* 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 the Chemical Society, 1951, p. 3512
2
[ 5345-47-1 ]
[ 13438-65-8 ]
Yield
Reaction Conditions
Operation in experiment
89%
With ammonium chloride; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In N,N-dimethyl-formamide at 20℃;
To the suspension of 2-aminonicotinic acid (1.38 g, 10.0 mmol) in DMF (50 mL) were added HOBt (1.35 g, 10.0 mmol), NH4Cl (1.07 g, 20.0 mmol), EDC*HCl (2.88 g, 15.0 mmol) and triethylamine (2.78 mL, 20.0 mmol). The mixture was stirred overnight at room temperature. Solvent was distilled off in vacuo, and CH2Cl2 (150 mL) and saturated NaHCO3 aqueous solution (150 mL) were added to the residue. Organic phase was separated, dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (3-->5percentMeOH-CH2Cl2) to obtain the title compound (1.21 g, 8.85 mmol, 89percent) as a white powder. 1H NMR (DMSO-d6) δ: 6.55 (1H, dd, J = 7.7, 4.8 Hz), 7.17 (2H, s), 7.30 (1H, s), 7.92 (2H, dd, J = 7.7, 1.8 Hz), 8.06 (1H, dd, J = 4.8, 1.8 Hz). ESI-MS m/z: 138 (M+H)+.
45%
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine In tetrahydrofuran at 20℃; for 5 h;
To a stirred solution of 2-aminopyridine-3-carboxylic acid (0.9 g, 6.52 mmol) in THF (15mL), was added EDC.HCl (1.86 g, 9.78 mmol), HOBt·NH3 (1.46 g, 9.78 mmol) and DIPEA(4.67 mL, 26.08 mmol) at RT. The reaction mixture was stirred at RT for 5 h (TLC indicatedcomplete consumption of starting material), diluted with water (30 mL) and extracted withEtOAc (3 x 75 mL). The combined organic extracts were washed with cold water (2 x 40mL), brine (40 mL), separated, dried over Na2S04 and concentrated under reduced pressureto give the crude residue which was purified by column chromatography (100-200 silica gel,20 g, 60percent EtOAc-Hexane) to afford 2-aminopyridine-3-carboxamide (0.4 g, 45percent) as a whitesolid.LCMS: m/z: 138.3 [M+Ht.
Reference：
[1] Bioorganic and Medicinal Chemistry, 2011, vol. 19, # 5, p. 1623 - 1642
[2] Medicinal Chemistry Research, 2011, vol. 20, # 4, p. 408 - 420
[3] Synthesis, 1998, # 10, p. 1467 - 1475
[4] Patent: WO2018/125961, 2018, A1, . Location in patent: Page/Page column 103; 104
[5] Monatshefte fuer Chemie, 1900, vol. 21, p. 963[6] Monatshefte fuer Chemie, 1902, vol. 23, p. 935
[7] Patent: EP2065377, 2009, A1, . Location in patent: Page/Page column 78
[8] European Journal of Medicinal Chemistry, 2018, vol. 152, p. 235 - 252
3
[ 5345-47-1 ]
[ 24517-64-4 ]
Reference：
[1] Synthesis, 1998, # 10, p. 1467 - 1475
4
[ 5345-47-1 ]
[ 364-22-7 ]
Reference：
[1] Journal of the Chemical Society, 1951, p. 3512
5
[ 5860-70-8 ]
[ 5345-47-1 ]
Yield
Reaction Conditions
Operation in experiment
98.2%
at 5 - 85℃; for 2.5 h;
Step 4. Add 30 ml of 5 mol·L-1 sodium hydroxide solution to a 100 ml flask, add 0.02 mol of bromine at 5 ° C, stir for 0.5 h, add 0.02 mol of 2-amide pyridine-3-carboxylic acid, and heat up to Reaction at 85 ° C for 2 h;Step 5: After completion of the reaction, a portion of the solvent was concentrated under reduced pressure, cooled, and adjusted to pH=7 with hydrochloric acid, filtered, filtered, dried and evaporated to give crystals of 2-aminopyridine-3-carboxylic acid as white solid.
Reference：
[1] Patent: CN108997207, 2018, A, . Location in patent: Paragraph 0008; 0029
Reference：
[1] Die Pharmazie, 1980, vol. 34, # 5-6, p. 253 - 256
9
[ 548740-14-3 ]
[ 5345-47-1 ]
[ 548740-06-3 ]
Reference：
[1] Synthesis, 2003, # 2, p. 277 - 287
10
[ 24517-64-4 ]
[ 5345-47-1 ]
Reference：
[1] Journal of Organic Chemistry, 1954, vol. 19, p. 1633,1636[2] Org. Synth. Coll., 1963, vol. Vol. IV, p. 166
[3] Chemische Berichte, 1943, vol. 76, p. 128,134
11
[ 7463-30-1 ]
[ 5345-47-1 ]
Reference：
[1] Journal of the American Chemical Society, 1955, vol. 77, p. 2256,2259
12
[ 861045-11-6 ]
[ 5345-47-1 ]
Reference：
[1] Journal of Organic Chemistry, 1954, vol. 19, p. 1633,1636[2] Org. Synth. Coll., 1963, vol. Vol. IV, p. 166
[3] Chemische Berichte, 1943, vol. 76, p. 128,134
13
[ 6602-54-6 ]
[ 5345-47-1 ]
Reference：
[1] Journal of Organic Chemistry, 1954, vol. 19, p. 1633,1636[2] Org. Synth. Coll., 1963, vol. Vol. IV, p. 166
14
[ 1986-81-8 ]
[ 5345-47-1 ]
Reference：
[1] Journal of Organic Chemistry, 1954, vol. 19, p. 1633,1636[2] Org. Synth. Coll., 1963, vol. Vol. IV, p. 166
15
[ 98-92-0 ]
[ 5345-47-1 ]
Reference：
[1] Journal of Organic Chemistry, 1954, vol. 19, p. 1633,1636[2] Org. Synth. Coll., 1963, vol. Vol. IV, p. 166
16
[ 2398-81-4 ]
[ 5345-47-1 ]
Reference：
[1] Die Pharmazie, 1980, vol. 34, # 5-6, p. 253 - 256
[2] Die Pharmazie, 1980, vol. 34, # 5-6, p. 253 - 256
17
[ 7664-93-9 ]
[ 5345-47-1 ]
Reference：
[1] Roczniki Chemii, vol. 3, p. 238,244[2] Chem.Abstr., 1925, vol. 19, p. 72[3] Chem. Zentralbl., 1924, vol. 95, # II, p. 660
18
[ 5345-47-1 ]
[ 446-26-4 ]
Reference：
[1] Journal of the Chemical Society, 1951, p. 3512
19
[ 67-56-1 ]
[ 5345-47-1 ]
[ 14667-47-1 ]
Yield
Reaction Conditions
Operation in experiment
93%
at 0 - 60℃; for 1.5 h; Inert atmosphere; Microwave irradiation
Concentrated sulfuric acid (96percent, 144 mL, 2.69 mol, 18.6 equiv) was added dropwise to a stirred suspension of 5 (20.0 g, 0.145 mol) in MeOH (228 mL, 7.12 mol, 49.2 equiv) maintained at 0 C. The mixture was irradiated at atmospheric pressure under microwaves (power input 300 W) at 60 C for 1.5 h. The light brown mixture was poured onto iced water, maintained at 0 C and carefully quenched by adding solid Na2CO3 portionwise until complete neutralization (pH>8). The aqueous layer was extracted three times with AcOEt. The combined organic layers were washed with brine and water and dried over MgSO4. Evaporation of the organic layer yielded the title compound 21 in analytically pure form (21.15 g, 93percent) as colourless needles
63%
at 80℃; for 7 h;
A mixture of 2-aminonicotinic acid (0.25 g, 1.80 mmol) and 1.80 mL of concentrated H2SO4 in 3.6 ml of methanol was heated at 80 °C for 7 h. After cooling, the methanol was removed by evaporation under reduced pressure and the obtained mixture was treated with the solution of NaHCO3 (pH 7-8). The precipitate thus formed was collected by filtration to give the title compound 5 (0.17 g, yield: 63percent) which was used for the next reaction without purification. 1H NMR (DMSO) δ 8.20 (dd, J = 4.9 and 2.0 Hz, 1H, Ar), 8.05 (dd, J = 7.7 and 2.0 Hz, 1H, Ar), 7.12 (br, 2H, NH2), 6.63 (m, 1H, Ar), 3.80 (s, 3H, OCH3).
49.1%
for 72 h; Heating / reflux
Example 7 Synthesis of Compound 33 General Method for the SYNTHESIS of Compounds 26-44 [0096] This example illustrates Reaction Scheme IV. Preparation OF IVA : [0097] 2-Amino NICOTINIC acid (SOG, 0. 362 mole) was dissolved in 500ml methanol and treated with thionyl chloride (66MOL, 107. 6g, 0. 905MOLLE) dropwise over 30 min. Reaction mixture was heated to reflux for 3 days. Removed solvent under vacuum, residue taken up in chloroform, washed with 5percent HCl (50ml), 10percent sodium bicarbonate (50ml), water, and chloroform layer dried over sodium sulfate (ANH). Removed solvent to give 27G product (49. 1 percent yield).
49.1%
for 72 h; Heating / reflux
Example 7 Synthesis of Compound 33 General Method for the SYNTHESIS of Compounds 26-44 [0096] This example illustrates Reaction Scheme IV. Preparation OF IVA : [0097] 2-Amino NICOTINIC acid (SOG, 0. 362 mole) was dissolved in 500ml methanol and treated with thionyl chloride (66MOL, 107. 6g, 0. 905MOLLE) dropwise over 30 min. Reaction mixture was heated to reflux for 3 days. Removed solvent under vacuum, residue taken up in chloroform, washed with 5percent HCl (50ml), 10percent sodium bicarbonate (50ml), water, and chloroform layer dried over sodium sulfate (ANH). Removed solvent to give 27G product (49. 1 percent yield).
48%
Stage #1: for 35 h; Heating / reflux Stage #2: With sodium hydrogencarbonate In methanol; water at 0℃;
Preparation Example A-2. 2-Amino-nicotinic acid methyl ester 2-Amino-nicotinic acid (10.0g, 72.4mmol) was dissolved in a mixed solution of methanol (200mL) and sulfuric acid (10mL), and the solution was stirred under reflux for 35 hours. A saturated aqueous solution of sodium bicarbonate was added to the reaction solution at 0°C, which was extracted with ethyl acetate, the organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was evaporated in vacuo, the residue was purified by NH silica gel column chromatography to obtain the title compound (5.26g, 34.6mmol, 48percent) as a white solid. 1H-NMR Spectrum (CDCl3) δ (ppm): 3.89 (3H, s), 6.63 (1H, ddd, J=1.1, 4.8, 7.7Hz), 8.13 (1 H, dd, J=1.6, 7.7Hz), 8.22 (1 H, dd, J=1.8, 4.8Hz).
48%
Stage #1: for 35 h; Heating / reflux Stage #2: With sodium hydrogencarbonate In water at 0℃;
2-Amino-nicotinic acid (10.0g, 72.4mmol) was dissolved in a mixed solution of methanol (200mL) and sulfuric acid (10mL), and the solution was stirred under reflux for 35 hours. A saturated aqueous solution of sodium bicarbonate was added to the reaction solution at 0°C, which was extracted with ethyl acetate, the organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was evaporated in vacuo, the residue was purified by NH silica gel column chromatography to obtain the title compound (5.26g, 34.6mmol, 48percent) as a white solid. 1H-NMR Spectrum (CDCl3) δ(ppm) : 3.89 (3H, s), 6.63 (1H, ddd, J=1.1, 4.8, 7.7Hz), 8.13 (1 H, dd, J=1.6, 7.7Hz), 8.22 (1 H, dd, J=1.8, 4.8Hz).
20%
Reflux
Synthesis of 2:A mixture of 1 (2.0 g, 14 mmol) in concentrated H2SO4 (a few drops) in MeOH (5 mL) was heated at reflux overnight. After concentration the residue was taken up into EtOAc, washed with saturated NaHCO3, H2O, and dried (Na2SO4) to provide 2 (400 mg, 20percent) as a yellow solid.
Reference：
[1] Tetrahedron, 2014, vol. 70, # 35, p. 5541 - 5549
[2] European Journal of Medicinal Chemistry, 2012, vol. 52, p. 284 - 294
[3] Synthetic Communications, 2006, vol. 36, # 2, p. 181 - 186
[4] Patent: WO2005/32481, 2005, A2, . Location in patent: Page/Page column 38
[5] Patent: WO2005/32481, 2005, A2, . Location in patent: Page/Page column 38
[6] Patent: EP1782811, 2007, A1, . Location in patent: Page/Page column 42
[7] Patent: EP1669348, 2006, A1, . Location in patent: Page/Page column 50
[8] Patent: US2010/160314, 2010, A1, . Location in patent: Page/Page column 61
[9] Monatshefte fuer Chemie, 1900, vol. 21, p. 963[10] Monatshefte fuer Chemie, 1902, vol. 23, p. 935
[11] Chemische Berichte, 1927, vol. 60, p. 408
[12] Patent: EP1790650, 2007, A1, . Location in patent: Page/Page column 51
[13] Chemical Communications, 2016, vol. 52, # 59, p. 9283 - 9286
20
[ 5345-47-1 ]
[ 74-88-4 ]
[ 14667-47-1 ]
Yield
Reaction Conditions
Operation in experiment
71%
With potassium carbonate In dimethyl sulfoxide at 20℃; for 18 h; Reflux
Containing 13.8 g of 2-amino acid (0.1 mmol) of potassium carbonate and 27.6 g (0.2 mole, 2.0 eq.) Of dimethyl sulfoxide was heated to reflux, then the solution was cooled to ambient temperature, was added 14.2 g of iodine methane (0.1 mole, 1.0 eq) to the mixture, and the solution was stirred for 18 hours, the mixture was filtered and concentrated to give a residual material containing 0.1percent aqueous ammonia (5/95 ethanol / dichloromethane) was eluted as after filtration of the liquid silicone pad and the resulting solution was concentrated, the residue was suspended in ether, filtered and dried to give 2-amino-nicotinic acid methyl ester (10.8 g, 71percent yield). Analysis of results:
58%
With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 18 h; Reflux
1 ) A suspension of 2-aminonicotinic acid (833 mg, 6.00 mmol) and potassium carbonate (912 mg, 6.60 mmol) in dimethylformamide (DMF, 8.5 ml) was heated to reflux. The reaction mixture was cooled to room temperature and 415 μΙ of iodomethane (6.60 mmol) were added. The mixture was then refluxed under stirring for 18 h; after subsequent cooling, the mixture was finally filtered and the filtrate was concentrated under reduced pressure. The crude product was purified by flash chromatography on silica gel (ethyl acetate/petroleum ether = 7/3). The isolated 2-aminonicotinic acid methyl ester was obtained in 58percent yield.
58%
Stage #1: With potassium carbonate In N,N-dimethyl-formamideReflux Stage #2: at 20℃; for 18 h; Reflux
1) A suspension of 2-aminonicotinic acid (833 mg, 6.00 mmol) and potassium carbonate (912 mg, 6.60 mmol) in dimethylformamide (DMF, 8.5 ml) was heated to reflux. The reaction mixture was cooled to room temperature and 415 μl of iodomethane (6.60 mmol) were added. The mixture was then refluxed under stirring for 18 h; after subsequent cooling, the mixture was finally filtered and the filtrate was concentrated under reduced pressure. The crude product was purified is by flash chromatography on silica gel (ethyl acetate/petroleum ether=7/3). The isolated 2-aminonicotinic acid methyl ester was obtained in 58percent yield.
e) Preparation of Methyl 2-aminonicotinate; [00309] To a mixture of 2-aminonicotinic acid(n) (30.0 g 217 mmol) and 2-chloro1,3-dimethyl imidazolinium chloride(55.2 g 326 mmol) in MeOH (750 ml) was added dropwise triethylamine (91 ml 652 mmol). The resultant mixture was stirred at room temperature for 1 h. The mixture was then evaporated under reduced pressure to afford a residue. The residue was purified by extraction with ethyl acetate (300 ml.x.2). The combined organic phase was washed with water (200 ml.x.2) and brine (200 ml). Dried over anhydrous sodium sulfate, filtered and concentrated to give an essentially pure methyl 2-aminonicotinate (31.3 g, yield 94percent). This compound was used in next step without further purification.
Stage #1: for 16 h; Heating / reflux Stage #2: With sodium hydroxide In water
Example 1A1 2 To a solution of 2-aminonicotinic acid (1 ) (5g, 36 mmol) in ethanol (100 mL) was added concentrated sulfuric acid (10 mL). The reaction mixture was heated at reflux for 16 hours, and then cooled to room temperature. LC-MS analysis of the reaction indicated that the reaction was complete. The volatiles were removed in vacuo, water was added and the crude basified to pA78.0 with 1λ/ NaOH. The product was extracted into ethyl acetate (x2), dried over magnesium sulfate and concentrated to afford compound 2 (6.0 g, 100 percent yield) as a white crystalline solid. HPLC-MS tR = 0.41 min (UV254 nm); mass calculated for formula C8H10N2O2 166.1 , observed LCMS m/z 167.1 (M+H).
84%
Reflux
Containing 5.01 g of 2-amino acid (0.0363 mole), 50 ml of ethanol (0.8 mole) and 6 ml of sulfuric acid (0.11 mole) was heated to reflux overnight, the reaction solution was diluted with water with sodium carbonate aqueous solution and, the solution was extracted with 100 ml of ethyl acetate three times, the organic collected extracts were dried over magnesium except through the water was evaporated to dryness, collected 5.05 g of a white solid (84percent).
