* 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.
[00265] Example 102A. 3-Amino-5-methylpyridin-2-ol: To a solution of 5-methyl-3- nitropyridin-2-ol (50 mg, 0.32 mmol) in MeOH (5 mL) was added ammonium chloride (174 mg, 3.24 mmol) and zinc (106 mg, 1.62 mmol). The reaction mixture was colored and stirred at rt for 1 h. The suspension was removed by a filter and washed the filter with MeOH. The solvent was evaporated under reduced pressure. The crude product was triturated with a mixed solvent of MeOH and EtOAc (1 : 1). The suspension was filtered and the solvent was removed under reduced pressure to Example 1013A (16 mg, 0.13 mmol, 40percent yield). NMR (400 MHz, MeOD) δ ppm 2.03 (s, 3 H), 6.56 (s, 1 H), 6.63 (s, 1 H).
Reference：
[1] Patent: WO2014/22343, 2014, A1, . Location in patent: Paragraph 00265
[2] Journal of the American Chemical Society, 1950, vol. 72, p. 2806
[3] Journal of the American Chemical Society, 1957, vol. 79, p. 3552
[4] Patent: EP2471792, 2012, A1, . Location in patent: Page/Page column 43
2
[ 7464-14-4 ]
[ 23056-40-8 ]
Yield
Reaction Conditions
Operation in experiment
97%
With benzyltrimethylammonium chloride; trichlorophosphate In acetonitrile for 6 h; Heating
a) Synthesis of 2-chloro-5-methyl-3-nitro-pyridine 5-methyl-3-nitro-pyridin-2-ol (5 g, 32.4 mmol) and benzyltrimethyl ammonium chloride (3.01 g, 16.2 mmol) were dissolved in acetonitrile, and phosphorus oxychloride (9.0 ml, 97.2 mmol) was added thereto and stirred at 800 for 6 hours. The reaction mixture was cooled and poured into ice water to quench the reaction, and extracted with dichloromethane. The combined organic layer was washed with saturated saline solution, dried over anhydrous sodium sulfate (Na2SO4), filtered and evaporated under reduced pressure. The residue was purified by column chromatography on silica eluding with a solvent of dichloromethane. The fractions containing the product were collected and evaporated to obtain 2-chloro-5-methyl-3-nitro-pyridine as yellow solid (5.39 g, 97percent). 1H-NMR (CDCl3, 300 MHz); δ=8.45 (d, 1H, J=2.3 Hz), 8.04 (d, 1H, J=2.3 Hz), 2.46 (s, 3H). MS (ESI); 173.0 (M++1).
88%
for 8 h; Reflux
Compound 3 (1.7 g, 11 mmol) and phosphorus oxychloride (20 mL) were refluxed for 8 h. The excess phosphorus oxychloride was then removed by vacuum distillation. The residue was poured into cracked ice. The solid precipitate was filtered off, washed with water, and dried to give product 4 as a pale yellow solid (1.7 g, 88percent). 1H NMR (300 MHz, DMSO-d6) δ: 8.58 (d, J = 2.4 Hz, 1H), 8.45 (d, J = 2.1 Hz, 1H), 3.38 (s, 3H).
76.8%
for 5 h; Reflux
Synthesis of the compound 15 The compound 14 (10 g, 0.065 mol) was added into 100 mL of phosphorus oxychloride, heated under reflux for 5 h, distilled to remove excessive phosphorus oxychloride, and poured into ice. A large amount of grey solid was precipitated and filtered to obtain 8.6 g of deep grey product with a yield of 76.8percent. The melting point is 49-51 °C(water) (M. P. 46-50 °C was reported in the reference) [J.O.C. , 1955, 20, 1729-1731].
