There will be a HazMat fee per item when shipping a dangerous goods. The HazMat fee will be charged to your UPS/DHL/FedEx collect account or added to the invoice unless the package is shipped via Ground service. Ship by air in Excepted Quantity (each bottle), which is up to 1g/1mL for class 6.1 packing group I or II, and up to 25g/25ml for all other HazMat items.
Type
HazMat fee for 500 gram (Estimated)
Excepted Quantity
USD 0.00
Limited Quantity
USD 15-60
Inaccessible (Haz class 6.1), Domestic
USD 80+
Inaccessible (Haz class 6.1), International
USD 150+
Accessible (Haz class 3, 4, 5 or 8), Domestic
USD 100+
Accessible (Haz class 3, 4, 5 or 8), International
USD 200+
Structure of 1603-40-3 * Storage: {[proInfo.prStorage]}
* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Reference：
[1] Journal of Fluorine Chemistry, 2011, vol. 132, # 8, p. 541 - 547
[2] Chemical and Pharmaceutical Bulletin, 1990, vol. 38, # 9, p. 2446 - 2458
[3] Journal of the American Chemical Society, 1949, vol. 71, p. 1125
[4] Journal of Organic Chemistry, 1949, vol. 14, p. 509,513
2
[ 1603-40-3 ]
[ 393-55-5 ]
Reference：
[1] Chemical and Pharmaceutical Bulletin, 1990, vol. 38, # 9, p. 2446 - 2458
[2] Journal of the American Chemical Society, 1949, vol. 71, p. 1125
[3] Journal of Fluorine Chemistry, 2011, vol. 132, # 8, p. 541 - 547
3
[ 1603-40-3 ]
[ 101860-97-3 ]
Reference：
[1] Journal of Medicinal Chemistry, 1990, vol. 33, # 10, p. 2697 - 2706
[2] Bioorganic and Medicinal Chemistry, 2014, vol. 22, # 1, p. 247 - 255
4
[ 108-99-6 ]
[ 1603-41-4 ]
[ 1603-40-3 ]
Yield
Reaction Conditions
Operation in experiment
1928 g
With ammonia; sodium; ethanolamine In toluene at 60 - 170℃; Autoclave; Inert atmosphere; Large scale
1) Add 9021g of toluene, 538g of sodium metal, 70g of ethanolamine and 1900g of 3-picoline to the autoclave. After tightening the autoclave, open the autoclave inlet and the addition port of the dropping tank, and open the dropping tank And the kettle body valve, the hose through the feeding port into the bottom of the tank, with nitrogen replacement air for 1min, closed the lid of the feeding port, warmed to 60 , dropping liquid ammonia, control the pressure in the autoclave 3MPa, the final Liquid ammonia added amount of 600g. Fully respond.2) The temperature was raised to 170 ° C, nitrogen was filled to a pressure of 5 MPa, and the reaction was sufficiently completed. When the pressure in the autoclave increased to 5.5 MPa,Pressure relief to 5MPa, repeat this operation until the pressure inside the reactor does not rise as the end of the reaction, down to room temperature.3) The ammoniated liquid was taken out and slowly added dropwise to water (9 kg). The mixture was stirred and hydrolyzed and extracted, and the mixture was allowed to stand still. After the aqueous phase was extracted again with 3 L of toluene, the oil phases were combined and the oil phase was quantified by gas chromatography.Among them, 1928g of 2-amino-5-methylpyridine and 144g of 2-amino-3-methylpyridine.
Reference：
[1] Journal of Organic Chemistry, 2007, vol. 72, # 12, p. 4554 - 4557
6
[ 1603-40-3 ]
[ 407-21-6 ]
Reference：
[1] Journal of Organic Chemistry, 1949, vol. 14, p. 328,331
[2] Journal of Organic Chemistry, 1949, vol. 14, p. 328,331
7
[ 1603-40-3 ]
[ 3430-19-1 ]
Reference：
[1] Journal of Organic Chemistry, 1949, vol. 14, p. 328,331
[2] Journal of Organic Chemistry, 1949, vol. 14, p. 328,331
8
[ 108-99-6 ]
[ 1603-41-4 ]
[ 1603-40-3 ]
Yield
Reaction Conditions
Operation in experiment
1928 g
With ammonia; sodium; ethanolamine In toluene at 60 - 170℃; Autoclave; Inert atmosphere; Large scale
1) Add 9021g of toluene, 538g of sodium metal, 70g of ethanolamine and 1900g of 3-picoline to the autoclave. After tightening the autoclave, open the autoclave inlet and the addition port of the dropping tank, and open the dropping tank And the kettle body valve, the hose through the feeding port into the bottom of the tank, with nitrogen replacement air for 1min, closed the lid of the feeding port, warmed to 60 , dropping liquid ammonia, control the pressure in the autoclave 3MPa, the final Liquid ammonia added amount of 600g. Fully respond.2) The temperature was raised to 170 ° C, nitrogen was filled to a pressure of 5 MPa, and the reaction was sufficiently completed. When the pressure in the autoclave increased to 5.5 MPa,Pressure relief to 5MPa, repeat this operation until the pressure inside the reactor does not rise as the end of the reaction, down to room temperature.3) The ammoniated liquid was taken out and slowly added dropwise to water (9 kg). The mixture was stirred and hydrolyzed and extracted, and the mixture was allowed to stand still. After the aqueous phase was extracted again with 3 L of toluene, the oil phases were combined and the oil phase was quantified by gas chromatography.Among them, 1928g of 2-amino-5-methylpyridine and 144g of 2-amino-3-methylpyridine.
Reference：
[1] Journal of Organic Chemistry, 2007, vol. 72, # 12, p. 4554 - 4557
13
[ 18368-76-8 ]
[ 1603-40-3 ]
Reference：
[1] Chemistry - A European Journal, 2010, vol. 16, # 6, p. 1983 - 1991
14
[ 108-99-6 ]
[ 1603-40-3 ]
Reference：
[1] Chemische Berichte, 1924, vol. 57, p. 1804[2] Chemische Berichte, 1925, vol. 58, p. 1733
[3] Journal of Chemical and Engineering Data, 2007, vol. 52, # 6, p. 2431 - 2435
15
[ 1003-73-2 ]
[ 1603-40-3 ]
Reference：
[1] Bioorganic and medicinal chemistry letters, 2000, vol. 10, # 17, p. 1975 - 1978
16
[ 56-23-5 ]
[ 108-99-6 ]
[ 1603-40-3 ]
Reference：
[1] Chemische Berichte, 1924, vol. 57, p. 1804[2] Chemische Berichte, 1925, vol. 58, p. 1733
17
[ 1603-40-3 ]
[ 3430-17-9 ]
Reference：
[1] Chemical and Pharmaceutical Bulletin, 1990, vol. 38, # 9, p. 2446 - 2458
[2] Tetrahedron, 2015, vol. 71, # 2, p. 252 - 258
[3] Phosphorus, Sulfur and Silicon and the Related Elements, 2002, vol. 177, # 11, p. 2579 - 2587
[4] Journal of the American Chemical Society, 1946, vol. 68, p. 2574,2576
[5] Journal of the American Chemical Society, 1948, vol. 70, p. 3126
[6] Journal of the Chemical Society, 1949, p. 2094
[7] Organic Magnetic Resonance, 1982, vol. 20, # 4, p. 242 - 248
[8] Gazzetta Chimica Italiana, 1983, vol. 113, # 3/4, p. 227 - 228
[9] Journal of Organic Chemistry, 1998, vol. 63, # 20, p. 6886 - 6890
[10] Tetrahedron Letters, 2005, vol. 46, # 36, p. 6033 - 6036
Reference：
[1] Journal of the American Chemical Society, 1934, vol. 56, p. 231
[2] Journal of the American Chemical Society, 1952, vol. 74, p. 5967,5969
[3] Journal of Organometallic Chemistry, 1997, vol. 529, # 1-2, p. 135 - 142
[4] Organic Magnetic Resonance, 1982, vol. 20, # 4, p. 242 - 248
20
[ 1603-40-3 ]
[ 23612-48-8 ]
Reference：
[1] Synthesis, 1996, # 7, p. 877 - 882
21
[ 1603-40-3 ]
[ 4021-07-2 ]
Reference：
[1] Journal of the American Chemical Society, 1952, vol. 74, p. 5967,5969
22
[ 1603-40-3 ]
[ 5654-93-3 ]
Reference：
[1] Synthesis, 1996, # 7, p. 877 - 882
23
[ 1603-40-3 ]
[ 402-66-4 ]
Reference：
[1] Journal of Organic Chemistry, 1949, vol. 14, p. 328,331
[2] Journal of Organic Chemistry, 1949, vol. 14, p. 328,331
24
[ 1603-40-3 ]
[ 10592-27-5 ]
Reference：
[1] Patent: CN106279156, 2017, A,
25
[ 1603-40-3 ]
[ 35905-85-2 ]
Reference：
[1] Chemical and Pharmaceutical Bulletin, 1990, vol. 38, # 9, p. 2446 - 2458
[2] Tetrahedron, 2015, vol. 71, # 2, p. 252 - 258
26
[ 1603-40-3 ]
[ 364-22-7 ]
Reference：
[1] Journal of the American Chemical Society, 1949, vol. 71, p. 1125
27
[ 1603-40-3 ]
[ 5654-95-5 ]
Reference：
[1] Bioorganic and Medicinal Chemistry, 2014, vol. 22, # 1, p. 247 - 255
[2] Bioorganic and Medicinal Chemistry, 2014, vol. 22, # 1, p. 247 - 255
28
[ 1603-40-3 ]
[ 18344-51-9 ]
Yield
Reaction Conditions
Operation in experiment
35%
Stage #1: at 0 - 50℃; Stage #2: With ammonia In water at 20℃;
3-Methyl-pyridin-2-ylamine (5.0 g, 46.2 mmol) was dissolved in concentrated sulfuric acid (24ml), the mixture was chilled to 0°C and a mixture of fuming nitric acid (d=1.5, 3.5ml) and concentrated sulfuric acid (3.5ml) was added dropwise to the reaction mixture while temperature was kept below 20°C. The stirred mixture was allowed to warm to 20°C and transferred in portions of 3-5ml into a second flask which was heated to 35-40°C (the temperature was not allowed to rise over 40°C - monitoring carefully the temperature after every addition of a new portion). The resulting reaction mixture was subsequently stirred for additional 30min at 50°C, cooled to ambient temperature and neutralized with concentrated aqueous ammonia. This led to the formation of a precipitated which was filtered, washed with water and aqueous DMFA (50percent, 6ml), and recrystallized from DMFA yielding 3-methyl-5-nitro-pyridin-2-ylamine (2.52g, 35percent).