83%
for 72 h; Heating / reflux
An ethanol (250 mL) solution of aminonicotinic acid ( 20.80 g, 150 mmol) and sulfuric acid (25 mL) was refluxed for three days. Upon cooling, the mixture was evaporated to 100 mL, poured to ice (800 mL) and neutralized with Na2CCV It was extracted with CH2Cl2, dried over MgSO4 and evaporated to afford 20.75 g (83percent) of the title compound. 1H NMR (300 MHz, CDCl3, δ) 8.20 (dd, J=4.7 and 1.9 Hz, IH), 8.13 (dd, J=7.8 and 1.9 Hz, IH), 6.61 (dd, J=4.7 and 7.8 Hz, IH), 4.34 (q, J=7.2 Hz, 2H), 1.38 (t, 1=1.2 Hz, 3H).
79%
Stage #1: at 60℃; for 15 h; Heating / reflux
To a suspension of 2-amino nicotinic acid (2.0 gm, 14.48 mmol) in ethanol (25 mL) was added thionyl chloride (5.7 gm, 43.37 mmol) drop wise at 60 0C under stirring. The resultant reaction mixture was then refluxed for 15 hrs. The volatile matters were removed under reduced pressure and the residue was diluted with ethyl acetate and the organic layer was washed with aqueous saturated sodium bicarbonate solution, water and brine followed by drying over sodium sulfate and concentrated to give the corresponding ester (1.90 gm, 79percent) which was used without further purification. 1H NMR(CDCl35 300 MHz, ppm): 58.21-8.16 (m, 2H), 6.67-6.23 (m,2H), 4.39-4.32 (q, J=7.2 Hz, 2H)5 1.41-1.37 (t, J=6.9 Hz, 3H).
66%
at 60℃; for 17 h; Reflux
[0241] To a stirred solution of compound I (10 g; 72 mmol; 1 eq) in ethanol (150 mL) was added thionyl chloride (15.7 mL; 217 mmol; 3 eq) dropwise at 60 °C and the resulting mixture was heated at reflux for 17 h. The mixture was evaporated to dryness and pH was adjusted to 7 by adding ice-cold saturated aqueous NaHCO3 solution and solid NaHCO3. The organic components were extracted from the aqueous layer with ethyl acetate (3 x 500 mL), and the combined organic layers were washed with brine solution, dried over anhydrous sodium sulfate, filtered and the solvent was removed in vacuo to afford the title compound (8 g, 66percent) as an off-white solid. 1H NMR (DMSO-d6) ö 8.20 (m, 1H), 8.05 (m, 1H), 7.13 (s, 2H), 6.62 (m, 1H), 4.28 (q, 2H, J = 7 Hz), 1.30 (t, 3H, J = 7 Hz).
Reference：
[1] Patent: WO2008/82490, 2008, A2, . Location in patent: Page/Page column 70
[2] Patent: TWI525093, 2016, B, . Location in patent: Page/Page column 101;
[3] Patent: WO2007/67416, 2007, A2, . Location in patent: Page/Page column 64; 134
[4] Patent: WO2007/86080, 2007, A2, . Location in patent: Page/Page column 37
[5] Heterocycles, 1993, vol. 36, # 11, p. 2513 - 2522
[6] Patent: WO2015/95128, 2015, A1, . Location in patent: Paragraph 0239; 0240; 0241
[7] Journal of the Chemical Society, 1956, p. 1045,1053
[8] Journal of Organic Chemistry, 1952, vol. 17, p. 547,553
[9] Pharmazie, 1995, vol. 50, # 11, p. 719 - 722
[10] Bioorganic and Medicinal Chemistry, 2001, vol. 9, # 8, p. 2061 - 2071
[11] Patent: WO2010/97335, 2010, A1, . Location in patent: Page/Page column 26
[12] Organic and Biomolecular Chemistry, 2011, vol. 9, # 20, p. 7113 - 7125
[13] Patent: WO2012/595, 2012, A1, . Location in patent: Page/Page column 73
[14] Patent: US2013/102603, 2013, A1, . Location in patent: Paragraph 0271; 0272; 0273
26
[ 5345-47-1 ]
[ 75-03-6 ]
[ 13362-26-0 ]
Yield
Reaction Conditions
Operation in experiment
80.8%
Stage #1: With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 0.5 h; Stage #2: at 20℃; for 1 h;
To a solution of 2-aminopyridine-3-carboxylic acid (6, 2.00 g,14.0 mmol) in DMF (56 mL) was added potassium carbonate (2.50 g, 28.0 mmol). After stirring the suspension for 30 min at room temperature, a solution of iodoethane (2.20 g, 14.0 mmol,1.10 mL) in DMF (14 mL) was added dropwise. After stirring for 1 h the mixture was poured on ice water (300 mL). The precipitated crystals were collected by filtration. The filtrate was extracted with ethyl acetate (4 x 75 mL). The combined ethyl acetate layers were dried (Na2SO4) and evaporated. To the remaining residue diethyl ether (100 mL) was added and the resulting solution was washed with aqueous 30percent lithium chloride solution (4 x 25 mL). After drying with Na2SO4, the organic solvent was evaporated. The residue was combined with the precipitate that was collected earlier and the material was crystallized from ethanol to yield 1.90 g (80.8percent) colorless crystals. mp: 93-94 °C (Lit.: 94-96 °C [42]); IR(KBr): 3428 (NH2), 1695 (C=O), 1625 (NH2), 1245, 770 cm-1; 1H NMR (600 MHz, CDCl3): δ = 8.22 (dd, 1H, 3JH,H=4.8 Hz,4JH,H=1.9 Hz), 8.15 (dd, 1H, 3JH,H=7.8 Hz, 4JH,H=1.9 Hz), 6.63 (dd,1H, 3JH,H=7.8 Hz, 3JH,H=4.8 Hz), 4.35 (q, 2H, 3JH,H=7.1 Hz), 1.39 (t,3H, 3JH,H=7.1 Hz); 13C NMR (150.9 MHz, CDCl3): δ=167.0, 159.4,106.5 (quat C); 153.5, 140.1, 112.7 (tert C); 60.9 (sec C); 14.3 (prim.C); C8H10N2O2 (166.18); calcd. C 57.82, H 6.07, N 16.86; found C57.68, H 6.22, N 17.20.
Reference：
[1] European Journal of Medicinal Chemistry, 2014, vol. 83, p. 274 - 283
[2] Patent: EP2168959, 2010, A1, . Location in patent: Page/Page column 79-80
[3] Patent: EP2168960, 2010, A1, . Location in patent: Page/Page column 66
27
[ 5345-47-1 ]
[ 13362-26-0 ]
Reference：
[1] Chemical Communications, 2013, vol. 49, # 2, p. 190 - 192
28
[ 5345-47-1 ]
[ 497-19-8 ]
[ 13362-26-0 ]
Reference：
[1] Patent: US5801183, 1998, A,
29
[ 5345-47-1 ]
[ 149-73-5 ]
[ 24410-19-3 ]
Yield
Reaction Conditions
Operation in experiment
100%
With ammonia In methanol at 105℃; for 8 h;
In a pressure resistant, 10 mL-volume stainless steel vessel, 1.00 g (7.2 mmol) of 2-aminonicotinic acid, 3.07 g (28.8 mmol) of methyl orthoformate, and 5.0 mL (38 mmol) of 15 wt.percent ammonia-methanol solution were heated at 105°C for 8 hours for performing a reaction. After the reaction was complete, the reaction mixture was cooled to room temperature and concentrated under reduced pressure, to give 1.06 g (yield after isolation: 100percent) of 3H-pyrido[2,3-d]pyrimidin-4-one as a black solid product. The 3H-pyrido[2,3-d]pyrimidin-4-one had the following properties: 1H-NMR (DMSO-d6, δ(ppm)): 3.36 (1H, brs), 7.46 (1H, dd, J=8.0, 4.5 Hz), 8.31 (1H, s), 8.45 (1H, dd, J=7.8, 2.1 Hz), 8.87 (1H, dd, J=4.8, 2.1 Hz) CI-MS (m/e): 148 (M+1)
Reference：
[1] Patent: US5965563, 1999, A,
[2] Patent: US5654307, 1997, A,
31
[ 5345-47-1 ]
[ 77287-34-4 ]
[ 24410-19-3 ]
Reference：
[1] Tetrahedron Letters, 2002, vol. 43, # 21, p. 3911 - 3913
[2] Bioorganic and Medicinal Chemistry, 2018, vol. 26, # 8, p. 1713 - 1726
[3] Journal of Medicinal Chemistry, 2016, vol. 59, # 6, p. 2794 - 2809
[4] Journal of Medicinal Chemistry, 2013, vol. 56, # 23, p. 9482 - 9495
[5] Journal of the Chemical Society, 1956, p. 1045,1053
[6] Journal of the American Chemical Society, 1955, vol. 77, p. 2256,2259
Reference：
[1] Archiv der Pharmazie, 2006, vol. 339, # 4, p. 182 - 192
[2] Tetrahedron Letters, 2005, vol. 46, # 35, p. 5851 - 5855
[3] Bioorganic and Medicinal Chemistry, 2005, vol. 13, # 6, p. 2031 - 2044
[4] Journal of the American Chemical Society, 1955, vol. 77, p. 2256,2259
[5] Molecules, 2012, vol. 17, # 8, p. 9961 - 9970
[6] Patent: US2012/316184, 2012, A1,
[7] Patent: EP2805947, 2014, A1,
[8] Patent: US2015/126500, 2015, A1,
[9] ChemMedChem, 2014, vol. 9, # 11, p. 2516 - 2527
[10] Patent: CN106083742, 2016, A,
[11] Patent: US2006/199803, 2006, A1,
35
[ 5345-47-1 ]
[ 593-51-1 ]
[ 870997-87-8 ]
Yield
Reaction Conditions
Operation in experiment
98%
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃;
Example 89; /V-MethvI-2-(2-(2-oxoindolin-5-ylamino)-5-(trifluoromethyl)pyridin-4-ylamino)nicotinamide; 2-Amino-./V-methylnicotinamide; To the mixture of 2-aminonicotinic acid (2.0 g, 14.5 mmol), methylamine hydrogen chloride (1.47 g, 1.5 eq), EDC (4.49 g, 1.5 eq), HOBt (2.35 g, 1.2 eq) in DMF (2OmL) was added DIEA (7.6 mL, 3.0 eq). The mixture was stirred at room temperature overnight. The crude was concentrated and dissolved in EtOAc. It was washed with saturated NaHCO3. The solvent was removed and the crude was purified by silica gel chromatography (0percent~20percent MeOH/DCM) to obtain the desired product 2-amino-iV- methylnicotinamide (2.16 g, isolated yield -98percent).
Stage #1: With lithium aluminium tetrahydride In tetrahydrofuran for 18 h; Heating / reflux Stage #2: With sodium hydroxide In tetrahydrofuran; water for 0.25 h;
To a solution of 2-aminonicotinic acid (20. 5g, 148mmol) in tetrahydrofuran (300mL) at room temperature was added lithium aluminum hydride (1. OM in tetrahydrofuran, 300mL, 300mmol) dropwise over 45 minutes. The resulting solution was heated to reflux for 18hrs. The mixture was cooled to room temperature and quenched by the sequential dropwise addition of water (11. 5mL), 15percent aqueous sodium hydroxide (11. 5mL), and water (34. 5mL). The mixture was stirred for 15min., then filtered through Celite 545. The filter pad was washed thoroughly with tetrahydrofuran (500mL) and 5percent methanol in chloroform (500mL). The combined filtrate and washings were evaporated to give 17.7g (96percent) of the title compound as a yellow waxy solid. MS (LC/MS/pos): 125.0 (M+H) +. 1H NMR (CDC13) 5 4.13 (br. s, 1H), 4.59 (s, 2H), 6.56 (m, 1H), 7.29 (d, 1H), 7.90 (d, 1H).
96%
With lithium aluminium tetrahydride In tetrahydrofuran at 0℃; for 18 h; Reflux
To a suspension of 2-aminonicotinic acid (25.0 g, 0.18 mol) in THF (500 mL) was added L1AIH4 (13.7 g, 0.36 mol) portion-wise at 0 °C. The mixture was heated to reflux and stirred further for 18 hours, then cooled to rt, and quenched by the sequential drop wise addition of water (16 mL), NaOH aqueous solution (16 mL, 15percent), and water (50 mL). The resulted mixture was stirred at rt for 20 minutes, then filtered through a CELITE®. The filter cake was washed thoroughly with THF (100 mL) and MeOH/CHCb (1/20 (v/v), 200 mL). The combined filtrates were concentrated in vacuo to give the title compound as yellow oil (21.6 g, 96percent). MS (ESI, pos. ion) m/z: 125.0 (M +1). 1H NMR (400 MHz, CDCb): δ 3.93 (s, 2H), 4.54 (s, 2H), 5.15 (s, 1H), 6.55-6.70 (s, 1H), 7.30- 7.40 (m, 1H), 7.83-7.90 (m, 1H).
96%
With lithium aluminium tetrahydride In tetrahydrofuran for 18 h; Reflux
The compound 2 - amino-nicotinic acid (25.0 g, 0 . 18 µM) suspended in THF (500 ml) in, cooling to 0 °C, then added to the reaction solution in the LiAlH in batches4 (13.7 G, 0 . 36 µM), heating to reflux, the reaction 18 hours, cooling to room temperature, and then sequentially dropwise adding water (16 ml), NaOH aqueous solution (16 ml, 15percent), water (50 ml) quenching the reaction, the resulting mixture stirring at room temperature 20 minutes later, for diatomite filter, the filter cake for sequentially THF (100 ml) and MeOH/CHCl3 (1/20, 200 Ml) washing, the combined filtrate is concentrated under reduced pressure to obtain the title compound as a yellow oily matter (21.6 g, 96percent).
95%
With sodium hydroxide; LiAlH4 In tetrahydrofuran; water
a) 2-Amino-3-(hydroxymethyl)pyridine To a stirred solution of 2-aminonicotinic acid (20 g, 145 mmole) in dry THF (200 mL) under argon was added 1.0 M LiAlH4 in THF (300 mL, 300 mmole) carefully, portionwise, through a reflux condenser, over 4 hr. The reaction became exothermic and refluxed without external heating. After the addition was complete, the reaction was heated at reflux for an additional 16 hr, then was cooled to 0 °C and carefully quenched by sequential addition of H2O (12 mL), 15percent NaOH in H2O (12 mL), and H2O (35 mL). The resulting thick suspension was stirred for 1 hr, then was filtered through a pad of celite.(R).. The filter pad was rinsed with THF (300 mL), and the filtrate was concentrated to dryness to give the title compound (17.04 g, 95percent) as a pale yellow waxy solid: LCMS (ES) m/e 125.1 (M + H)+; 1H NMR (400 MHz, DMSO-d6) δ 7.84 (dd, 1 H), 7.37 (m, 1 H), 6.53 (dd, 1 H), 5.65 (br s, 2 H), 5.16 (t, 1 H), 4.34 (d, J = 4.6 Hz, 2 H).
90%
Stage #1: With lithium aluminium tetrahydride In tetrahydrofuran at 0℃; Reflux Stage #2: With water; sodium hydroxide In tetrahydrofuran at 0℃;
Step 1: 2-Amino-3-(hydroxymethyl)pyridineLithium aluminum hydride (12.4 g, 326.7 mmol) was portionwisely added to a suspension of 2-amino-3-carboxypyridine (30.0 g, 217.2 mmol) in THF (350 mL) at 0°C. Once the addition was completed, the reaction mixture was stirred at room temperature for 15 minutes and then at reflux overnight. The mixture was then cooled to 0°C and hydrolyzed by the successive addition of water (18 mL), a solution of sodium hydroxyde (18 mL) and water (30 mL) again. The resulting white suspension was filtered on Clarcel.(R). and the cake was washed with THF (200 mL) and a mixture of CHCI3/MeOH (250 mL, 9 : 1). After concentration to dryness of the filtrate, the title product was obtained as a yellow solid (24.2 g, 90percent).*H NMR (DMSO-c/6, 400 MHz) : δ (ppm) : 7.84 (d, J = 4Hz, 1H), 7.37 (d, J = 7.2 Hz, 1H), 6.55-6.52 (m, 1H), 5.64 (br s, NH2), 4.34 (s, 2H).
83%
With sodium hydroxide In tetrahydrofuran; methanol; chloroform; water
a) 2-Amino-3-(hydroxymethyl)pyridine To a solution of 2-aminonicotinic acid (20.5 g, 148.1 mmole) in THF was added lithium aluminum hydride (300 mL, 1.0 M in THF) over 30 minutes. The reaction solution was heated to reflux for 18 hrs and then was cooled to room temperature. The reaction was quenched by the sequential dropwise addition of H2O (11.5 mL), 15percent NaOH (11.5 mL), and H2O (34.5 mL). The mixture was stirred for 15 min, then was filtered through celite.(R)., and the filter pad was washed thoroughly with THF followed by 5percent CH3OH/CHCl3. The filtrate was concentrated to give the title compound (15.24 g, 83percent) as a waxy light yellow solid: MS (ES) m/e 125 (M + H)+.
