, 50.1 mmol). Stir the reaction for 2 h and pass HCl gas through the mixture for 10 min. The reaction mixture was washed with a saturated sodium bicarbonate solution, a saturated sodium chloride solution and dried over magnesium sulfate, filtered and concentrated to afford, 2-chloro-1-(6-chloropyridin-3-yl)ethanone as a light brown solid, (1.85 g, 97%): ESI-LRMS m/e calcd for C7H5Cl2NO [M+] 190, found 191 [M+H']
General procedure: To 6-chloronicotinic acid 19a (10 g) in methylene chloride(100 ml) solution, N,N?-diisopropyl-O-tert-butylisourea (50 g) wasadded and the mixture was stirred under heating and reflux for16 h. The insoluble compound was filtered out, and the filtratewas concentrated. The residue was purified by silica gel column chromatography (chloroform/ethyl acetate = 6/1) to obtain the compound 20a (11.66 g). To the compound 20a (6.0 g) in dimethylacetoamide (30 ml) solution, tris(dibenzylideneacetone)dipalladium (0.51 g), zinc cyanide (0.22 g), diphenylphosphinoferrocene (0.62 g), and zinc powder (1.98 g) were added and the mixture was stirred under argon atmosphere at 120 C for 3 h. The reaction solution was filtered by sellite, which was then washed with ethyl acetate. Then, the filtrate was washed with distilled water and saturated saline, then the organic layer was dried over with anhydrous sodium sulfate and concentrated. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate= 5/1) to obtain the compound 21a (3.59 g). To copper(I) iodide(0.93 g) in tetrahydrofuran (50 ml) suspension, ethylmagnesium bromide (0.86 M tetrahydrofuran solution)(12.5 ml) was added dropwise under cooling at 0 C, the mixture was stirred at 0 C for 30 min, then the compound 21a (1.0 g) obtained above in tetrahydrofuran (10 ml) solution was added atthe 20 C. After stirring for 30 min at that temperature, 28% ammonia solution in water and ethyl acetate were added to the mixture and the solution separated. The aqueous layer was extracted with ethyl acetate, while the combined organic layer was washed with saturated saline, then was dried over with anhydrous sodium sulfate and concentrated. The obtained residue was purifiedby silica gel column chromatography (hexane/ethyl acetate= 8/1) to obtained the compound 22a (0.47 g). To the compound 22a (200 mg) in tetrahydrofuran (1 ml) solution, (-)-B-chlorodiisopinocampheylborane (65% hexane solution) (0.92 ml) was added dropwise under cooling at 20 C, then the mixture was stirred at that temperature for 18 h. Then, ether and distilled water were added to the reaction mixture, and the solution was separated. The organic layer was extracted with distilled water and 1 M hydrogen chloride. Then, the combined aqueous layer was neutralized by sodium hydrogen carbonate, and extracted with ethyl acetate. Organic layer was washed with saturated saline, then was dried over with anhydrous sodium sulfate and concentrated to obtained the title compound (150 mg, 84% ee). The optical purity was determined using CHIRALCEL AD-H(Daicel Chemical Industries) (movement phase: hexane/ethanol= 98/2, 1.0 ml/min).
6-chloro-N-(4-methoxy-3-nitrophenyl)nicotinamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
34.1 g
With 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 16h;
15.0 g (89.2 mmol) of <strong>[577-72-0]4-methoxy-3-nitroaniline</strong>, 77.7 mL (446 mmol, 5 equiv) of N,N- diisopropylethylamine and 28.1 g (178 mmol, 2 equiv) of 6-chloronicotinic acid were provided in 300 mL of DMF at room temperature. 104 mL (178 mmol, 2 equiv) of a 50% solution of 2,4,6-tripropyl- 1,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide (T3P) in DMF were added, and the mixture was stirred for 16 h at room temperature. The resulting mixture was concentrated to half of the original volume, poured onto water, and stirred for 15 minutes. The precipitate was filtered off, washed with water and dried. 34.1 g of the title compound were obtained, which were used without further purification. 1H-NM (300 MHz, DMSO-d6): delta [ppm] = 3.92 (s, 3H), 7.39 (d, 1H), 7.65 - 7.75 (m, 1H), 7.97 (dd, 1H), 8.31 - 8.43 (m, 2H), 8.97 (d, 1H), 10.81 (s, 1H). LC-MS (Method 1): Rt = 1.02 min; MS (ESIpos): m/z = 308 [M+H]+.
