* 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 American Chemical Society, 1945, vol. 67, p. 1468,1469
2
[ 2524-52-9 ]
[ 141-78-6 ]
[ 26510-52-1 ]
Yield
Reaction Conditions
Operation in experiment
91%
Stage #1: With sodium ethanolate In ethanol; toluene at 26℃; for 1 h; Stage #2: at 90℃; for 18 h; Heating / reflux
Stir a mixture of sodium ethoxide (360 g, 5.29 mol), toluene (4 L), ethanol (18 mL, 0.265 mol), and ethyl acetate (1.04 L, 10.6 mol) in a 22 L flask equipped with a reflux condenser, nitrogen inlet, and mechanical stirrer. Stir for 1 h as the mixture warms to 26 °C. Add pyridine-2-carboxylic acid ethyl ester (Fluka; 400 g, 2.65 mol) and heat the mixture to reflux (90 °C) for 18 h. Cool the mixture to room temperature, dilute with toluene (8 L), wash with water (6 L), and separate the layers. Acidify the aqueous layer to pH 5 with glacial acetic acid. Extract with ethyl acetate (2 x 4 L), dry the combined organic layers (sodium sulfate), filter, and concentrate in vacuo to yield 466 g (91percent) the subtitled compound as a dark oil in 93percent purity by HPLC analysis. MS ES+ m/e 194 (M+1).
60%
With sodium methylate In benzene at 80℃; for 1 h; Heating / reflux
To 8 g of compound 130 in 30 mL of methanol. 11.8 ml of thionyl chloride was added slowly at 5° C. The mixture was allowed to stir for 30 min at room temperature, and was refluxed overnight. The reaction mixture was concentrated under high vacuum, then dissolve in sodium bicarbonate solution. Then compound was extracted into dichloromethane, then dried and concentrated to give a 70percent yield of compound 131. To 6 g of compound 131 in 100 mL benzene, 2.6 g of NaOMe was added. The reaction mass was heated to 80° C. and 5 ml of ethyl acetate was added to the reaction and further refluxed for an additional one hour. The reaction was neutralized with citric acid and extracted with dichloromethane. Removal of solvent afforded a 60percent yield of compound 132. To 4 g of compound 132 was added 40 mL of 20percent sulphuric acid, which was then refluxed for two hours. Then reaction mixture was neutralized with the sodium hydroxide, extracted into dichloromethane, and concentrated to give a yield of 60percent of desired compound 133. To a 1 liter round bottom flask with 150 mL of DMF was added compound 133 added at 0° C. To the reaction mixture was added hydrogen peroxide and ferrous sulphate heptahydrate simultaneously at 0° C. The reaction mixture was allowed to stir overnight. The reaction mixture was poured in the water, then extracted with dichloromethane. The organic layer was dried over sodium sulphate and concentrated to afford 2percent of desired compound 134. To 1 g of compound 134 in 10 mL benzene was added 0.8 g of sodium methoxide. The reaction mixture was heated gently to reflux, and allowed to stir for two hours. The reaction mixture was neutralized with citric acid then extracted with ethyl acetate. The organic layer was dried and concentrated to give 80percent yield of the compound 135. To 200 mg of compound 135 in ethanol was added methyl hydrazine. The mixture was allowed to stir for six hours at room temperature. Then reaction mixture was neutralized with sodium bicarbonate and extracted with ethyl acetate. The organic layer was then dried and concentrated to afford a 50percent yield of the final compound 136.
1.87 g
Stage #1: With sodium ethanolate In ethanol; toluene at 20℃; for 1 h; Stage #2: at 90℃; for 14 h;
6-1. Synthesis of Compound (15)1.35 g of sodium ethoxide, 8.7 g of ethyl acetate and 0.05 g of ethanol were suspended in 100 ml of toluene. After stirring at room temperature for 1 hour, a solution of 1.5 g of ethyl picolinate (14) in 10 ml of toluene was added and stirred at 90 ° C. for 14 hours. After completion of the reaction, the reaction mixture was poured into water and extracted twice with toluene. The organic layers were combined, washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to give ethyl 3-oxo-3- (pyridin-2-yl) propionate (15)1.87 g was obtained.