59%
With trichlorophosphate In N,N-dimethyl-formamide at 0 - 80℃; for 4 h;
Synthesis of 2-Chloro-5-methyl-3-nitro-pyridine (XXVIII): To a cold (0 °C) solution of commercially available 2-hydroxy -5-methyl-3-nitro pyridine (5.00 g, 0.032 mol) in N,N- dimethylformamide (30 mL) was added phosphoryl chloride (7.4 g, 0.049 mol). The reaction mixture was allowed to slowly warm to room temperature and was then heated at 80 °C for 4 h. After cooling to room temperature, the reaction was quenched with ice water and then 10 extracted with ethyl acetate (3 x 50 mL). The combined organic extracts were washed with water and brine solution. The organic layer was then dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the crude product mixture. The crude product was purified by column chromatography on silica to afford compound XXVIII (3.30 g, 59percent) as a pale yellow solid.1H NMR (400 MHz, CDCl3): δ 8.43 (d, J=1.5 Hz, 1H), 8.03 (d, J= 1.5 15 Hz, 1H), 2.45 (s, 3H); MS (ESI, positive mode) m/z 173 (MH+).
Reference：
[1] Patent: US2011/28467, 2011, A1, . Location in patent: Page/Page column 51
[2] Bioorganic and Medicinal Chemistry, 2015, vol. 23, # 5, p. 985 - 995
[3] Patent: EP2366691, 2011, A1, . Location in patent: Page/Page column 9
[4] Patent: WO2015/73528, 2015, A1, . Location in patent: Page/Page column 118
[5] Journal of the American Chemical Society, 1951, vol. 73, p. 3504
[6] Journal of the American Chemical Society, 1954, vol. 76, p. 3167
[7] Bioorganic and Medicinal Chemistry, 2008, vol. 16, # 23, p. 9948 - 9956
[8] Bioorganic and Medicinal Chemistry Letters, 2013, vol. 23, # 13, p. 3983 - 3987
3
[ 7464-14-4 ]
[ 23056-40-8 ]
Reference：
[1] Journal of Organometallic Chemistry, 1996, vol. 517, # 1-2, p. 25 - 36
[2] Journal of Medicinal Chemistry, 2014, vol. 57, # 6, p. 2275 - 2291
[3] Patent: WO2011/161446, 2011, A1, . Location in patent: Page/Page column 40-41
4
[ 1603-41-4 ]
[ 7464-14-4 ]
Yield
Reaction Conditions
Operation in experiment
61.9%
Stage #1: at 0 - 5℃; for 2 h; Stage #2: for 4 h; Cooling with ice
Example 3: Synthesis of 2-(1-ethyleneimine)-5-carbamoyl-3-nitropyridine (compound III) [Show Image] The reagents used is ( i ) HNO3/H2SO4, followed by NaNO2; (ii) POCl3; (iii) Na2Cr2O7; (iv) SOCl2, followed by NH4OH/THF; (v) aziridine.Synthesis of the compound 14 A concentrated sulphuric acid (25 mL) was cooled in an ice bath, the starting material compound 13 (5 g, 0.0462 mol) was slowly added and cooled to 0°C, 6 mL of a mixture in volumetric ratio of 1:1 of a concentrated sulphuric acid (98percent) and a concentrated nitric acid (72percent) was slowly added, and the reaction proceeded at 0-5°C for 2 h. The reaction liquid was introduced into 100 mL of ice-water, supplemented further with 6g sodium nitrite, and stirred in an ice-bath for additional 4h. A solid was precipitated and filtered. The filter cake was dried to obtain 4.4g of the compound 14. The yield was 61.9percent. The melting point is 177-178 °C (water) (M.P. 178-180 °C was reported in the reference) [J.O.C. , 1944, 14, 328-332].