83%
With sodium hydroxide In tetrahydrofuran; methanol; chloroform; water
a 2-Amino-3-(hydroxymethyl)pyridine To a solution of 2-aminonicotinic acid (20.5 g, 148.1 mmole) in THF was added lithium aluminum hydride (300 mL, 1.0 M in THF) over 30 minutes. The reaction solution was heated to reflux for 18 hrs and then was cooled to room temperature. The reaction was quenched by the sequential dropwise addition of H2O (11.5 mL), 15percent NaOH (11.5 mL), and H2O (34.5 mL). The mixture was stirred for 15 min, then was filtered through celite.(R)., and the filter pad was washed thoroughly with THF followed by 5percent CH3OH/CHCl3. The filtrate was concentrated to give the title compound (15.24 g, 83percent) as a waxy light yellow solid: MS (ES) m/e 125 (M+H)+.
0.74 g
With lithium aluminium tetrahydride In tetrahydrofuran; diethyl ether at 0 - 20℃; for 48 h; Inert atmosphere
To a suspension of 2-aminonicotinic acid (5-Si, 1.58 g, 11.45 mmol) in THF (80 mL), LAH (1M in ether, 22.9 mL, 22.9 mmol) was added slowly at 0 °C under argon with stirring. After completion of the addition, the ice bath was removed and the mixture was stirred at room temperature. Additional LAH (1M in ether, 11.4 mL) was added after 48 hours and the reaction was again cooled with an ice bath before saturated NH4C1 aqueous solution (20 mL) was added with stirring to form slurry. The organic layer was separated by decantation and the slurry was washed with EtOAc. The combined organic layer was washed with iN NaOH aqueous solution, brine, and dried over anhydrous Na2SO4. Solvent was removed under reduced pressure to afford (2-aminopyridin-3-yl)methanol (5-S2, 0.74 g) as an off-white solid.
EXAMPLE 1 2-Amino-5-bromo-3-pyridine carboxylic acid To a solution of 2-amino-nicotinic acid (10 g, 72.5 mmol) in acetic acid (70 mL) was dropwise added bromine (9.8 mL, 79.8 mmol) at room temperature under nitrogen. Upon completion of the reaction, the solvent was removed in vacuo, the residue triturated with ether and collected on a filter to give 2-amino-5-bromo-3-pyridine carboxylic acid as a yellow solid (15.7 g, 99percent): mp 272° C., (decomposed); 1H-NMR (DMSO-d6) δ8.8-7.8 (bs, 2H), 8.44 (d, 1H, J=2.48 Hz), 8.34 (d, 1H, J=2.48 Hz); MS (EI) m/z 216/218 ([M+]+, 100percent)
99%
With bromine In acetic acid
EXAMPLE 1 2-Amino-5-bromo-3-pyridine Carboxylic Acid To a solution of 2-amino-nicotinic acid (10 g, 72.5 mmol) in acetic acid (70 mL) was dropwise added bromine (9.8 mL, 79.8 mmol) at room temperature under nitrogen. Upon completion of the reaction, the solvent was removed in vacuo, the residue triturated with ether and collected on a filter to give 2-amino-5-bromo-3-pyridine carboxylic acid as a yellow solid (15.7 g, 99percent): mp 272° C., (decomposed); 1H-NMR (DMSO-d6) δ 8.8-7.8 (bs, 2H), 8.44 (d, 1H, J=2.48 Hz), 8.34 (d, 1H, J=2.48 Hz); MS (EI) m/z 216/218 ([M+H]+, 100percent).
98%
With bromine In acetic acid at 20℃; for 20 h;
Step 1: Synthesis of 2-amino-5-bromonicotinic acid 25.00 g (0.181 mol) of 2-aminonicotinic acid were dispersed in 100 ml of glacial acetic acid. To this suspension was added a solution of 12.0 ml (0.23 mol) of bromine in 50 ml of glacial acetic acid. The mixture was stirred at room temperature for 20 hours. The precipitate formed was filtered off and washed with 100 ml of glacial acetic acid in several portions until the filtrate remained colorless. The crude was dried by suction and crystallized from boiling methanol to afford 38.63 g (0.178 mol, 98percent yield) of 2-amino-5-bromonicotinic acid as slightly greenish to off-white crystalline needles. 1H-NMR (d6-DMSO) d: 8.45 [1H] d, 8.34 [1H] d.; MS: m/z 217 [MH+].
96%
at 20℃;
Equipped with a blender,Reflux condenser 500mL three-necked flask,20.7 g (0.15 mol) of 2-aminonicotinic acid,80 mL acetic acid,Stirred at room temperature,A constant pressure dropping funnel was added dropwise with a mixed solution of 40 mL of acetic acid and 4.1 mL of bromine (0.08 mol)Drop end to continue mixing 4-5h.filter,Washed with acetic acid,dry,The solid was refluxed with methanol 100mL 10min 10min at room temperature,Filter and dry.31.2g of white solid was obtained,Yield 96percent.
95%
With bromine In acetic acid at 20℃; for 20 h;
2-Amino-nicotinic acid (2 g, 14.48 mmol) was dispersed in glacial acetic acid. To this suspension was added a solution of bromine (1.2 mL) in glacial acetic acid (5 mL). The mixture was stirred at room temperature for 20 h. The mixture was filtered and washed with glacial acetic acid (10 mL) and water in several portions. The precipitate was collected and dried to give 2-amino-5-bromonicotinic acid (3.0 g, 95 percent yield) as yellow solid. XH-NMR (DMSO- d6, 400 MHz) δ 8.31 (d, J= 2.4 Hz, 1H), 8.18 (d, J= 2.8 Hz, 1H), 5.06-5.27 (m, 2H). MS (M+H)+: 218 / 220.
95%
at 25℃; for 20 h;
2-Amino-nicotinic acid (2 g, 14.48 mmol) was dispersed in glacial acetic acid. To this suspension was added a solution of bromine (1.2 mL) in glacial acetic acid (5 mL). The mixturewas stirred at room temperature for 20 h. The mixture was filtered and washed with glacial aceticacid (10 mE) and water in several portions. The precipitate was collected and dried to give 2-amino-5-bromonicotinic acid (3.0 g, 95 percent yield) as yellow solid. ‘H-NMR (DMSO-d6, 400 MHz) ö 8.31(d, J= 2.4 Hz, 1H), 8.18 (d, J= 2.8 Hz, 1H), 5.065.27 (m, 2H). MS (M+Hj: 218 / 220.
92%
at 20℃; for 0.5 h;
2-Aminonicotinic acid (10.00 g, 72.40 mmol) was suspended in 40 ml of glacial acetic acid. To this suspension was added dropwise a solution of 4.82 ml (94.12 mmol) of bromine in 20 ml of glacial acetic acid. The mixture was stirred vigorouly at room temperature for 30 min. The formed precipitate was filtered off and washed with glacial acetic acid. The filter cake was collected and crystallized from the boiling methol to afford compound 8 as a white solid (14.5 g, 92percent yield). 1H NMR (300 MHz, DMSO-d6) δ 8.30 (d, J = 2.4 Hz, 1H), 8.16 (d, J = 2.4 Hz, 1H); MS (ESI, m/z): 216.8 [M+H]+.
92.6%
at 20℃; for 18 h;
2-Amino-5-bromo-nicotinic acid: To a solution of pyridine-2-amino-3-carboxylic acid (2.05 g, 81.1 mmol) in AcOH (250 mL) was added bromine (11.0 mL, 199.2 mmol) at RT. The reaction mixture was stirred for 18 h at RT. On completion of the reaction, the solvent was evaporated completely under reduced pressure, filtered, washed with diethyl ether (3 x 75 mL) to afford the title compound as a yellow solid. Yield: 50.0 g (92.6percent) 'HNMR (DMSO-de, 400 MHz, TMS) δ: 11.7 (3H, br, s), 8.33 (1H, s), 8.20 (1H, s).
90%
at 20℃; for 2 h;
2-aminonicotinic acid (10.0 g, 72 mmol) was dissolved in acetic acid (40 ml),Slowly add bromine (9.64 mL,388 mmol) in acetic acid (20 mL),Stir at room temperature for 2 hours, filter by suction, and wash the filter cake with acetic acid.The cake was recrystallized from methanol,After suction filtration and drying, 14.1 g of a white solid is obtained.The yield is 90percent.
90%
at 25℃; for 20 h; Inert atmosphere
This compound was prepared following a literature procedure.25 Toa suspension of 2-aminonicotinic acid 21 (3.75 g, 27 mmol) in glacialacetic acid (15 mL) was added a solution of bromine (1.8 mL, 35 mmol)in glacial acetic acid (3 mL) and the mixture was stirred at RT for 20 h.After completion monitored by TLC, the resulting precipitate was filteredand washed with glacial acetic acid 3 times. The remaining solidwas air dried and then recrystallised from boiling methanol to affordthe product 22 as white crystalline needles (5.2 g, 90percent). 1H NMR(400 MHz, d6-DMSO): δ 8.36 (1H, d, J=2.6 Hz), 8.25 (1H, d,J=2.6 Hz), 7.95–7.79 (2H, br.s); 13C NMR (100 MHz, d6-DMSO): δ166.6, 156.5, 149.9, 143.8, 109.3, 103.7. The spectroscopic data matchedthat reported in the literature.
70%
at 20℃; for 20 h; Inert atmosphere
2-aminonicotinic acid (25.0 g, 181.00 mmol) was added to a well-dried 1000 mL three-neck round bottom flask, and acetic acid (150 mL) was added thereto. Bromine (11.85 mL, 230.02 mmol) was slowly added dropwise to acetic acid (50 mL). And the mixture was stirred at room temperature for 20 hours in a stream of nitrogen. The resulting product was poured into 500 mL of distilled water and stirred for 30 minutes. The product was filtered through a glass filter, washed with ether and acetone, and dried to obtain Compound 1 (27.4 g, yield 70percent).
Reference：
[1] Patent: US6369056, 2002, B1,
[2] Patent: US6399593, 2002, B1,
[3] Patent: US2006/30583, 2006, A1, . Location in patent: Page/Page column 113
[4] Patent: CN106565684, 2017, A, . Location in patent: Paragraph 0177; 0178; 0179; 0180
[5] Patent: WO2014/209727, 2014, A1, . Location in patent: Page/Page column 60-61
[6] Patent: WO2014/205593, 2014, A1, . Location in patent: Page/Page column 64
[7] Bioorganic and Medicinal Chemistry, 2012, vol. 20, # 17, p. 5169 - 5180
[8] Patent: WO2014/106612, 2014, A1, . Location in patent: Page/Page column 22
[9] Patent: CN104592217, 2018, B, . Location in patent: Paragraph 0029; 0030; 0031
[10] Bioorganic and Medicinal Chemistry, 2018, vol. 26, # 22, p. 5852 - 5869
[11] Patent: KR2018/82356, 2018, A, . Location in patent: Paragraph 0154-0157
[12] Organic Process Research and Development, 2009, vol. 13, # 4, p. 698 - 705
[13] Patent: US3974161, 1976, A,
[14] Patent: WO2007/67416, 2007, A2, . Location in patent: Page/Page column 111
[15] European Journal of Medicinal Chemistry, 2016, vol. 118, p. 276 - 289
[16] Bioorganic and Medicinal Chemistry Letters, 2017, vol. 27, # 18, p. 4500 - 4505
[17] Patent: US3950160, 1976, A,
42
[ 5345-47-1 ]
[ 133427-07-3 ]
Reference：
[1] Patent: WO2011/56440, 2011, A1,
43
[ 107-20-0 ]
[ 5345-47-1 ]
[ 133427-08-4 ]
Reference：
[1] Journal of Medicinal Chemistry, 2006, vol. 49, # 3, p. 1125 - 1139
[2] Patent: WO2011/56440, 2011, A1, . Location in patent: Page/Page column 46
44
[ 5345-47-1 ]
[ 7252-83-7 ]
[ 133427-08-4 ]
Yield
Reaction Conditions
Operation in experiment
0.924 g
at 150℃; for 2 h; Microwave irradiation
To a mixture of 2-aminonicotinic acid (0.69 g, 5.00 mmol) in CH3CN (20 mL) was added bromoacetaldehyde dimethyl acetal (0.59 mL, 5.00 mmol). The resulting slurry was heated to 150 °C under microwave irradiation for 2 h. The resulting precipitate was filtered off and washed with CH3CN and hexane to afford H-imidazo[1,2-α]pyridine-8-carboxylic acid (0.924 g) as a grey solid.
Reference：
[1] Patent: WO2009/23253, 2009, A2, . Location in patent: Page/Page column 52
[2] Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 5, p. 1870 - 1873
With sulfuric acid; at 0 - 60℃; under 760.051 Torr; for 1.5h;Inert atmosphere; Microwave irradiation;
Concentrated sulfuric acid (96%, 144 mL, 2.69 mol, 18.6 equiv) was added dropwise to a stirred suspension of 5 (20.0 g, 0.145 mol) in MeOH (228 mL, 7.12 mol, 49.2 equiv) maintained at 0 C. The mixture was irradiated at atmospheric pressure under microwaves (power input 300 W) at 60 C for 1.5 h. The light brown mixture was poured onto iced water, maintained at 0 C and carefully quenched by adding solid Na2CO3 portionwise until complete neutralization (pH>8). The aqueous layer was extracted three times with AcOEt. The combined organic layers were washed with brine and water and dried over MgSO4. Evaporation of the organic layer yielded the title compound 21 in analytically pure form (21.15 g, 93%) as colourless needles
86%
With thionyl chloride; at 0 - 80℃; for 3h;
To a solution of 2-aminonicotinic acid (5 g, 36.2 mmol) in methanol (20 mL) was added thionyl chloride (7.93 mL, 109 mmol) at 0 C. The mixture was brought to room temperature and stirred at 80 C for 3 h. The reaction mixture was concentrated to remove methanol, diluted with DCM (100 mL) and washed with water (2 x 20 mL) and sodium bicarbonate (2 x 20 mL). The layer was dried over sodium sulphate and concentrated under vacuum to afford methyl 2-aminonicotinate (5.2 g, 31.0 mmol, 86% yield) as a white solid. MS (M+1) m/z: 153.1 (MH+). LC retention time 0.71 min [L].
63%
With sulfuric acid; at 80℃; for 7h;
A mixture of 2-aminonicotinic acid (0.25 g, 1.80 mmol) and 1.80 mL of concentrated H2SO4 in 3.6 ml of methanol was heated at 80 C for 7 h. After cooling, the methanol was removed by evaporation under reduced pressure and the obtained mixture was treated with the solution of NaHCO3 (pH 7-8). The precipitate thus formed was collected by filtration to give the title compound 5 (0.17 g, yield: 63%) which was used for the next reaction without purification. 1H NMR (DMSO) delta 8.20 (dd, J = 4.9 and 2.0 Hz, 1H, Ar), 8.05 (dd, J = 7.7 and 2.0 Hz, 1H, Ar), 7.12 (br, 2H, NH2), 6.63 (m, 1H, Ar), 3.80 (s, 3H, OCH3).
49.1%
With thionyl chloride; for 72h;Heating / reflux;
Example 7 Synthesis of Compound 33 General Method for the SYNTHESIS of Compounds 26-44 [0096] This example illustrates Reaction Scheme IV. Preparation OF IVA : [0097] 2-Amino NICOTINIC acid (SOG, 0. 362 mole) was dissolved in 500ml methanol and treated with thionyl chloride (66MOL, 107. 6g, 0. 905MOLLE) dropwise over 30 min. Reaction mixture was heated to reflux for 3 days. Removed solvent under vacuum, residue taken up in chloroform, washed with 5% HCl (50ml), 10% sodium bicarbonate (50ml), water, and chloroform layer dried over sodium sulfate (ANH). Removed solvent to give 27G product (49. 1 % yield).
48%
Preparation Example A-2. 2-Amino-nicotinic acid methyl ester 2-Amino-nicotinic acid (10.0g, 72.4mmol) was dissolved in a mixed solution of methanol (200mL) and sulfuric acid (10mL), and the solution was stirred under reflux for 35 hours. A saturated aqueous solution of sodium bicarbonate was added to the reaction solution at 0C, which was extracted with ethyl acetate, the organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was evaporated in vacuo, the residue was purified by NH silica gel column chromatography to obtain the title compound (5.26g, 34.6mmol, 48%) as a white solid. 1H-NMR Spectrum (CDCl3) delta (ppm): 3.89 (3H, s), 6.63 (1H, ddd, J=1.1, 4.8, 7.7Hz), 8.13 (1 H, dd, J=1.6, 7.7Hz), 8.22 (1 H, dd, J=1.8, 4.8Hz).
48%
2-Amino-nicotinic acid (10.0g, 72.4mmol) was dissolved in a mixed solution of methanol (200mL) and sulfuric acid (10mL), and the solution was stirred under reflux for 35 hours. A saturated aqueous solution of sodium bicarbonate was added to the reaction solution at 0C, which was extracted with ethyl acetate, the organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was evaporated in vacuo, the residue was purified by NH silica gel column chromatography to obtain the title compound (5.26g, 34.6mmol, 48%) as a white solid. 1H-NMR Spectrum (CDCl3) delta(ppm) : 3.89 (3H, s), 6.63 (1H, ddd, J=1.1, 4.8, 7.7Hz), 8.13 (1 H, dd, J=1.6, 7.7Hz), 8.22 (1 H, dd, J=1.8, 4.8Hz).
20%
With sulfuric acid;Reflux;
Synthesis of 2:A mixture of 1 (2.0 g, 14 mmol) in concentrated H2SO4 (a few drops) in MeOH (5 mL) was heated at reflux overnight. After concentration the residue was taken up into EtOAc, washed with saturated NaHCO3, H2O, and dried (Na2SO4) to provide 2 (400 mg, 20%) as a yellow solid.
