* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Reference：
[1] Journal of Fluorine Chemistry, 2011, vol. 132, # 8, p. 541 - 547
[2] Archiv der Pharmazie, 1995, vol. 328, # 3, p. 247 - 255
[3] Archiv der Pharmazie, 1995, vol. 328, # 3, p. 247 - 255
[4] Yakugaku Zasshi, 1952, vol. 72, p. 434[5] Chem.Abstr., 1953, p. 6404
[6] Journal of the American Chemical Society, 1955, vol. 77, p. 3154
[7] Journal of the American Chemical Society, 1947, vol. 69, p. 63,66
[8] Journal of Molecular Structure, 2013, vol. 1043, p. 15 - 27
2
[ 1824-81-3 ]
[ 22280-62-2 ]
[ 25864-34-0 ]
[ 21901-29-1 ]
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2007, vol. 17, # 11, p. 2987 - 2991
3
[ 33986-37-7 ]
[ 7664-93-9 ]
[ 22280-62-2 ]
[ 21901-29-1 ]
Reference：
[1] Zhurnal Russkago Fiziko-Khimicheskago Obshchestva, 1920, vol. 50, p. 536[2] Chem. Zentralbl., 1923, vol. 94, # III, p. 1022
4
[ 22280-62-2 ]
[ 3430-10-2 ]
Reference：
[1] Russian Journal of Organic Chemistry, 2009, vol. 45, # 1, p. 115 - 118
[2] Journal of Fluorine Chemistry, 2011, vol. 132, # 8, p. 541 - 547
5
[ 22280-62-2 ]
[ 164666-68-6 ]
Reference：
[1] Journal of the American Chemical Society, 1947, vol. 69, p. 63,66
6
[ 22280-62-2 ]
[ 22280-60-0 ]
Reference：
[1] Journal of the American Chemical Society, 1952, vol. 74, p. 3828,3830
[2] Journal of Fluorine Chemistry, 2011, vol. 132, # 8, p. 541 - 547
[3] Patent: CN105906621, 2016, A,
[4] Patent: US6358972, 2002, B1,
[5] Patent: WO2005/42464, 2005, A1,
[6] Patent: WO2009/155156, 2009, A1,
7
[ 22280-62-2 ]
[ 22280-60-0 ]
[ 28489-45-4 ]
Reference：
[1] Journal of the American Chemical Society, 1947, vol. 69, p. 63,66
8
[ 22280-62-2 ]
[ 28489-45-4 ]
Yield
Reaction Conditions
Operation in experiment
78%
at 0 - 10℃; for 1 h;
(b) 6-Amino-3-nitro-2-picoline (20 g, 0.131 mol) was suspended in a mixture of conc. H2S04 (23.7 ml) and water (335 ml). More cone. H2S04 (20 ml) was added under ice- cooling, but the amine did not dissolve completely. The suspension was added in ice (100 g) before a solution of NaNO2 (13.53 g, 0.196 mol) in water (40 ml) was added drop wise. Gas evolution was observed. The brown suspension was stirred at 10°C for 1 hr, filtered and washed with water. The brown product was dried (freeze dryer) to achieve 15.78 g (78 percent) of 6-hydroxy-3-nitro-2-picoline.
56.3%
With sulfuric acid; sodium nitrite In water at -5 - 20℃; for 2 h;
The raw material 2 (5g) was added to 15mL water, the external temperature -5 dropping concentrated sulfuric acid 25mL, keep the internal temperature 0 ~ -5 under the conditions of slowly dropping NaNO2(2.48 g / 8 mL), and the mixture was stirred at 20 ° C for 2 hours. The reaction solution was poured into ice water and precipitated as a solid. The product 3 (4.7 g) was obtained by filtration under reduced pressure in a yield of 56.3percent.