Reference：
[1] Patent: WO2005/92894, 2005, A1, . Location in patent: Page/Page column 22
[2] Asian Journal of Chemistry, 2015, vol. 27, # 5, p. 1667 - 1670
[3] Patent: US2007/203154, 2007, A1, . Location in patent: Page/Page column 54-55
[4] Helvetica Chimica Acta, 1955, vol. 38, p. 1289
[5] Journal of the American Chemical Society, 1948, vol. 70, p. 2755,2757
[6] Journal of the Chemical Society, 1938, p. 753
[7] Patent: WO2004/50659, 2004, A1, . Location in patent: Page 31-32
[8] Patent: JP5743418, 2015, B2, . Location in patent: Paragraph 0129; 0130; 0131
3
[ 2459-07-6 ]
[ 141-78-6 ]
[ 26510-52-1 ]
Yield
Reaction Conditions
Operation in experiment
87%
With lithium hexamethyldisilazane In tetrahydrofuran at -50℃; for 0.5 h;
General procedure: To the solution of ethyl acetate (60 mol), aryl ester (10 mol) in dry THF (20 mL), LiHMDS (30 mol) was added quickly at -50 °C and stirred at this temperature for 30 min. The reaction was monitored by TLC and it was quenched with acetic acid (20 mol) and water (25 mL), basified with sat. solution of sodium bicarbonate (20 ml) and extracted with ethyl acetate (2 .x. 20 mL). The combined organic extract was washed with water (10 mL) and brine solution (10 mL) and dried over anhyd Na2SO4. The crude product was purified by column chromatography (hexane/ethyl acetate, 20:80) to get the pure product
Stage #1: With ethanol; sodium ethanolate In toluene at 26℃; for 1 h; Stage #2: at 90℃; for 18 h;
A. Preparation of 3-Oxo-3-(pyridin-2-yl)-propionic acid ethyl ester; Stir a mixture of sodium ethoxide (360 g, 5.29 mol), toluene (4 L), ethanol (18 mL, 0.265 mol), and ethyl acetate (1.04 L, 10.6 mol) in a 22 L flask equipped with a reflux condenser, nitrogen inlet, and mechanical stirrer. Stir for 1 h as the mixture warms to 26°C. Add pyridine-2-carboxylic acid ethyl ester (Fluka; 400 g, 2.65 mol) and heat the mixture to reflux (90 0C) for 18 h. Cool the mixture to room temperature, dilute with toluene (8 L), wash with water (6 L), and separate the layers. Acidify the aqueous layer to pH 5 with glacial acetic acid. Extract with ethyl acetate (2 x 4 L), dry the combined organic layers (sodium sulfate), filter, and concentrate in vacuo to yield 466 g (91percent) the subtitled compound as a dark oil in 93percent purity by HPLC analysis. MS (ES) m/z = 194 (M+H).
With lithium hexamethyldisilazane In tetrahydrofuran at -40℃; for 0.333333 h; Inert atmosphere
General procedure: To the solution of ester (10 mmol) in THF (20 mL) and ethyl acetate (70 mmol), LiHMDS (30 mmol) was added very quickly at -40 °C, and stirred at this temperature for 20 min. After completion of the reaction, reaction mixture was quenched with acetic acid (50 mmol) and then basified using 10percent NaHCO3 solution, extracted with ethyl acetate (2.x.100 mL), the combined organic layer was washed with water and brine solution and dried over Na2SO4. The specific purification procedure for each compound has been included along with their characterization data.
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 12, p. 4193 - 4197
6
[ 1122-62-9 ]
[ 105-58-8 ]
[ 26510-52-1 ]
Reference：
[1] Synthesis, 2005, # 4, p. 555 - 558
[2] MedChemComm, 2016, vol. 7, # 5, p. 832 - 836
[3] Arkivoc, 2014, vol. 2014, # 2, p. 135 - 149
[4] Bioorganic and Medicinal Chemistry, 2017, vol. 25, # 15, p. 3922 - 3946
Stir a mixture of sodium ethoxide (360 g, 5.29 mol), toluene (4 L), ethanol (18 mL, 0.265 mol), and ethyl acetate (1.04 L, 10.6 mol) in a 22 L flask equipped with a reflux condenser, nitrogen inlet, and mechanical stirrer. Stir for 1 h as the mixture warms to 26 C. Add pyridine-2-carboxylic acid ethyl ester (Fluka; 400 g, 2.65 mol) and heat the mixture to reflux (90 C) for 18 h. Cool the mixture to room temperature, dilute with toluene (8 L), wash with water (6 L), and separate the layers. Acidify the aqueous layer to pH 5 with glacial acetic acid. Extract with ethyl acetate (2 x 4 L), dry the combined organic layers (sodium sulfate), filter, and concentrate in vacuo to yield 466 g (91%) the subtitled compound as a dark oil in 93% purity by HPLC analysis. MS ES+ m/e 194 (M+1).