The mixture of 138 mg of 2-aminonicotinic acid and 6 mL of hydrochloric acid-methanol solution was stirred overnight in a sealed-tube at 90C. The reaction mixture was concentrated under reduced pressure, the residue was added with a saturated aqueous solution of sodium hydrogen carbonate, and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, the insolubles were filtered, and the filtrate was concentrated under reduced pressure, to obtain 106 mg of 2-aminonicotinic acid methylester [25-1]. The obtained compound [25-1] was used in the subsequent reaction without further purification.
Example 1A1 2 To a solution of 2-aminonicotinic acid (1 ) (5g, 36 mmol) in ethanol (100 mL) was added concentrated sulfuric acid (10 mL). The reaction mixture was heated at reflux for 16 hours, and then cooled to room temperature. LC-MS analysis of the reaction indicated that the reaction was complete. The volatiles were removed in vacuo, water was added and the crude basified to pA78.0 with 1lambda/ NaOH. The product was extracted into ethyl acetate (x2), dried over magnesium sulfate and concentrated to afford compound 2 (6.0 g, 100 % yield) as a white crystalline solid. HPLC-MS tR = 0.41 min (UV254 nm); mass calculated for formula C8H10N2O2 166.1 , observed LCMS m/z 167.1 (M+H).
84%
With sulfuric acid;Reflux;
Containing 5.01 g of 2-amino acid (0.0363 mole), 50 ml of ethanol (0.8 mole) and 6 ml of sulfuric acid (0.11 mole) was heated to reflux overnight, the reaction solution was diluted with water with sodium carbonate aqueous solution and, the solution was extracted with 100 ml of ethyl acetate three times, the organic collected extracts were dried over magnesium except through the water was evaporated to dryness, collected 5.05 g of a white solid (84%).
83%
With sulfuric acid; for 72h;Heating / reflux;
An ethanol (250 mL) solution of aminonicotinic acid ( 20.80 g, 150 mmol) and sulfuric acid (25 mL) was refluxed for three days. Upon cooling, the mixture was evaporated to 100 mL, poured to ice (800 mL) and neutralized with Na2CCV It was extracted with CH2Cl2, dried over MgSO4 and evaporated to afford 20.75 g (83%) of the title compound. 1H NMR (300 MHz, CDCl3, delta) 8.20 (dd, J=4.7 and 1.9 Hz, IH), 8.13 (dd, J=7.8 and 1.9 Hz, IH), 6.61 (dd, J=4.7 and 7.8 Hz, IH), 4.34 (q, J=7.2 Hz, 2H), 1.38 (t, 1=1.2 Hz, 3H).
79%
To a suspension of 2-amino nicotinic acid (2.0 gm, 14.48 mmol) in ethanol (25 mL) was added thionyl chloride (5.7 gm, 43.37 mmol) drop wise at 60 0C under stirring. The resultant reaction mixture was then refluxed for 15 hrs. The volatile matters were removed under reduced pressure and the residue was diluted with ethyl acetate and the organic layer was washed with aqueous saturated sodium bicarbonate solution, water and brine followed by drying over sodium sulfate and concentrated to give the corresponding ester (1.90 gm, 79%) which was used without further purification. 1H NMR(CDCl35 300 MHz, ppm): 58.21-8.16 (m, 2H), 6.67-6.23 (m,2H), 4.39-4.32 (q, J=7.2 Hz, 2H)5 1.41-1.37 (t, J=6.9 Hz, 3H).
66%
With thionyl chloride; at 60℃; for 17h;Reflux;
[0241] To a stirred solution of compound I (10 g; 72 mmol; 1 eq) in ethanol (150 mL) was added thionyl chloride (15.7 mL; 217 mmol; 3 eq) dropwise at 60 C and the resulting mixture was heated at reflux for 17 h. The mixture was evaporated to dryness and pH was adjusted to 7 by adding ice-cold saturated aqueous NaHCO3 solution and solid NaHCO3. The organic components were extracted from the aqueous layer with ethyl acetate (3 x 500 mL), and the combined organic layers were washed with brine solution, dried over anhydrous sodium sulfate, filtered and the solvent was removed in vacuo to afford the title compound (8 g, 66%) as an off-white solid. 1H NMR (DMSO-d6) oe 8.20 (m, 1H), 8.05 (m, 1H), 7.13 (s, 2H), 6.62 (m, 1H), 4.28 (q, 2H, J = 7 Hz), 1.30 (t, 3H, J = 7 Hz).
(A) EtOH (500 mL) was added to <strong>[5345-47-1]2-amino-nicotinic acid</strong> (25 g), followed by H2SO4 (25 mL, cone), and the mixture stirred at 75C overnight. The reaction mixture was then redissolved in H2O, neutralized with Na2CO3 (aq), and the resulting precipitate filtered and dried to provide <strong>[5345-47-1]2-amino-nicotinic acid</strong> ethyl ester, which was used without further purification.
Example 1 - Synthesis of 2,4-dichloro-[1 ,8]naphthyridine; slurry of 4.90 kg (34.5 mol) 2-aminonicotinic acid in 50 I ethanol was treated with5.67 I (106 mol) sulfuric acid (98%). The reaction mixture was stirred for 60 hours at 79 C. The reaction mixture was then cooled to 40C and ethanol was distilled off under vacuum. The residue was dissolved in a mixture of 45 kg ice and 55 I water. Then 13 I aqueous sodium hydroxide solution (32% by weight) was added slowly under stirring and external cooling to reach a pH of 7. The precipitate was filtered off and washed with water. The residue was taken up in water, stirred for 1 hour and filtered. The residue was washed with water and dried under vacuum yielding 2- amino-nicotinic acid ethyl ester as colourless crystals; HPLC/MS: 0.99 min, [M+H] 167.1H NMR (400 MHz, DMSO) delta = 8.22 (dd, J=4.7, 2.0, 1 H), 8.07 (dd, J=7.8, 1.9, 1 H), 7.17 (s, 2H), 6.64 (dd, J=7.8, 4.7, 1 H), 4.29 (q, J=7.1 , 2H), 1 .32 (t, J=7.1 , 3H).
With sulfuric acid; at 79℃; for 60h;Large scale;
1. A slurry of 4.90 kg (34.5 mol) 2-aminonicotinic acid in 50 l ethanol was treated with 5.67 l (106 mol) sulfuric acid (98%). The reaction mixture was stirred for 60 hours at 79 C. The reaction mixture was then cooled to 40 C. and ethanol was distilled off under vacuum. The residue was dissolved in a mixture of 45 kg ice and 55 l water. Then 13 l aqueous sodium hydroxide solution (32% by weight) was added slowly under stirring and external cooling to reach a pH of 7. The precipitate was filtered off and washed with water. The residue was taken up in water, stirred for 1 hour and filtered. The residue was washed with water and dried under vacuum yielding <strong>[5345-47-1]2-amino-nicotinic acid</strong> ethyl ester as colourless crystals; HPLC/MS: 0.99 min, [M+H] 167. 1H NMR (400 MHz, DMSO) delta=8.22 (dd, J=4.7, 2.0, 1H), 8.07 (dd, J=7.8, 1.9, 1H), 7.17 (s, 2H), 6.64 (dd, J=7.8, 4.7, 1H), 4.29 (q, J=7.1, 2H), 1.32 (t, J=7.1, 3H).
A finely powdered mixture of 2-aminonicotinic acid (7.0 g, 50.7 mmol) and urea (13.0 g, 216 mmol) was heated to180-190 C and maintained for 15 minutes at the same temperature. The temperature was gradually raised to200 C and the clear melt started to solidify. The temperature was raised to210 C and the heating was discontinued. The mixture was cooled to room temperature and 2 NNaOH solution (70 ml) was added. It was heated at50-55 C to get a clear solution. This warm solution was saturated with carbon dioxide, cooled and filtered and the solid was washed with water (2 x 25ml) to give desired product (7. 71 g,76%). H NMR 8 7.16 (m, 1 H), 8.22 (d, J = 6.4 Hz, 1 H), 8. 53 (m, 1 H).
26%
at 200℃; for 5h;
(1) 4 g of 2-aminonicotinic acid (starting material A4), 20 g of urea was refluxed at 200 C for 5 h to give intermediate B1, The yield of 26%; reaction equation is as follows:
A mixture of 2-aminopicotinic acid (1.4 g, 10 mmol) and urea (3.7 g, 61 mmol) was heated to 190C for 3 hours, after which it was cooled to 100C, and water, then aqueous hydrochloric acid (1 M) were added, until an acidic pH was reached. The mixture was refluxed for an hour before being cooled to ambient temperature. The resulting solid was filtered and dried in vacuo. 1H NMR (DMSO-d6): 7.24 (dd, 1 H), 8.26 (dd, 1 H), 8.59 (dd, 1 H), 10.95 (s, 1 H), 1 1.70 (s, 1 H).
In neat (no solvent); at 150℃; for 12h;
General procedure: The typical procedure to aromatic fused pyrimidine-2,4(1H,3H)-diones (2) is as follows. Aromatic-3-amine-2-carboxylic acid (0.1 mol) and urea (2 mol) were both mixed in a flask and then heated at 150 C for 12 h. When the mixture was cooled down to 100 C, 40 mL of water was added and the resultant mixture was stirred for another 10 min to dissolve the unreacted urea. After the reaction mixture was cooled down to room temperature, it was filtered and 400 mL, 1 mol/L NaOH aqueous solution was then added. Another 1 h later 55 mL of acetic acid was dropwise added for acidification and the resultant light yellow or white precipitates were filtered and dried to give the desired product 2 in a yield of 80-95%.
f) Preparation of 1H-pyrido[2,3-d]pyrimidine-2,4-dione: A mixture of 2-aminopicotinic acid (1.4 g, 10 mmol) and urea (3.7 g, 61 mmol) was heated to 190 C. for 3 hours, after which it was cooled to 100 C., and water, then aqueous hydrochloric acid (1 M) were added, until an acidic pH was reached. The mixture was refluxed for an hour before being cooled to ambient temperature. The resulting solid was filtered and dried in vacuo. 1H NMR (DMSO-d6): 7.24 (dd, 1H), 8.26 (dd, 1H), 8.59 (dd, 1H), 10.95 (s, 1H), 11.70 (s, 1H).
15.A
Step A: A solution of 2-aminonicotinic acid (1.01 g, 7.31 mmol) was dissolved in concentrated H2SO4 (ca 5 mL) and cooled to 0°C. Fuming nitric acid (0.4 mL, 8.6 mmol) was slowly added, and the reaction mixture was allowed to warm to room temperature. The mixture was then poured into ice water (100 mL). The resulting precipitates were filtered, washed with water (3 X 15 mL) and then Et2O (3 X 10 mL) to afford 2-amino-5-nitronicotinic acid as a solid (1.06 g, 52% yield).
With sulfuric acid; nitric acid at 60℃; Erwaermen des Reaktionsprodukts mit Aethanol;
2-amino-3,4,5,6-tetrahydropyridine-3-carboxylic acid hydrochloride[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
1.22 g (100%)
With hydrogenchloride;PtO2; In methanol;
Example 15 2-Amino-3,4,5,6-Tetrahydropyridine-3-carboxylic acid HCl <strong>[5345-47-1]2-Aminonicotinic acid</strong> (0.912 g, 6.6 mmol) was dissolved in 90% methanol (137 ml) and conc. HCl (3.5 ml, 40 mmol) was added. The solution was hydrogenated over PtO2 (200 mg) in a Parr shaker apparatus at room temperature and 29 psig for 2 hours. Filtration and evaporation gave 1.22 g (100%) oily product identified by ir 3300-2500, 1724 cm-1.
With ammonium chloride; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In N,N-dimethyl-formamide; at 20℃;
To the suspension of 2-aminonicotinic acid (1.38 g, 10.0 mmol) in DMF (50 mL) were added HOBt (1.35 g, 10.0 mmol), NH4Cl (1.07 g, 20.0 mmol), EDC·HCl (2.88 g, 15.0 mmol) and triethylamine (2.78 mL, 20.0 mmol). The mixture was stirred overnight at room temperature. Solvent was distilled off in vacuo, and CH2Cl2 (150 mL) and saturated NaHCO3 aqueous solution (150 mL) were added to the residue. Organic phase was separated, dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (3?5%MeOH-CH2Cl2) to obtain the title compound (1.21 g, 8.85 mmol, 89%) as a white powder. 1H NMR (DMSO-d6) delta: 6.55 (1H, dd, J = 7.7, 4.8 Hz), 7.17 (2H, s), 7.30 (1H, s), 7.92 (2H, dd, J = 7.7, 1.8 Hz), 8.06 (1H, dd, J = 4.8, 1.8 Hz). ESI-MS m/z: 138 (M+H)+.
45%
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; at 20℃; for 5h;
To a stirred solution of 2-aminopyridine-3-carboxylic acid (0.9 g, 6.52 mmol) in THF (15mL), was added EDC.HCl (1.86 g, 9.78 mmol), HOBt·NH3 (1.46 g, 9.78 mmol) and DIPEA(4.67 mL, 26.08 mmol) at RT. The reaction mixture was stirred at RT for 5 h (TLC indicatedcomplete consumption of starting material), diluted with water (30 mL) and extracted withEtOAc (3 x 75 mL). The combined organic extracts were washed with cold water (2 x 40mL), brine (40 mL), separated, dried over Na2S04 and concentrated under reduced pressureto give the crude residue which was purified by column chromatography (100-200 silica gel,20 g, 60% EtOAc-Hexane) to afford 2-aminopyridine-3-carboxamide (0.4 g, 45%) as a whitesolid.LCMS: m/z: 138.3 [M+Ht.
With ammonium chloride; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In dimethyl sulfoxide; at 20℃; for 16h;
Manufacturing Example 14-1: 2-Amino-nicotinamide 2-Aminonicotinic acid (5.0 g), WSC (10 g), HOBt (7.3 g), ammonium chloride (5.8 g), diisopropylethylamine (28 g), and DMSO (100 mL) were stirred for 16 hours at room temperature. Water was added and then extraction was performed with ethyl acetate and THF. The organic layer was concentrated and purified by silica gel chromatography (ethyl acetate) to obtain the titled compound (2.6 g). 1H-NMR spectrum (DMSO-d6) delta (ppm): 6.53-6.58 (1H, m), 7.17 (2H, brs), 7.29 (1 H, brs), 7.92 (1 H, brs), 7.92 (1 H, dd, J = 2.0 Hz, 8.0 Hz), 8.06 (1 H, dd, J = 2.0 Hz, 4.8 Hz).
With ammonium chloride; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In dimethyl sulfoxide; at 20℃; for 15h;
General procedure: The syntheses of compounds 3a-3x were mainly referred to literature method [35]. A mixture of 1a-1q, 1w, 1x (2mmol), EDC?HCl (575mg, 3mmol), HOBt (446mg, 3.3mmol), NH4Cl (348mg, 6.5mmol) and DIPEA (2.3mL, 13mmol) in DMSO (7mL) was stirred at room temperature for 15h. The mixture was extracted with EtOAc three times, and the combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford 3a-3q, 3w, 3x. A mixture of 2r-2v (2mmol) and NH3·H2O (25-28wt%, 80mmol) in sealed tube was heated at 100C for 12h. The mixture was cooled to room temperature and extracted with EtOAc three times. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford 3r-3v.
With water; ammonium chloride; at 80 - 200℃; for 2.5h;
A slurry of 2-aminonicotinic acid (10 g, 72.5 mmol), ammonium chloride (39 g, 725 mmol) and potassium cyanate (30 g, 362 mmol) in water (80 ml) was heated to 80 C. and maintained at this temperature with stirring for 30 minutes before being heated to 200 C. The mixture was stirred for 2 hours at this elevated temperature and then left to cool. Water (200 ml) was then added and the resultant mixture filtered. The solid was washed with hot water (100 ml) and then with cold water (2*100 ml) to give a yellow solid which corresponded to the title compound (11.79 g, 99%) in suitably clean form to be used without any further purification. m/z (LC-MSW, ESP):164 [M+H]+, R/T=2.11 mins.
With ammonium chloride; In water; at 20 - 200℃; for 2.66667h;
(i) 1H-Pyridopyrimidine-2, 4-diones (2) The appropriate amino acid (1)(1 equivalent), potassium cyanate (5 equivalents) and ammonium chloride (10 equivalents) were suspended in water. The slurry was heated (160 C.) and mixed manually for 2 hours as water vapour was expelled from the reaction vessel. The reaction temperature was then raised to 200 C. for 40 minutes before being cooled to 90 C. whereupon hot water was added and then the mixture was allowed to cool to room temperature. The precipitate that formed during cooling was removed by filtration, washed with water (twice), and diethyl ether (once) before being dried in a desiccator to give the desired product in suitably clean form to be used without further purification. 2a: 1H-Pyrido[2,3-d]pyrimidine-2,4-dione: m/z (LC-MS, ESP): does not ionise R/T=0.76 mins 2b: 1H-Pyrido[3,4-d]pyrimidine-2,4-dione: m/z (LC-MS, ESP): 164 [M-K+H]+, R/T=0.38 mins 2c: 1H-Pyrido[3,2-d]pyrimidine-2,4-dione: m/z (LC-MS, ESP): 164 [M-K+H]+,R/T=0.45 mins.
Example 9: Synthesis of 3-(4-Fluorophenyl)-imidazo[l,2-a]pyridine-8-carboxylic acid (9); Chloroacetaldehyde (45% aqueous solution) (6.6 mL, 38 mmol) is added to the stirred solution of 2-aminonicotinic acid (5.0 g, 25 mmol) in ethanol (35 mL) and warmed at reflux for 14 hours. The reaction mixture is concentrated and the crude material is triturated with EtOH-Et20 to afford imidazo[l,2-a]pyridine-8-carboxylic acid. Mp: 296-299C.