80%
With sulfuric acid; sodium nitrite In water
6-hydroxy-3-nitro-2-picoline A suspension of 3.0 gm (19.6 mMol) 6-amino-3-nitro-2-picoline in 50 mL water containing 3.5 mL concentrated sulfuric acid was heated to effect solution. The resultant solution was cooled to 0° C. and a solution of 2.0 gm (29.4 mMol) sodium nitrite in 10 mL water was added with vigorous stirring at a rate to maintain the reaction mixture <=10° C. After 4 hours the reaction mixture was filtered. The solid was washed with water and dried under reduced pressure to provide 2.4 gm (80percent) of the desired compound as a pale yellow solid. MS(m/e): 153 (M+)
80%
With sulfuric acid; sodium nitrite In water
6-hydroxy-3-nitro-2-picoline A suspension of 3.0 gm (19.6 mMol) 6-amino-3-nitro-2-picoline in 50 mL water containing 3.5 mL concentrated sulfuric acid was heated to effect solution. The resultant solution was cooled to 0°C and a solution of 2.0 gm (29.4 mMol) sodium nitrite in 10 mL water was added with vigorous stirring at a rate to maintain the reaction mixture <=10°C. After 4 hours the reaction mixture was filtered. The solid was washed with water and dried under reduced pressure to provide 2.4 gm (80percent) of the desired compound as a pale yellow solid. MS(m/e): 153 (M+)
Reference：
[1] Patent: WO2005/42464, 2005, A1, . Location in patent: Page/Page column 33
[2] Journal of Fluorine Chemistry, 2011, vol. 132, # 8, p. 541 - 547
[3] Patent: CN105906621, 2016, A, . Location in patent: Paragraph 0020
[4] Journal of the American Chemical Society, 1952, vol. 74, p. 3828,3830
[5] Yakugaku Zasshi, 1952, vol. 72, p. 434[6] Chem.Abstr., 1953, p. 6404
[7] Journal of the American Chemical Society, 1947, vol. 69, p. 63,66
[8] Patent: US5874427, 1999, A,
[9] Patent: EP875513, 1998, A1,
[10] Patent: EP1857444, 2007, A1, . Location in patent: Page/Page column 21
[11] Patent: WO2009/155156, 2009, A1, . Location in patent: Page/Page column 74
9
[ 22280-62-2 ]
[ 39745-39-6 ]
[ 21901-29-1 ]
[ 28489-45-4 ]
Reference：
[1] Patent: US6011029, 2000, A,
10
[ 22280-62-2 ]
[ 22280-60-0 ]
[ 28489-45-4 ]
Reference：
[1] Journal of the American Chemical Society, 1947, vol. 69, p. 63,66
11
[ 1824-81-3 ]
[ 22280-62-2 ]
Yield
Reaction Conditions
Operation in experiment
75%
at -1 - 50℃; for 11.5 h;
10 mL of concentrated sulfuric acid was cooled at 0-1 ° C, slowly adding raw material 1 (20 g), cooled to 0 ° C, slowly added 110 mL of nitric acid at a volume ratio of 1: 1, stirred at -1 ° C and stirred at room temperature for 30 min. Reaction was carried out at 50 ° C for 11 h. The reaction solution was extracted with EA. The EA layer was washed with aqueous ammonia and the aqueous ammonia was concentrated. The solid layer 2 (18 g) was precipitated and the yield was 75percent.
48%
at 0 - 100℃;
Example 8 2-Methyl-2- (6-methyl-5-nitro-pyridin-2-ylamino)-propan-1-ol (a) Conc. H2S04 (140 ml) was cooled in an ice-salt bath and molten 6-amino-2-picoline (30 g, 0.277 mol) was added in portions with good stirring. To this brown, viscous solution which was maintained at 0°C was added a cooled (0°C) mixture of conc. H2SO4 (21 ml) and conc. HNO3 (21 ml) drop wise over a period of approx. 1.5 hrs. The red- orange reaction mixture was stirred for an additional hour at 0°C and then allowed to warm slowly to room temperature over night. The brown solution was heated at 60° C (oil bath) for 1 hr followed by lhr at 100°C (carefully controlled temperature). The reaction mixture was cooled to 0°C (ice bath), poured over cracked ice and neutralised by addition of a concentrated aqueous NaOH solution. The yellow precipitate was filtered and washed well with ice-water. (The filtrate was put in the refrigerator, additional product was precipitated together with the salts. ) The yellow product was suspended in water and divided into two portions, each of them subjected to steam distillation in turn. The yellow reaction mixture became more"transparent'after some hrs, but the collected steam, containing 4-amino-3-nitro-2-picoline, was still yellow after 6 hrs. The steam distillation was stopped after 8 hrs, the residual part of the reaction mixture was filtered and evaporated to dryness. 1HNMR (D2O) showed a mixture of 2-3 compounds. The mixture was washed with; CHCI ;, EtOH (x 2) and CHC leaving 20.4 g (48percent) of pure 6-amino- 3-nitro-2-picoline.
