* 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.
Stage #1: With potassium hydroxide In methanol at 20℃; Stage #2: With hydrogenchloride In methanol; water
To a solution of OH (7.0 g) in methanol (50 ml) was added 3-acetoxy-4-methylpyridine 1 - oxide (51; 1 5.0 g, 106 mmol). The mixture was stirred at room temperature overnight. The methanol was removed under vacuum and the residue was dissolved in water. The solution was neutralized to pH 7 with cone. HC1 and extracted with CH2CI2 and EtOAc. The extracts were combined, dried and concentrated to obtain 4-methylpyridin-3-ol (52; 8.40 g, 80percent yield) as an oil. MS (ESI) calcd for C6H7NO (m/z) 109. 13.
Reference：
[1] Journal of Heterocyclic Chemistry, 1985, vol. 22, p. 1419 - 1420
3
[ 1006-96-8 ]
[ 1121-19-3 ]
Yield
Reaction Conditions
Operation in experiment
21%
With lithium hydroxide monohydrate In tetrahydrofuran; water for 6 h;
Lithium hydroxide monohydrate (32.1 g, 764 mmol) was added to Intermediate 61 (127 g, 841 mmol) in THF (500 mL) and water (500 mL). After 6 h, THF was removed in vacuo, then DCM and 1M aqueous sodium hydroxide solution were added. The layers were separated. The aqueous phase was acidified with concentrated HC1 until the pH was approximately 4-5, then saturated with sodium chloride and extracted with EtOAc. The combined organic layers were washed with brine, dried (Na2S04), and evaporated in vacuo, to afford the title compound (19 g, 21percent). δΗ (300 MHz, CDC13) 10.72 (s, 1H), 8.16 (s, 1H), 7.93 (d, J4.9 Hz, 1H), 7.14 (d, J4.9 Hz, 1H), 2.31 (s, 3H)
Reference：
[1] Patent: WO2016/198400, 2016, A1, . Location in patent: Page/Page column 62
[2] Bioorganic and Medicinal Chemistry Letters, 2015, vol. 25, # 17, p. 3636 - 3643
4
[ 98976-77-3 ]
[ 1121-19-3 ]
Reference：
[1] Journal of Organic Chemistry, 1985, vol. 50, # 25, p. 5436 - 5438
[2] Patent: US5914328, 1999, A,
5
[ 7664-93-9 ]
[ 98976-77-3 ]
[ 1121-19-3 ]
Reference：
[1] Patent: US5948793, 1999, A,
6
[ 101925-10-4 ]
[ 1121-19-3 ]
Reference：
[1] Journal of Heterocyclic Chemistry, 1985, vol. 22, p. 1419 - 1420
7
[ 51581-40-9 ]
[ 1121-19-3 ]
Reference：
[1] Journal of Organic Chemistry, 1985, vol. 50, # 25, p. 5436 - 5438
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2015, vol. 25, # 17, p. 3636 - 3643
10
[ 1003-67-4 ]
[ 108-24-7 ]
[ 1121-19-3 ]
[ 586-95-8 ]
Reference：
[1] Journal of Medicinal Chemistry, 1987, vol. 30, # 11, p. 2031 - 2046
11
[ 3430-27-1 ]
[ 1121-19-3 ]
Reference：
[1] Roczniki Chemii, 1956, vol. 30, p. 475,479[2] Chem.Abstr., 1957, p. 14722
12
[ 1003-67-4 ]
[ 108-24-7 ]
[ 1121-19-3 ]
[ 1007-48-3 ]
Reference：
[1] Journal of the American Chemical Society, 1955, vol. 77, p. 1281
[2] Journal of the American Chemical Society, 1955, vol. 77, p. 1281
13
[ 1121-19-3 ]
[ 15128-89-9 ]
Yield
Reaction Conditions
Operation in experiment
83%
at 0 - 40℃; for 2.75 h;
While cooling in an ice/water bath, Intermediate 62 (59 g, 545 mmol) was added portionwise to concentrated sulfuric acid (290 mL), keeping the temperature below 40°C. At 0°C, an ice-cooled mixture of fuming nitric acid (25.5 mL, 600 mmol) in concentrated sulfuric acid (58 mL) was added dropwise over about 45 minutes, keeping the (0626) temperature below 20°C. After the addition was complete, the reaction mixture was stirred at r.t. for 2 h, then poured into a mixture of ice and water (1.5 L). Ammonium hydroxide was added carefully to the resulting mixture until the pH was approximately 1- 2. The resulting precipitate was filtered and dried to afford the title compound (69.5 g, 83percent). δΗ (300 MHz, DMSO-de) 10.40 (s, 1H), 7.93 (d, J4.5 Hz, 1H), 7.57 (d, J4.5 Hz, 1H), 2.32 (s, 3H)
67%
Stage #1: at 10 - 20℃; for 2 h;
4-Methylpyridin-3-ol (52; 8.4 g, 78.5 mmol) was added to ice cold cone. H2S04 (42 m L). Fuming nitric acid (4 mL) was added dropwise while maintaining the temperature below 1 0 °C and the mixture was stirred at 10 - 20 °C for 2 hours. The mixture was poured onto crushed ice and adjusted to pH 2 with 8N NaOH and extracted with EtOAc. The extracts were combined, dried, and concentrated. The residue was purified by column chromatography to obtain 4- methyl-2-nitropyridin-3-ol (53; 8.0 g, 67percent yield). M S (ESI) calcd for C6H6N203 (m/z) 1 54.1 2.