With potassium carbonate; In dimethyl sulfoxide; at 20℃; for 18h;Reflux;
Containing 13.8 g of 2-amino acid (0.1 mmol) of potassium carbonate and 27.6 g (0.2 mole, 2.0 eq.) Of dimethyl sulfoxide was heated to reflux, then the solution was cooled to ambient temperature, was added 14.2 g of iodine methane (0.1 mole, 1.0 eq) to the mixture, and the solution was stirred for 18 hours, the mixture was filtered and concentrated to give a residual material containing 0.1% aqueous ammonia (5/95 ethanol / dichloromethane) was eluted as after filtration of the liquid silicone pad and the resulting solution was concentrated, the residue was suspended in ether, filtered and dried to give <strong>[5345-47-1]2-amino-nicotinic acid</strong> methyl ester (10.8 g, 71% yield). Analysis of results:
58%
With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 18h;Reflux;
1 ) A suspension of 2-aminonicotinic acid (833 mg, 6.00 mmol) and potassium carbonate (912 mg, 6.60 mmol) in dimethylformamide (DMF, 8.5 ml) was heated to reflux. The reaction mixture was cooled to room temperature and 415 muIota of iodomethane (6.60 mmol) were added. The mixture was then refluxed under stirring for 18 h; after subsequent cooling, the mixture was finally filtered and the filtrate was concentrated under reduced pressure. The crude product was purified by flash chromatography on silica gel (ethyl acetate/petroleum ether = 7/3). The isolated 2-aminonicotinic acid methyl ester was obtained in 58% yield.
58%
1) A suspension of 2-aminonicotinic acid (833 mg, 6.00 mmol) and potassium carbonate (912 mg, 6.60 mmol) in dimethylformamide (DMF, 8.5 ml) was heated to reflux. The reaction mixture was cooled to room temperature and 415 mul of iodomethane (6.60 mmol) were added. The mixture was then refluxed under stirring for 18 h; after subsequent cooling, the mixture was finally filtered and the filtrate was concentrated under reduced pressure. The crude product was purified is by flash chromatography on silica gel (ethyl acetate/petroleum ether=7/3). The isolated 2-aminonicotinic acid methyl ester was obtained in 58% yield.
With bromine; In acetic acid; at 0 - 20℃; for 48h;
Bromine (7.5 mL, 146 mmol) was added dropwise over 10 min to a suspension of 2- amino-nicotinic acid (20.0 g, 145 mmol) in glacial acetic acid (250 mL) cooled in an ice bath. After the bromine addition was complete, the mixture was stirred at ambient temperature for 2 d. The resulting light yellow solid was isolated by filtration, washed with ET2O, and dried under high vacuum (40 C) for several hours to give the title compound (40.0 g, 93%) : IH NMR (300 MHz, DMSO-D6) 8 8.33 (d, J= 2.5 Hz, 1H), 8.20 (d, J= 2.5 Hz, 1H), 8.02 (bs, 3H); ESI MS mule 217 (M + H) +.
93%
With bromine; acetic acid; at 20℃; for 1h;
PREPARATION 8 PREPARATION OF 2-AMINO-5 -BROMONICOTINOHYDRAZIDE 1. To a suspension of 2-aminonicotinic acid 1 (13.8 g, 100 mmol) in 100 mL of acetic acid was added bromine (5.70 mL, 110 mmol) dropwise over 20 min. The mixture was stirred at ambient temperature for 1 h, evaporated, triturated with ether (50 mL). The solid was collected by filtration, washed with diethyl ether (2 x 20 mL) and dried in air. The product, 2-amino-5-bromonicotinic acid hydrobromide, was obtained as a brown solid in 93 % yield (27.8 g). 1H NMR (400 MHz, OMSO-d6): delta 8.28 (d, J= 2.4 Hz, 1H), 8.15 (d, J= 2.4 Hz, 1H), 5.00 (br s, 4H).
91%
With bromine; acetic acid; at 20℃;Cooling with ice;
Bromine (1.01 eq, 36.49 mmol) was added dropwise to a suspension of <strong>[5345-47-1]2-amino-nicotinic acid</strong> (1 eq, 36.13 mmol) in glacial acetic acid (55 mL) cooled in an ice bath. After the addition of bromine was complete, the mixture was stirred at room temperature overnight. The solid was filtered and rinsed with ether to afford 2-amino-5-bromo-nicotinic acid hydrobromide (9.77g, 33.02, 91%) as a yellow solid. 1H NMR (500 MHz, DMSO-ifc) d 8.33 (d, / = 2.6 Hz, 1H), 8.21 (d, / = 2.5 Hz, lH).13C NMR (126 MHz, DMSO) d 166.82, 156.91, 150.85, 143.19, 108.72, 103.73
2-chloro-1,3-dimethyl imidazolium chloride[ No CAS ]
[ 14667-47-1 ]
Yield
Reaction Conditions
Operation in experiment
94%
With triethylamine; In methanol; at 20℃; for 1h;
e) Preparation of Methyl 2-aminonicotinate; [00309] To a mixture of 2-aminonicotinic acid(n) (30.0 g 217 mmol) and 2-chloro1,3-dimethyl imidazolinium chloride(55.2 g 326 mmol) in MeOH (750 ml) was added dropwise triethylamine (91 ml 652 mmol). The resultant mixture was stirred at room temperature for 1 h. The mixture was then evaporated under reduced pressure to afford a residue. The residue was purified by extraction with ethyl acetate (300 ml×2). The combined organic phase was washed with water (200 ml×2) and brine (200 ml). Dried over anhydrous sodium sulfate, filtered and concentrated to give an essentially pure methyl 2-aminonicotinate (31.3 g, yield 94%). This compound was used in next step without further purification.
2-Methyl-pyrido [2,3-d] pyrimidin-4-ol: To a solution of 2-amino- nicotinic acid (277 mg, 2 mmol), 4-N, N-DIMETHYLAMINOPYRIDINE (20 mg, 0.16 mmol), triethylamine (1.1 mL, 7.9 mmol) in DMF (2 mL) was added acetyl chloride (0.35 mL, 4.9 mmol) slowly at 0 C under argon. The white precipitate was formed immediately. The mixture was then heated at 90 C for 3.5 h, then ammonium acetate (0.601 g, 7.8 mmol) was added. The mixture was stirred for 1 h, cooled to rt and diluted with water (20 mL). It was extracted with EtOAc (2X50 mL), and the extracts were dried over MGS04, and evaporated. The crude was purified by column chromatography (SI02, EtOAc: MeOH/0-10%) to give an off-white solid (47 mg, 16%) : H NMR (DMSO-d6) 11.40 (s, 1H), 9.01 (dd, J = 2.1, 4.8 Hz, 1H), 8.61 (dd, J = 2.4, 8.1 Hz, 1H), 7.44 (dd, J = 4.8, 8.1 Hz, 1H), 2.66 (s, 3H).
78.1
To a solution of 2-aminonicotinic acid (91.1 g, 8.0 mmol), triethylamine (2.7 mL, 19.1 mmol) and acetone/H2O (3:1, 100 mL) was added 1-benzothiophene-2-carbonyl chloride (2.04 g, 10.4 mmol) at 0° C. The resulting solution was allowed to warm to rt and stir overnight. The volatile solvent was removed under reduced pressure and the aqueous solution was acidified with HCl (conc.). The resulting precipitate was filtered and then washed with EtOAc and dried under reduced pressure to afford the product. (1.2 g, 52%). NMR (DMSO): 11.7(1H, broad), 8.60(1H, m); 8.36(1H, s); 8.25(1H, d); 8.07(1H, d); 8.02(1H, d); 7.51(2H, m); 7.36(1H, m).
To a solution of 2-aminonicotinic acid (20. 5g, 148mmol) in tetrahydrofuran (300mL) at room temperature was added lithium aluminum hydride (1. OM in tetrahydrofuran, 300mL, 300mmol) dropwise over 45 minutes. The resulting solution was heated to reflux for 18hrs. The mixture was cooled to room temperature and quenched by the sequential dropwise addition of water (11. 5mL), 15% aqueous sodium hydroxide (11. 5mL), and water (34. 5mL). The mixture was stirred for 15min., then filtered through Celite 545. The filter pad was washed thoroughly with tetrahydrofuran (500mL) and 5% methanol in chloroform (500mL). The combined filtrate and washings were evaporated to give 17.7g (96%) of the title compound as a yellow waxy solid. MS (LC/MS/pos): 125.0 (M+H) +. 1H NMR (CDC13) 5 4.13 (br. s, 1H), 4.59 (s, 2H), 6.56 (m, 1H), 7.29 (d, 1H), 7.90 (d, 1H).
96%
With lithium aluminium tetrahydride; In tetrahydrofuran; at 0℃; for 18h;Reflux;
To a suspension of 2-aminonicotinic acid (25.0 g, 0.18 mol) in THF (500 mL) was added L1AIH4 (13.7 g, 0.36 mol) portion-wise at 0 C. The mixture was heated to reflux and stirred further for 18 hours, then cooled to rt, and quenched by the sequential drop wise addition of water (16 mL), NaOH aqueous solution (16 mL, 15%), and water (50 mL). The resulted mixture was stirred at rt for 20 minutes, then filtered through a CELITE. The filter cake was washed thoroughly with THF (100 mL) and MeOH/CHCb (1/20 (v/v), 200 mL). The combined filtrates were concentrated in vacuo to give the title compound as yellow oil (21.6 g, 96%). MS (ESI, pos. ion) m/z: 125.0 (M +1). 1H NMR (400 MHz, CDCb): delta 3.93 (s, 2H), 4.54 (s, 2H), 5.15 (s, 1H), 6.55-6.70 (s, 1H), 7.30- 7.40 (m, 1H), 7.83-7.90 (m, 1H).
96%
With lithium aluminium tetrahydride; In tetrahydrofuran; for 18h;Reflux;
The compound 2 - amino-nicotinic acid (25.0 g, 0 . 18 muM) suspended in THF (500 ml) in, cooling to 0 C, then added to the reaction solution in the LiAlH in batches4 (13.7 G, 0 . 36 muM), heating to reflux, the reaction 18 hours, cooling to room temperature, and then sequentially dropwise adding water (16 ml), NaOH aqueous solution (16 ml, 15%), water (50 ml) quenching the reaction, the resulting mixture stirring at room temperature 20 minutes later, for diatomite filter, the filter cake for sequentially THF (100 ml) and MeOH/CHCl3 (1/20, 200 Ml) washing, the combined filtrate is concentrated under reduced pressure to obtain the title compound as a yellow oily matter (21.6 g, 96%).
95%
With sodium hydroxide; LiAlH4; In tetrahydrofuran; water;
a) 2-Amino-3-(hydroxymethyl)pyridine To a stirred solution of 2-aminonicotinic acid (20 g, 145 mmole) in dry THF (200 mL) under argon was added 1.0 M LiAlH4 in THF (300 mL, 300 mmole) carefully, portionwise, through a reflux condenser, over 4 hr. The reaction became exothermic and refluxed without external heating. After the addition was complete, the reaction was heated at reflux for an additional 16 hr, then was cooled to 0 C and carefully quenched by sequential addition of H2O (12 mL), 15% NaOH in H2O (12 mL), and H2O (35 mL). The resulting thick suspension was stirred for 1 hr, then was filtered through a pad of celite. The filter pad was rinsed with THF (300 mL), and the filtrate was concentrated to dryness to give the title compound (17.04 g, 95%) as a pale yellow waxy solid: LCMS (ES) m/e 125.1 (M + H)+; 1H NMR (400 MHz, DMSO-d6) delta 7.84 (dd, 1 H), 7.37 (m, 1 H), 6.53 (dd, 1 H), 5.65 (br s, 2 H), 5.16 (t, 1 H), 4.34 (d, J = 4.6 Hz, 2 H).
90%
Step 1: 2-Amino-3-(hydroxymethyl)pyridineLithium aluminum hydride (12.4 g, 326.7 mmol) was portionwisely added to a suspension of 2-amino-3-carboxypyridine (30.0 g, 217.2 mmol) in THF (350 mL) at 0C. Once the addition was completed, the reaction mixture was stirred at room temperature for 15 minutes and then at reflux overnight. The mixture was then cooled to 0C and hydrolyzed by the successive addition of water (18 mL), a solution of sodium hydroxyde (18 mL) and water (30 mL) again. The resulting white suspension was filtered on Clarcel and the cake was washed with THF (200 mL) and a mixture of CHCI3/MeOH (250 mL, 9 : 1). After concentration to dryness of the filtrate, the title product was obtained as a yellow solid (24.2 g, 90%).*H NMR (DMSO-c/6, 400 MHz) : delta (ppm) : 7.84 (d, J = 4Hz, 1H), 7.37 (d, J = 7.2 Hz, 1H), 6.55-6.52 (m, 1H), 5.64 (br s, NH2), 4.34 (s, 2H).
83%
With sodium hydroxide; In tetrahydrofuran; methanol; chloroform; water;
a) 2-Amino-3-(hydroxymethyl)pyridine To a solution of 2-aminonicotinic acid (20.5 g, 148.1 mmole) in THF was added lithium aluminum hydride (300 mL, 1.0 M in THF) over 30 minutes. The reaction solution was heated to reflux for 18 hrs and then was cooled to room temperature. The reaction was quenched by the sequential dropwise addition of H2O (11.5 mL), 15% NaOH (11.5 mL), and H2O (34.5 mL). The mixture was stirred for 15 min, then was filtered through celite, and the filter pad was washed thoroughly with THF followed by 5% CH3OH/CHCl3. The filtrate was concentrated to give the title compound (15.24 g, 83%) as a waxy light yellow solid: MS (ES) m/e 125 (M + H)+.
83%
With sodium hydroxide; In tetrahydrofuran; methanol; chloroform; water;
a 2-Amino-3-(hydroxymethyl)pyridine To a solution of 2-aminonicotinic acid (20.5 g, 148.1 mmole) in THF was added lithium aluminum hydride (300 mL, 1.0 M in THF) over 30 minutes. The reaction solution was heated to reflux for 18 hrs and then was cooled to room temperature. The reaction was quenched by the sequential dropwise addition of H2O (11.5 mL), 15% NaOH (11.5 mL), and H2O (34.5 mL). The mixture was stirred for 15 min, then was filtered through celite, and the filter pad was washed thoroughly with THF followed by 5% CH3OH/CHCl3. The filtrate was concentrated to give the title compound (15.24 g, 83%) as a waxy light yellow solid: MS (ES) m/e 125 (M+H)+.
To 100 mL of tetrahydrofuran solution containing 5.7 g of lithium aluminum hydride, 20 mL of tetrahydrofuran solution containing 13.8 g of 2-aminonicotinic acid was added, and heated for 2 hours under reflux. After cooling the reaction mixture back to room temperature, sodium sulfate decahydrate was slowly added until there are no bubbles, and stirred for 2 hours at room temperature. The insolubles were filtered through celite, the filtrate was concentrated under reduced pressure, and 10.7 g of (2-aminopyridin-3-yl)methanol [147-1] was obtained as a white solid.
With lithium aluminium tetrahydride; In tetrahydrofuran; for 16h;Reflux;
(i) LAH, Dry THF, reflux, 16h; (ii) Br2, HOAc, 20-35C, 3h: (iii) 48% HBr.refhix, dimethyl malonate, CH3OH, 20-35C, 16h; (v) NaOH, CH3OH, reflux, 4h, then HC1, reflux, 16h; (vi) tert-butyl acrylate, Pd(OAc)2, P(o- tolyl)3, DIEA, DMF.Propionitrile, 90C, 16h; (vii) TFA, CH2C12 , 20-35T, 4h, then 4% dioxane. HC1, 20-35C, 2h. (Reference for Step-(i): WO 2005095391 and Step-(ii-vii): J. Med. Chem. 2003, 46, 1627-1635)
0.74 g
With lithium aluminium tetrahydride; In tetrahydrofuran; diethyl ether; at 0 - 20℃; for 48h;Inert atmosphere;
To a suspension of 2-aminonicotinic acid (5-Si, 1.58 g, 11.45 mmol) in THF (80 mL), LAH (1M in ether, 22.9 mL, 22.9 mmol) was added slowly at 0 C under argon with stirring. After completion of the addition, the ice bath was removed and the mixture was stirred at room temperature. Additional LAH (1M in ether, 11.4 mL) was added after 48 hours and the reaction was again cooled with an ice bath before saturated NH4C1 aqueous solution (20 mL) was added with stirring to form slurry. The organic layer was separated by decantation and the slurry was washed with EtOAc. The combined organic layer was washed with iN NaOH aqueous solution, brine, and dried over anhydrous Na2SO4. Solvent was removed under reduced pressure to afford (2-aminopyridin-3-yl)methanol (5-S2, 0.74 g) as an off-white solid.