36%
at -6 - 20℃; for 7.5 h;
The 6-methylpyridin-2-amine (20g, 185mmol) was dissolved in 98percent H2SO4 (91mL). A mixture of fuming HNO3 (9mL) and 98percent H2SO4 (9mL) was added dropwise to the vigorously stirring solution over 30min at −6°C. The mixture was stirred for 2h at 0°C and slowly warmed to 10°C over 1h and kept stirring for an additional hour. Afterwards, the solution was warmed to 20°C over 1h and stirred for 2h. The reaction mixture was poured onto ice and basified with ammonium hydroxide (pH∼9). The precipitated solid was collected by filtration and purified by steam distillation to afford compound 9 (9.99g). Yellow solid (36percent), mp: 189–191°C. 1H NMR (500MHz, DMSO-d6) δ 7.77 (d, 1H, J=9.2Hz), 6.09 (d, 1H, J=9.2Hz), 6.11 (s, 2H), 2.36 (s, 3H). ESI-MS: m/z=154 [M+1]+.
Reference：
[1] Patent: CN105906621, 2016, A, . Location in patent: Paragraph 0019
[2] Patent: WO2005/42464, 2005, A1, . Location in patent: Page/Page column 32-33
[3] Bioorganic and Medicinal Chemistry, 2015, vol. 23, # 8, p. 1858 - 1868
[4] Patent: WO2009/30725, 2009, A2, . Location in patent: Page/Page column 58
[5] Patent: EP1857444, 2007, A1, . Location in patent: Page/Page column 20
12
[ 18605-16-8 ]
[ 22280-62-2 ]
Reference：
[1] Organic and Biomolecular Chemistry, 2018, vol. 16, # 41, p. 7564 - 7567
13
[ 1824-81-3 ]
[ 22280-62-2 ]
[ 21901-29-1 ]
Reference：
[1] Journal of Fluorine Chemistry, 2011, vol. 132, # 8, p. 541 - 547
[2] Archiv der Pharmazie, 1995, vol. 328, # 3, p. 247 - 255
[3] Archiv der Pharmazie, 1995, vol. 328, # 3, p. 247 - 255
[4] Yakugaku Zasshi, 1952, vol. 72, p. 434[5] Chem.Abstr., 1953, p. 6404
[6] Journal of the American Chemical Society, 1955, vol. 77, p. 3154
[7] Journal of the American Chemical Society, 1947, vol. 69, p. 63,66
[8] Journal of Molecular Structure, 2013, vol. 1043, p. 15 - 27
14
[ 1824-81-3 ]
[ 22280-62-2 ]
Reference：
[1] Journal of Medicinal Chemistry, 2006, vol. 49, # 2, p. 727 - 739
15
[ 109-06-8 ]
[ 22280-62-2 ]
Reference：
[1] Journal of the American Chemical Society, 1947, vol. 69, p. 63,66
16
[ 1824-81-3 ]
[ 22280-62-2 ]
[ 25864-34-0 ]
[ 21901-29-1 ]
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2007, vol. 17, # 11, p. 2987 - 2991
17
[ 33986-37-7 ]
[ 7664-93-9 ]
[ 22280-62-2 ]
[ 21901-29-1 ]
Reference：
[1] Zhurnal Russkago Fiziko-Khimicheskago Obshchestva, 1920, vol. 50, p. 536[2] Chem. Zentralbl., 1923, vol. 94, # III, p. 1022
18
[ 22280-62-2 ]
[ 5467-69-6 ]
Reference：
[1] Journal of the American Chemical Society, 1952, vol. 74, p. 3828,3830
[2] Patent: US6358972, 2002, B1,
[3] Patent: WO2009/155156, 2009, A1,
19
[ 22280-62-2 ]
[ 856834-95-2 ]
Reference：
[1] Journal of the American Chemical Society, 1947, vol. 69, p. 63,66
20
[ 22280-62-2 ]
[ 17288-40-3 ]
Reference：
[1] Patent: US6358972, 2002, B1,
21
[ 22280-62-2 ]
[ 31224-43-8 ]
Reference：
[1] Journal of Fluorine Chemistry, 2011, vol. 132, # 8, p. 541 - 547
With sulfuric acid; nitric acid; at -1 - 50℃; for 11.5h;
10 mL of concentrated sulfuric acid was cooled at 0-1 C, slowly adding raw material 1 (20 g), cooled to 0 C, slowly added 110 mL of nitric acid at a volume ratio of 1: 1, stirred at -1 C and stirred at room temperature for 30 min. Reaction was carried out at 50 C for 11 h. The reaction solution was extracted with EA. The EA layer was washed with aqueous ammonia and the aqueous ammonia was concentrated. The solid layer 2 (18 g) was precipitated and the yield was 75%.