Reference：
[1] Patent: EP1894924, 2008, A1, . Location in patent: Page/Page column 36
[2] Journal of Organic Chemistry, 1949, vol. 14, p. 328,331
[3] Journal of the American Chemical Society, 1955, vol. 77, p. 3154
29
[ 1603-40-3 ]
[ 21901-34-8 ]
Yield
Reaction Conditions
Operation in experiment
75%
With sulfuric acid; nitric acid In water at 10 - 35℃;
A 3-necked, 2-L, round-bottomed flask equipped with a mechanical stirrer, an addition funnel and a thermometer was placed in an ice-water bath. Conc. H2SO4 (150 mL) was added to the flask. 2-Amino-3-methylpyridine (50.0 g, 0.463 mol, Lancaster, CAS 1603-40-3, mp. 29° C., prewarmed in a warm water bath to melt it) was weighed out in a 125 mL Erlenmeyer flask and was subsequently added in small portions via a prewarmed Pasteur pipet with the narrow tip broken off. The Erlenmeyer flask was kept in a warm water bath during the addition to prevent the starting material from solidifying. The temperature rose to ca. 45° C. during the addition and white smoke/fog formed within the flask. Conc. H2SO4 (100 mL) was added to the residual starting material and the mixture was added to the reaction flask. The resulting mixture was a milky-white suspension. A solution of conc. H2SO4 (35 mL) and 70percent nitric acid (35 mL) was premixed with ice-water bath cooling and transferred into the addition funnel. After the internal temperature of the reaction mixture had cooled to 10-15° C. (but not below 10° C.), the premixed H2SO4/HNO3 acid mixture was added dropwise at a rate such that the internal reaction temperature rose to 20-25° C. (5-10 min addition time). After the addition was complete, the ice-water bath was replaced with a tap-water bath. The reaction temperature slowly increased to ca. 30° C. range and then cooled down to room temperature. The reaction should be monitored during this time to ensure that the temperature does not rise too high. The reaction mixture was then stirred overnight and then 70percent nitric acid (35 mL) was added dropwise via the addition funnel to the dark red-brown mixture at a rate of addition such that the temperature did not exceed 35° C. At this time, the reaction flask was sitting in a water bath containing water at room temperature. Water (500 mL) was then added to the reaction flask in portions via addition funnel. The first ca. 150 mL of water was added dropwise while allowing the internal temperature to climb slowly to 50-60° C. The rate of stirring was increased in order to break up any foaming that occurred. Brown gas evolved during the addition of the initial ca. 150 mL of water. The remaining ca. 350 mL of water was added at a faster rate after gas evolution had stopped and a temperature increase was no longer observed. The reaction turned from a dark cloudy brown to a clear orange solution. Some yellow precipitate may form as the reaction cools to below 50° C. The water bath was then removed, and replaced with a heating mantle, and the addition funnel was replaced with a condenser. The reaction mixture (a light orange solution or bright yellow solution) was then heated at 115-118° C. for 1.75-2 h. Additional gas evolution occurred at ca. 115° C. during this time. The reaction mixture was then cooled to room temperature with the aid of an ice-water bath and was then cooled further to 0° C. by adding ice directly into the reaction mixture. The solid that formed was collected on a Buchner funnel and was washed with cold water followed by a minimal amount of cold ethanol followed by a minimal amount of cold ether. The solid was then dried under vacuum to afford 3-methyl-5-nitropyridin-2-ol (53.5 g, 75percent yield) as a pale yellow solid. mp 228-229° C.; 1H NMR (400 MHz, DMSO-d6) δ 12.55 (s, br, 1H), 8.54 (d, J=3.0 Hz, 1H), 8.04 (d, J=2.0 Hz, 1H), 2.04 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 162.2, 135.4, 130.0, 129.5, 128.1, 15.8; LRMS, (ESI) m/e 152.96 [(M-H)-, calcd for C6H5N2O3, 153.03]. Anal. calcd. for C6H6N2O3; C, 46.75, H, 3.92, N, 18.17. Found: C, 46.80, H, 3.79, N, 18.14.
69.2%
Stage #1: at 0 - 30℃; for 18 h; Stage #2: at 100℃; for 1 h;
Example 5: Synthesis of the 2-(1-ethyleneimine)-3-carbamoyl-5-nitropyridine (compound IV) [Show Image] The reagents used is ( i ) HNO3/H2SO4, followed by H2O; (ii) POCl3; (iii) Na2Cr2O7; (iv) SOCl2, followed by NH4OH; (v) aziridine.Synthesis of the compound 19 A concentrated sulphuric acid (240 mL) was cooled in an ice bath, the starting material compound 18 (50 g, 0.462mol) was slowly added and cooled to 0°C, 35 mL of a mixture in volumetric ratio of 1:1 of a concentrated sulphuric acid (98percent) and a concentrated nitric acid (72percent) was slowly added, the reaction proceeded at 25°C for 15 h, and 35 mL of 72percent HNO3 was added, followed by agitation at 30°C for 3 h. 50 mL of the reaction liquid was taken out and placed into a 1000mL flask. 100 mL of water was added, and the solution so obtained was heated to boiling; then the rest part of the reaction liquid was added in batches to the boiling solution with 50mL per batch. The reaction system so obtained was stirred at 100 °C for additional 1 h. After the reaction was completed, the reaction mixture was poured into 2000 g of ice, and 49.0 g of a yellow precipitate was precipitated. The melting point is 225.9-226.5 °C (water) (M. P. 228.5-229.5°C (water) was reported in the reference)[J.O.C. , 1949, 14, 328-332]. The yield was 69.2percent.
53%
Stage #1: at 20℃; for 15 h; Cooling Stage #2: at 120℃;
A solution of 2-amino-3-picoline (5 g, 46 mmol) in c-H2SO4 (24 mL) was cooled in an ice bath. A mixture of c-H2SO4 (3.5 mL) and c-HNO3 (3.5 mL) was added slowly with stirring. This mixture was then warmed up to rt and stirred for 15 h. The solution was stirred rapidly while c-HNO3 (3.5 mL) was added. The mixture was then poured into 60 mL of water and heated to 120 °C until the solvent volume was reduced by half. The solution was cooled rapidly by placing in an ice bath and by adding ice directly to the solution. The solid precipitate was filtered, washed with water, and dried to give product 9 as a light brown solid (5.3 g, 75percent). 1H NMR (300 MHz, DMSO-d6) δ: 12.55 (s, 1H), 8.53 (d, J = 3.0 Hz, 1H), 8.04 (d, J = 3.3 Hz, 1H), 2.03 (s, 3H).
Reference：
[1] Patent: US2010/29684, 2010, A1, . Location in patent: Page/Page column 5; 13-14
[2] Journal of Medicinal Chemistry, 2009, vol. 52, # 23, p. 7653 - 7668
[3] Patent: EP2366691, 2011, A1, . Location in patent: Page/Page column 9-10
[4] Bioorganic and Medicinal Chemistry, 2015, vol. 23, # 5, p. 985 - 995
[5] Journal of Organic Chemistry, 1949, vol. 14, p. 328,331
[6] Journal of Organic Chemistry, 1949, vol. 14, p. 328,331
30
[ 1603-40-3 ]
[ 22280-56-4 ]
Reference：
[1] Journal of Organic Chemistry, 1949, vol. 14, p. 328,331
[2] Journal of Organic Chemistry, 1949, vol. 14, p. 328,331
[3] Patent: EP2366691, 2011, A1,
[4] Bioorganic and Medicinal Chemistry, 2015, vol. 23, # 5, p. 985 - 995
31
[ 1603-40-3 ]
[ 3430-21-5 ]
Yield
Reaction Conditions
Operation in experiment
100%
Stage #1: With bromine In dichloromethane at 0 - 20℃; for 4.66667 h; Stage #2: With sodium hydroxide In dichloromethane; water
Bromine (15.4 mL, 0.30 mol) was added dropwise to a stirred and cooled (0-2 [°C)] solution of 2-amino-3-picoline (1; 32.44 g, 0.30 mol) in dry [CH2CI2] (1000 mL) over a period of 1 h. The cooling bath was then removed, and the yellowish suspension was stirred at r. t. for 3 h 40 min. The mixture was basified to pH 9 with 2N [NAOH] (145 mL) followed by a mixture of saturated aqueous [NAHC03] (100 mL) -saturated aqueous Na2S203 (10 mL). The organic layer was separated and washed with brine, dried [MGS04] and concentrated to afford 14 (56.83 g, 102percent) as brown solid, which was used in the next step without purification.
68%
Stage #1: Reflux Stage #2: at 20 - 55℃; for 2.5 h; Stage #3: With sodium hydroxide In water for 0.5 h;
Example 2 2-amino-3-methylpyridine (10.8g, 0.1mol) and acetic anhydride (12.3g, 0.12mol) was added to a 250ml four-necked flask and was heated to reflux in an oil bath, tracking by thin layer chromatography until the reaction is complete. Afterwards, the reaction was cooled to 20-25°C, the solution was slowly added dropwise bromine (17.6g, 0.11mol) and was reacted at 55°C for 2.5h. Water was added to dissolve all solids. 40mL 40percent sodium hydroxide solution was slowly added dropwise. After the addition, he reaction was continued for 30min. The solution was then filtered, dried, and recrystallized to give 2-amino-3-methyl-5-bromopyridine with a molar yield of 68percent.
65%
With N-Bromosuccinimide; ammonium acetate In acetonitrile at 0 - 23℃; for 0.416667 h;
5-Bromo-3-methylpyridin-2-amine (48) [0174] (J. Mol. Catal. A: Chem. 2007, 267, 30-33.) N-Bromosuccinimide (170 g, 0.95 mol) was added to a solution of 47 (99 g, 0.92 mol) and ammonium acetate (7 g, 10 mol percent) in acetonitrile (500 mL). The temperature of the reaction mixture during addition was controlled with an ice bath. After the full amount of NBS was added, the ice bath was removed and the reaction mixture was stirred at room temperature for 25 min, and acetonitrile was removed under reduced pressure. A mixture of ethyl acetate (1 L) and water (1 L) was added to the solid residue. The resulting mixture was stirred and the organic layer was separated. The water layer was extracted with ethyl acetate (3×500 mL). The combined extracts were washed with water (300 mL), saturated sodium bicarbonate solution (500 L), dried with sodium sulfate and evaporated to dryness to give a dark brown solid. The crude product was redissolved in chloroform (300 mL); and the solution was filtered through a thin pad of silica gel, eluting with chloroform. The combined filtrates were evaporated under reduced pressure to yield 48 as a light-brown solid (113 g, 65percent): mp 89-90° C. (lit. (J. Am. Chem. Soc. 1976, 98, 1478-1486) mp 91-93° C.). 1H NMR (300 MHz, CDCl3) 7.97 (d, J=2.3 Hz, 1H), 7.36 (d, J=2.3 Hz, 1H), 4.50 (s, 2H), 2.09 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 156.10, 146.29, 140.03, 118.79, 108.58, 77.72, 77.30, 76.88, 17.27.
56%
With dihydrogen peroxide; 1-butylpyridinium bromide; toluene-4-sulfonic acid In 1,2-dimethoxyethane at 80℃; for 24 h; Schlenk technique; Inert atmosphere; Green chemistry
General procedure: To a mixture of 2-aminopyridine (0.5 mmol, 1 equiv), p-TSA (0.4 mmol,0.8 equiv), 1-butylpyridinium bromide (1.5 mmol, 3 equiv) in a 50 mL Schlenk tube were added 1,2-dimethoxyethane (2 mL) under air. Then H2O2 (1.2 mmol, 2.4 equiv) was added. The mixture was stirred at 80°C for 24 h. And then the mixture was purified by silica gel column chromatography (petroleum ether/ethyl acetate) to give the products.