EXAMPLE 1 2-Amino-5-bromo-3-pyridine carboxylic acid To a solution of <strong>[5345-47-1]2-amino-nicotinic acid</strong> (10 g, 72.5 mmol) in acetic acid (70 mL) was dropwise added bromine (9.8 mL, 79.8 mmol) at room temperature under nitrogen. Upon completion of the reaction, the solvent was removed in vacuo, the residue triturated with ether and collected on a filter to give 2-amino-5-bromo-3-pyridine carboxylic acid as a yellow solid (15.7 g, 99%): mp 272 C., (decomposed); 1H-NMR (DMSO-d6) delta8.8-7.8 (bs, 2H), 8.44 (d, 1H, J=2.48 Hz), 8.34 (d, 1H, J=2.48 Hz); MS (EI) m/z 216/218 ([M+]+, 100%)
99%
With bromine; In acetic acid;
EXAMPLE 1 2-Amino-5-bromo-3-pyridine Carboxylic Acid To a solution of <strong>[5345-47-1]2-amino-nicotinic acid</strong> (10 g, 72.5 mmol) in acetic acid (70 mL) was dropwise added bromine (9.8 mL, 79.8 mmol) at room temperature under nitrogen. Upon completion of the reaction, the solvent was removed in vacuo, the residue triturated with ether and collected on a filter to give 2-amino-5-bromo-3-pyridine carboxylic acid as a yellow solid (15.7 g, 99%): mp 272 C., (decomposed); 1H-NMR (DMSO-d6) delta 8.8-7.8 (bs, 2H), 8.44 (d, 1H, J=2.48 Hz), 8.34 (d, 1H, J=2.48 Hz); MS (EI) m/z 216/218 ([M+H]+, 100%).
98%
With bromine; In acetic acid; at 20℃; for 20h;
Step 1: Synthesis of 2-amino-5-bromonicotinic acid 25.00 g (0.181 mol) of 2-aminonicotinic acid were dispersed in 100 ml of glacial acetic acid. To this suspension was added a solution of 12.0 ml (0.23 mol) of bromine in 50 ml of glacial acetic acid. The mixture was stirred at room temperature for 20 hours. The precipitate formed was filtered off and washed with 100 ml of glacial acetic acid in several portions until the filtrate remained colorless. The crude was dried by suction and crystallized from boiling methanol to afford 38.63 g (0.178 mol, 98% yield) of 2-amino-5-bromonicotinic acid as slightly greenish to off-white crystalline needles. 1H-NMR (d6-DMSO) d: 8.45 [1H] d, 8.34 [1H] d.; MS: m/z 217 [MH+].
96%
With bromine; acetic acid; at 20℃;
Equipped with a blender,Reflux condenser 500mL three-necked flask,20.7 g (0.15 mol) of 2-aminonicotinic acid,80 mL acetic acid,Stirred at room temperature,A constant pressure dropping funnel was added dropwise with a mixed solution of 40 mL of acetic acid and 4.1 mL of bromine (0.08 mol)Drop end to continue mixing 4-5h.filter,Washed with acetic acid,dry,The solid was refluxed with methanol 100mL 10min 10min at room temperature,Filter and dry.31.2g of white solid was obtained,Yield 96%.
95%
With bromine; In acetic acid; at 20℃; for 20h;
2-Amino-nicotinic acid (2 g, 14.48 mmol) was dispersed in glacial acetic acid. To this suspension was added a solution of bromine (1.2 mL) in glacial acetic acid (5 mL). The mixture was stirred at room temperature for 20 h. The mixture was filtered and washed with glacial acetic acid (10 mL) and water in several portions. The precipitate was collected and dried to give 2-amino-5-bromonicotinic acid (3.0 g, 95 % yield) as yellow solid. XH-NMR (DMSO- d6, 400 MHz) delta 8.31 (d, J= 2.4 Hz, 1H), 8.18 (d, J= 2.8 Hz, 1H), 5.06-5.27 (m, 2H). MS (M+H)+: 218 / 220.
95%
With bromine; acetic acid; at 25℃; for 20h;
2-Amino-nicotinic acid (2 g, 14.48 mmol) was dispersed in glacial acetic acid. To this suspension was added a solution of bromine (1.2 mL) in glacial acetic acid (5 mL). The mixturewas stirred at room temperature for 20 h. The mixture was filtered and washed with glacial aceticacid (10 mE) and water in several portions. The precipitate was collected and dried to give 2-amino-5-bromonicotinic acid (3.0 g, 95 % yield) as yellow solid. ?H-NMR (DMSO-d6, 400 MHz) oe 8.31(d, J= 2.4 Hz, 1H), 8.18 (d, J= 2.8 Hz, 1H), 5.065.27 (m, 2H). MS (M+Hj: 218 / 220.
92%
With bromine; acetic acid; at 20℃; for 0.5h;
<strong>[5345-47-1]2-Aminonicotinic acid</strong> (10.00 g, 72.40 mmol) was suspended in 40 ml of glacial acetic acid. To this suspension was added dropwise a solution of 4.82 ml (94.12 mmol) of bromine in 20 ml of glacial acetic acid. The mixture was stirred vigorouly at room temperature for 30 min. The formed precipitate was filtered off and washed with glacial acetic acid. The filter cake was collected and crystallized from the boiling methol to afford compound 8 as a white solid (14.5 g, 92% yield). 1H NMR (300 MHz, DMSO-d6) delta 8.30 (d, J = 2.4 Hz, 1H), 8.16 (d, J = 2.4 Hz, 1H); MS (ESI, m/z): 216.8 [M+H]+.
92.6%
With bromine; acetic acid; at 20℃; for 18h;
2-Amino-5-bromo-nicotinic acid: To a solution of <strong>[5345-47-1]pyridine-2-amino-3-carboxylic acid</strong> (2.05 g, 81.1 mmol) in AcOH (250 mL) was added bromine (11.0 mL, 199.2 mmol) at RT. The reaction mixture was stirred for 18 h at RT. On completion of the reaction, the solvent was evaporated completely under reduced pressure, filtered, washed with diethyl ether (3 x 75 mL) to afford the title compound as a yellow solid. Yield: 50.0 g (92.6%) 'HNMR (DMSO-de, 400 MHz, TMS) delta: 11.7 (3H, br, s), 8.33 (1H, s), 8.20 (1H, s).
90%
With bromine; acetic acid; at 20℃; for 2h;
2-aminonicotinic acid (10.0 g, 72 mmol) was dissolved in acetic acid (40 ml),Slowly add bromine (9.64 mL,388 mmol) in acetic acid (20 mL),Stir at room temperature for 2 hours, filter by suction, and wash the filter cake with acetic acid.The cake was recrystallized from methanol,After suction filtration and drying, 14.1 g of a white solid is obtained.The yield is 90%.
90%
With bromine; acetic acid; at 25℃; for 20h;Inert atmosphere;
This compound was prepared following a literature procedure.25 Toa suspension of 2-aminonicotinic acid 21 (3.75 g, 27 mmol) in glacialacetic acid (15 mL) was added a solution of bromine (1.8 mL, 35 mmol)in glacial acetic acid (3 mL) and the mixture was stirred at RT for 20 h.After completion monitored by TLC, the resulting precipitate was filteredand washed with glacial acetic acid 3 times. The remaining solidwas air dried and then recrystallised from boiling methanol to affordthe product 22 as white crystalline needles (5.2 g, 90%). 1H NMR(400 MHz, d6-DMSO): delta 8.36 (1H, d, J=2.6 Hz), 8.25 (1H, d,J=2.6 Hz), 7.95-7.79 (2H, br.s); 13C NMR (100 MHz, d6-DMSO): delta166.6, 156.5, 149.9, 143.8, 109.3, 103.7. The spectroscopic data matchedthat reported in the literature.
89%
With bromine; acetic acid; In water; at 0 - 20℃; for 8h;
2-Amino-5-bromonicotinicacid (3) (C6H5BrN2O2): Acetic acid (250 mL) and water (10 mL)were poured into the solution of 2-aminonicotinic acid 1 (10 g, 72.4mmol). The suspension was placed at 0C and Br2 (4 mL, 79 mmol,1.1 equiv) was added dropwise. After 8 h of stirring at room temperature,the mixture was filtered and then concentrated underreduced pressure. The crude material obtained was washed withEt2O to afford compound 3 as a white solid in 89% yield.
70%
With bromine; acetic acid; at 20℃; for 20h;Inert atmosphere;
2-aminonicotinic acid (25.0 g, 181.00 mmol) was added to a well-dried 1000 mL three-neck round bottom flask, and acetic acid (150 mL) was added thereto. Bromine (11.85 mL, 230.02 mmol) was slowly added dropwise to acetic acid (50 mL). And the mixture was stirred at room temperature for 20 hours in a stream of nitrogen. The resulting product was poured into 500 mL of distilled water and stirred for 30 minutes. The product was filtered through a glass filter, washed with ether and acetone, and dried to obtain Compound 1 (27.4 g, yield 70%).
With bromine; In diethyl ether; acetic acid;
B. 2-Amino-5-bromonicotinic acid and hydrobromide <strong>[5345-47-1]2-Aminonicotinic acid</strong> (3.6 g.) in 450 ml. of acetic acid is treated dropwise over a period of 10-15 minutes with 4 ml. of bromine in 50 ml. of acetic acid. The reaction mixture is allowed to stir at room temperature for 1.5-2 hours, and is then diluted with 2 liters of diethyl ether. The precipitate which forms, 2-amino-5-bromonicotinic acid hydrobromide, is filtered and dried, 5.6 g., m.p. 280 C. (dec.). The free acid is liberated by adding sufficient ammonium hydroxide to an aqueous solution of the hydrobromide salt to provide a solution of pH 5. The resulting free acid is filtered from the cooled mixture and dried in vacuo.
A solution of bromine (7 mL, 136 mmol) in acetic acid (20 mL) was added dropwise to an acetic acid (230 mL) suspension of 2-aminonicotinic acid (9.37 g, 68 mmol) at 100C. After stirring the mixture for 6 hours, ether (600 mL) was added and the stirring was continued for 14 hours. The mixture was cooled to 00C, the precipitate was filtered, washed with ether and dried to give 18.2 g (90%) of a hydrobromide salt. The salt was dissolved in water (200 mL) and sodium hydroxide solution (60 mL, 2N) then neutralized with IN HCl. The resulting precipitate was filtered and dried to afford of the title compound (12.01 g, 82%). 1H NMR (300 MHz, OMSO-d6, delta): 8.25 (d, J= 2.6Hz, IH), 8.09 (d, J= 2.6Hz, IH).
With bromine; In diethyl ether; acetic acid;
h. 2-Amino-5-bromonicotinic acid and hydrobromide In a manner similar to Preparation D-g, 3.6 g. of 2-aminonicotinic acid in 450 ml. of acetic acid is treated dropwise over a period of 10-15 min. with 4 ml. of bromine in 50 ml. of the same solvent. The reaction mixture is allowed to stir at room temperature for 1.5-2 hrs., and is then diluted with 2 l. of diethyl ether. The precipitate which is formed, 2-amino-5-bromonicotinic acid hydrobromide, is filtered and dried, 5.6 g., m.p. 280 C. (dec.). The free acid is liberated by adding sufficient ammonium hydroxide to an aqueous solution of the hydrobromide salt to provide a solution of pH 5. The resulting free acid is filtered from the cooled mixture and dried in vacuo.
With (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate; triethylamine; In N,N-dimethyl-formamide; at 20℃; for 48h;
Preparation Example A+-6. 2-(Ethoxymethyl-amino)-N-(5-phenoxy-thiophen-2-ylmethyl)-nicotinamide To a solution of 2-aminonicotinic acid (3245mg, 23.49mmol) in N,N-dimethylformamide (200mL) were added C-(5-phenoxy-thiophen-2-yl)methylamine (5305mg, 25.84mmol) described in Preparation Example 24, benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (12.49g, 28.19mmol) and triethylamine (7.86mL, 56.38mmol), and the solution was stirred for 2 days at room temperature. Water was added to the reaction mixture, which was then extracted with ethyl acetate, the organic layer was sequentially washed with an aqueous solution of saturated sodium bicarbonate, water, then brine, the solvent was evaporated in vacuo, and 2-amino-N-(5-phenoxy-thiophen-2-ylmethyl)-nicotinamide (4999mg, 15.36mmol, 65%) was obtained as crude product. To a solution of the resulting 2-amino-N-(5-phenoxy-thiophen-2-ylmethyl)-nicotinamide (602mg, 1.85mmol) in ethanol (40mL) were added 5,5-dimethylhydantoin (260mg, 2.04mmol), 37% formic acid aqueous solution (3.00mL, 23.6mmol), and the solution was stirred under reflux for 1 hour. Water was added to the reaction mixture, which was then extracted with ethyl acetate, the organic layer was sequentially washed with water and brine, dried over anhydrous sodium sulfate, and then, evaporated in vacuo. The resulting residue was purified by silica gel chromatography (hexane-ethyl acetate), and the title compound (430mg, 1.12mmol, 61 %) was obtained. 1H-NMR Spectrum (DMSO-d6) delta (ppm):1.03 (3H, t, J=6.8Hz), 3.41 (2H, q, J=6.8Hz), 4.48 (2H, d, J=5.6Hz), 4.90 (2H, d, J=7.2Hz), 6.49 (1H, d, J=3.6Hz), 6.68 (1H, dd, J=4.8, 7.6Hz), 6.77 (1 H, d, J=3.6Hz), 7.06-7.14 (3H, m), 7.33-7.38(2H, m), 7.94 (1 H, dd, J=1.6, 7.6Hz), 8.19 (1 H, dd, J=1.6, 4.8Hz), 8.91 (1 H, t, J=7.2Hz), 9.16-9.20 (1 H, m).
65%
With (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate; triethylamine; In N,N-dimethyl-formamide; at 20℃; for 48h;
To a solution of 2-aminonicotinic acid (3245mg, 23.49mmol) in N,N-dimethylformamide (200mL) were added C-(5-phenoxy-thiophen-2-yl)methylamine (5305mg, 25.84mmol) described in Preparation Example 24, benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (12.49g, 28.19mmol) and triethylamine (7.86mL, 56.38mmol), and the solution was stirred for 2 days at room temperature. Water was added to the reaction mixture, which was then extracted with ethyl acetate, the organic layer was sequentially washed with an aqueous solution of saturated sodium bicarbonate, water, then brine, the solvent was evaporated in vacuo, and 2-amino-N-(5-phenoxy-thiophen-2-ylmethyl)-nicotinamide (4999mg, 15.36mmol, 65%) was obtained as crude product. To a solution of the resulting 2-amino-N-(5-phenoxy-thiophen-2-ylmethyl)-nicotinamide (602mg, 1.85mmol) in ethanol (40mL) were added 5,5-dimethylhydantoin (260mg, 2.04mmol), 37% formic acid aqueous solution (3.00mL, 23.6mmol), and the solution was stirred under reflux for 1 hour. Water was added to the reaction mixture, which was then extracted with ethyl acetate, the organic layer was sequentially washed with water and brine, dried over anhydrous sodium sulfate, and then, evaporated in vacuo. The resulting residue was purified by silica gel chromatography (hexane-ethyl acetate), and the title compound (430mg, 1.12mmol, 61 %) was obtained. 1H-NMR Spectrum (DMSO-d6) delta(ppm) :1.03 (3H, t, J=6.8Hz), 3.41 (2H, q, J=6.8Hz), 4.48 (2H, d, J=5.6Hz), 4.90 (2H, d, J=7.2Hz), 6.49 (1H, d, J=3.6Hz), 6.68 (1H, dd, J=4.8, 7.6Hz), 6.77 (1H, d, J=3.6Hz), 7.06-7.14 (3H, m), 7.33-7.38(2H, m), 7.94 (1H, dd, J=1.6, 7.6Hz), 8.19 (1H, dd, J=1.6, 4.8Hz), 8.91 (1H, t, J=7.2Hz), 9.16-9.20 (1H, m).
In a pressure resistant, 10 mL-volume stainless steel vessel, 1.00 g (7.2 mmol) of 2-aminonicotinic acid, 3.07 g (28.8 mmol) of methyl orthoformate, and 5.0 mL (38 mmol) of 15 wt.% ammonia-methanol solution were heated at 105C for 8 hours for performing a reaction. After the reaction was complete, the reaction mixture was cooled to room temperature and concentrated under reduced pressure, to give 1.06 g (yield after isolation: 100%) of 3H-pyrido[2,3-d]pyrimidin-4-one as a black solid product. The 3H-pyrido[2,3-d]pyrimidin-4-one had the following properties: 1H-NMR (DMSO-d6, delta(ppm)): 3.36 (1H, brs), 7.46 (1H, dd, J=8.0, 4.5 Hz), 8.31 (1H, s), 8.45 (1H, dd, J=7.8, 2.1 Hz), 8.87 (1H, dd, J=4.8, 2.1 Hz) CI-MS (m/e): 148 (M+1)
EXAMPLE 9 Pyrido[2,3-d]pyrimidin-4(3H)-one 2-aminonicotinic acid (1.381 g, 10 mM) and formamide (2.70 g, 60 mM) are heated at 165-170 C. for 2 h by means of an oil bath. The reaction mixture is cooled and the resulting solid recrystallized from water to give about 1.030 g of title compound (70% yield). mp 255-8 C.
49.4%
In formamide;
EXAMPLE 63 4-(3-Bromoanilino)pyrido[2,3-d]pyrimidine 3H-pyrido[2,3-d]pyrimidin-4-one. 2-Amino nicotinic acid (15 g, 108.6 mmol) in formamide (35 mL) is heated to 165-170 C. for 3.5 h. Upon cooling a solid precipitates. The solid is filtered and washed with H2 O and dried in a vacuum oven to give 3H-pyrido[2,3-d]pyrimidin-4-one (7.87 g, 49.4%). 1 H NMR (DMSO) delta 12.50 (1H, s),8.97 (1H, dd, J=1.9, 4.5 Hz), 8.53 (1H, dd, J=2.1, 7.9 Hz), 8.34 (1H, s), 7.57 (1H, dd, J=4.6, 8.0 Hz).