48%
With sulfuric acid; nitric acid; at 0 - 100℃;
Example 8 2-Methyl-2- (6-methyl-5-nitro-pyridin-2-ylamino)-propan-1-ol (a) Conc. H2S04 (140 ml) was cooled in an ice-salt bath and molten 6-amino-2-picoline (30 g, 0.277 mol) was added in portions with good stirring. To this brown, viscous solution which was maintained at 0C was added a cooled (0C) mixture of conc. H2SO4 (21 ml) and conc. HNO3 (21 ml) drop wise over a period of approx. 1.5 hrs. The red- orange reaction mixture was stirred for an additional hour at 0C and then allowed to warm slowly to room temperature over night. The brown solution was heated at 60 C (oil bath) for 1 hr followed by lhr at 100C (carefully controlled temperature). The reaction mixture was cooled to 0C (ice bath), poured over cracked ice and neutralised by addition of a concentrated aqueous NaOH solution. The yellow precipitate was filtered and washed well with ice-water. (The filtrate was put in the refrigerator, additional product was precipitated together with the salts. ) The yellow product was suspended in water and divided into two portions, each of them subjected to steam distillation in turn. The yellow reaction mixture became more"transparent'after some hrs, but the collected steam, containing 4-amino-3-nitro-2-picoline, was still yellow after 6 hrs. The steam distillation was stopped after 8 hrs, the residual part of the reaction mixture was filtered and evaporated to dryness. 1HNMR (D2O) showed a mixture of 2-3 compounds. The mixture was washed with; CHCI ;, EtOH (x 2) and CHC leaving 20.4 g (48%) of pure 6-amino- 3-nitro-2-picoline.
36%
With sulfuric acid; nitric acid; at -6 - 20℃; for 7.5h;
The 6-methylpyridin-2-amine (20g, 185mmol) was dissolved in 98% H2SO4 (91mL). A mixture of fuming HNO3 (9mL) and 98% H2SO4 (9mL) was added dropwise to the vigorously stirring solution over 30min at -6C. The mixture was stirred for 2h at 0C and slowly warmed to 10C over 1h and kept stirring for an additional hour. Afterwards, the solution was warmed to 20C over 1h and stirred for 2h. The reaction mixture was poured onto ice and basified with ammonium hydroxide (pH?9). The precipitated solid was collected by filtration and purified by steam distillation to afford compound 9 (9.99g). Yellow solid (36%), mp: 189-191C. 1H NMR (500MHz, DMSO-d6) delta 7.77 (d, 1H, J=9.2Hz), 6.09 (d, 1H, J=9.2Hz), 6.11 (s, 2H), 2.36 (s, 3H). ESI-MS: m/z=154 [M+1]+.
1 a) 6-Methyl-5-nitropyridin-2-ylamine; A solution of 211 g of 6-amino-2-picoline in 994 ml of concentrated sulfuric acid is admixed dropwise at 00C with a cooled mixture of 145 ml of concentrated nitric acid and 145 ml of concentrated sulfuric acid. The reaction mixture is stirred at 00C for one hour and then at 25C for 16 hours. Subsequently it is heated at 600C for one hour and finally at 1000C for one hour. The reaction mixture is then poured cautiously onto ice and adjusted to a pH of 5 to 6 with a concentrated sodium hydroxide solution. The resultant solid is filtered off and washed with ethanol. The resulting crude product is prepuhfied by column chromatography on silica gel with chloroform/0 - 50% methanol. The material is then partly dissolved in 100 ml of 1 N hydrochloric acid, the precipitate is removed by filtration, and the solution is admixed with sodium carbonate. The resulting solid is recovered by filtration. Drying gives 33 g of the title compound as a yellow-orange solid.NMR (300 MHz, DMSO-d6): delta = 2.60 (3H), 6.37(1 H), 7.35 (2H), 8.09 (1 H).