24%
Stage #1: at 0℃; for 2 h; Stage #2: at 0℃; for 4 h;
A solution of 2-amino-5-picoline (5 g, 46 mmol) in c-H2SO4 (25 mL) was cooled in an ice bath. A mixture of c-H2SO4 (3 mL) and c-HNO3 (3 mL) was added slowly with stirring. This mixture was then stirred at 0 °C for 2 h. The mixture was poured into 100 mL of ice water and then NaNO2 (6 g) was added. The resulting mixture was stirred for 4 h at 0 °C. The precipitate solid obtained was filtered off, washed with water, and dried to give product 3 as an orange solid (1.7 g, 24percent). 1H NMR (300 MHz, DMSO-d6) δ: 12.69 (s, 1H), 8.35 (d, J = 2.7 Hz, 1H), 7.73 (d, J = 2.4 Hz, 1H), 2.10 (s, 3H).
Reference：
[1] Patent: EP2366691, 2011, A1, . Location in patent: Page/Page column 8-9
[2] Bioorganic and Medicinal Chemistry, 2015, vol. 23, # 5, p. 985 - 995
[3] Bioorganic and Medicinal Chemistry, 2008, vol. 16, # 23, p. 9948 - 9956
5
[ 1003-68-5 ]
[ 7464-14-4 ]
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2013, vol. 23, # 13, p. 3983 - 3987
6
[ 7464-14-4 ]
[ 2047-49-6 ]
Reference：
[1] Journal of the American Chemical Society, 1954, vol. 76, p. 3167
7
[ 7464-14-4 ]
[ 7477-10-3 ]
Reference：
[1] Patent: EP2366691, 2011, A1,
[2] Bioorganic and Medicinal Chemistry, 2015, vol. 23, # 5, p. 985 - 995
8
[ 7464-14-4 ]
[ 23056-46-4 ]
Yield
Reaction Conditions
Operation in experiment
86%
With phosphorus(V) oxybromide In N,N-dimethyl-formamide at 0 - 80℃; for 12 h;
[00257] POBr3 (222.8 g, 0.78 mol) was added in portions to 2-hydroxy-5- methyl-3-nitropyridine (100 g, 0.65 mol) in DMF (500 mL) with stirring at 0-10 °C then the reaction mixture was stirred at 80 0C under nitrogen for 12 hours. Reaction mixture was cooled and poured into crushed ice (1 Kg), obtained solid was filtered, washed thoroughly with ice-cold water (2 x 500 mL), dried in a desiccator under high vacuum for one day to obtain 2-bromo-5-methyl-3- nitropyridine as yellow solid (121 g) in 86percent yield. (M+H) Expected: 217; found 216.9.
With ammonium chloride; zinc; In methanol; at 20.0℃;
[00265] Example 102A. 3-Amino-5-methylpyridin-2-ol: To a solution of 5-methyl-3- nitropyridin-2-ol (50 mg, 0.32 mmol) in MeOH (5 mL) was added ammonium chloride (174 mg, 3.24 mmol) and zinc (106 mg, 1.62 mmol). The reaction mixture was colored and stirred at rt for 1 h. The suspension was removed by a filter and washed the filter with MeOH. The solvent was evaporated under reduced pressure. The crude product was triturated with a mixed solvent of MeOH and EtOAc (1 : 1). The suspension was filtered and the solvent was removed under reduced pressure to Example 1013A (16 mg, 0.13 mmol, 40% yield). NMR (400 MHz, MeOD) delta ppm 2.03 (s, 3 H), 6.56 (s, 1 H), 6.63 (s, 1 H).
With hydrogen;palladium 10% on activated carbon; In tetrahydrofuran; methanol; at 20.0℃; for 24.0h;
(Reference Example 5-1) At room temperature, to a mixed solvent solution of 5-methyl-3-nitropyridin-2-ol (5.0 g) in tetrahydrofuran (200 ml) and methanol (200 ml) was added 10% palladium carbon (0.5 g), followed by stirring for 24 hours under a hydrogen atmosphere. The reaction solution was filtered through Celite, and then the filtrate was concentrated under reduced pressure to afford 3-amino-5-methylpyridin-2-ol (4.03 g). 1H NMR (400 MHz, CDCl3) delta: 2.03(s, 3H), 4.11 (br s, 2H), 6.53 (s, 1H), 6.59 (s, 1H), 12.21 (br s, 1H).