N-(biphenyl-3-ylmethyl)-6-chloronicotinamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
81%
6-Chloronicotinic acid (0.29 g) and 1,1?-carbonylbis(1H-imidazole) (0.34 g) were dissolved in N,N-dimethylformamide (5 mL), and the solution was heated with stirring at 100 C. for 45 minutes. The reaction solution was brought back to room temperature. 1-Biphenyl-3-ylmethanamine (0.37 g) and triethylamine (0.51 mL) were added thereto, and the mixture was stirred at 70 C. for 2 hours. Ethyl acetate was added thereto, and the organic layer was washed with water and dried over sodium sulfate. After concentration under reduced pressure, the obtained residue was purified by silica gel column chromatography (Moritex Corporation, elution solvent: hexane/ethyl acetate) to obtain the title compound (0.48 g) as a white solid (yield: 81%). [0318] MS m/z: 323 (M+H)+ [0319] 1H-NMR (400 MHz, CDC3) delta: 8.77 (1H, d, J=2 Hz), 8.11 (1H, dd, J=8 Hz, 2 Hz), 7.60-7.54 (4H, m), 7.49-7.40 (4H, m), 7.39-7.33 (2H, m), 6.42 (1H, t, J=5 Hz), 4.72 (2H, d, J=5 Hz).
With acetic acid; isopentyl nitrite; at 80℃; for 6h;Inert atmosphere;
6-Chloronicotinamide (0.1566 g, 1 mmol) was dissolved in acetic acid (2mL), and to the stirring solution was added amyl nitrite (0.40 mL, 3 mmol). The reaction was placedunder N2 atmosphere and heated to 80 C for 6 hours, whereupon the reaction was complete byconsumption of starting material by TLC. The solution was condensed and co-evaporated with toluene(2 x 5 mL), then purified via column chromatography (gradient 0% 75% EtOAc in Hexane).Fractions containing product were combined and condensed to afford colourless powder (0.0839 g,0.53 mmol). 1H-NMR (400 MHz; DMSO-d6): delta 13.62 (s, 1H), 8.86 (d, J = 2.2 Hz, 1H), 8.26 (dd, J =8.3, 2.2 Hz, 1H), 7.62 (d, J = 8.3 Hz, 1H); MS m/z 156 (M-, 100%); melting point: dec. 188 C; IR (inDMSO) numax 3436 (w br, O-H stretch), 1705 (s, C=O stretch), 1587 (C=C stretch), 1272 (acyl C-O)cm-1
6-Chloronicotinic acid (0.2 mmol), HATU (0.2 mmol) and DIPEA (0.4 mmol) were dissolved in acetonitrile (1 mE). Afier 1 mm the dark-red solution was added to 2-amino-4-(2-pyridyl)thiazole (0.2 mmol) and the mixture was heated to 50 C. for 20 mi Afier cooling to room temperature, the solvent was evaporated and the residue was dissolved in ethyl acetate and washed with aqueous citric acid (5%), saturated aqueous sodium carbonate and water. After evaporation of the solvent, 1 ,3-diaminopropane (1 mE) was added and the mixture was heated to 100 C. for 2 h under microwave irradiation. Afier removal of the solvent with a stream of nitrogen, the residue was purified by preparative reverse-phase HPEC-MS. ESI-MS: 355 (M+1).
General procedure: The synthetic route is outlined in Scheme 1A 100 mL, three-necked, round-bottomed flask, fittedwith a nitrogen inlet adapter, was charged with6-chloronicotinic acid (500.0 mg, 3.18 mmol) and substitutedamine (15.92 mmol). The resulting mixture wasstirred for 30 min until it became homogeneous and thenstirred at 120-130 °C for 6 h, when thin layer chromatography(TLC) (eluent:dichloromethane/methanol/acetic acid(15:1:1, v/v/v)) indicated that the reaction was complete.The resulting mixture was partially purified by flash columnchromatography on silica gel, using dichloromethane/methanol/acetic acid (30:1:1, v/v/v) as the eluent. Theresulting crude product was dissolved in ethanol (10 mL)and precipitated by the addition of acetic acid (0.5 mL).This process was repeated three times and the suspensionwas then centrifuged for 10 min at 4000 g. The sedimentwas collected and washed with Et2O to obtain pure 6-substituted nicotinic acid (6a-6c).