With pyridine In dichloromethane; acetonitrile at 55℃; Inert atmosphere;
To a solution of 2-aminonicotinic acid 3c (250.0 mg, 1.81 mmol, 1 eq) in MeCN (2.8 mL) was addeddropwise at 55 °C pyridine (0.3 mL, 3.71 mmol, 2.05 eq.), followed by a solution of triphosgene (0.12g, 0.72 mmol, 0.4 eq) in CH2Cl2 (1.8 mL). The reaction mixture gradually turns yellow and 1 ml of MeCNwas added in order to solubilize it well. The reaction mixture was stirred at 55 °C for 2 days undernitrogen. After reaction completion, the reaction mixture was concentrated and then water was addedin order to precipitate the product. The product was filtered and washed with cold CH2Cl2 to give thedesired isatoic anhydride derivative 4c as a yellow solid (80 mg, 27% yield).
With sodium carbonate In water
10 7-Azaisatin STR18
EXAMPLE 10 7-Azaisatin STR18 To a solution of 2-aminonicotinic acid (5 mmol) and sodium carbonate (5.1 mmol) in water is added triphosgene (1.6 mmol) at room temperature. The reaction mixture is allowed to stir for 16 h after which time the pH is adjusted to 3 and the resulting precipitate, 3-azaisatoic anhydride, is filtered.
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃;
Example 89; /V-MethvI-2-(2-(2-oxoindolin-5-ylamino)-5-(trifluoromethyl)pyridin-4-ylamino)nicotinamide; 2-Amino-./V-methylnicotinamide; To the mixture of 2-aminonicotinic acid (2.0 g, 14.5 mmol), methylamine hydrogen chloride (1.47 g, 1.5 eq), EDC (4.49 g, 1.5 eq), HOBt (2.35 g, 1.2 eq) in DMF (2OmL) was added DIEA (7.6 mL, 3.0 eq). The mixture was stirred at room temperature overnight. The crude was concentrated and dissolved in EtOAc. It was washed with saturated NaHCO3. The solvent was removed and the crude was purified by silica gel chromatography (0%~20% MeOH/DCM) to obtain the desired product 2-amino-iV- methylnicotinamide (2.16 g, isolated yield -98%).
In acetonitrile; at 150℃; for 2h;microwave irradiation;Product distribution / selectivity;
Step A: Preparation of Imidazo[l,2-alpha]pyridine-8-carboxylic Acid.2-Aminonicotinic acid (2.0 g, 14.48 mmol) and 2-bromo-l,l-diethoxyethane (2.247 mL, 14.48 mmol) in acetonitrile (10 mL) were heated at 150 0C for 2 h under microwave irradiation. The resulting precipitate was filtered off and washed with acetonitrile and hexane to afford the title compound (2.783 g) as a solid. Exact mass calculated for C8H6N2O2: 162.0. Found: LCMS mlz = 163.1 (M + H)+. 1H NMR (400 MHz, Methanol-^) delta 7.62 (dd, J = 6.82, 7.33 Hz, IH), 8.06 (d, J = 2.27 Hz, IH), 8.36 (d, J = 2.02 Hz, IH), 8.62 (d, J = 7.33 Hz, IH), 9.04 (d, J = 6.82 Hz, IH). Step B: Preparation of 3-Bromoimidazo[l,2-alpha]pyridine-8-carboxylic Acid.Imidazo[l,2-alpha]pyridine-8-carboxylic acid (100 mg, 617 mumol), l-bromopyrrolidine-2,5- dione (110 mg, 617 mumol) and N,N-dimethylformamide (1.5 mL) were stirred at room temperature for 1 h. The resulting precipitate was filtered off and washed with acetonitrile and hexane to afford the title compound as a solid (68 mg).
Example 1.6: Preparation of (4-(4-Fluorophenethyl)piperazin-l-yl)(2- (trifluoromethyl)imidazo[l,2-alpha]pyridin-8-yI)methanone (Compound 6).Step A: Preparation of Methyl 2-AminonicotinateTo a slurry of 2-aminonicotinic acid (2.07 g, 15 mmol) in methanol (45 mL) was added 2.0 M TMS-diazomethane in hexane (15 mL, 30 mmol) and the mixture was stirred for 30 min. <n="57"/>The resulting yellow solution was quenched with acetic acid (10 mL) and concentrated under reduced pressure and azeotroped with hexane. The residue was taken up in MeOH and treated with MP-carbonate resin (1O g, -30 mmol) for 30 min. The mixture was filtered to remove the resin and the filtrate was concentrated under vacuum. The residue was purified via column chromatography (1 :9-l :2 EtOAc/hexane) to afford the title compound as a white solid (1.63 g).
Example 1.12: Preparation of (4-(2,4-Difluorophenethyl)piperazin-l-yl)(imidazo[l,2- alpha]pyridin-8-yl)methanone Hydrochloride Salt (Compound 3).Step A: Preparation of Imidazo[l,2-alpha]pyridine-8-carboxylic Acid Hydrochloride.To a mixture of 2-aminonicotinic acid, (152.19 g, 1.102 mol) was added chloroacetaldehyde (45 wt % in water, 230 mL and 1.31 mol). The resulting slurry was heated <n="62"/>to 60 0C in an oil bath with efficient stirring. The slurry gradually became homogenous and a strong exothermic reaction increasing the temperature by 20-22 0C was noticed. The heating was discontinued and the reaction mixture was allowed to cool to room temperature. Solids started separating out, the resulting slurry was diluted with isopropanol (870 mL) and the mixture was stirred at room temperature for 1 h followed by cooling to 0-10 0C for an additional 1 h. The solids were filtered off and washed with isopropanol (435 mL) and heptanes (2 x 140 mL) and dried at 40 C in vacuum oven to afford the title compound (200.3 g, 92%) as a pale tan solid.
In acetonitrile; at 150℃; for 2h;microwave irradiation;Product distribution / selectivity;
Example 1.3: Preparation of (4-(2,4-Difluorophenethyl)piperazin-l-yl)(imidazo[l,2- alpha]pyridin-8-yl)methanone (Compound 3).Step A: Preparation of Imidazo[l,2-alpha]pyridine-8-carboxylic Acid.To a mixture of 2-aminonicotinic acid (0.6906 g, 5.00 mmol) in acetonitrile (20 mL) was added bromoacetaldehyde dimethyl acetal (0.591 mL, 5.00 mmol). The resulting slurry was heated at 150 0C under microwave irradiation for 2 h. The resulting precipitate was filtered off and washed with acetonitrile and hexane to afford the title compound (0.924 g) as a grey solid.
0.924 g
In acetonitrile; at 150℃; for 2h;Microwave irradiation;
To a mixture of 2-aminonicotinic acid (0.69 g, 5.00 mmol) in CH3CN (20 mL) was added bromoacetaldehyde dimethyl acetal (0.59 mL, 5.00 mmol). The resulting slurry was heated to 150 C under microwave irradiation for 2 h. The resulting precipitate was filtered off and washed with CH3CN and hexane to afford H-imidazo[1,2-alpha]pyridine-8-carboxylic acid (0.924 g) as a grey solid.
The 5-bromo-3-(7-methoxy-1,3-benzoxazol-2-yl)pyridine-2-amine used as starting material was prepared as follows: A mixture of 2-aminonicotinic acid (9.4 g), 2-amino-6-fluoro-phenol (8.65 g) and polyphosphoric acid (90 g) was stirred at 200 C. for 16 hours. The reaction mixture was allowed to cool to room temperature, quenched with water and basified with sodium hydroxide solution 6N until pH 12 to give a solid which was collected by filtration and dried under vacuum; The resultant product was diluted in dichloromethane/methanol and filtered through a plug of silica gel and washed with ethyl acetate. The filtrate was concentrated to dryness to give 3-(7-fluoro-1,3-benzoxazol-2-yl)pyridin-2-amine (7.5 g) as a solid. NMR Spectrum: (DMSOd6) 6.76 (dd, 1H), 7.33-7.46 (m, 2H), 7.66 (bs, 2H), 7.68 (dd, 1H), 8.26 (dd, 1H), 8.30 (dd, 1H); Mass spectrum: M+H+ 230.
With sodium hydroxide; (1S,2R)-(+)-norphedrine; In methanol; dichloromethane; water; ethyl acetate;
The 5-bromo-3-(4-methoxy-1,3-benzoxazol-2-yl)pyridin-2-amine used as starting material was prepared as follows: PPA (10 ml) at 50° C. was added to a stirred mixture of 2-aminonicotinic acid (2 g) and <strong>[53981-23-0]2-amino-3-fluoro-phenol</strong> (1.841 g). The resulting suspension was stirred at 200° C. for 16 hours. The mixture was cooled and quenched with ice and water (100 ml) and the pH was adjusted to 12 with an aqueous solution of sodium hydroxide (6N then 2N). The resultant solid was filtered and washed with water. The solid was dried under reduce pressure with phosphorus pentoxide. The solid was adsorbed on silica gel with methylene chloride (100 ml) and methanol (10 ml) and purified by flash chromatography on silica gel eluding with 20 to 30percent ethyl acetate in dichloromethane. The solvent was evaporated to dryness to afford 3-(4-fluoro-1,3-benzoxazol-2-yl)pyridin-2-amine (2.060 g) as a solid. NMR Spectrum: (CDCl3): 6.78 (dd, 1H), 6.97 (bs, 2H), 7.09 (dd, 1H), 7.31 (ddd, 1H), 7.38 (d, 1H), 8.30 (d, 1H), 8.33 (bs, 1H); Mass spectrum: M+H+ 230
To a solution of <strong>[5345-47-1]2-aminopyridine-3-carboxylic acid</strong> (6, 2.00 g,14.0 mmol) in DMF (56 mL) was added potassium carbonate (2.50 g, 28.0 mmol). After stirring the suspension for 30 min at room temperature, a solution of iodoethane (2.20 g, 14.0 mmol,1.10 mL) in DMF (14 mL) was added dropwise. After stirring for 1 h the mixture was poured on ice water (300 mL). The precipitated crystals were collected by filtration. The filtrate was extracted with ethyl acetate (4 x 75 mL). The combined ethyl acetate layers were dried (Na2SO4) and evaporated. To the remaining residue diethyl ether (100 mL) was added and the resulting solution was washed with aqueous 30% lithium chloride solution (4 x 25 mL). After drying with Na2SO4, the organic solvent was evaporated. The residue was combined with the precipitate that was collected earlier and the material was crystallized from ethanol to yield 1.90 g (80.8%) colorless crystals. mp: 93-94 C (Lit.: 94-96 C [42]); IR(KBr): 3428 (NH2), 1695 (C=O), 1625 (NH2), 1245, 770 cm-1; 1H NMR (600 MHz, CDCl3): delta = 8.22 (dd, 1H, 3JH,H=4.8 Hz,4JH,H=1.9 Hz), 8.15 (dd, 1H, 3JH,H=7.8 Hz, 4JH,H=1.9 Hz), 6.63 (dd,1H, 3JH,H=7.8 Hz, 3JH,H=4.8 Hz), 4.35 (q, 2H, 3JH,H=7.1 Hz), 1.39 (t,3H, 3JH,H=7.1 Hz); 13C NMR (150.9 MHz, CDCl3): delta=167.0, 159.4,106.5 (quat C); 153.5, 140.1, 112.7 (tert C); 60.9 (sec C); 14.3 (prim.C); C8H10N2O2 (166.18); calcd. C 57.82, H 6.07, N 16.86; found C57.68, H 6.22, N 17.20.
With potassium carbonate; In acetone;Reflux;
Ethyl 2-aminonicotinate ester <strong>[5345-47-1]2-Aminonicotinic acid</strong> (24.8 g) was dissolved in acetone (540 mL), and iodoethane (43.1 mL) and potassium carbonate (124 g) were added thereto, followed by stirring for 16 hours under the condition of heating to reflux, and iodoethane (29.0 mL) was added thereto, by further stirring for 15 hours. After removing the insoluble materials by filtration, the solvent of the filtrate was evaporated under reduced pressure, and the obtained residue was recrystallized from ethyl acetate to obtain the desired product (17.3 g). The mother liquid was purified by silica gel column chromatography (hexane:ethyl acetate=2:1?1:1) to obtain the desired product (1.60 g), and a combined product thereof (18.9 g) as yellow powders. 1H NMR (CDCl3, 400 MHz): delta 1.38 (3H, t, J=7.3 Hz), 4.34 (2H, q, J=7.3 Hz), 6.62 (1H, dd, J=7.9, 4.9 Hz), 8.13 (1H, dd, J=7.9, 1.8 Hz), 8.21 (1H, dd, J=4.9, 1.8 Hz).
With potassium carbonate; In acetone;Reflux;
Ethyl 2-aminonicotinate Commercially available 2-aminonicotinic acid (24.8 g) was dissolved in acetone (540 mL), and iodoethane (43.1 mL) and potassium carbonate (124 g) were added thereto, followed by stirring for 16 hours under the condition of heating under reflux, and iodoethane (29.0 mL) was added thereto, followed by further stirring for 15 hours. After removing the insoluble materials by filtration, the solvent of the filtrate was evaporated under reduced pressure, and the obtained residue was recrystallized with the addition of ethyl acetate to obtain the desired product (17.3 g). The mother liquid was purified by silica gel column chromatography (hexane:ethyl acetate=2:1 ? 1:1) to obtain the desired product (1.60 g, total amount: 18.9 g) as a yellow powder. 1H-NMR (CDCl3, 400 MHz): delta 1.38 (3H, t, J=7.3 Hz), 4.34 (2H, q, J=7.3 Hz), 6.62 (1H, dd, J=7.9, 4.9 Hz), 8.13 (1H, dd, J=7.9, 1.8 Hz), 8.21 (1H, dd, J=4.9, 1.8 Hz).
General procedure: A suspension of alkynoic acids 1 (0.6 mmol), amine nucleophiles 2 or 3 (0.5 mmol), andAuPPh3Cl/AgSbF6 (with the amount indicated) in H2O (4.0 mL) was stirred at the temperatureindicated for 20 h. Then the reaction mixture was cooled to room temperature, and CF3COOH(0.5 mmol) was added, and the resulting mixture was stirred for another 4 h at the temperatureindicated. At ambient temperature, saturated Na2CO3 solution (25.0 mL) was added to the reactionmixture. The resulting mixture was then extracted with ethyl acetate (3 15 mL). The combinedorganic layers were washed with brine, and dried over Na2SO4. After filtration and removal of thesolvents in vacuo, the crude product was purified by flash chromatography on silica gel to yield thedesired product.
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In N,N-dimethyl-formamide at 140℃; for 4h;
35
A mixture of 0.50 g of the thus obtained crude 4-(4-methoxyphenoxy)benzylamine, 0.25 g of 2,-aminonicotinic acid, 0.25 g of 1-hydroxybenzotriazole, 0.50 g of WSC and 4 ml of DMF was stirred at 140°C for 4 hours. Thereafter, a sodium bicarbonate aqueous solution was added to the reaction mixture, and it was then extracted with ethyl acetate. The organic layer was washed with a saturated saline solution, and it was then dried over magnesium sulfate, followed by concentration under reduced pressure. The obtained residue was subjected to silica gel column chromatography, so as to obtain 0.29 g of N-[4-(4-methoxyphenoxy)phenyl]methyl-2-aminonicotinic acid amide (hereinafter referred to as the present compound 49).The present compound 49 [Show Image] 1H-NMR (CDCl3) δ: 3.81 (3H, s), 4.55 (2H, d, J = 5.6 Hz), 6.26 (1H, br s), 6.35 (2H, br s), 6.58 (1H, dd, J = 7.7, 4.7 Hz), 6,87-7.00 (6H, m), 7.25-7.29 (2H, m), 7.58 (1H, dd, J = 7.7, 1.5 Hz), 8.16 (1H, dd, J = 4.7, 1.5 Hz
With (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate; triethylamine; In N,N-dimethyl-formamide; at 20℃; for 4h;
Production example 3 0.88 g of a BOP reagent and 0.40 g of triethylamine were successively added to a mixture of 0.28 g of 2-aminonicotinic acid, 0.40 g of <strong>[107622-80-0]4-phenoxybenzylamine</strong> and 10 ml of DMF. The obtained mixture was stirred at a room temperature for 4 hours. Thereafter, ice and a saline solution were successively added to the reaction mixture, and it was then extracted with ethyl acetate. The organic layer was further washed with a saline solution 3 times, and it was then dried over anhydrous magnesium sulfate, followed by concentration under reduced pressure. 0.80 g of the obtained residue was subjected to silica gel column chromatography, so as to obtain 0.62 g of N-(4-phenoxyphenyl)methyl-2-aminonicotinic acid amide (hereinafter referred to as the present compound 3).The present compound 3 [Show Image] 1H-NMR (DMSO-D6) delta: 4.42 (2H, d, J = 5.9 Hz), 6.59 (1H, dd, J = 7.8, 4.9 Hz), 6.97-6.99 (4H, m), 7.08 (2H, br), 7.10-7.13 (1H, m), 7.32-7.40 (4H, m), 7.95 (1H, dd, J = 7.8, 1.7 Hz), 8.08 (1H, dd, J = 4.9, 1.7 Hz), 8.98 (1H, t, J = 5.9 Hz).