With sulfuric acid; nitric acid; at 0 - 40℃; for 2.75h;
While cooling in an ice/water bath, Intermediate 62 (59 g, 545 mmol) was added portionwise to concentrated sulfuric acid (290 mL), keeping the temperature below 40C. At 0C, an ice-cooled mixture of fuming nitric acid (25.5 mL, 600 mmol) in concentrated sulfuric acid (58 mL) was added dropwise over about 45 minutes, keeping the (0626) temperature below 20C. After the addition was complete, the reaction mixture was stirred at r.t. for 2 h, then poured into a mixture of ice and water (1.5 L). Ammonium hydroxide was added carefully to the resulting mixture until the pH was approximately 1- 2. The resulting precipitate was filtered and dried to afford the title compound (69.5 g, 83%). deltaEta (300 MHz, DMSO-de) 10.40 (s, 1H), 7.93 (d, J4.5 Hz, 1H), 7.57 (d, J4.5 Hz, 1H), 2.32 (s, 3H)
67%
4-Methylpyridin-3-ol (52; 8.4 g, 78.5 mmol) was added to ice cold cone. H2S04 (42 m L). Fuming nitric acid (4 mL) was added dropwise while maintaining the temperature below 1 0 C and the mixture was stirred at 10 - 20 C for 2 hours. The mixture was poured onto crushed ice and adjusted to pH 2 with 8N NaOH and extracted with EtOAc. The extracts were combined, dried, and concentrated. The residue was purified by column chromatography to obtain 4- methyl-2-nitropyridin-3-ol (53; 8.0 g, 67% yield). M S (ESI) calcd for C6H6N203 (m/z) 1 54.1 2.
With sulfuric acid; nitric acid; at 10 - 30℃; for 2h;
4-Methylpyridin-3-ol (5.00 g, J. Heterocyclic Chem. , 1985, 22, 1419) was added to cone. H2SO4 (25 mL) under ice- <n="343"/>cooling (below 300C). Nitric acid (fuming, 2.2 mL) was added dropwise below 100C, and the mixture was stirred at 10-200C for 2 hr and then poured onto crashed ice. The mixture was adjusted to pH 2 by the addition of 8N NaOH and extracted with ethyl acetate (2 x) . The extracts were combined, dried over MgSO4 and concentrated, and the residue was chromatographed on silica gel using n-hexane/ethyl acetate as an eluent to give the title compound as yellow crystals (4.89 g) . mp. 87-880C.1H-NMR (300 MHz, DMSO-d6) delta: 2.31 (s, 3H), 7.56 (d, J = 4.2 Hz, IH), 7.93 (d, J = 4.2 Hz, IH), 10.55 (br, IH).
With H2SO4; sodium methylate; In methanol; water; ethyl acetate;
27b. 4methyl-3-pyridinol To the solution of 4-methyl-3-pyridyl diethylcarbamate (760 mg, 3.65 mmol) in methanol (10 mL) was added sodium methoxide (623 mg, 11.0 mmol), and the resultant mixture was refluxed for 20 hours. Methanol was evaporated, EtOAc (15 mL) and water (1 mL) were added, pH was adjusted to 9 using 20% yield H2SO4. Organic layer was decanted and the residue washed with EtOAc (3*5 mL). The combined organic layers were dried (Na2 SO4) and concentrated. The crude product was purified by flash chromatography on silica gel eluding with CHCl3 /MeOH (20:1 and 10:1) to provide 325 mg (82% yield) of the title compound. TLC Rf 030 (10:1 CHCl3 /MeOH). MS (DCI/NH3) m/e 110 (M+H)+. 1 H NMR (CDCl3, 300 MHz) delta: 8.24 (s, 1H, ArH), 7.98 (d, J=7.2 Hz, 1H, ArH), 7.16 (d, J=7.2 Hz, 1H, ArH).