6-chloro-N-(2,6-dichloro-3,5-dimethoxyphenyl)nicotinamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
To a solution of 6-chloro nicotinic acid ( 0.568 mg, 3.602 mmol) in THF (27 mL) was added 2 drops of DMF and oxalyl chloride (3.6 ml, 7.205 mmol) in a dropwise manner at room temperature. The reaction mixture was allowed to stir at room temperature under nitrogen for 2 h. Thereafter, the reaction was diluted in DCM (9 mL) and cooled to 0 C, then added 2,6- dichloro-3,5-dimethoxyaniline (Procedure 5 A; 0.2 g, 0.901 mmol) and triethylamine (2.0 mL, 14.41 mmol). The mixture was allowed to warm to room temperature. After stirring for 3 h, NH4OH solution (2 mL) was added and stirred at room temperature for 18 h. The reaction mixture was concentrated to afford an off-white solid, containing the product, which was used without further purification. MS ESI): 360.9 [M+H]+
6-chloro-N-(2,6-difluoro-3,5-dimethoxyphenyl)nicotinamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
80%
TEA (0.15mL) was added to a solution of 6-chloro nicotinic acid (0.12g, 0.79 mmol) in DMF (2mL) followed by the addition of T3P (0.67mg, 1.0 mmol). Stirred the reaction mass for 10 min. and added <strong>[651734-54-2]2,6-difluoro-3,5-dimethoxyaniline</strong> (O. lg, 0.52mmol). Continued the stirring with heating at 100 C for 24h. Quenched the reaction mass with ice cold water and the solid separated is filtered, dried under vacuum to afford desired title compound (0.14g, 80%). LCMS: m/z = 329.0 (M+H)+.
With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 20℃; for 2h;
General procedure: To a solution of 6- chloro-2-methoxypyridine-3-carboxylic acid (190 mg, 1.01 mmol) in N,N-dimethylformamide (2 mL) was added HATU (722 mg, 1.90 mmol), dimethylamine hydrochloride (165 mg, 2.03 mmol) and DIEA (614 mg, 4.75 mmol) at room temperature. The resulting mixture was stirred for 6 h at 35 C. When the reaction was done, the reaction mixture was diluted with H20 (20 mL) and extracted with ethyl acetate (50 mL x 3). The organic phases were combined, washed with brine and dried over Na2S04. The solvent was removed under reduced pressure and the residue was purified by flash chromatography eluting with MeOH in EtOAc (0 % to 10 % gradient) to yield 6-chloro-2-methoxy-N,N-dimethylpyridine-3-carboxamide as an yellow oil (129 mg, 59 %). MS: m/z = 214.9 [M+H]+.
N-(2,4-dimethoxybenzyl)-6-chloropyridine-3-carboxamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
88%
General procedure: The 6-chloronicotinic acid (2g, 12.73 mmol) was dissolved inDMF (20 ml). In the prepared solution, TBTU (4.90 g, 15.28 mmol)and TEA (2.66 mL, 19.10 mmol) was added. The reaction mixture was stirred for 30 min at room temperature. An amine(12.73 mmol) was added and stirred for 3 h at room temperature.The progress of the reaction was monitored by TLC. The reactionmixture was then quenched with crushed ice (50g) and stirred for30 min. The obtained precipitate was filtered and dried. Finally the product was purified by column chromatography using ethyl acetate:petroleum ether as eluent. Yield: (2a:87%, 2c:86%, 2l: 88%).
2-methoxy-5-(3,4,5-trimethoxyphenethyl)phenyl-6-chloronicotinate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
72.31%
With dmap; dicyclohexyl-carbodiimide In tetrahydrofuran at 20℃; for 12h;
5
Dissolve 6-chloronicotinic acid (108.87mg, 691.02μmol) in anhydrous THF (5mL), add Erianin (200mg, 628.20μmol), DCC (142.58mg, 691.02μmol), 4-DMAP (7.67mg) in turn , 62.82μmol), the mixture was stirred at room temperature for 12h, TLC monitored the complete reaction of the raw materials, quenched with water, extracted with ethyl acetate (10mL×3), and the organic phase was washed with saturated brine (10mL×3), anhydrous sodium sulfate Dry, filter, remove the organic solvent, and perform column chromatography on silica gel (petroleum ether: ethyl acetate = 3:1) to obtain a pale yellow oily liquid, which is the above-mentioned Erianin heterocyclic derivative (208.23 mg, yield 72.31) %)
Chemistry
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