60%
With sodium methylate; In benzene; at 80℃; for 1h;Heating / reflux;
To 8 g of compound 130 in 30 mL of methanol. 11.8 ml of thionyl chloride was added slowly at 5 C. The mixture was allowed to stir for 30 min at room temperature, and was refluxed overnight. The reaction mixture was concentrated under high vacuum, then dissolve in sodium bicarbonate solution. Then compound was extracted into dichloromethane, then dried and concentrated to give a 70% yield of compound 131. To 6 g of compound 131 in 100 mL benzene, 2.6 g of NaOMe was added. The reaction mass was heated to 80 C. and 5 ml of ethyl acetate was added to the reaction and further refluxed for an additional one hour. The reaction was neutralized with citric acid and extracted with dichloromethane. Removal of solvent afforded a 60% yield of compound 132. To 4 g of compound 132 was added 40 mL of 20% sulphuric acid, which was then refluxed for two hours. Then reaction mixture was neutralized with the sodium hydroxide, extracted into dichloromethane, and concentrated to give a yield of 60% of desired compound 133. To a 1 liter round bottom flask with 150 mL of DMF was added compound 133 added at 0 C. To the reaction mixture was added hydrogen peroxide and ferrous sulphate heptahydrate simultaneously at 0 C. The reaction mixture was allowed to stir overnight. The reaction mixture was poured in the water, then extracted with dichloromethane. The organic layer was dried over sodium sulphate and concentrated to afford 2% of desired compound 134. To 1 g of compound 134 in 10 mL benzene was added 0.8 g of sodium methoxide. The reaction mixture was heated gently to reflux, and allowed to stir for two hours. The reaction mixture was neutralized with citric acid then extracted with ethyl acetate. The organic layer was dried and concentrated to give 80% yield of the compound 135. To 200 mg of compound 135 in ethanol was added methyl hydrazine. The mixture was allowed to stir for six hours at room temperature. Then reaction mixture was neutralized with sodium bicarbonate and extracted with ethyl acetate. The organic layer was then dried and concentrated to afford a 50% yield of the final compound 136.
Stir a mixture of sodium ethoxide (360 g, 5.29 mol, 2 EQ), toluene (4 L), ethanol (18 mL, 0.265 mol, 0.1 eq) and ethyl acetate (1.04 L, 10.58 mol, 4 eq) in a 22 L flask equipped with a reflux condenser, nitrogen inlet and mechanical stirrer. Stir for 1 h as the mixture warms to 26 C. Add pyridine-2-carboxylic acid ethyl ester (Fluka ; 400 g, 2.65 mol, 1 eq) and heat the mixture to reflux (90 C) for 18 h. Cool the mixture to room temperature. Dilute with toluene (8 L), wash with water (6 L), and separate the layers. Acidify the aqueous layer to pH 5 with glacial acetic acid. Extract with ethyl acetate (2 x 4 L), dry the combined organic layers (sodium sulfate), filter and concentrate in vacuo to yield the subtitled compound (466 g, 91 % yield) as a dark oil in 93% purity by HPLC analysis. MS ES+ m/e 194 (M+1).
1.87 g
6-1. Synthesis of Compound (15)1.35 g of sodium ethoxide, 8.7 g of ethyl acetate and 0.05 g of ethanol were suspended in 100 ml of toluene. After stirring at room temperature for 1 hour, a solution of 1.5 g of ethyl picolinate (14) in 10 ml of toluene was added and stirred at 90 C. for 14 hours. After completion of the reaction, the reaction mixture was poured into water and extracted twice with toluene. The organic layers were combined, washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to give ethyl 3-oxo-3- (pyridin-2-yl) propionate (15)1.87 g was obtained.