According to the method described in Tetrahedron Lett., 24, 2211-2212 (1971), the title compound was synthesized by means of the following. To concentrated sulfuric acid (75 mL) was added 2-amino-6-methylpyridine (19.3 g) to be dissolved at 20C or below, a solution of fuming nitric acid (8.0 mL) in concentrated sulfuric acid (8 mL) was added dropwise at 5C or below over 15 min, and the mixture was further stirred at the same temperature for 2 hr. The reaction mixture was poured into ice water (1.4 L), pH of the mixture was adjusted to 10 with aqueous ammonia (300 mL), and the precipitate was collected by filtration. The precipitate was dissolved in ethyl acetate (600 mL), and the solution was washed successively with 10% aqueous ammonia and saturated brine, and dried over sodium sulfate. Then, ethyl acetate was evaporated under reduced pressure to give a powder (22.5 g). Toluene (200 mL) was added to this powder, and the mixture was refluxed for 1 hr and allowed to cool. The obtained powder was collected by filtration. The obtained powder was washed with methylene chloride (100 mL) and collected by filtration to give the title compound as a powder (14.5 g). IR nu (Nujol) cm-1; 1662, 1594, 1404, 1287, 1076. 1H-NMR (DMSO-d6) delta (ppm); 2.62 (3H, s), 6.38 (1H, d, J=9.3 Hz), 7.34 (2H, br-s), 8.09 (1H, d, J=9.3 Hz).
Preparation 4 2-Oxo-5-Nitro-6-Methyl-1,2-Dihydropyridine To a suspension of 2-amino-5-nitro-6-methylpyridine (40.24 g, 260 mmol) was added concentrated sulfuric acid (48 mL). The homogeneous solution was cooled to 0 C., and sodium nitrate (26.97 g, 390 mmol) dissolved in 120 mL of water was added. The reaction mixture was warmed to room temperature over 4 hours, then cooled to 0 C. The resulting ivory precipitate was collected, washed with cold water, and dried at 40 C. in vacuo overnight to provide 39.05 g (97%) of the title compound. EA calculated for C6H6N2O3: C, 46.76; H, 3.92; N, 18.18. Found: C, 46.49; H, 3.94; N, 17.99.
Step 1 Preparation of 2-amino-6-methyl-3,5-dinitropyridine To a stirred solution of 2-amino-6-methylpyridine (38 g, 352 mmol) in conc. H2 SO4 (70 mL) at 0 C. was added HNO3 (16.5 mL, d=1.49) drop-wise over 30 min. The mixture was warmed stirred an additional 1 h at 0 C. then poured into 500 g of ice. This heterogeneous mixture was stirred for 1 h at r.t., filtered, washed with 50 mL H2 O and the residue was briefly dried to give 58 g of crude moist 6-methyl-2-nitraminopyridine. This solid was carefully added in 1-2 g portions to stirred H2 SO4 (70 mL) at 40 C. After complete addition, the reaction mixture was stirred 1 h at 40 C., cooled and poured into 500 g of ice. The resulting precipitate was filtered, washed with 50 mL of H2 O, and air dried to give a yellow solid. 8.5 g of this mixture of 2-amino-6-methyl-3-nitropyridine and 2-amino-6-methyl-5-nitropyridine was dissolved in H2 SO4 (100 mL) at 0 C. and HNO3 (2.74 mL, d=1.49) was added drop-wise over 10 min. After complete addition, the mixture was warmed to 50 C. for 90 min., cooled, then poured onto 200 g of ice. The residue was collected by filtration and washed with cold H2 O (2*50 mL) to give 2-amino-6-methyl-3,5-dinitropyridine as a yellow solid.
Step 1 2,5-Diamino-6-methylpyridine A mixture of 2-amino-5-nitro-6-methylpyridine (5.42 g, 0.0354 mol) (E. D. Parker and W. Shive, J. Amer. Chem. Soc., 69:63 (1947)), absolute EtOH (150 ml) and 10% palladium-on-carbon catalyst (0.488 g) was hydrogenated at an initial pressure of 40 p.s.i. for 18 hours. The catalyst was removed by filtration through celite and the filtrate was concentrated to give 4.34 g of the titled product.
With hydrogen;palladium 10% on activated carbon; In tetrahydrofuran; methanol; under 2585.81 Torr;
6-Methyl-5-nitropyridin-2-amine [CAS 22280-62-2] (0.38 g, 2.48 mmol) was hydrogenated at 50 psi with 10% Pd/C (0.35 g) in MeOH/THF (10 mL) overnight to give 6-methylpyridine-2,5-diamine as a light yellow solid.