Reference：
[1] Patent: WO2004/13139, 2004, A2, . Location in patent: Page 25-26
[2] Tetrahedron Letters, 2009, vol. 50, # 9, p. 1007 - 1009
[3] Indian Journal of Chemistry - Section B Organic and Medicinal Chemistry, 2001, vol. 40, # 11, p. 1129 - 1131
[4] Patent: CN105348177, 2016, A, . Location in patent: Paragraph 0012; 0016
[5] Journal of Medicinal Chemistry, 2012, vol. 55, # 4, p. 1682 - 1697
[6] Patent: US2014/18360, 2014, A1, . Location in patent: Paragraph 0174
[7] Journal fuer Praktische Chemie (Leipzig), 1989, vol. 331, # 3, p. 369 - 374
[8] Journal fuer Praktische Chemie (Leipzig), 1989, vol. 331, # 3, p. 369 - 374
[9] Journal of Organic Chemistry, 2001, vol. 66, # 4, p. 1310 - 1315
[10] Tetrahedron Letters, 2014, vol. 55, # 36, p. 5058 - 5061
32
[ 1603-40-3 ]
[ 60524-15-4 ]
Reference：
[1] Patent: EP2366691, 2011, A1,
33
[ 1603-40-3 ]
[ 2032-35-1 ]
[ 874-10-2 ]
Yield
Reaction Conditions
Operation in experiment
98%
With hydrogen bromide In ethanol; water at 90℃; for 26 h;
2-amino-3-methylpyridine (10 g, 92.5 mmol) and 2-bromo-1,1-diethoxyethane (36.4 g, 185 mmol) were dissolved in ethanol (100 mL) Then, 48percent aqueous hydrogen bromide solution (9 mL) was slowly added dropwise to the reaction solution. After the reaction system was heated to 90 ° C for 26 hours, LC-MS detection reaction has ended, And then cooled to room temperature. The first reaction in the system of ethanol decompression distillation, The excess hydrobromic acid in the reaction was neutralized with excess saturated sodium bicarbonate water (100 mL) and sodium bicarbonate solids (15 g). The remaining mixture was extracted with ethyl acetate (200 mL x 3) All organic phases were then mixed and washed once with deionized water (100 mL) and saturated brine (100 mL) Dried over anhydrous sodium sulfate, Press the steam to remove the solvent. The remaining mixture was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 0-10percent), To give 8-methyl-imidazo [1,2-a] pyridine (12 g, yield 98percent).
Reference：
[1] Patent: CN106279160, 2017, A, . Location in patent: Paragraph 0259; 0263; 0264; 0265
[2] Bulletin of the Chemical Society of Japan, 1999, vol. 72, # 6, p. 1327 - 1334
34
[ 107-20-0 ]
[ 1603-40-3 ]
[ 874-10-2 ]
Yield
Reaction Conditions
Operation in experiment
62%
With sodium chloride; sodium hydrogencarbonate In water
EXAMPLE IV 8-METHYLIMIDAZO[1,2-A]PYRIDINE To a mixture of chloroacetaldehyde [25.4 mL (0.2 mole) of a 50percent aqueous solution]and 18.8 g (0.2 mole) of 2-amino-3-methylpyridine in 150 mL of water was added 16.8 g (0.2 mole) of sodium bicarbonate. After being stirred at 25° C. for 3 days, the mixture was acidified with concentrated hydrochloric acid and stirred an additional 30 minutes. After the pH was adjusted to 10 by addition of sodium hydroxide, the mixture was saturated with sodium chloride and extracted with ether. The ether extracts were dried and concentrated to give 16.3 g (62percent) of a liquid residue, bp 68°-70° C. at 0.1 Torr. Imidazo[1,2-a]pyridine, bp 61°-66° C. at 0.1 Torr., was prepared in an analogous manner.
Reference：
[1] Journal of Medicinal Chemistry, 1992, vol. 35, # 23, p. 4415 - 4424
[2] Patent: US5039691, 1991, A,
[3] Patent: EP1790650, 2007, A1, . Location in patent: Page/Page column 45
35
[ 1603-40-3 ]
[ 17157-48-1 ]
[ 874-10-2 ]
Reference：
[1] Journal of Medicinal Chemistry, 1996, vol. 39, # 14, p. 2856 - 2859
36
[ 1603-40-3 ]
[ 70-23-5 ]
[ 67625-40-5 ]
Reference：
[1] Farmaco, Edizione Scientifica, 1983, vol. 38, # 12, p. 911 - 928
[2] Bioorganic and Medicinal Chemistry Letters, 2005, vol. 15, # 11, p. 2790 - 2794
37
[ 1603-40-3 ]
[ 3430-18-0 ]
Reference：
[1] European Journal of Medicinal Chemistry, 1989, vol. 24, # 3, p. 249 - 258
[2] Journal of Medicinal Chemistry, 2012, vol. 55, # 4, p. 1682 - 1697
[3] Patent: US2014/18360, 2014, A1,
38
[ 1603-40-3 ]
[ 65550-77-8 ]
Reference：
[1] European Journal of Medicinal Chemistry, 1989, vol. 24, # 3, p. 249 - 258
39
[ 1603-40-3 ]
[ 65550-78-9 ]
Reference：
[1] Journal of Organic Chemistry, 1995, vol. 60, # 16, p. 5356 - 5359
40
[ 1603-40-3 ]
[ 36404-90-7 ]
Reference：
[1] Chemical and Pharmaceutical Bulletin, 1990, vol. 38, # 9, p. 2446 - 2458
[2] Journal of Fluorine Chemistry, 2011, vol. 132, # 8, p. 541 - 547
41
[ 1603-40-3 ]
[ 128071-75-0 ]
Reference：
[1] Tetrahedron Letters, 2005, vol. 46, # 36, p. 6033 - 6036
[2] Chemical and Pharmaceutical Bulletin, 1990, vol. 38, # 9, p. 2446 - 2458
42
[ 1603-40-3 ]
[ 131747-55-2 ]
Reference：
[1] Chemical and Pharmaceutical Bulletin, 1990, vol. 38, # 9, p. 2446 - 2458
43
[ 1603-40-3 ]
[ 116308-35-1 ]
Reference：
[1] Chemical and Pharmaceutical Bulletin, 1990, vol. 38, # 9, p. 2446 - 2458
44
[ 1603-40-3 ]
[ 131747-57-4 ]
Reference：
[1] Chemical and Pharmaceutical Bulletin, 1990, vol. 38, # 9, p. 2446 - 2458
45
[ 1603-40-3 ]
[ 131747-43-8 ]
Reference：
[1] Chemical and Pharmaceutical Bulletin, 1990, vol. 38, # 9, p. 2446 - 2458
46
[ 1603-40-3 ]
[ 24424-99-5 ]
[ 138343-75-6 ]
Yield
Reaction Conditions
Operation in experiment
86%
at 20 - 58℃; for 4.5 h;
A solution of di-tert-butyl dicarbonate (50.0 g) in n-hexane (55 mL) was heated to 58°C and stirred. To this solution, a solution of 2-aminopicoline (15.5 g) in ethyl acetate (20 mL) was added dropwise. After heated at 58°C for three hours, it was cooled to room temperature. After addition of n-hexane (30 mL), it was stirred for 1.5 hours. The deposited precipitate was collected by filtration and dried and 25.8 g (86percent) of the title compound was obtained as a white solid. MS(FAB) m/z:209 (M + H)+.
82%
for 2 h; Reflux; Large scale
BOC anhydride (3.2 kg, 14.7 mmol) was dissolved in hexane (3.5 L) and heated to reflux. 3-Methyl-pyridin-2-ylamine S5 (995 g, 9.2mmol) in EtOAc (1 L) was added dropwise over 2 hours, then the reaction was cooled to 20°C. Following dilution with hexane (2 L), the mixture was stirred for a further hour and the resultent solid collected by filtration, washing with hexane to affords (3-methyl-pyridin-2-yl)-carbamicacid tert-butyl ester S6 (1.56 kg, 82percent yield) 1H NMR (400 MHz, CDCl3):1.55 (9H, s), 2.32 (3H, s), 6.87 (1H, s(b)), 7.07 (1H, dd), 7.55 (1H, d), 8.29 (1H, d)
71%
at 25 - 60℃; for 19 h;
Step 1 (3-Methyl-pyridin-2-yl)-carbamic acid tert-butyl ester 3-Methylpyridin-2-amine (20 g, 185 mmol) was dissolved in ethyl acetate (30 mL) and added drop-wise to a solution of di-tert-butyldicarbonate (64.6 g, 296 mmol) in hexanes (72 mL) at 60° C. After 3 h, the mixture was cooled to 25° C. After 16 h, hexanes (70 mL) were added. After 2 h, the solid precipitate was filtered, the cake rinsed with hexanes, and then dried to give (3-methyl-pyridin-2-yl)-carbamic acid tert-butyl ester (27.4 g, 71percent) as a white solid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.24-8.29 (m, 1H) 7.49-7.54 (m, 1H) 7.00-7.07 (m, 1H) 2.30 (s, 3H) 1.52 (s, 9H); LCMS (EI/CI) m/z: 209 [M+H].
68.6%
at 20℃; for 4 h;
Example 175[0447] (5)-N-(benzo[ ][l,3]dioxol-5-yl)-2-(2-(3-ethyl-2-methyl-lH-pyrrolo[2,3- b]pyridin- 1 -yl)acetamido)-N-methyl-3-phenylpropanamideExample 175 A. Preparation of tert-butyl (3-methylpyridin-2-yl)carbamate[0448] To a solution of 3-methylpyridin-2-amine (15 g, 0.14 mol, 1.0 eq) in EtOAc (30 mL) and petroleum ether (120 mL), was added Boc20 (48.5 g, 0.55 mol, 1.6 eq). The reaction mixture was stirred at room temperature for 4 hours. TLC (petroleum ether/EtOAc 3: 1) showed the reaction was completed. The reaction mixture concentrated in vacuum to give the crude product, which was purified by column chromatography on silica gel to give tert-butyl (3-methylpyridin-2-yl)carbamate (20 g, 0.096 mmol, yield: 68.6percent), LC/MS: m/z M++l = 209.
4.45 g
With caesium carbonate In N,N-dimethyl-formamide at 20℃; for 48 h;
BOC anhydride (9.6 g, 44 mmol) was added slowly to a solution of 3-methylpyridin-2-amine (4 g, 37 mmol) and cesium carbonate (7.2 g) dry in DMF (20 mL) and the reaction was maintained at rt for 2 d. The reaction mixture was poured into water (300 mL) with stirring. The resulting white precipitate was collected by filtration and dried under vacuum to give 4.45 g of tert-butyl 3-methylpyridin-2-ylcarbamate: 1H NMR (300 MHz, CDCl3) δ 8.26 (m, 1H); 7.52 (m, 1H); 7.02 (m, 1H); 6.88 (br s, 1H); 2.29 (s, 3H); 1.52 (s, 9H).