4-methyl-3-(2-(S)-pyrrolidinylmethoxy)pyridine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With trifluoroacetic acid; In tetrahydrofuran; water; ethyl acetate;
27c. 4-methyl-3-(2-(S)-pyrrolidinylmethoxy)pyridine (S)-1-t-Butoxycarbonyl-2-pyrrolidinemethanol (590 mg, 2.94 mmol), <strong>[1121-19-3]4-methyl-3-pyridinol</strong> (320 mg, 2.94 mmol), DEAD (509 uL, 3.23 mmol) and PPh3 (848 mg, 3.23 mmol) in THF (100 mL) were allowed to react as described in Example 2a. Solvent was removed, and the residue was chromatographed with CHCl3 /MeOH (10:1) to provide 1.8 g of the crude mixture. This material was immediately treated with trifluoroacetic acid (2.0 mL) at room temperature for 3 hours, and excess trifluoroacetic acid was removed under reduced pressure. Water (3 mL) and EtOAc (20 mL) were added, and the mixture was stirred for 5 minutes. The organic layer was decanted, and the residue washed with EtOAc (3*10 mL). The combined organic layers were dried (Na2 SO4) and evaporated. The crude product was purified by flash chromatography on silica gel eluding with CHCl3 /MeOH/NH4 OH (10:1:0.02 and 10:1.5:0.1) to provide 52 mg (14% yield from <strong>[1121-19-3]4-methyl-3-pyridinol</strong>) of the title compound. TLC Rf 0.18 (10:1:0.02 CHCl3 /MeOH/NH40 H). MS (DCI/NH3) m/e 193 (M+H)+. 1 H NMR (CDCl3, 300 MHz) delta: 8.16 (s, 1H, ArH), 8.12 (d, J=6.9 Hz, 1H, ArH), 7.07 (d, J=6.9 Hz, 1H, ArH), 4.12-4.00 (m, 2H, OCH2), 3.75-3.63 (m, 1H, NCH), 3.18-3.02 (m, 2H, NCH2), 2.24 (s, 3H, NCH3), 2.08-1.64 (m, 4H, 2CH2).
With sodium methylate; In methanol; water; ethyl acetate;
27b. 4-methyl-3-pyridinol To the solution of 4-methyl-3-pyridyl diethylcarbamate (760 mg, 3.65 mmol) in methanol (10 mL) was added sodium methoxide (623 mg, 11.0 mmol), and the resultant mixture was refluxed for 20 hours. Methanol was evaporated, EtOAc (15 mL) and water (1 mL) were added, pH was adjusted to 9 using 20% yield H2 SO4. Organic layer was decanted and the residue washed with EtOAc (3*5 mL). The combined organic layers were dried (Na2 SO4) and concentrated. The crude product was purified by flash chromatography on silica gel eluding with CHCl3 /MeOH (20:1 and 10:1) to provide 325 mg (82% yield) of the title compound. TLC Rf 0.30 (10:1 CHCl3 /MeOH). MS (DCI/NH3) m/e 110 (M+H)+. 1 H NMR (CDCl3, 300 MHz) delta: 8.24 (s, 1H, ArH), 7.98 (d, J=7.2 Hz, 1H, ArH), 7.16 (d, J=7.2 Hz, 1H, ArH).
A. A mixture of 218.0 g of <strong>[1121-19-3]4-methyl-3-pyridinol</strong> and 78.0 g of sodium amide are placed in a pressure vessel and heated at 150 for 6 hours. The vessel is allowed to cool, the solid mass is removed and added portionwise to 1 l. of cold 2-propanol. Subsequently, 20% aqueous acetic acid is added until the pH is 5.5 and the whole concentrated to dryness in vacuo. The residue is extracted thoroughly with chloroform and the chloroform extracts washed with saturated aqueous sodium chloride, dried and concentrated. The residue is fractionally crystallized from ethyl acetate to give 2-amino-<strong>[1121-19-3]4-methyl-3-pyridinol</strong>.