With benzyltrimethylammonium chloride; trichlorophosphate; In acetonitrile; for 6h;Heating;
a) Synthesis of 2-chloro-5-methyl-3-nitro-pyridine <strong>[7464-14-4]5-methyl-3-nitro-pyridin-2-ol</strong> (5 g, 32.4 mmol) and benzyltrimethyl ammonium chloride (3.01 g, 16.2 mmol) were dissolved in acetonitrile, and phosphorus oxychloride (9.0 ml, 97.2 mmol) was added thereto and stirred at 800 for 6 hours. The reaction mixture was cooled and poured into ice water to quench the reaction, and extracted with dichloromethane. The combined organic layer was washed with saturated saline solution, dried over anhydrous sodium sulfate (Na2SO4), filtered and evaporated under reduced pressure. The residue was purified by column chromatography on silica eluding with a solvent of dichloromethane. The fractions containing the product were collected and evaporated to obtain 2-chloro-5-methyl-3-nitro-pyridine as yellow solid (5.39 g, 97%). 1H-NMR (CDCl3, 300 MHz); delta=8.45 (d, 1H, J=2.3 Hz), 8.04 (d, 1H, J=2.3 Hz), 2.46 (s, 3H). MS (ESI); 173.0 (M++1).
88%
With trichlorophosphate; for 8h;Reflux;
Compound 3 (1.7 g, 11 mmol) and phosphorus oxychloride (20 mL) were refluxed for 8 h. The excess phosphorus oxychloride was then removed by vacuum distillation. The residue was poured into cracked ice. The solid precipitate was filtered off, washed with water, and dried to give product 4 as a pale yellow solid (1.7 g, 88%). 1H NMR (300 MHz, DMSO-d6) delta: 8.58 (d, J = 2.4 Hz, 1H), 8.45 (d, J = 2.1 Hz, 1H), 3.38 (s, 3H).
76.8%
With trichlorophosphate; for 5h;Reflux;
Synthesis of the compound 15 The compound 14 (10 g, 0.065 mol) was added into 100 mL of phosphorus oxychloride, heated under reflux for 5 h, distilled to remove excessive phosphorus oxychloride, and poured into ice. A large amount of grey solid was precipitated and filtered to obtain 8.6 g of deep grey product with a yield of 76.8%. The melting point is 49-51 C(water) (M. P. 46-50 C was reported in the reference) [J.O.C. , 1955, 20, 1729-1731].
59%
With trichlorophosphate; In N,N-dimethyl-formamide; at 0 - 80℃; for 4h;
Synthesis of 2-Chloro-5-methyl-3-nitro-pyridine (XXVIII): To a cold (0 C) solution of commercially available 2-hydroxy -5-methyl-3-nitro pyridine (5.00 g, 0.032 mol) in N,N- dimethylformamide (30 mL) was added phosphoryl chloride (7.4 g, 0.049 mol). The reaction mixture was allowed to slowly warm to room temperature and was then heated at 80 C for 4 h. After cooling to room temperature, the reaction was quenched with ice water and then 10 extracted with ethyl acetate (3 x 50 mL). The combined organic extracts were washed with water and brine solution. The organic layer was then dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the crude product mixture. The crude product was purified by column chromatography on silica to afford compound XXVIII (3.30 g, 59%) as a pale yellow solid.1H NMR (400 MHz, CDCl3): delta 8.43 (d, J=1.5 Hz, 1H), 8.03 (d, J= 1.5 15 Hz, 1H), 2.45 (s, 3H); MS (ESI, positive mode) m/z 173 (MH+).