Reference：
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[2] Patent: EP1764360, 2007, A1, . Location in patent: Page/Page column 195
[3] Synthesis, 1996, # 7, p. 877 - 882
[4] Tetrahedron, 2008, vol. 64, # 3, p. 500 - 507
[5] Bioorganic and Medicinal Chemistry, 2013, vol. 21, # 21, p. 6582 - 6591
[6] Organic Letters, 2009, vol. 11, # 6, p. 1357 - 1360
[7] Journal of Medicinal Chemistry, 2014, vol. 57, # 13, p. 5702 - 5713
[8] Patent: US5681959, 1997, A,
[9] European Journal of Organic Chemistry, 2015, vol. 2015, # 19, p. 4214 - 4223
[10] Patent: US2013/178478, 2013, A1, . Location in patent: Paragraph 0252
[11] Patent: US5681959, 1997, A,
[12] Patent: WO2012/65062, 2012, A1, . Location in patent: Page/Page column 125-126
[13] Patent: WO2006/75638, 2006, A1, . Location in patent: Page/Page column 69-70
[14] Journal of Medicinal Chemistry, 2010, vol. 53, # 3, p. 942 - 950
[15] Synthesis, 1991, # 10, p. 871 - 878
[16] Patent: US5380739, 1995, A,
[17] Patent: US5559081, 1996, A,
[18] Patent: US2008/125459, 2008, A1, . Location in patent: Page/Page column 10
[19] Patent: US2009/298865, 2009, A1, . Location in patent: Page/Page column 6-7
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[21] Patent: US2011/112104, 2011, A1, . Location in patent: Page/Page column 5
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47
[ 1603-40-3 ]
[ 42959-38-6 ]
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[2] Bioorganic and Medicinal Chemistry, 2015, vol. 23, # 5, p. 985 - 995
48
[ 1603-40-3 ]
[ 145901-11-7 ]
Reference：
[1] Patent: US2013/178478, 2013, A1,
49
[ 1603-40-3 ]
[ 166266-19-9 ]
Yield
Reaction Conditions
Operation in experiment
6.0 g
at 0 - 20℃; for 3 h; Inert atmosphere
In a 250-mL round-bottomed flask, a solution of 3-methylpyridin-2-amine (4.57 g, 42.3 mmol) in AcOH (50 mL) was cooled to 0 °C. NIS (9.5 g, 42 mmol, Sigma- Aldrich, India) was added in portions to the above solution at the same temperature under nitrogen atmosphere. The reaction mixture was warmed to room temperature and stirred at room temperature for 3 h. The reaction mixture was diluted with cold water (100 mL), followed by a mixture of 5percent Na2S203 (40 mL) and NaHC03 (100 mL) at room temperature. The solid that formed was filtered, washed thoroughly with water and dried rigorously under reduced pressure at 50 °C to give 5-iodo-3-methyl-2-pyridinamine (6.0 g) as a yellow solid.
Reference：
[1] Journal of Organic Chemistry, 1995, vol. 60, # 16, p. 5356 - 5359
[2] Bioorganic Chemistry, 2001, vol. 29, # 4, p. 198 - 210
[3] Journal of the American Chemical Society, 2000, vol. 122, # 27, p. 6512 - 6513
[4] Patent: WO2013/123444, 2013, A1, . Location in patent: Page/Page column 213
Reference：
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[2] Patent: US2014/18360, 2014, A1,
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[ 1603-40-3 ]
[ 289681-47-6 ]
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[2] Bioorganic Chemistry, 2001, vol. 29, # 4, p. 198 - 210
With sulfuric acid; sodium carbonate; sodium nitrite; In ethanol; water;
PREPARATION 4 2-Hydroxy-3-methylpyridine A solution of 2.30 g (33.3 mole) of sodium nitrite in 5 ml of water was added dropwise at room temperature to a solution of 3.60 g (33.3 mole) of 2-amino-3-picoline in a mixture of 65 ml of water and 4 ml of concentrated sulfuric acid, and the resulting mixture was stirred at room temperature for 2 hours. At the end of this time, the pH of the reaction mixture was adjusted to a value of 7 by the addition of sodium carbonate, and the water was removed by distillation under reduced pressure. The mixture was then extracted three times, each time with 80 ml of warm ethanol. The extract was then freed from the ethanol by distillation under reduced pressure, and the resulting residue was recrystallized from ethyl acetate, to give 3.38 g (yield 93%) of the title compound as colorless crystals, melting at 137-139 C. 1 H Nuclear Magnetic Resonance Spectrum (CDCl3), delta ppm: 2.18 (3H, singlet); 6.22 (1H, doublet of doublets, J=7 & 7 Hz); 7.3-7.4 (2H, multiplet); 13.14 (1H, singlet).
Stage #1: 3-methylpyridin-2-ylamine With hydrogen bromide; bromine In water at -20℃; for 0.833333h;
Stage #2: With sodium nitrite In water at -20℃; for 2.5h;
With hydrogen bromide; bromine; sodium nitrite In water at -20℃;
With hydrogen bromide; bromine; sodium nitrite at -20℃;
Example 1; Synthesis of 3-amino-1-hydroxy-3,4-dihydro-1,8-naphthyridin-2(1H)-one, trifluoroacetate salt (8); 3-Methyl-2-nitropyridine (2); To a solution of H2O2 (120 g, 1.1 mol) in fuming sulfuric acid (250 mL) was added a solution of 3-methylpyridin-2-amine (1) (16 g, 0.15 mol) in concentrated sulfuric acid (50 mL) drop-wise, while keeping the reaction temperature at 0 C. After stirring for 3 h at 10-25 C., the reaction mixture was brought to pH=11-12 by adding an aqueous 40% NaOH solution at 0-5 C. The resulting mixture was extracted with ethyl acetate (3×500 mL). The combined organic layers were washed with saturated aqueous sodium chloride solution, dried over Na2SO4 and filtered. The solvent was removed in vacuo to give the desired compound (18.2 g, 89%) as a yellow oil.
13.13%
With sulfuric acid; dihydrogen peroxide; at 20℃; for 29.0h;Cooling with ice;
Hydrogen peroxide (187.5 g, 1.72 mol) was dissolved in 390 mL fuming sulfuric acid,2-amino-3-methylpyridine (25 g, 0.23 mmol) was dissolved in 80 mL of concentrated sulfuric acid under stirring,And dropping into the solution dropwise under ice-cooling,In the ice bath conditions for 5h,Returned to room temperature for 24 h.With 40% sodium hydroxide aqueous solution to adjust the pH to neutral, with ethyl acetate(700 mL X 3). The extract was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated to a crude product,The crude product was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 1:10) to give 2-nitro-2-methylpyridine (4.2 g, 13.13%).
3-Methyl-pyridin-2-ylamine (5.0 g, 46.2 mmol) was dissolved in concentrated sulfuric acid (24ml), the mixture was chilled to 0C and a mixture of fuming nitric acid (d=1.5, 3.5ml) and concentrated sulfuric acid (3.5ml) was added dropwise to the reaction mixture while temperature was kept below 20C. The stirred mixture was allowed to warm to 20C and transferred in portions of 3-5ml into a second flask which was heated to 35-40C (the temperature was not allowed to rise over 40C - monitoring carefully the temperature after every addition of a new portion). The resulting reaction mixture was subsequently stirred for additional 30min at 50C, cooled to ambient temperature and neutralized with concentrated aqueous ammonia. This led to the formation of a precipitated which was filtered, washed with water and aqueous DMFA (50%, 6ml), and recrystallized from DMFA yielding 3-methyl-5-nitro-pyridin-2-ylamine (2.52g, 35%).
With sodium chloride; sodium hydrogencarbonate; In water;
EXAMPLE IV 8-METHYLIMIDAZO[1,2-A]PYRIDINE To a mixture of chloroacetaldehyde [25.4 mL (0.2 mole) of a 50% aqueous solution]and 18.8 g (0.2 mole) of 2-amino-3-methylpyridine in 150 mL of water was added 16.8 g (0.2 mole) of sodium bicarbonate. After being stirred at 25 C. for 3 days, the mixture was acidified with concentrated hydrochloric acid and stirred an additional 30 minutes. After the pH was adjusted to 10 by addition of sodium hydroxide, the mixture was saturated with sodium chloride and extracted with ether. The ether extracts were dried and concentrated to give 16.3 g (62%) of a liquid residue, bp 68-70 C. at 0.1 Torr. Imidazo[1,2-a]pyridine, bp 61-66 C. at 0.1 Torr., was prepared in an analogous manner.
18.27 g of 2-amino-3-picoline was dissolved in 150 mL of water, 14.2 g of sodium hydrogen carbonate and 33.2 g of chloroacetaldehyde (40% aqueous solution) were added thereto, and then stirred at room temperature for 4 hours. The solution was adjusted to pH 10 with a 3N aqueous solution of sodium hydroxide, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and then dried over anhydrous sodium sulfate. The insolubles were separated by filtration, and then the filtrate was concentrated to obtain 8-methylimidazo[1,2-a]pyridine [3-1] as a brown oily product.
A solution of di-tert-butyl dicarbonate (12.11 g, 55.49 mmol)in tetrahydrofuran (55 mL) was stirred at 60 C. To thissolution, 2-amino-3-methlypyridine (5 g, 46.24 mmol)was added. The mixture was heated at 70 C for 3 h and subsequently allowed to cool to room temperature. Theprecipitate was collected by filtration and dried. The rawproduct (8.67 g) was recrystallized from dichloromethane.White crystals suitable for X-ray diffraction analysis wereobtained in a yield of 90%. m.p. 134-138 C (Lit [16]. m.p.138-140 C). HRMS (ESI) m/z: calcd for C11N2O2H16[M]+208.0726, found 208.0767. 1H NMR (400 MHz, CDCl3)δ8.27 (d, J = 4.8 Hz, 1H), 7.94 (s, 1H), 7.51 (d, J = 4.4 Hz,1H), 7.02 (dd, J = 7.5, 4.9 Hz, 1H), 2.28 (s, 3H), 1.50 (s,9H). 13C NMR (100 MHz, CDCl3)δ 152.74, 149.91, 145.54,139.56, 126.83, 120.47, 80.29, 28.13, 17.89.
86%
In hexane; ethyl acetate; at 20 - 58℃; for 4.5h;
A solution of di-tert-butyl dicarbonate (50.0 g) in n-hexane (55 mL) was heated to 58C and stirred. To this solution, a solution of 2-aminopicoline (15.5 g) in ethyl acetate (20 mL) was added dropwise. After heated at 58C for three hours, it was cooled to room temperature. After addition of n-hexane (30 mL), it was stirred for 1.5 hours. The deposited precipitate was collected by filtration and dried and 25.8 g (86%) of the title compound was obtained as a white solid. MS(FAB) m/z:209 (M + H)+.
82%
In hexane; ethyl acetate; for 2h;Reflux; Large scale;
BOC anhydride (3.2 kg, 14.7 mmol) was dissolved in hexane (3.5 L) and heated to reflux. 3-Methyl-pyridin-2-ylamine S5 (995 g, 9.2mmol) in EtOAc (1 L) was added dropwise over 2 hours, then the reaction was cooled to 20C. Following dilution with hexane (2 L), the mixture was stirred for a further hour and the resultent solid collected by filtration, washing with hexane to affords (3-methyl-pyridin-2-yl)-carbamicacid tert-butyl ester S6 (1.56 kg, 82% yield) 1H NMR (400 MHz, CDCl3):1.55 (9H, s), 2.32 (3H, s), 6.87 (1H, s(b)), 7.07 (1H, dd), 7.55 (1H, d), 8.29 (1H, d)
75%
In hexane; ethyl acetate;
a 2-(tert-Butoxycarbonylamino)-3-methylpyridine To a stirred solution of di-tert-butyldicarbonate (326.2 g) in hexane (200 ml) at reflux temperature was added, over 40 minutes, a solution of 2-amino-3-methylpyridine (100 g) in ethyl acetate (50 ml). The mixture was heated at reflux for a further 10 minutes and then allowed to cool to ambient temperature (crystallisation occurred at ca. 50 C.). The suspension was diluted with hexane (300 ml) and aged for 1 hour at 20 C. The product was isolated by filtration, washed with hexane (750 ml) and dried under vacuum to give the title compound (143 g, 75% yield); mp 131-134 C. ›lit. 132-133[C.]; Analysis Found C 63.65, H 7.79, N 13.5. C11 H16 N2 O2 requires C 63.44, H 7.74, N 13.45%.