A. Preparation of 3-Oxo-3-(pyridin-2-yl)-propionic acid ethyl ester; Stir a mixture of sodium ethoxide (360 g, 5.29 mol), toluene (4 L), ethanol (18 mL, 0.265 mol), and ethyl acetate (1.04 L, 10.6 mol) in a 22 L flask equipped with a reflux condenser, nitrogen inlet, and mechanical stirrer. Stir for 1 h as the mixture warms to 26C. Add pyridine-2-carboxylic acid ethyl ester (Fluka; 400 g, 2.65 mol) and heat the mixture to reflux (90 0C) for 18 h. Cool the mixture to room temperature, dilute with toluene (8 L), wash with water (6 L), and separate the layers. Acidify the aqueous layer to pH 5 with glacial acetic acid. Extract with ethyl acetate (2 x 4 L), dry the combined organic layers (sodium sulfate), filter, and concentrate in vacuo to yield 466 g (91%) the subtitled compound as a dark oil in 93% purity by HPLC analysis. MS (ES) m/z = 194 (M+H).
Example 94: N-(5-tert-Butyl-3-metha. nesulfonylamino-2-methoxy-phenyl)-3- [4- (l- cyclopropyl-5-pyridin-2-yl-IH-pyrazoll-4-yl)- [1, 2,3] triazol-1-yl]-4-methyl- benzamide; A solution of isopropylmagnesium bromide (2M in Et2O ; 36.5 mL, 73.0 mmol) was added to 4.36 mL (36.6 mmol) of malonic acid monoethyl ester in 30 mL of THF under N2 at 0 C. The reaction was stirred at 0 C for 30 min, at room temperature for 30 rnin, and then at 40 C for 30 min. The mixture was subsequently cooled to 0 C and a imidazol-l-yl-pyridin-2-yl-methanone solution (prepared by stirring 3.00 g (24.3 mrnol) of pyridine-2-carboxylic acid with 4.7 g (29 mmol) of CDI in 30 mL of THF for 12h) was slowly added. The reaction was allowed to warm to room temperature and stirred for 12 h. The mixture was then poured into ice cold 1M H3P04 (150 mL). Solid NaHCOs was added to the mixture until the pH reached 7. The mixture was extracted with EtOAc (3 x 100 mL). The combined organic extracts were washed with NaHCO3 (100 mL) and brine, dried with MgS04, filtered, and concentrated to provide 2.5 g ethyl 3-oxo-3-pyridin-2-yl-propionate as an oil.
(prepared according to an analogous procedure described in Polish J. Chem., 56 (1982) p 963) 3-Oxo-3-(pyridin-2-yl)propionic acid ethyl ester (2 g, 0.01035 mol) and 5-methyl-2H-pyrazol-3-ylamine (1 g, 1 eq) were heated together at 140 C. for 2 h; after cooling to rt, the solid residue was stirred with EtOAc and the solid collected by filtration to give 1.84 g of 2-methyl-5-pyridin-2-yl-4H-pyrazolo[1,5-a]pyrimidin-7-one.
73 ml of diethyl carbonate was added to a mixture of 30 g of hexane-washed sodium hydride and 150 ml of benzene, and the resulting mixture was heated at reflux temperature for 30 minutes, when 33 ml of 2-acetylpyridine was added dropwise over 60 minutes. The mixture was cooled to room temperature, 75 ml of glacial acetic acid and 250 ml of water were added, and the mixture was extracted with diethyl ether. The extract was dried, stripped of solvent and the residue was distilled in a Kugelrohr apparatus to give 6A.
With sodium ethanolate; sodium; In ethanol; water; acetic acid; ethyl acetate; benzene;
EXAMPLE 6 Diethyl 2-methyl-5-(2-pyridinyl)pyrrole-3,4-dicarboxylate (6) 5.75 g of sodium was treated with 100 ml of ethanol, the unreacted ethanol was stripped and the solid sodium ethoxide was dried by azeotroping with benzene. The sodium ethoxide was mixed with 150 ml of benzene, the mixture was stirred and heated to reflux and a mixture of 25 g of ethyl picolinate and 32.3 ml of ethyl acetate was added dropwise over 15 minutes. Then the mixture was stirred for 30 minutes and cooled. After 150 ml of water was added, glacial acetic acid was added until the mixture was acidic. The two liquid phases were separated. The organic phase was dried (Na2 SO4), stripped of solvent and distilled in a Kugelrohr apparatus to give ethyl 3-(2-pyridinyl)-3-oxopropanoate (6A), as a light yellow oil, b.p.: 95-110/0.05 Torr. 6A also was prepared as follows:
Phenyl azide (596 mg) was dissolved in methanol (50 ml) , and ethyl 3-oxo-3- (pyridin-2-yl) propaoate (1.06 g) was added thereto at room temperature. Next, a 28% solution -of sodium methoxide in methanol (1.06 g) was added dropwise thereto, and 'the mixture was stirred at 6O0C for 3 hr. A l N aqueous sodium hydroxide solution (5 ml) was added thereto and stirred at 500C for 1 hr. The reaction mixture was neutralized with 1 N hydrochloric acid. The liberated oil was washed with ethyl acetate (10 ml x 2) and removed. The aqueous layer was concentrated and dried, and the residue was then subjected to silica gel column chromatography. The fraction eluted with ethyl acetate-methanol (10:1 to 5:1) was concentrated in vacuo, and the crystals were collected by filtration to give the desired product (150 mg) .1H-NMR (DMSO-de) delta 7.24-7.43 (5H, m) , 7.52 (IH, s), 7.83-7.89 (2H, m), 8.03 (IH, t), 8.40 (IH, d)
To 8 g of compound 130 in 30 mL of methanol. 11.8 ml of thionyl chloride was added slowly at 5 C. The mixture was allowed to stir for 30 min at room temperature, and was refluxed overnight. The reaction mixture was concentrated under high vacuum, then dissolve in sodium bicarbonate solution. Then compound was extracted into dichloromethane, then dried and concentrated to give a 70% yield of compound 131. To 6 g of compound 131 in 100 mL benzene, 2.6 g of NaOMe was added. The reaction mass was heated to 80 C. and 5 ml of ethyl acetate was added to the reaction and further refluxed for an additional one hour. The reaction was neutralized with citric acid and extracted with dichloromethane. Removal of solvent afforded a 60% yield of compound 132. To 4 g of compound 132 was added 40 mL of 20% sulphuric acid, which was then refluxed for two hours. Then reaction mixture was neutralized with the sodium hydroxide, extracted into dichloromethane, and concentrated to give a yield of 60% of desired compound 133. To a 1 liter round bottom flask with 150 mL of DMF was added compound 133 added at 0 C. To the reaction mixture was added hydrogen peroxide and ferrous sulphate heptahydrate simultaneously at 0 C. The reaction mixture was allowed to stir overnight. The reaction mixture was poured in the water, then extracted with dichloromethane. The organic layer was dried over sodium sulphate and concentrated to afford 2% of desired compound 134. To 1 g of compound 134 in 10 mL benzene was added 0.8 g of sodium methoxide. The reaction mixture was heated gently to reflux, and allowed to stir for two hours. The reaction mixture was neutralized with citric acid then extracted with ethyl acetate. The organic layer was dried and concentrated to give 80% yield of the compound 135. To 200 mg of compound 135 in ethanol was added methyl hydrazine. The mixture was allowed to stir for six hours at room temperature. Then reaction mixture was neutralized with sodium bicarbonate and extracted with ethyl acetate. The organic layer was then dried and concentrated to afford a 50% yield of the final compound 136.
With acetic acid; sodium nitrite; In water; at 20℃; for 4h;
Example C-1; 2-(2,6-difluorophenyl)-4-(pyridin-2-yl)-1H-imidazole-5-carboxamide; Step a - ethyl 2-(hydroxyimino)-3-oxo-3-(pyridin-2-yl)propanoate; To a stirred solution of ethyl picolinoylacetate (0.50Og, 2.6mmol) in acetic acid (0.5mL) was added a solution of sodium nitrite (0.238g, 3.4mmol) in water (0.5ml_), dropwise. The resulting solution was stirred at room temperature for 2 hours after which water (0.5mL) was added and the reaction was stirred for a further 2 hours. The mixture was extracted with Et2O and the combined organic phase was washed with water, saturated sodium bicarbonate solution and brine, dried over MgSO4 and the solvent removed in vacuo to afford ethyl 2-(hydroxyimino)-3-oxo-3-(pyridin-2-yl)propanoate (0.353g, 1.6mmol, 61%) as a white solid. 1H NMR (DMSO) delta 1.17 (3H, t), 4.22 (2H, q), 7.74 (1 H, m), 8.04-8.11 (2H, m), 8.74 (1 H, m), 12.87 (1 H, s). LCMS (2) Rt: 1.09min; m/z (ES+) 223.