Example 3: Synthesis of 2-(1-ethyleneimine)-5-carbamoyl-3-nitropyridine (compound III) [Show Image] The reagents used is ( i ) HNO3/H2SO4, followed by NaNO2; (ii) POCl3; (iii) Na2Cr2O7; (iv) SOCl2, followed by NH4OH/THF; (v) aziridine.Synthesis of the compound 14 A concentrated sulphuric acid (25 mL) was cooled in an ice bath, the starting material compound 13 (5 g, 0.0462 mol) was slowly added and cooled to 0C, 6 mL of a mixture in volumetric ratio of 1:1 of a concentrated sulphuric acid (98%) and a concentrated nitric acid (72%) was slowly added, and the reaction proceeded at 0-5C for 2 h. The reaction liquid was introduced into 100 mL of ice-water, supplemented further with 6g sodium nitrite, and stirred in an ice-bath for additional 4h. A solid was precipitated and filtered. The filter cake was dried to obtain 4.4g of the compound 14. The yield was 61.9%. The melting point is 177-178 C (water) (M.P. 178-180 C was reported in the reference) [J.O.C. , 1944, 14, 328-332].
24%
A solution of 2-amino-5-picoline (5 g, 46 mmol) in c-H2SO4 (25 mL) was cooled in an ice bath. A mixture of c-H2SO4 (3 mL) and c-HNO3 (3 mL) was added slowly with stirring. This mixture was then stirred at 0 C for 2 h. The mixture was poured into 100 mL of ice water and then NaNO2 (6 g) was added. The resulting mixture was stirred for 4 h at 0 C. The precipitate solid obtained was filtered off, washed with water, and dried to give product 3 as an orange solid (1.7 g, 24%). 1H NMR (300 MHz, DMSO-d6) delta: 12.69 (s, 1H), 8.35 (d, J = 2.7 Hz, 1H), 7.73 (d, J = 2.4 Hz, 1H), 2.10 (s, 3H).
With phosphorus(V) oxybromide; In N,N-dimethyl-formamide; at 0 - 80℃; for 12h;
[00257] POBr3 (222.8 g, 0.78 mol) was added in portions to 2-hydroxy-5- methyl-3-nitropyridine (100 g, 0.65 mol) in DMF (500 mL) with stirring at 0-10 C then the reaction mixture was stirred at 80 0C under nitrogen for 12 hours. Reaction mixture was cooled and poured into crushed ice (1 Kg), obtained solid was filtered, washed thoroughly with ice-cold water (2 x 500 mL), dried in a desiccator under high vacuum for one day to obtain 2-bromo-5-methyl-3- nitropyridine as yellow solid (121 g) in 86% yield. (M+H) Expected: 217; found 216.9.
With potassium carbonate; In N,N-dimethyl-formamide; at 60℃; for 2h;Sealed tube;
In a sealed tube, a mixture of 2-hydroxy-5-methyl-3-nitropyridine (463 mg; 3.00 mmol), <strong>[78385-26-9]3-bromomethyl-3-methyloxetane</strong> (991 mg; 6.01 mmol) and K2C03 (1.25 g; 9.01 mmol) in DMF (6 mL) was stirred at 60C for 2h. The reaction mixture was cooled down to room temperature. The insoluble material was filtered off and thefiltrate was concentrated. The residue poured onto a mixture of water and brine, then extracted with EtOAc. The organic layer was decanted, washed with brine, dried over MgSO4, filtered and the solvent was evaporated to give 750 mg of crude product as a yellow oil. The crude was purified by chromatography over silica gel (irregular SiOH, 24 g; gradient: from 100% DCM to 98% DCM, 2% MeOH). The pure fractions werecollected and the solvent was evaporated to give intermediate 471 in 2 fractions: 287 mg of a yellow oil (40% yield) and 365 mg of a yellow solid (51% yield).