71%
In ethyl acetate; at 25 - 60℃; for 19h;
Step 1 (3-Methyl-pyridin-2-yl)-carbamic acid tert-butyl ester 3-Methylpyridin-2-amine (20 g, 185 mmol) was dissolved in ethyl acetate (30 mL) and added drop-wise to a solution of di-tert-butyldicarbonate (64.6 g, 296 mmol) in hexanes (72 mL) at 60 C. After 3 h, the mixture was cooled to 25 C. After 16 h, hexanes (70 mL) were added. After 2 h, the solid precipitate was filtered, the cake rinsed with hexanes, and then dried to give (3-methyl-pyridin-2-yl)-carbamic acid tert-butyl ester (27.4 g, 71%) as a white solid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.24-8.29 (m, 1H) 7.49-7.54 (m, 1H) 7.00-7.07 (m, 1H) 2.30 (s, 3H) 1.52 (s, 9H); LCMS (EI/CI) m/z: 209 [M+H].
68%
In ethyl acetate; petrol;
a 2-tert-Butoxycarbonylamino-3-methylpyridine To a stirred solution of di-tert-butyldicarbonate (163.1 g, 748 mmol) in petrol (60-80) (100 ml) at reflux was added a solution of 2-amino-3-methylpyridine (50 g, 463 mmol) in ethyl acetate (25 ml) over 45 minutes. When addition was complete the reaction was stirred at reflux for a further 15 minutes, then allowed to cool to room temperature during which it solidified. The mixture was diluted with petrol (60-80) (150 ml) and filtered. The solid was washed with a further portion of petrol and dried to give the title compound as a white solid (65.9 g, 68%). δH (CDCl3) 1.44 (9H, s, OC(CH3)3), 2.22 (3H, s, ArCH3), 6.93-6.98 (1H, m, 5-H), 7.44 (1H, d, J 9.5 Hz, 4H), 8.19 (1H, d, J 4.8 Hz, 6H).
68.6%
In ethyl acetate; Petroleum ether; at 20℃; for 4h;
Example 175[0447] (5)-N-(benzo[ ][l,3]dioxol-5-yl)-2-(2-(3-ethyl-2-methyl-lH-pyrrolo[2,3- b]pyridin- 1 -yl)acetamido)-N-methyl-3-phenylpropanamideExample 175 A. Preparation of tert-butyl (3-methylpyridin-2-yl)carbamate[0448] To a solution of 3-methylpyridin-2-amine (15 g, 0.14 mol, 1.0 eq) in EtOAc (30 mL) and petroleum ether (120 mL), was added Boc20 (48.5 g, 0.55 mol, 1.6 eq). The reaction mixture was stirred at room temperature for 4 hours. TLC (petroleum ether/EtOAc 3: 1) showed the reaction was completed. The reaction mixture concentrated in vacuum to give the crude product, which was purified by column chromatography on silica gel to give tert-butyl (3-methylpyridin-2-yl)carbamate (20 g, 0.096 mmol, yield: 68.6%), LC/MS: m/z M++l = 209.
In tetrahydrofuran;
A. Preparation of (41) where Y and Z are Hydrogen A solution of 2-amino-3-methylpyridine (10.8 g) and di-tert-butyl dicarbonate (21.8 g) in tetrahydrofuran was heated under reflux for 12 hours. Evaporation afforded a solid, which was recrystallized from ether-tetrahydrofuran to yield 2-(t-butoxycarbonylamino)-3-methylpyridine (10.2 g), a compound of Formula (41), m.p. 132-133 C.
In tetrahydrofuran; ethyl acetate;
(a) t-Butyl (3-methyl-2-pyridyl)carbamate A solution of 2-amino-3-methylpyridine (20 g) plus di-t-butyl dicarbonate (46.8 ml) in dry tetrahydrofuran was refluxed for 3 hours. The solution was evaporated to give a dark brown oil. This was dissolved in ethyl acetate (400 ml), washed with 1.0N citric acid (3*200 ml) and saturated sodium chloride solution, dried, and evaporated to give a pale yellow solid which was crystallized from hexane/diisopropyl ether (1:2) to give 6.5 g of the desired compound as a pale yellow solid, mp 135-137 C.
In hexane; ethyl acetate; for 3h;
EXAMPLE 5Compound 8N-(1-methyl-1H-indol-5-yl)-1-[(3-fluorophenyl)methyl]-1H-pyrrolo[2,3-b]pyridine-2-carboxamide5.1 2-(t-butyloxycarbonylamino)-3-methylpyridine; 31 g (142.03 mmol) of di-tert-butyl dicarbonate and 35 ml of hexane are placed in a 100 ml three-necked flask equipped with a magnetic stirrer, and are brought to reflux. A solution of 10 g (88.77 mmol) of 2-amino-3-methylpyridine in 10 ml of ethyl acetate is then added dropwise over a period of 2 hours. Refluxing is continued for 1 hour after the end of the addition. After cooling to room temperature, 20 ml of hexane are added and the white precipitate formed after stirring the reaction mixture is collected by filtration, rinsed with hexane and dried under reduced pressure. 15.5 g (74.43 mmol) of white crystals are obtained.1H NMR (CDCl3), δ (ppm): 8.3 (dd, 1H); 7.5 (dd, 1H); 7.4 (s, NH); 7.1 (ddd, 1H); 2.3 (s, 3H); 1.5 (s, 9H).
In hexane; ethyl acetate; for 3h;Reflux;
Example 3; Compound 3N-(1,2-dimethyl-1H-benzimidazol-5-yl)-1-[(4-pyridyl)methyl]-1H-pyrrolo[2,3-b]pyridine-2-carboxamide3.1 2-(t-butyloxycarbonylamino)-3-methylpyridine31 g (142.03 mmol) of di-tert-butyl dicarbonate and 35 mL of hexane are introduced into a 100 mL three-necked flask equipped with a magnetic stirrer, and the solution is brought to reflux. A solution of 10 g (88.77 mmol) of 2-amino-3-methylpyridine in 10 mL of ethyl acetate is then added dropwise over a period of 2 hours. Refluxing is continued for 1 hour after the end of the addition. After returning to room temperature, 20 mL of hexane are added and the white precipitate formed after stirring the reaction mixture is collected by filtration, rinsed with hexane and dried under reduced pressure. 15.5 g of white crystals are obtained.1H NMR (CDCl3), δ (ppm): 8.3 (dd, 1H); 7.5 (dd, 1H); 7.4 (s, 1H); 7.1 (ddd, 1H); 2.3 (s, 3H); 1.5 (s, 9H).
In hexane; ethyl acetate; at 65℃; for 1.5h;Reflux;
To a refluxing solution of di-tert-butyldicarbonate (211.7 g, 0.97 mol) in hexane (500 mL), a solution of 2-amino-3-methylpyridine (100 g, 0.9247 mol) in AcOEt (150 mL) was added over 30 min. The mixture was stirred at reflux temperature (65 C.) for an additional hour and then cooled to room temperature. The suspension was diluted with hexane (500 mL) and stirred for 1 h at room temperature. The product was isolated by filtration, washed with hexane and dried under vacuum to afford 130 g of 2 (tert-butyl 3-methylpyridin-2-ylcarbamate) that was used in the next step without further purification.
In hexane; ethyl acetate; for 1h;Reflux;
Step A: tert-Butyl 3-methyl-2-pyridylcarbamateTo a solution of di-tert-butyldicarbonate (161.5 g) in 400 mL of hexane there is added, over 2 hours, a solution of 3-methyl-2-aminopyridine (50 g) in 50 mL of ethyl acetate. The reaction mixture is heated at reflux for 1 hour, and then diluted with 550 mL of hexane and stirred at ambient temperature for 2 hours. The precipitate is filtered off to yield the title product in the form of a white solid.
4.45 g
With caesium carbonate; In N,N-dimethyl-formamide; at 20℃; for 48h;
BOC anhydride (9.6 g, 44 mmol) was added slowly to a solution of 3-methylpyridin-2-amine (4 g, 37 mmol) and cesium carbonate (7.2 g) dry in DMF (20 mL) and the reaction was maintained at rt for 2 d. The reaction mixture was poured into water (300 mL) with stirring. The resulting white precipitate was collected by filtration and dried under vacuum to give 4.45 g of tert-butyl 3-methylpyridin-2-ylcarbamate: 1H NMR (300 MHz, CDCl3) δ 8.26 (m, 1H); 7.52 (m, 1H); 7.02 (m, 1H); 6.88 (br s, 1H); 2.29 (s, 3H); 1.52 (s, 9H).
With triethylamine; In ethanol; at 20℃; for 20.5h;
(2) The 2-amino-3-methyl pyridine was added to ethanol, stirred until completely dissolved triethylamine, 30 minutes at room temperature was added dropwise di-tert-butyl dicarbonate,20 hours after the reaction was distilled off ethanol, the product was added to distilled water and extracted three times with methyl acetate,The combined extracts were washed repeatedly with sodium chloride and then dried over sodium sulfate.Concentration and recrystallization from methyl acetate gave 2-N-BOC-amino-3-methylpyridine, 2-amino-3-methylpyridine, ethanol, triethylamine, di- tert- butyl dicarbonate, distilled water, Ester weight ratio of 4: 20: 11: 10: 4: 30;
In tetrahydrofuran;
A. Preparation of (X) where Y and Z are Hydrogen A solution of 2-amino-3-methylpyridine (10.8 g) and di-tert-butyl dicarbonate (21.8 g) in tetrahydrofuran was heated under reflux for 12 hours. Evaporation afforded a solid which was recrystallized from ether-tetrahydrofuran to yield 2-(t-butoxycarbonylamino)-3-methylpyridine (10.2 g), a compound of Formula (X), m.p. 132-133 C.
With caesium carbonate; In N,N-dimethyl-formamide; at 20℃; for 48h;
BOC anhydride (9.6 g, 44 mmol) was added slowly to a solution of 3-methylpyridin-2-amine (4 g, 37 mmol) and cesium carbonate (7.2 g) dry in DMF (20 mL) and the reaction was maintained at rt for 2 d. The reaction mixture was poured into water (300 mL) with stirring. The resulting white precipitate was collected by filtration and dried under vacuum to give 4.45 g of tert-butyl 3-methylpyridin-2-ylcarbamate: 1H NMR (300 MHz, CDCl3) δ 8.26 (m, 1 H); 7.52 (m, 1 H); 7.02 (m, 1 H); 6.88 (br s, 1 H); 2.29 (s, 3 H); 1.52(s, 9 H).