2-dimethylaminomethyl-3-hydroxy-4-methylpyridine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
In water;
EXAMPLE 2 A solution consisting of <strong>[1121-19-3]3-hydroxy-4-methylpyridine</strong> (32.7 g.), 30% aqueous dimethylamine (46.5 ml.) and formalin (25 ml.) in water (50 ml.) was heated on a steam bath for a period of two hours. The cooled reaction solution was then extracted with ten-100 ml. portions of diethyl ether and the combined ether and extracts were subsequently dried over anhydrous magnesium sulfate and filtered. After removal of the volatile liquids by means of evaporation under reduced pressure, there was finally obtained an oil as residue which was subsequently distilled in vacuo to give pure 2-dimethylaminomethyl-<strong>[1121-19-3]3-hydroxy-4-methylpyridine</strong> (yield, 34.5 g.), b.p. 71-74 C./0.6 mm. Hg. The corresponding dihydrochloride salt melted at 214-217 C. (decomp.) after recrystallization from ethanol/diethyl ether. Anal. Calcd. for C9 H14 N2 O2.2HCl: C, 45.20; H, 6.74; N, 11.71. Found: C, 45.26; H, 6.74; N, 11.76.
N-[(2S)-5-bromo-2,3-dihydro-1H-inden-2-yl]-2-propanesulfonamide[ No CAS ]
[ 1162085-26-8 ]
Yield
Reaction Conditions
Operation in experiment
With copper(l) iodide; dimethylaminoacetic acid; caesium carbonate; In dimethyl sulfoxide; at 190℃; for 0.5h;Microwave irradiation;
A mixture of <strong>[1121-19-3]4-methyl-3-pyridinol</strong> (71.1 mg, 0.652 mmol), lambda/-[(2S)-5-bromo-2,3-dihydro-1H- inden-2-yl]-2-propanesulfonamide (200 mg, 0.628 mmol, Description 1 ), N, N- dimethylglycine (78 mg, 0.754 mmol), caesium carbonate (410 mg, 1.257 mmol) and copper(l) iodide (132 mg, 0.691 mmol) in DMSO (2 ml) was heated under microwave conditions at 190 0C for 30 minutes. The mixture was filtered through kieselguhr and partitioned between ethyl acetate and water. The organic solution was dried and evaporated under reduced pressure to yield the crude product. This material was purified using MDAP and then partitioned between ethyl acetate and saturated aqueous sodium bicarbonate solution. The organic layer was dried (Na2SO4) and evaporated under reduced pressure. The resulting free base was treated with 1 ml of ethereal HCI and the ether was evaporated to yield the desired product as an orange gum (30 mg). <n="40"/>LC/MS (ES): Found 347 (ES+), retention time 2.01 mins. C18H22N2O3S requires 346. 1H NMR free base (400MHz, DMSO-d6): delta 8.28 (1 H, d, J = 5 Hz), 8.1 1 (1 H, s), 7.45 (1 H, d, J = 8 Hz), 7.37 (1 H, d, J = 5 Hz), 7.18 (1 H, d, J = 8 Hz), 6.78 (1 H, d, J = 2 Hz), 6.73 (1 H, dd, J = 8, 2 Hz), 4.09 (1 H, m), 3.21 (1 H, septet, J = I Hz), 3.14 (2H, m), 2.81 (2H, m), 2.20 (3H, s), 1.24 (6H, d, J = 7 Hz).
To a solution of OH (7.0 g) in methanol (50 ml) was added 3-acetoxy-4-methylpyridine 1 - oxide (51; 1 5.0 g, 106 mmol). The mixture was stirred at room temperature overnight. The methanol was removed under vacuum and the residue was dissolved in water. The solution was neutralized to pH 7 with cone. HC1 and extracted with CH2CI2 and EtOAc. The extracts were combined, dried and concentrated to obtain 4-methylpyridin-3-ol (52; 8.40 g, 80% yield) as an oil. MS (ESI) calcd for C6H7NO (m/z) 109. 13.