With potassium carbonate; In N,N-dimethyl-formamide; at 60℃; for 2h;Sealed tube;
In a sealed tube, a mixture of <strong>[7464-14-4]2-hydroxy-5-methyl-3-nitropyridine</strong> (1.00 g, 6.49 mmol), (2-bromoethoxy)-tert-butyldimethylsilane (2.80 mL, 12.98 mmol) and K2C03 (2.70 g, 19.46 mmol) in DMF (13 mL) was stirred at 60 C for 2 h. The reaction mixture was cooled down to rt, poured onto a mixture of water and brine, then extracted with Et20. The organic layer was decanted, washed with brine, dried over MgSO4, filtered andevaporated to dryness. The residue was purified by column chromatography on silica gel (irregular SiOH, 80 g, mobile phase: heptane/EtOAc, gradient from 80:20 to 60:40). The pure fractions were collected and evaporated to dryness to give 1.68 g of intermediate 8i (83% yield, 94% purity based on LC/MS).
With potassium carbonate; sodium iodide; In N,N-dimethyl-formamide; at 60℃; for 3h;
To a suspension of <strong>[7464-14-4]2-hydroxy-5-methyl-3-nitropyridine</strong> (0.60 g, 3.89 mmol) in DMF (8 mL) at rt, K2C03 (1.61 g, 11.7 mmol), Nal (58.40 mg, 0.39 mmol) were added then (2- bromoethyl)cyclopropane (0.87 g, 5.84 mmol) and the reaction mixture was stirred at 60 C for 3 h. The mixture was combined with two other batches (from each 50 mg of<strong>[7464-14-4]2-hydroxy-5-methyl-3-nitropyridine</strong>) and filtered on a pad of celite. The cake was washed with EtOAc and the filtrate was evaporated in vacuo to give a brown oil. The residue was purified by column chromatography on silica gel (irregular SiOH, 15-40 jim, 50 g, dry loading on celite, mobile phase gradient: from heptane 90%, EtOAc/MeOH (9:1)10% to heptane 50%, EtOAc/MeOH (9:1) 50%). The fractionscontaining the product were combined and evaporated to dryness to give 775 mg of intermediate 24i (77% yield, orange gum).
With potassium carbonate; In N,N-dimethyl-formamide; at 60℃; for 5h;
General procedure: To a suspension of 5-fluoro-2-hydroxy-3-nitropyridine (1.03 g, 6.49 mmol) in DMF(13 mL) at rt, K2C03 (3.59 g, 25.95 mmol) then N-(2-chloroethyl)morpholinehydrochloride (2.42 g, 12.98 mmol) were added, and the reaction mixture was stirred at 60 C for 2 h. The mixture was cooled down to rt and filtered off. The filtrate was extracted with EtOAc. The organic layer was washed with brine, dried over MgSO4, filtered and evaporated in vacuo. The residue was purified by column chromatographyon silica gel (irregular SiOH, 15-40 jim, 120 g, mobile phase gradient: from heptane/EtOAc/MeOH: 100/0/0 to 0/80/20). The pure fractions were mixed and the solvent was evaporated to give and 0.846 g of intermediate 18i (48% yield).
2-(chloromethyl)-1-methyl-1H-imidazole hydrochloride[ No CAS ]
C11H12N4O3[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
17%
With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 2h;
General procedure: To a suspension of 5-fluoro-2-hydroxy-3-nitropyridine (1.03 g, 6.49 mmol) in DMF(13 mL) at rt, K2C03 (3.59 g, 25.95 mmol) then N-(2-chloroethyl)morpholinehydrochloride (2.42 g, 12.98 mmol) were added, and the reaction mixture was stirred at 60 C for 2 h. The mixture was cooled down to rt and filtered off. The filtrate was extracted with EtOAc. The organic layer was washed with brine, dried over MgSO4, filtered and evaporated in vacuo. The residue was purified by column chromatographyon silica gel (irregular SiOH, 15-40 jim, 120 g, mobile phase gradient: from heptane/EtOAc/MeOH: 100/0/0 to 0/80/20). The pure fractions were mixed and the solvent was evaporated to give and 0.846 g of intermediate 18i (48% yield).
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