In hexane; ethyl acetate; at 60℃; for 2h;
A solution of 3-methylpyridin-2-amine (10.0 g, 92.5 mmol) in EtOAc (10 mL) was added dropwise to a 60 C. solution of Boc2O (32.0 g, 147 mmol) in hexane (50 mL), and the resulting mixture was stirred at 60 C. for 2 h before it was allowed to cool to rt and poured it into water. The aqueous mixture was extracted twice with EtOAc, and the combined organic layers were washed with brine, dried with anhydrous Na2SO4, filtered, and then concentrated. The concentrate was purified by silica gel chromatography (10%→20% EtOAc/petroleum ether) to give the title compound as a colorless solid.
With triethylamine; In tetrahydrofuran; hexane; acetone;
a 2,2-Dimethyl-N-(3-methyl-2-pyridinyl)propanamide 2-Amino-3-methylpyridine (108 g) and triethylamine (180 ml) were dissolved in tetrahydrofuran (500 ml) and the solution cooled to 0 C. in an acetone/ice bath. A solution of pivaloyl chloride (135.4 ml) in tetrahydrofuran (250 ml) was added over 70 minutes at such a rate that the temperature remained between 0 C. and 5 C. The mixture was aged at 0 C. for 15 minutes, allowed to warm to room temperature and aged for 3 hours. The reaction mixture was quenched into water (1 liter), the phases separated and the aqueous phase extracted with ethyl acetate (2*200 ml). The organic phases were combined, washed with saturated sodium bicarbonate solution (2*200 ml), brine (200 ml) and dried (sodium sulphate). The solvent was removed under reduced pressure and the solid residue flushed with hexane (100 ml). The solid was dissolved in hot hexane, filtered and allowed to crystallise. The title compoundcompound was collected by filtration, washed with hexane (200 ml) and dried (147.4 g, 76.8% yield; mp 90-92 C.).
76%
With triethylamine; In dichloromethane; at 0 - 20℃; for 3h;
Trimethylacetyl chloride (13.26 g, 0.11 mol) in methylene chloride (20 mL) was slowly added to a solution of 2-amino-3-methylpyridine (10.81 g, 0.1 mol) and triethylamine (12.63 g, 0.12 mol) in 150 ml of methylene chloride at 0C. The mixture was stirred in an ice bath for 1 h and further at room temperature for 2 h. Subsequently, the mixture was washed three times with an equal volume of aqueous sodium hydrogen carbonate (5%). The organic layer was dried with magnesium sulphate and concentrated to yield a colorless solid (14.52 g, 0.076 mol, 76 %). 1H-NMR (400 MHz, DMSO-d6, delta = 2.49 ppm): 9.55 (s, 1H, NH), 8.25 (d, 1H, 3JH,H = 4.7 Hz, 6-CH), 7.64 (d, 1H, 3JH,H = 7.4 Hz, 4-CH), 7.19 (dd, 1H, 3JH,H = 7.4 Hz, 4JH,H = 4.7 Hz, 5-CH), 2.10 (s, 3H, 3-CH3),1.22 (s, 9H, Pv-CH3). 13C-{1H}-NMR (150 MHz, DMSO-d6, delta = 39.5 ppm): 176.5 (CO), 150.6 (C2), 145.7 (C6), 139.0 (C4), 129.9 (C3), 121.9 (C5), 38.7 (Pv-C), 27.3 (Pv-CH3), 17.4 (3-CH3).
76%
With triethylamine; In dichloromethane; at 0 - 20℃; for 3h;
Trimethylacetyl chloride (13.26 g, 0.11 mol) in methylene chloride (20 mL) was slowly added to a solution of 2-amino-3-methylpyridine (10.81 g, 0.1 mol) and triethylamine (12.63 g, 0.12 mol) in 150 ml of methylene chloride at 0 C. The mixture was stirred in an ice bath for 1 h and further at room temperature for 2 h. Subsequently, the mixture was washed three times with an equal volume of aqueous sodium hydrogen carbonate (5%). The organic layer was dried with magnesium sulfate and concentrated to yield a colourless solid (14.52 g, 0.076 mol, 76%).1H NMR (400 MHz, DMSO-d6, delta = 2.49 ppm): 9.55 (s, 1H), 8.25 (d, 1H, 3JH,H = 4.7 Hz), 7.64 (d, 1H, 3JH,H = 7.4 Hz), 7.19 (dd, 1H, 3JH,H = 7.4 Hz, 4JH,H = 4.7 Hz), 2.10 (s, 3H),1.22 (s, 9H). 13C-{1H} NMR (150 MHz, DMSO-d6, delta = 39.5 ppm): 176.5, 150.6, 145.7, 139.0, 129.9, 121.9, 38.7, 27.3, 17.4.
Bromine (15.4 mL, 0.30 mol) was added dropwise to a stirred and cooled (0-2 [C)] solution of 2-amino-3-picoline (1; 32.44 g, 0.30 mol) in dry [CH2CI2] (1000 mL) over a period of 1 h. The cooling bath was then removed, and the yellowish suspension was stirred at r. t. for 3 h 40 min. The mixture was basified to pH 9 with 2N [NAOH] (145 mL) followed by a mixture of saturated aqueous [NAHC03] (100 mL) -saturated aqueous Na2S203 (10 mL). The organic layer was separated and washed with brine, dried [MGS04] and concentrated to afford 14 (56.83 g, 102%) as brown solid, which was used in the next step without purification.
95.2%
With bromine; iodine; acetic acid; at 0 - 10℃;
Add 108.1 g (1 mol) of 2-amino-3-methylpyridine, 324.4 g of acetic acid, and 8.6 g of iodine to a 2L four-necked flask, turn on the stirring, and lower the temperature to below 10 C;175.8.0 g (1.1 mol) of bromide was added dropwise, and the dropping temperature was controlled at 0 to 5 C, and the dropping time was 1-2 hours. After the dropwise addition was completed, the mixture was kept under stirring at 0 to 5 C for 2 hours.After the incubation is completed, add 300ml of water and stir for 15min; add 30% liquid alkali to adjust the pH to 9-10, and control the drop temperature at 15-20 C. End of dripping,Stir at 15-20 C for 1 h. Suction filtration, washing with water to neutrality, drying at 45-50 C to obtain 178.1 g of dry product, yield 95.2%, HPLC content 98.0%;
68%
Example 2 2-amino-3-methylpyridine (10.8g, 0.1mol) and acetic anhydride (12.3g, 0.12mol) was added to a 250ml four-necked flask and was heated to reflux in an oil bath, tracking by thin layer chromatography until the reaction is complete. Afterwards, the reaction was cooled to 20-25C, the solution was slowly added dropwise bromine (17.6g, 0.11mol) and was reacted at 55C for 2.5h. Water was added to dissolve all solids. 40mL 40% sodium hydroxide solution was slowly added dropwise. After the addition, he reaction was continued for 30min. The solution was then filtered, dried, and recrystallized to give 2-amino-3-methyl-5-bromopyridine with a molar yield of 68%.
65%
With N-Bromosuccinimide; ammonium acetate; In acetonitrile; at 0 - 23℃; for 0.416667h;
5-Bromo-3-methylpyridin-2-amine (48) [0174] (J. Mol. Catal. A: Chem. 2007, 267, 30-33.) N-Bromosuccinimide (170 g, 0.95 mol) was added to a solution of 47 (99 g, 0.92 mol) and ammonium acetate (7 g, 10 mol %) in acetonitrile (500 mL). The temperature of the reaction mixture during addition was controlled with an ice bath. After the full amount of NBS was added, the ice bath was removed and the reaction mixture was stirred at room temperature for 25 min, and acetonitrile was removed under reduced pressure. A mixture of ethyl acetate (1 L) and water (1 L) was added to the solid residue. The resulting mixture was stirred and the organic layer was separated. The water layer was extracted with ethyl acetate (3×500 mL). The combined extracts were washed with water (300 mL), saturated sodium bicarbonate solution (500 L), dried with sodium sulfate and evaporated to dryness to give a dark brown solid. The crude product was redissolved in chloroform (300 mL); and the solution was filtered through a thin pad of silica gel, eluting with chloroform. The combined filtrates were evaporated under reduced pressure to yield 48 as a light-brown solid (113 g, 65%): mp 89-90 C. (lit. (J. Am. Chem. Soc. 1976, 98, 1478-1486) mp 91-93 C.). 1H NMR (300 MHz, CDCl3) 7.97 (d, J=2.3 Hz, 1H), 7.36 (d, J=2.3 Hz, 1H), 4.50 (s, 2H), 2.09 (s, 3H); 13C NMR (75 MHz, CDCl3) delta 156.10, 146.29, 140.03, 118.79, 108.58, 77.72, 77.30, 76.88, 17.27.
56%
With dihydrogen peroxide; 1-butylpyridinium bromide; toluene-4-sulfonic acid; In 1,2-dimethoxyethane; at 80℃; for 24h;Schlenk technique; Inert atmosphere; Green chemistry;
General procedure: To a mixture of 2-aminopyridine (0.5 mmol, 1 equiv), p-TSA (0.4 mmol,0.8 equiv), 1-butylpyridinium bromide (1.5 mmol, 3 equiv) in a 50 mL Schlenk tube were added 1,2-dimethoxyethane (2 mL) under air. Then H2O2 (1.2 mmol, 2.4 equiv) was added. The mixture was stirred at 80C for 24 h. And then the mixture was purified by silica gel column chromatography (petroleum ether/ethyl acetate) to give the products.
With N-Bromosuccinimide; ammonium acetate; In acetonitrile; at 0 - 20℃; for 0.5h;
To a solution of 3-methylpyridin-2-amine (3, 5 g, 46.23 mmol) inCH3CN (50 mL) was added NH4OAc (356 mg, 4.62 mmol) and N-bromosuccinimide(9.05 g, 50.86 mmol) at 0 C. The mixture was stirred atroom temperature for 0.5 h. Solvent was concentrated in vacuo andwater (100 mL) was added. After extraction with EtOAc (100 mL×3),the combined organic phase was washed with saturated sodium bicarbonatesolution (100 mL×3) and water (100 mL×3), dried overNa2SO4, filtered, and concentrated in vacuo. The crude product 4 was given as a brown solid (7.91 g, 91%) and could be used in the next stepwithout further purification.
With bromine; In dichloromethane; at 0 - 20℃; for 5h;
Bromine (0.50 mL, 9.8 mmol) was added dropwise to a 0-5 C. solution of 3-methylpyridin-2-amine (1.0 g, 9.2 mmol) in DCM (30 mL), and the resulting mixture was stirred for 5 h, during which time it was allowed to warm to rt. The mixture was then diluted with water, mixed, and the pH of the aqueous layer was adjusted to pH 9 with 2 N aqueous NaOH. The layers were separated, and the organic layer was washed with a saturated aqueous NaHCO3 solution, washed with a saturated Na2SO3 solution, washed with brine, dried with anhydrous Na2SO4, filtered, and then concentrated to afford the title compound as a brown solid.
With N-iodo-succinimide; sodium nitrite; at 0 - 20℃; for 3h;Inert atmosphere;
In a 250-mL round-bottomed flask, a solution of 3-methylpyridin-2-amine (4.57 g, 42.3 mmol) in AcOH (50 mL) was cooled to 0 C. NIS (9.5 g, 42 mmol, Sigma- Aldrich, India) was added in portions to the above solution at the same temperature under nitrogen atmosphere. The reaction mixture was warmed to room temperature and stirred at room temperature for 3 h. The reaction mixture was diluted with cold water (100 mL), followed by a mixture of 5% Na2S203 (40 mL) and NaHC03 (100 mL) at room temperature. The solid that formed was filtered, washed thoroughly with water and dried rigorously under reduced pressure at 50 C to give 5-iodo-3-methyl-2-pyridinamine (6.0 g) as a yellow solid.