EXAMPLE 3 Preparation of 3-tert. butyl-5-nitro-6-methyl-N-(5'-nitro-6-methylpyrid-2'-yl)salicylamide p-Nitrophenyl-3-tert. butyl-5-nitro-6-methylsalicylate (3.74 g 0.01M) and 2-amino-5-nitro-6methylpyridine (1.53 g 0.01M) were fused together for an hour at 180C and then allowed to cool. The resultant solid mass was chromatographed on a column of silica using dichloromethane as eluent. The crude product was recrystallized from petroleum ether (b.p. 100-120) to give 3-tert. butyl-5-nitro-6-methyl-N-(5'-nitro-6'-methylpyrid-2'-yl)salicylamide (2.85 g), m.p. 164.5-165.5C. [Found: C, 55.8; H, 5.3; N, 14.4%. C18 H20 N4 O6 requires: C. 55.7; H, 5.2; N, 14.4%].
EXAMPLE 8 Preparation of 3-tert. butyl-5-nitro-N-(5'-nitro-6'-methylpyrid-2'-yl) salicylamide A mixture of p-nitrophenyl-3-tert. butyl-5-nitrosalicylate (7.26 g 0.02M) and 2-amino-5-nitro-6-methylpyridine (3.0 g 0.022M) was heated for 40 minutes at 180C and, after cooling, was allowed to stand under diethyl ether for 16 hours. The product was filtered off and recrystallized three times from dioxan/ethanol to yield 3-tert. butyl-5-nitro-N-(5'-nitro-6'-methylpyrid-2'-yl) salicylamide (3.0 g), m.p. 197-198C. [Found: C, 54.4; H, 4.9; N, 14.8% C17 H18 N4 O6 requires: C, 54.5; H, 4.9; N, 15.0%.]
With hydrogenchloride; In methanol; ethanol; dichloromethane; acetic acid; ethyl acetate;
A. 5-Methyl-imidazo[1,2-a]pyridin-6-ylamine (843A) 2-Methyl-3-nitro-6-amino pyridine (63 mg, 0.41 mmol) was suspended in 1.3 mL EtOH containing 0.3 mL conc. HCl. 2-Bromo-1,1-dimethoxy-ethane (73 muL, 0.62 mmol) was added and the resulting mixture was refluxed for 8 h, at which point additional 2-bromo-1,1-dimethoxy-ethane (0.1 mL, 0.85 mmol) was added. The mixture was stirred at reflux overnight, cooled and diluted with CH2Cl2. The organics were washed with sat. NaHCO3 solution, dried over MgSO4 and concentrated in vacuo. The residue was dissolved in 4 mL AcOH/EtOAc (1:1) and the resulting solution was heated to 75 C. Iron powder (46 mg, 0.82 mmol, 325 Mesh) was added and the mixture was stirred for 20 min. Additional iron powder (46 mg, 0.82 mmol, 325 Mesh) was added and stirring was continued for 30 min. The mixture was cooled to room tempearture and concentrated. The resulting residue was purified by silica gel silica gel flash chomatography with 20% MeOH in CH2Cl2 to give compound 843A (51 mg, 85%) as a yellow-brown solid. HPLC: 72% at 0.18 min and 28% at 0.27 min (retention time) (YMC S5 ODS-A column 4.6*50 mm Ballistic, 10-90% aqueous methanol over 4 mincontaining 0.2% H3PO4, 4 mL/min, monitoring at 220 nm). MS (ES): m/z 147.85 [M+H]+.
With dmap; In dichloromethane; water; at 20℃; for 16h;
To a solution of 2-amino-6-methyl-5-nitropyridine (3.02 g, 19.72 mmol) in dichloromethane (25 ml), N,N-dimethylaminopyridine (43.4 mg, 0.355 mmol) and di-tert-butyl dicarbonate (8.61 g, 39.44 mmol) were added, and the mixture was stirred at room temperature for 16 hours. Water was added to the reaction solution, followed by extraction with dichloromethane. The organic layer was washed with water twice and with a saturated saline solution, then dried over sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure to obtain the title compound (7.93 g, 100%). 1H-NMR (DMSO-d6, 300 MHz) delta 8.51 (d, J = 9.0 Hz, 1H), 8.31 (s, 1H), 7.63 (d, J =9.0 Hz, 1H), 2.69 (s, 3H), 1.45 (s, 18H).