With sodium ethanolate; In ethanol; at 20 - 70℃; for 24 - 76.5h;Product distribution / selectivity;
Intermediate 15: 1 -(2-Fluorophenyl)-5-pyridin-2-yl-1 H-1 ,2,3-triazole-4-carboxylic acidTo a solution of ethyl picolinoylacetate (0.77 g; 4.01 mmol; 1.10 eq.) and 1-azido-2- fluorobenzene, prepared according to Platz, M. S. et al. J. Org. Chem. 1989, 54, 5938-5945 (0.50 g; 3.65 mmol; 1 eq.), in EtOH (25 mL) under argon was added sodium ethoxide (0.50 g; 7.29 mmol; 2 eq.). The reaction mixture was heated to 70C for 4.5 h and stirred for 3 days at RT. A 5 N solution of NaOH (3.65 mL) was added and the reaction mixture was stirred for 2h at RT. Once the saponification was complete, the mixture was diluted with water (20 mL), and washed with ether (2x20 mL). After cooling to 0C, the aqueous layer was adjusted to a pH = 4 with HCI (5 N), and the product was extracted with EtOAc (3x30 mL). The combined organic layers were washed with brine (20 mL) and dried over MgSO4. The solvents were evaporated and the product was dried to afford Intermediate 15 as an off-white solid. 1H- NMR (DMSO-de, 300MHz) delta 13.45 (s, 1 H), 8.47 (d, J = 4.80 Hz, 1 H), 7.96 (dt, J = 7.96 Hz, J = 1.71 Hz, 1 H), 7.86 (d, J = 7.86 Hz, 1 H), 7.68-7.58 (m, 2H), 7.47-7.35 (m, 3H). LC/MS: 284.74 (M+H)+. HPLC (Method A) Rt 2.30 min (Purity: 100%).; Intermediate 53: Ethyl 1 -(2-fluorophenyl)-5-pyridin-2-yl-1 H-1 ,2,3-triazole-4-carboxylateTo a solution of 1 -azido-2-fluorobenzene (25 g; 182 mmol; 1 eq.) and ethyl picolinoylacetate (38.04 g; 196.9 mmol; 1.08 eq.) in EtOH (250 ml) under argon was added portionwise sodium ethoxide (24.8 g; 365 mmol; 2 eq.) and the mixture was stirred at 7OC for 24h. The suspension was filtered and the resulting solid was washed with EtOH (2x100 mL). Combined filtrate was concentrated. NaOH 1 N (400 mL) was added to the residue and was extracted with ethyl acetate (2x250 mL). Organic layers were dried over MgSO4, affording <n="124"/>Intermediate 53 as a brown solid. 1H-NMR (DMSO-d6, 300MHz) delta 8.47-8.43 (m, 1 H), 7.93 (dt, J=1 .76, 7.80Hz, 1 H), 7.84 (td, J=1.15, 7.80Hz, 1 H), 7.67-7.55 (m, 2H), 7.46-7.31 (m, 3H), 4.26 (q, J=7.11 Hz, 2H), 1.18 (t, J=7.11 Hz, 3H). LC/MS (Method B): 313.2 (M+H)+; 309.2 (M- H)-. HPLC (Method A) Rt 3.23 min (Purity: 94.8%).
To 10 ml of methanol, 12.5 g of sodium methoxide (28% methanol solution) , 5 g of acetoamidine hydrochloride and 2.5 g of 3-OXO-3- (2-pyridyl) propanoic acid ethyl ester were added. This mixture was heated under reflux for 20 hours. The reaction mixture was left standing to cool and then concentrated. To the residue, 10% hydrochloric acid was added. A precipitated crystal was collected by filtration and then washed with water and hexane to obtain 1.7 g of 2- methyl-6- (2-pyridyl) pyrimidin-4-ol . 2-methyl-6- (2-pyridyl ) pyrimidin-4-ol 1H-NMR (DMSO-d6): 2.39(s,3H), 7.06(s,lH), 7.48-7.50 (m, IH) , 7.93-7.98 (m, IH) , 8.26(d,lH), 8.68-8.70 (m, IH) , 12.57(bs,lH)
With lithium hexamethyldisilazane; In tetrahydrofuran; at -50℃; for 0.5h;
General procedure: To the solution of ethyl acetate (60 mol), aryl ester (10 mol) in dry THF (20 mL), LiHMDS (30 mol) was added quickly at -50 C and stirred at this temperature for 30 min. The reaction was monitored by TLC and it was quenched with acetic acid (20 mol) and water (25 mL), basified with sat. solution of sodium bicarbonate (20 ml) and extracted with ethyl acetate (2 × 20 mL). The combined organic extract was washed with water (10 mL) and brine solution (10 mL) and dried over anhyd Na2SO4. The crude product was purified by column chromatography (hexane/ethyl acetate, 20:80) to get the pure product
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