With hydrogen bromide; In ethanol; water; at 90℃; for 26.0h;
2-amino-3-methylpyridine (10 g, 92.5 mmol) and 2-bromo-1,1-diethoxyethane (36.4 g, 185 mmol) were dissolved in ethanol (100 mL) Then, 48% aqueous hydrogen bromide solution (9 mL) was slowly added dropwise to the reaction solution. After the reaction system was heated to 90 C for 26 hours, LC-MS detection reaction has ended, And then cooled to room temperature. The first reaction in the system of ethanol decompression distillation, The excess hydrobromic acid in the reaction was neutralized with excess saturated sodium bicarbonate water (100 mL) and sodium bicarbonate solids (15 g). The remaining mixture was extracted with ethyl acetate (200 mL x 3) All organic phases were then mixed and washed once with deionized water (100 mL) and saturated brine (100 mL) Dried over anhydrous sodium sulfate, Press the steam to remove the solvent. The remaining mixture was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 0-10%), To give 8-methyl-imidazo [1,2-a] pyridine (12 g, yield 98%).
Reference Production Example 23; 2-(Chlromethyl)-8-methylimidazo [1, 2-a] pyridine; 3. 81 g of 1,3-dichloroacetone and 3.24 g of 2-amino-3- methylpyridine were dissolved in 30 ml of ethanol, and the solution was heated to reflux for 5 hours. The reaction mixture was cooled to room temperature and then concentrated under reduced pressure. To the residue, 50 ml of aqueous saturated sodium hydrogen carbonate was added and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography and then recrystallized from hexane-methyl-t-butyl ether to obtain 1.52 g of 2-(chloromethyl)-8-methylimidazo [1, 2-a] pyridine. H-NMR (CDCl3, TMS, 8 (ppm) ): 2.60 (3H, s), 4.80 (2H, s), 6.68 (1H, t), 6.96 (1H, dd), 7.61 (1H, s), 7.93 (1H, d)
Step 1 2-Hydroxy-3-methylpyridine To 10% aqueous H2 SO4 (90 mL) at 0 C. was added 2-amino-3-methylpyridine (6.0 g, 56 mmol). The mixture was stirred at 0 C. for 30 mins and a solution of 4N aqueous NaNO2 (13 mL) was added dropwise over a period of 15 min. The mixture was further stirred and warmed to rt over 1 h. The pH was then adjusted to 6-7 by the addition of ION aqueous NaOH. The whole mixture was then extracted with CHCl13, washed with H2 O, dried (anhydrous MgSO4) and concentrated in vacuo. The crude material was swished with Et2 O to give the title compound (2.5 g, 42%) as a white solid. 1 H NMR(CD3 COCD3) delta 2.02(3H, s), 6.10(1H, m), 7.30(2H, m).
42%
With sodium hydroxide;
Step 1: 2-Hydroxy-3-methylpyridine To 10% aqueous H2 SO4 (90 mL) at 0C was added 2-amino-3-methylpyridine (6.0 g, 56 mmol). The mixture was stirred at 0 C. for 30 mins and a solution of 4N aqueous NaNO2 (13 mL) was added dropwise over a period of 15 min. The mixture was further stirred and warmed to rt over 1 h. The pH was then adjusted to 6-7 by the addition of 10N aqueous NaOH. The whole mixture was then extracted with CHCl3, washed with H2 O, dried (anhydrous MgSO4) and concentrated in vacuo. The crude material was swished with Et2 O to give the title compound (2.5 g, 42%) as a white solid. 1 H NMR(CD3 COCD3) delta 2.02(3H, s), 6.10(1H, m), 7.30(2H, m).
42%
With sodium hydroxide;
Step 1 2-Hydroxy-3-methylpyridine To 10% aqueous H2 SO4 (90 mL) at 0 C. was added 2-amino-3-methylpyridine (6.0 g, 56 mmol). The mixture was stirred at 0 C. for 30 mins and a solution of 4N aqueous NaNO2 (13 mL) was added dropwise over a period of 15 min. The mixture was further stirred and warmed to rt over 1 h. The pH was then adjusted to 6-7 by the addition of 10N aqueous NaOH. The whole mixture was then extracted with CHCl3, washed with H2 O, dried (anhydrous MgSO4) and concentrated in vacuo. The crude material was swished with Et2 O to give the title compound (2.5 g, 42%) as a white solid. 1 H NMR(CD3 COCD3) delta 2.02(3H, s), 6.10(1H, m), 7.30(2H, m).
EXAMPLE XIII 1-(3-Methyl-2-pyridinyl)-3-(tetrahydro-1-methyl-4-oxo-1H-imidazol-2-ylidene) urea A mixture of 5.0 g (21.4 mM) of the phenyl carbamate 8 and 1.2 g (10.7 mM) of 2-amino-3-methyl-pyridine in 25 ml of anhydrous DMF was heated at 55 for 3 hrs. and then cooled. The solid was collected via filtration and washed successively with cold DMF, ethyl acetate and ether. Recrystallization from ethanol and a final wash with water gave 0.07 g of the above urea as a pale yellow solid, m.p. 219-221 C. (dec.). Anal. calcd. for C11 H13 N5 O2: C, 53.43; H, 5.30; N, 28.32. Found: C, 53.32; H, 5.36; N, 28.51.
With sodium hydrogencarbonate; In isopropyl alcohol; at 80℃; for 16h;
[00193] A mixture of crude 2-bromo-i-(4-iodophenyl)ethanone (18.2 g), 2-amino-3- picoline (1.1 equiv, 61.6 mmol), and sodium bicarbonate (1.3 equiv, 72.8 mmol) in isopropanol(160 mL) was heated at 80 0C for 16 h. After concentrating the reaction mixture in vacuo, water (100 mL) was added and the resultant tan slurry was filtered, rinsing with water (2 x 50 mL). The brown solid was recrystallized from hot isopropanol and further dried in vacuo to provide the title product as a brown solid (13.2 g, 71%). ESMS [M+H]+: 335.0.
Step A: Preparation of N-(5-pyrimidinylmethyl)-3-methyl-2-pyridinamine To a solution of <strong>[10070-92-5]5-pyrimidinecarboxaldehyde</strong> (5.0 g, 46 mmol) in toluene (100 rnL) was added 2-amino-3-picoline (5.0 g, 46 mmol). The reaction mixture was heated to 80 0C on a rotary evaporator while under reduced pressure. After 10 min an additional 200 mL of toluene was added. Continued heating under reduced pressure resulted in a white solid which was dissolved in methanol (200 mL). This solution was stirred vigorously under a nitrogen atmosphere, and granular sodium borohydride (10.0 g, 265 mmol) was added portionwise, resulting in vigorous bubbling. The reaction was allowed to stir for 1 h at room temperature after completion of the sodium borohydride addition. Acetic acid (1 mL) was then added, and the reaction mixture was stirred for 5 min, followed by the addition of water (100 mL). The volatiles were removed under reduced pressure, and the aqueous suspension was extracted with dichloromethane (2 x 100 mL). The organic layers were combined and dried over MgSO4, filtered, and the solvent was removed under reduced pressure to yield an off-white solid. The crude solid was adsorbed onto Celite and purified by column chromatography (gradient of 100% hexanes to 100% ethyl acetate over 30 minutes) to yield 8.848 g of a white solid.1H NMR (CDCl3) delta 9.11 (s, IH), 8.77 (s, 2H), 8.00 (d, IH), 7.26 (s, IH), 6.60 (dd, IH), 4.73 (d, 2H), 4.59 (br s, NH), 2.12 (s, 3H).
(8-methylimidazo[1,2-a]pyridin-3-yl)(phenyl)methanone[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
74%
With iron(III) chloride; In toluene; at 60℃; for 18h;
General procedure: A mixture of 2-aminopyridine (0.2 mmol), <strong>[2579-22-8]3-phenylpropiolaldehyde</strong> (0.2 mmol) and ferric chloride (5 mol%) in toluene (1 mL) was placed in a test tube (10 mL) equipped with a magnetic stirring bar. The mixture was stirred at 60 C for 18 h. After the reaction was finished, water (5 mL) was added and the solution was extracted with ethyl acetate (3×5 mL), the combined extract was dried with anhydrous MgSO4. Solvent was removed, and the residue was separated by column chromatography to give the pure sample.
2-(2-fluorophenyl)-8-methyl-3-nitroimidazo[1,2-a]pyridine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
77%
With pyridine; tert.-butylhydroperoxide; iodine; In acetonitrile; at 79℃;
Implementation steps: 0.108 g (1 mmol) of 3-methyl-2-aminopyridine and 0.175 g (1.05 mmol) of <strong>[399-25-7]2-fluoro-β-nitrostyrene</strong>, 0.051 g (0.2 mmol) of iodine, 0.180 g (2 mmol) of tert-butyl hydroperoxide and 0.049 g (0.62 mmol) of pyridine were placed in a reaction flask. 10 mL of acetonitrile was added and heated to reflux (reaction temperature was about 81 C), followed by TLC until the end of the reaction. After cooling to room temperature, acetonitrile was removed by rotary evaporation, and the concentrated product was separated by chromatography to afford product (yield: 77%)
47%
With pyridine; tert.-butylhydroperoxide; iodine; In acetonitrile; at 20℃; for 12h;Green chemistry;
General procedure: In a 50-mL round-bottomed flask, a mixture of2-aminopyridine (1 mmol) and nitroolefin (1.05 mmol)was stirred in 10 mL acetonitrile. Then, I2 (0.2 mmol),TBHP (2 mmol), and pyridine (0.05 mL) were added to theabove mixture, and the resulting mixture was allowed tostir under reflux or at room temperature for the specifiedtime (Table 2). The progress of the reaction was monitoredby thin-layer chromatography (TLC). After the completionof the reaction, the reaction mixture was cooled to roomtemperature and poured into saturated sodium bisulfite solution (15 mL). After sonication for 10 min, the mixturewas extracted with ethyl acetate (3 × 15 mL), followed bydrying with anhydrous MgSO4. After evaporation of thesolvent, the residue was purified by flash chromatographyto afford the desired product.