With lithium hydroxide monohydrate; In tetrahydrofuran; water; for 6h;
Lithium hydroxide monohydrate (32.1 g, 764 mmol) was added to Intermediate 61 (127 g, 841 mmol) in THF (500 mL) and water (500 mL). After 6 h, THF was removed in vacuo, then DCM and 1M aqueous sodium hydroxide solution were added. The layers were separated. The aqueous phase was acidified with concentrated HC1 until the pH was approximately 4-5, then saturated with sodium chloride and extracted with EtOAc. The combined organic layers were washed with brine, dried (Na2S04), and evaporated in vacuo, to afford the title compound (19 g, 21%). deltaEta (300 MHz, CDC13) 10.72 (s, 1H), 8.16 (s, 1H), 7.93 (d, J4.9 Hz, 1H), 7.14 (d, J4.9 Hz, 1H), 2.31 (s, 3H)
1-(2-fluoro-4-iodophenyl)-3-(4-methoxybenzyl)-8-methyl-2,4,7-trioxo-pyrido[2,3-d]pyrimidin-5-yl trifluoromethanesulfonate[ No CAS ]
5-((4-methylpyridin-3-yl)oxy)-1-(2-fluoro-4-iodophenyl)-3-(4-methoxybenzyl)-8-methylpyrido[2,3-d]pyrimidine-2,4,7(1H,3H,8H)-trione[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
4-methyl-3-hydroxy-pyridine (44 mg, 0.40 mmol) and 1-(2-fluoro-4-iodophenyl)-3-(4-methoxybenzyl)-8-methyl-2,4,7-trioxo-pyrido[2,3-d]pyr imidin-5-yl trifluoromethanesulfonate 1j (140 mg, 0.20 mmol) were dissolved in 5 mL of tetrahydrofuran, followed by addition of sodium hydride (24 mg , 0.60 mmol). After stirring for 1 hour, the reaction was added with, and stirred for 12 hours. The reaction solution was concentrated under reduced pressure to obtain the crude title compound 5-((4-methylpyridin-3-yl)oxy)-1-(2-fluoro-4-iodophenyl)-3-(4-methoxybenzyl)-8-methy lpyrido[2,3-d]pyrimidine-2,4,7(1H,3H,8H)-trione 33a (128 mg, yellow liquid), which was used directly in the next step without further purification.
4,5,6,7-tetrahydro-3-[(4-methylpyridin-3-yl)oxy]-4-oxobenzo[c]thiophene-1-carboxylic acid ethyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
65%
With potassium carbonate; In ethyl acetate; toluene; at 80℃; for 16h;Sealed tube;
General procedure: In a sealed tube, a solution of 35 (2.0 g, 6.62 mmol) in EtOAc (5 mL)/toluene (5 mL) were added methanol (0.30 mL, 7.28 mmol) and K2CO3 (1.37 g, 9.93 mmol) at rt. The resulting mixture was stirred at 80 C for 16 h. The reaction mixture was diluted with water (20 mL) and extracted with EtOAc twice. The organic layers were washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, eluted with 15% EtOAc in hexane) to yield the title compound.
With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile); In tetrachloromethane; at 65℃; for 48h;Inert atmosphere;
The reaction bottle prior use of nitrogen to get rid of the air,Add CCl4300ml,<strong>[1121-19-3]3-hydroxy-4-methylpyridine</strong>1 g and azobisisobutyronitrile (AIBN) 165 mg,1.64 g of N-bromosuccinimide (NBS)65 reflux 48h.
1 mol of <strong>[1121-19-3]4-methyl-3-hydroxypyridine</strong> and 1.1 mol of di-tert-butyl dicarbonate (BOC2O) were heated under reflux for 10 hours. TLC showed complete reaction of the raw materials, and the reaction system was cooled to room temperature and diluted with ethanol. After cooling to 0 C, 0.9 mol of sodium borohydride was added, the addition was completed, and the mixture was stirred at 0 C for 2 hours. TLC showed the reaction was completed, then a 1 mol/L aqueous hydrochloric acid solution was added thereto, and extracted with methyl tert-butyl ether, and purified to obtain 1-tert-butoxycarbonyl-4-methyl-3-piperidone (0.86momicronl), yield 86%
0.5 mol of <strong>[1121-19-3]4-methyl-3-hydroxypyridine</strong> and 0.55 mol of acetyl chloride (AcCl) were dissolved in 10 volumes of tetrahydrofuran, and heated under reflux for 10 hours. TLC showed complete reaction of the raw materials, athe reaction system was cooled to room temperature and diluted with ethanol. After cooling to 0 C, 0.45 mol of sodium borohydride was added, the addition was completed, and the mixture was stirred at 0 C for 2 hours. TLC showed the reaction was completed, then a 1 mol/L aqueous hydrochloric acid solution was added thereto, and extracted with methyl tert-butyl ether, and purified to obtain 1-acetyl-4-methyl-3-piperidone (0.4 mol), yield 80%
Chemistry
Pharmaceutical Intermediates
Inhibitors/Agonists
Material Science
For Research Only
110K+ Compounds
Competitive Price
1-2 Day Shipping