dmap; In dichloromethane; at 25℃; for 16h;
1 b) 6-Methyl-5-nitro-2-(N,N-di-tert-butyloxycarbonylamino)pyridine; A solution of 24.3 g of the above-prepared nitro compound and 0.35 g of DMAP in 500 ml of methylene chloride is admixed with a solution of 69 g of BOC2O in 500 ml of methylene chloride and stirred at 25C for 16 hours. The organic <n="60"/>phase is subsequently washed with three times 700 ml of water and dried over sodium sulfate. Filtration gives, without further purification, 49 g of the title compound as a yellow solid. NMR (300 MHz, DMSO-d6): delta = 1.46 (18H), 2.69 (3H), 7.63 (1 H), 8.51 (1 H).
With dmap; In dichloromethane; at 25℃; for 12h;
To a solution of 6-methyl-5-nitro-pyridin-2-amine (500 mg, 3.27 mmol, 1 eq) in anhydrous DCM (10 mL) was added DMAP (79.78 mg, 653.00 mol, 0.2 eq) and (Boc)2O (1.78 g, 8.16 mmol, 1.88 mL, 2.5 eq). The mixture was stirred at 25 C. for 12 h. H2O (10 mL) was added and the mixture was extracted with DCM (10 mL*3). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4, filtered and concentrated to afford the crude product which was purified on silica gel column chromatography (from PE/EtOAc=1/0 to 10/1, TLC: PE/EtOAc=2/1, Rf=0.73) to give tert-butyl N-tert-butoxycarbonyl-N-(6-methyl-5-nitro-2-pyridyl)carbamate (847 mg, 1.65 mmol, 50.7% yield, 69.0% purity) 1H NMR (400 MHz, CDCl3) 8.39-8.32 (m, 1H), 7.97-7.60 (m, 1H), 2.81-2.77 (m, 3H), 1.56-1.53 (m, 18H); ES-LCMS m/z 198.0 [M-t-Bu+H]+.
(Boc)2O (16.94g, 77.62mmol) was added to a solution of 9 (9.99g, 65.2mmol) and DMAP (160.2mg, 1.31mmol) in THF (306mL). After stirring at room temperature for 30min, THF was removed under reduced pressure. The obtained crude product was purified by chromatography (petroleum ether/ethyl acetate=25:1, v/v) to afford compound 10 (14.3g). White solid (87%), mp: 127-129C. 1H NMR (500MHz, DMSO-d6) delta 10.52 (s, 1H), 8.41 (d, 1H, J=8.8Hz), 7.84 (d, 1H, J=8.8Hz), 2.67 (s, 3H), 1.46 (s, 9H). ESI-MS: m/z=254 [M+1]+.
6-methyl-5-nitropyridin-2-amine (1.225g; 8 mmol) was dissolved in anhydrous DMF (15 ml_), cooled to 00C and treated with NaH (419 mg; 9.6 mmol) for 30 min. Methyliodide (1 136 mg; 8 mmol) was added, followed by removal of the ice bath and the reaction was continued at RT for 2h. After addition of EtOAc (100 ml_), as a side product, methyl-(6-methyl-5-nitro-pyridin- 2-yl)-amine, precipitated and was filtered off. After washing the organic layer with water (2x), the solvent was evaporated to dryness to obtain the crude product. Purification was done over silica gel (solvent system:CH2CI2/Me0H = 95:5) to yield the title compound as a bright yellow solid. HPLC: tR = 4.992 min (method A); ESI-MS: [M+H]+ 182.1 .
6-Methyl-5-nitropyridin-2-amine (938 mg; 6.0 mmol) was dissolved in THF (10 mL) at RT, followed by portionwise addition of CDI (1 ,1 '-carbonyl-diimidazol) and kept strring for 5 days. After removal of the solvent under reduced pressure the crude product was purified by chromatography over silica gel (eluting with DCM / MeOH; 98/2) to obtain the title compound as a bright beige powder (320 mg). (HPLC: tR 4.825 min (Method A); M+H = 226.1 MS-ES).
tert-butyl 3-(1-(tert-butoxycarbonyl)-5-((tert-butoxycarbonyl)(methyl)amino)-1H-pyrrolo[3,2-b]pyridin-2-yl)-6-cyano-1H-indazole-1-carboxylate[ No CAS ]
Chemistry
Pharmaceutical Intermediates
Inhibitors/Agonists
Material Science
For Research Only
120K+ Compounds
Competitive Price
1-2 Day Shipping