(R)-2-(4-isobutylphenyl)-N-(3-methylpyridin-2-yl)propanamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
58%
General procedure: The respective (R)(-)-ibuprofen or (S)(+)-ibuprofen (0.21 g, 1 mmol), EDC (0.21 g, 1.1 mmol), andHOBt (0.13 g, 1 mmol) in dry acetonitrile (10 mL) was stirred at room temperature for 30 minand then treated with 2-amino-3-methylpyridine (0.11 g, 1 mmol). The mixture was stirred atroom temperature for additional 48 h. Then the solution was evaporated to dryness in vacuo.The residue was taken up with brine (15 mL) and extracted with AcOEt (2 x 10 mL). Theorganic layer was washed sequentially with 10percent aqueous sodium carbonate (2 x 5 mL), 10percentaqueous citric acid (2 x 5 mL) and water (2 x 5 mL). The organic layer was dried over anhydrousmagnesium sulphate, filtered and concentrated to dryness under reduced pressure. Therespective (R)(+)-Ibu-AM5 or (S)(-)-Ibu-AM5 was obtained (58 and 57percent yield respectively) inanalytically pure form. 1H NMR (CDCl3): delta 0.86 (d, J = 6.5Hz, 6H, CH3), 1.47 (d, J = 7.0 Hz,3H, CH3), 1.83 (hept, J = 6.5 Hz, 1H, CH), 2.03 (s, 3H, CH3), 2.41 (d, J = 7.0 Hz, 2H, CH2),3.88 (q, J = 7.0 Hz, 1H, CH), 6.15 (s, 1H, NH), 6.70 (m, 1H, Py), 7.22 (d, J = 8.0 Hz, 2H, Ar),7.26 (d, J = 8.0 Hz, 2H, Ar), 7.35 (m, 1H, Py), 7.90 (m, 1H, Py). NMR spectra agree with literaturereport for the racemate [23]. IR (nujol) 3297, 3253, 3087, 3050, 1672, 1620, 1579 cm-1.Optical rotation [alpha] = -60.9° for (R)(-)-Ibu-AM5 and [alpha] = +60.8° for (S)(+)-Ibu-AM5. m/z297 (M + H)+ Anal. Calcd. for C19H24N2O: C, 76.99; H, 8.16; N, 9.45. Found: C, 77.05; H, 8.18;N, 8.13 for (R)(-)-Ibu-AM5 and C, 76.94; H, 8.19; N, 8.20 for (S)(-)-Ibu-AM5.
(S)-2-(4-isobutylphenyl)-N-(3-methylpyridin-2-yl)propanamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
57%
General procedure: The respective (R)(-)-ibuprofen or (S)(+)-ibuprofen (0.21 g, 1 mmol), EDC (0.21 g, 1.1 mmol), andHOBt (0.13 g, 1 mmol) in dry acetonitrile (10 mL) was stirred at room temperature for 30 minand then treated with 2-amino-3-methylpyridine (0.11 g, 1 mmol). The mixture was stirred atroom temperature for additional 48 h. Then the solution was evaporated to dryness in vacuo.The residue was taken up with brine (15 mL) and extracted with AcOEt (2 x 10 mL). Theorganic layer was washed sequentially with 10% aqueous sodium carbonate (2 x 5 mL), 10%aqueous citric acid (2 x 5 mL) and water (2 x 5 mL). The organic layer was dried over anhydrousmagnesium sulphate, filtered and concentrated to dryness under reduced pressure. Therespective (R)(+)-Ibu-AM5 or (S)(-)-Ibu-AM5 was obtained (58 and 57% yield respectively) inanalytically pure form. 1H NMR (CDCl3): delta 0.86 (d, J = 6.5Hz, 6H, CH3), 1.47 (d, J = 7.0 Hz,3H, CH3), 1.83 (hept, J = 6.5 Hz, 1H, CH), 2.03 (s, 3H, CH3), 2.41 (d, J = 7.0 Hz, 2H, CH2),3.88 (q, J = 7.0 Hz, 1H, CH), 6.15 (s, 1H, NH), 6.70 (m, 1H, Py), 7.22 (d, J = 8.0 Hz, 2H, Ar),7.26 (d, J = 8.0 Hz, 2H, Ar), 7.35 (m, 1H, Py), 7.90 (m, 1H, Py). NMR spectra agree with literaturereport for the racemate [23]. IR (nujol) 3297, 3253, 3087, 3050, 1672, 1620, 1579 cm-1.Optical rotation [alpha] = -60.9 for (R)(-)-Ibu-AM5 and [alpha] = +60.8 for (S)(+)-Ibu-AM5. m/z297 (M + H)+ Anal. Calcd. for C19H24N2O: C, 76.99; H, 8.16; N, 9.45. Found: C, 77.05; H, 8.18;N, 8.13 for (R)(-)-Ibu-AM5 and C, 76.94; H, 8.19; N, 8.20 for (S)(-)-Ibu-AM5.
2-(4-isobutylphenyl)-N-(3-methylpyridin-2-yl)acetamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
64%
A mixtureof <strong>[1553-60-2]ibufenac</strong> (0.19 g, 1 mmol), EDC (0.21 g, 1.1 mmol), and HOBt (0.13 g, 1 mmol) in dryacetonitrile (10 mL) was stirred at room temperature for 30 min and then treated with2-amino-3-methylpyridine (0.11 g, 1 mmol). The mixture was stirred at room temperature foran additional 24 h. Then the solution was evaporated to dryness in vacuo. The residue wastaken up with brine (15 mL) and extracted with AcOEt (2 x 10 mL). The organic layer waswashed sequentially with 10% aqueous sodium carbonate (2 x 5 mL), 10% aqueous citric acid(2 x 5 mL) and water (2 x 5 mL). Concentration of the dried extracts yielded the title compoundin analytically pure form. Yield 64%; 1H NMR (DMSO-d6) delta 0.86 (d, J = 6.5Hz, 6H, CH3), 1.82(hept, J = 6.5Hz, 1H, CH), 2.11 (s, 3H, CH3), 2.48 (d, J = 7.0 Hz, 2H, CH2), 3.85 (s, 2H, CH2),7.08-8.25 (m, 7H, Ar and Py), 10.16 (s, 1H, NH). IR (nujol) 3310, 3270, 3070, 3050, 1668,1620, 1569 cm-1. m/z 283 (M + H)+ Anal. Calcd. for C18H22N2O: C, 76.56; H, 7.85; N, 9.92.Found: C, 76.64; H, 7.87; N, 9.87.Inhibition of FAAH by the Enantiomers of Flu-AM1 and Ibu-AM5PLOS
N-(tert-butyl)-2-(5-chloro-2-ethynylphenyl)-8-methylimidazo[1,2-a]pyridin-3-amine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
47%
With toluene-4-sulfonic acid; In methanol; at 20℃; for 12h;Inert atmosphere;
General procedure: To a solution of 2-aminopyridine (1a, 0.5 mmol), 2-ethynylbenzaldehyde (2a, 0.5 mmol), and tert-butylisocyanide (3,0.6 mmol) in 1 mL of methanol were added p-toluenesulfonicacid (4.7 mg, 0.025 mmol) and the reaction mixture was stirredat rt for 12 h. The mixture was diluted with 15 mL of dichloromethane and washed successively with water (10 mL), saturated NaHCO3 solution (10 mL) and brine (10 mL). Afterdrying over anhydrous Na2SO4, the mixture was concentratedunder vacuum and the resulting residue was purified by flashchromatography (hexane/ethyl acetate 8:1) to afford GBBadduct 4a (90% yield).
tert-butyl 6-methyl-3,4-dihydroimidazo[1,2-a:5,4-c']dipyridin-2(1H)-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
In 1,4-dioxane; at 140℃; for 1.25h;Microwave irradiation;
2-Amino-3-methylpyridine (70 mg, 0.65 mmol) and tert-butyl 3-bromo-4-oxopiperidine- 1 -carboxylate (0.18 g, 0.65 mmol) were weighed into a 10 mL microwave reaction vessel , Ethanol (2 mL) was added, and the mixture was stirred at 140 ° C. for 75 minutes using a microwave reactor. The crude product obtained by concentrating the reaction mixture was purified by flash silica gel column chromatography (n - hexane only to n - hexane / ethyl acetate = 34/66) to obtain tert - butyl 6 - methyl - 3, Dihydroimidazo [1,2-a: 5,4-c '] dipyridine-2 (1 H) -carboxylate (hereinafter, Intermediate 2) was obtained as a colorless oil.
3,9-dimethyl-2H-pyrido[1,2-a]pyrimidin-2-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
92%
With 1,1,1,3',3',3'-hexafluoro-propanol Reflux;
With N-heterocyclic carbene palladium(II) complex supported on fibrous nanosilica In trifluoroacetic acid for 1h; Reflux; Green chemistry; chemoselective reaction;
2.7 General procedure for synthesis of pyridopyrimidinones
General procedure: A mixture of 2-aminopyridine derivative (1.0mmol) and Baylis-Hillman adducts (1.0mmol), and KCC-1/Pd-NHC-Py NPs (1mg) was stirred heating under reflux in TFA (3mL) for 1h. The catalyst was separated by filtration. Evaporation of the solvent of the filtrate under reduced pressure gave the crude products. The pure products were isolated by chromatography on silica gel eluted with petroleum ether:EtOAc (3:1).
4-chloro-6-methyl-11H-pyrido[2,1-b]quinazolin-11-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
60%
With potassium tert-butylate; dimethyl sulfoxide; at 20.0℃; for 12.0h;Inert atmosphere;
General procedure: An oven-dried round bottomed flask (50 mL capacity) equipped with a magnetic stir bar was evacuated and purged with argon. 2-Aminopyridine (1 mmol, 1 euiv), 2-fluorobenzonitrile (1.2 mmol, 1.2 euiv), KtOBu (4 mmol, 4 euiv) and DMSO (5 mL) were added successivelyat room temperature and the reaction mixture was allowed to stir at room temperature for 12 h. Water (10 mL) was added to the reaction mixture and the organic layer was extracted with ethyl acetate (2×20 mL). The combined organic phases were washed with brine and dried over sodium sulfate. The solvent was removed and the residue was purified by column chromatography on silica gel using hexanes/ethyl acetate as an eluent.
With phosphorus pentachloride In dichloromethane; N,N-dimethyl-formamide for 4h; Cooling with ice;
1.1-1.4
1.2 in a single-mouth bottle,2.0 g of 2-amino-3-methylpyridine and 2.5 g of N-methylformanilide were addedIn 40 mL of dichloromethane, 4.62 g of PCl5 was added with stirring in an ice water bath.After reacting for 4 hours, the reaction system was slowly poured into 40 mL of ammonia water.The insoluble matter was removed by suction filtration. The organic layer is separated and the organic layer is washed twice.Dry over anhydrous sodium sulfate and evaporated to dryness to give a pale yellow solid, 3.87 g.The yield was 93%.
Stage #1: 3-methylpyridin-2-ylamine With sodium hydride In tetrahydrofuran; mineral oil at 0℃; for 0.5h; Inert atmosphere; Sealed tube;
Stage #2: methyl iodide In tetrahydrofuran; mineral oil at 0 - 20℃; for 1h; Inert atmosphere; Sealed tube;
With sodium hypobromide; water; sodium hydroxide; at 0 - 60℃; for 0.5h;
Step 2:320 ml of 12% NaOH aqueous solution was cooled to 0 to 5 C with iced water, 25 ml of liquid bromine was slowly added dropwise, and the mixture was incubated for 0.5 h to prepare a sodium hypobromite solution;The white solid obtained in the previous step was put into 250 ml of 12% NaOH aqueous solution, and the newly prepared sodium hypobromite solution was added dropwise at 0 C. After the dropwise addition, the white solid gradually dissolved.The temperature was raised to 60 C for 0.5 h to stop the reaction.The reaction solution was cooled, extracted with 250 ml of ethyl acetate three times, and the organic phase was washed twice with 50 ml of water, dried and concentrated to give a red liquid.Collect 107~108. 5 C, 2.67 kPa fraction,Down to room temperature,The white final product was obtained 33 g.The yield was 87.8%.
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