With (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate; triethylamine In N,N-dimethyl-formamide at 20℃; for 4h;
4
Production example 4 0.88 g of a BOP reagent and 4.44 g of triethylamine were successively added to a mixture of 0.28 g of 2-aminonicotinic acid, 0.37 g of 4-phenylbenzylamine and 10 ml of DMF. The obtained mixture was stirred at a room temperature for 4 hours. Thereafter, ice and a saline solution were successively added to the reaction mixture, and it was then extracted with ethyl acetate. The organic layer was further washed with a saline solution 3 times, and it was then dried over anhydrous magnesium sulfate, followed by concentration under reduced pressure. 0.71 g of the obtained residue was subjected to silica gel column chromatography, so as to obtain 0.53 g of N-(4-phenylphenyl)methyl-2-aminonicotinic acid amide (hereinafter referred to as the present compound 4).The present compound 4 [Show Image] 1H-NMR (DMSO-Db) δ: 4.48 (2H, d, J = 5.8 Hz), 6.60 (1H, dd, J = 7.8, 4.9 Hz), 7.09 (2H, br), 7.33-7.48 (5H, m), 7.62-7.65 (4H, m), 7.98 (1H, dd, J = 7.8, 1.5 Hz), 8.09 (1H, m), 9.01-9.04 (1H, m).
With pyridine; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride at 20℃; for 7h; Reflux;
78
5.0 g of WSC and 3.5 g of 1-hydroxybenzotriazole were added to a mixture of 3.0 g of 2-aminonicotinic acid, 6.5 g of 4-benzyloxybenzylamine hydrochloride and 50 ml of pyridine. The obtained mixture was stirred at a room temperature for 3 hours, and it was then heated to reflux for 4 hours. Thereafter, the reaction mixture was concentrated under reduced pressure, and water was then added thereto. The obtained crystal was washed with hexane and was then dried, so as to obtain N-(4-benzyloxyphenyl)methyl-2-aminonicotinic acid amide.
With (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate; triethylamine; In N,N-dimethyl-formamide; at 20℃; for 4h;
Production example 5 0.88 g of a BOP reagent and 0.40 g of triethylamine were successively added to a mixture of 0.28 g of 2-aminonicotinic acid, 0.37 g of <strong>[177976-49-7]3-phenylbenzylamine</strong> and 10 ml of DMF. The obtained mixture was stirred at a room temperature for 4 hours. Thereafter, ice and a saline solution were successively added to the reaction mixture, and it was then extracted with ethyl acetate. The organic layer was further washed with a saline solution 3 times, and it was then dried over anhydrous magnesium sulfate, followed by concentration under reduced pressure. 0.77 g of the obtained residue was subjected to silica gel column chromatography, so as to obtain 0.58 g of N-(3-phenylphenyl)methyl-2-aminonicotinic acid amide (hereinafter referred to as the present compound 5).The present compound 5 [Show Image] [Show Image] 1H-NMR (DMSO-D6) delta: 4.52 (2H, d, J = 5.8 Hz), 6.60 (1H, dd, J = 7.8, 4.9 Hz), 7.07 (2H, br), 7.31-7.49 (5H, m), 7.53-7.55 (1H, m), 7.61-7.65 (3H, m), 7.97 (1H, dd, J = 7.8, 2.0 Hz), 8.07-8.09 (1H, m), 9.01-9.04 (1H, m).
With (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate; triethylamine In N,N-dimethyl-formamide at 20 - 110℃; for 13h;
56; 94
Reference production example 56 8.0 g of triethylamine was added to a mixture of 7.0 g of2-fluoro-3-hydroxybenzylamine hydrobromide and 70 ml of DMF. Subsequently, 7.7 g of 2-aminonicotinic acid was added thereto, and 18.1 g of a BOP reagent was further added thereto. The obtained mixture was stirred at a room temperature for 10 hours. Thereafter, 30 ml of pyridine was added to the reaction mixture, and the obtained mixture was stirred at 110°C for 3 hours. Thereafter, the reaction mixture was cooled to a room temperature, and water was then added thereto, followed by extraction with ethyl acetate. The organic layer was successively washed with a saturated sodium bicarbonate solution, water and a saturated saline solution, and it was then dried over anhydrous sodium sulfate, followed by concentration under reduced pressure. The obtained residue was washed with hexane and MTBE, so as to obtain 5.4 g ofN-(2-fluoro-3-hydroxyphenylmethyl)-2-aminonicotinic acid amide.N-(2-fluoro-3-hydroxyphenylmethyl)-2-aminonicotinic acid amide [Show Image] 1H-NMR (DMSO-D6) δ: 4.44 (2H, d, J = 5.6 Hz), 6.59 (1H, dd, = 7.7, 4.8 Hz), 6.71-6.75 (1H, m), 6.84 (1H, td, J = 8.2,1.7 Hz), 6.90-6.94 (1H, m), 7.06 (2H, br s), 7.95 (1H, dd, J = 7.7, 1.9 Hz), 8.08 (1H, dd, J = 4.7, 1.8 Hz), 8.91 (1H, t, J = 5.8 Hz), 9.77 (1H, s).
Stage #1: 2-aminopyridin-3-carboxylic acid With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In N,N-dimethyl-formamide at 20℃; for 0.166667h; Inert atmosphere;
Stage #2: 5-chloro-2-phenoxyaniline With triethylamine In N,N-dimethyl-formamide at 20℃; for 16h;
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In N,N-dimethyl-formamide; at 20℃; for 12h;
To a solution of 2-amino nicotinic acid (2.74 g, 20 mmol) in anhydrous DMF (100 mL) was added EDC (4.2 g, 22 mmol), HOBt (2.97 g, 22 mmol), and triethylamine (8.2 mL, 60 mmol). L-proline methyl ester (22 mmol) was then added, and the reaction mixture was stirred overnight. Water (100 mL) was added, and the mixture was extracted with methylene chloride, dried over MgSO4, and concentrated. Compound 2 was purified by silica gel chromatography (silica gel, 90:10 ethyl acetate/cyclohexane) to yield the title compound as a yellow oil (3.71 g, 75%).
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In N,N-dimethyl-formamide; at 20℃;
General procedure: Method B: To a solution of 3-aminopyridine-2-carboxylic acid (2.74 g, 20 mmol) in anhydrous DMF (100 mL) was added EDC (4.2 g, 22 mmol), HOBt (2.97 g, 22 mmol) and triethylamine (8.2 mL, 60 mmol). alpha-Amino acid methyl ester (22 mmol) was added, and the reaction mixture was stirred overnight. Water (100 mL) was added, and the mixture was extracted with methylene chloride (4 × 100 mL), dried over MgSO4 and concentrated. The compound was purified by silica gel chromatography to give the oil-like open product 6; this was then dissolved in THF (125 mL) under argon. Sodium hydride (0.93 g, 60% dispersion in oil, 26.8 mmol) was added, and the reaction mixture was stirred overnight. Water (5 mL) was carefully added, and the resulting white precipitate was collected. The precipitate was dissolved in ethyl acetate (200 mL), washed with water (50 mL) and brine (50 mL), dried over MgSO4 and concentrated to give product 8.
Multi-step reaction with 3 steps
1.1: 3 h / 190 °C
1.2: 1 h / 100 °C
2.1: N,N-diethylaniline; trichlorophosphate / 3 h / Reflux
3.1: tri-n-butyl-tin hydride / tetrakis(triphenylphosphine) palladium(0) / toluene / 3 h / 100 °C / Inert atmosphere
Multi-step reaction with 3 steps
1.1: 3 h / 190 °C
1.2: 1 h / Reflux
2.1: N,N-diethylaniline; trichlorophosphate / 3 h / Reflux
3.1: tri-n-butyl-tin hydride / tetrakis(triphenylphosphine) palladium(0) / toluene / 3 h / Inert atmosphere; Heating
Multi-step reaction with 3 steps
1.1: 0.33 h / 280 °C
2.1: trichlorophosphate / 150 °C
3.1: tri-n-butyl-tin hydride; tetrakis(triphenylphosphine) palladium(0) / toluene / 1 h / 100 °C / Inert atmosphere
3.2: 0.5 h
With benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate; triethylamine In N,N-dimethyl-formamide at 160℃; for 0.166667h; Microwave irradiation; Inert atmosphere;
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃; for 6.0h;
General procedure: A solution of <strong>[883535-89-5]2-(2-methyl-1H-indol-1-yl)ethanamine</strong> (4a) (65 mg, 0.373 mmol) and 4-(piperidin-1-yl)benzoic acid (5) (76 mg, 1 eq.), and dimethylaminopyridine (catalytic, ?5 mg) in dichloromethane (6 mL) was added 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide.hydrochloride (EDCI) (92 mg, 1.3 eq.) at room temperature. The resulting reaction mixture was stirred for 6h. At the conclusion of the reaction (TLC), water (15 mL) was added to quench the reaction. The product was extracted with ethyl acetate (20mL×3). Organics were washed with dilute HCl (10 mL), saturated NaHCO3 solution (10 mL), water (10 mL) and brine solution (10 mL) and dried over Na2SO4 and concentrated. The resulting crude product was subjected to silica gel chromatography eluting with 0-40% ethyl acetate in hexane to furnish 7k (TG7-152) (100mg, 74% yield). 1H NMR (CDCl3): delta 7.52 (d, J=5.6Hz, 1H), 7.49 (d, J=8.8Hz, 2H), 7.30 (d, J=8Hz, 1H), 7.07 (m, 2H), 6.80 (d, J=8.2Hz, 2H), 6.23 (s, 1H), 5.98 (t, J=5.4Hz, 1H), 4.33 (t, J=6Hz, 2H), 3.76 (q, J=6Hz, 2H), 3.25 (t, J=4.8Hz, 4H), 2.37 (s, 3H), 1.6 (m, 6H). LCMS (ESI): >97% purity at lambda 254, MS; m/z, 362 [M+H]+. Anal. Calcd. for C23H27N3O: C, 76.42; H, 7.53; N, 11.62; found; C, 76.48; H, 7.55; N, 11.59.
tert-butyl 4-(2-aminonicotinoyl)piperazine-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
93.4%
With (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate; triethylamine; In N,N-dimethyl-formamide; at 60℃; for 2h;Inert atmosphere;
To a solution of tert-butyl 1-piperazinecarboxylate (5.18 g,27.8 mmol) in DMF (40 mL) were added triethylamine (7.4 mL,53.4 mmol), 2-aminonicotinic acid (3.7 g, 26.8 mmol) and benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (14.2 g, 32.1 mmol) at room temperature under nitrogen. The stirred mixture was heated at 60C for 2 h. The reaction mixture was cooled to room temperature and diluted with water and EtOAc. The aqueous layer was extracted with EtOAc. The combined organic extracts were washed with water and brine, dried over Na2SO4, filtrated and then concentrated. The crude solid was purified with column chromatography on NH silica gel (n-heptane/EtOAc 1:1-1:2) to afford the title compound as a light orange solid (7.67 g, 25.0 mmol, 93.4%). 1H NMR (600 MHz, CDCl3): delta = 1.47 (s, 9H), 3.44-3.51 (m, 4H), 3.58 (br s, 4H), 5.18 (s, 2H), 6.67 (dd, J = 7.5, 4.9 Hz, 1H), 7.35 (dd, J = 7.5, 1.6 Hz, 1H), 8.13 (dd, J = 4.9, 1.6 Hz, 1H); 13C NMR (150 MHz, CDCl3): delta = 28.4, 44.2, 80.4, 113.0, 113.1, 136.3, 150.1, 154.5, 157.1, 169.0; HRMS-ESI m/z [M+H]+ calcd for C15H23N4O3 + :307.1765, found: 307.1745.
With diphenyl phosphoryl azide; triethylamine; In 1,4-dioxane; for 21.75h;Reflux;
2-Aminopyridine-3-carboxylic acid (CAS 5345-47-1 ) (10.00 g, 72.40 mmol) was dispersed into 1 ,4-dioxane (300 ml_) to obtain a light-brown suspension. Triethylamine (1 1.1 ml_, 79.64 mmol) was then added slowly followed by diphenylphosphoryl azide (16.09 ml_, 72.40 mmol) which was added dropwise over 15 minutes. The resulting light-brown suspension was slowly heated to reflux and stirred at reflux for 21 hours 30 minutes and allowed to cool to room temperature. The reaction medium was concentrated under reduced pressure at 40C to afford a brown oil. A minimum amount of MeOH was added and the precipitate formed was filtered through a sintered disc filter funnel. The solid press cake was washed with Et20 and dried to afford 1 ,3-dihydroimidazo[4,5-b]pyridin-2-one. The filtrate was evaporated and purified by chromatography. Solids from the filtration and chromatography were mixed to afford 1 ,3-dihydroimidazo[4,5-b]pyridin-2-one. NMR (400 MHz, d6- DMSO): d ppm 1 1.28 (br s, 1 H), 10.81 (br s, 1 H), 7.85 (dd, J=5.32, 1.28 Hz, 1 H), 7.21 (dd, J=7.70, 1.10 Hz, 1 H), 6.93 (dd, J=7.52, 5.32 Hz, 1 H). LC-MS (Method A) : Rt = 0.19 min, MS ES+ = 136 (M+H).
Multi-step reaction with 3 steps
1: acetic acid / water / 25 °C / Green chemistry
2: sodium hydroxide / water / 4 h / Green chemistry
3: hydrogenchloride / water / pH < 1 / Green chemistry
With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In chloroform; at 20℃; for 16h;
<strong>[5345-47-1]2-amino-nicotinic acid</strong> (0.100g,0.724mmol) was dissolved in chloroform (1.81mL), and then diisopropylethylamine(0.190mL, 1.09mmol), HBTU (0.357g, 0.941mmol) and phenethylamine ( 0.109mL,0.869mmol) were added at room temperature. After stirring for 16 hours at thesame temperature, aqueous sodium hydrogen carbonate solution was added to thereaction mixture, followed by extraction with chloroform. The organic layer waswashed with saturated brine, dried over anhydrous sodium sulfate, filtered, andthe filtrate was concentrated under reduced pressure. The residue was purifiedby silica gel column chromatography (hexane / ethyl acetate = 60 / 40-20 / 80)to give the title compound (0.145 g, 0.600 mmol, 83%) as a white solid.
(S)-2-amino-N-(1-(4-fluorophenyl)ethyl)nicotinamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
74%
With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; triethylamine; In dichloromethane; at 20℃; for 18h;
In 100 ml of methylene chloride solution containing 3 g of 2-amino acid (21.7 mmol) was added 16.5 g of benzotriazole -N, N, N ', N'- tetramethyluronium hexafluorophosphate salt (43.4 mmol, 2.0 equiv.), 3.02 g (S) -1- (4- fluorophenyl) ethylamine (21.7 mmol, 1.0 equiv.), and 10.97 g of triethylamine (0.11 mole, 5.0 eq.). After the reaction mixture was stirred at room temperature for 18 hours and filtered off the solvent, the residual material was purified through column chromatography (petroleum ether / ethyl acetate = 2: 1) to obtain 4.2 g of the desired product, yield 74% .
2-[3-bromo-1-(3-chloro-2-pyridyl)-1H-pyrazol-5-yl]-4H-pyrido[2,3-d][1,3]oxazin-4-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
91%
In a 100 mL three-necked flask, A solution of 3.02 g of 3-bromo-1-(3-chloro-2-pyridyl)-1H-pyrazole-5-carboxylic acid, 2.02 g of triethylamine and 15 mL of acetonitrile, -5C under the conditions of adding POCl3 4.59g, drop finished Keep heating for half an hour, Further, 1.86 g of <strong>[5345-47-1]2-amino-3-picolinic acid</strong> was added and reacted at room temperature for 2 hours. Add 20mL water for 0.5 hours, filter, filter cake with 3: 2 acetonitrile - water washing, drying product 3.67g, the yield of 91%.
With chlorine; acetic acid; In water; at 20℃; for 8h;
2-Amino-5-chloronicotinicacid (2) (C6H5ClN2O2): Acetic acid (200 mL) and water (5 mL)were poured into the solution of 2-aminonicotinic acid 1 (5 g, 36.20mmol). Chlorine generated by the action of 24 mL of hydrochloricacid and 30 g of KMnO4 was bubbled into the acid suspension. Themixture was reacted for 8 h at room temperature, and then filteredand the solvent evaporated under reduced pressure. The obtainedcrude material was washed with Et2O and methanol to give compound2 as a white solid in 81% yield. 2-Amino-5-bromonicotinicacid (3) (C6H5BrN2O2): Acetic acid (250 mL) and water (10 mL)were poured into the solution of 2-aminonicotinic acid 1 (10 g, 72.4mmol). The suspension was placed at C and Br2 (4 mL, 79 mmol,1.1 equiv) was added dropwise. After 8 h of stirring at room temperature,the mixture was filtered and then concentrated under reduced pressure. The crude material obtained was washed with Et2O to afford compound 3 as a white solid in 89% yield.
With ammonium hydroxide; L-2-O-methyl-chiro-inositol; copper(II) acetate monohydrate In 1-methyl-pyrrolidin-2-one at 110℃; for 12h;
Synthesis of 5a-z, 5aa; General Procedure C
General procedure: To a sealed reaction vessel were added ammonia (aq, 25%) (1.8 mL, 12.8 mmol),Cu(OAc)2·H2O (0.13 mmol), QCT (0.26 mmol) in NMP (1.8 mL) and aryl halides(1.28 mmol). The resulting mixture was heated in an oil bath with appropriatetemperature under rapid stirring for the indicated time. After complete consumption ofthe aryl halide as monitored by TLC, the reaction vessel was cooled to r.t. It was openedto air, and the reaction mixture was extracted with ethyl acetate (3×10 mL), and theorganic layer was washed with water (2×10 mL) and once with brine (10 mL), driedwith magnesium sulfate and concentrated in vacuo. The product was purified bycolumn chromatography on silica gel.
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