* 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.
To a suspension of 3-hydroxypicolinic acid 1 (10 g, 72 mmol, 1equiv) in methanol (150 mL, 0.5 M) was added dropwise at 0 °C aconcentrated sulfuric acid (12 mL, 216 mmol, 3 equiv.). The obtainedsolution was stirred at reflux 6 h. The cooled reaction mixture wasconcentrated under reduced pressure. The pH was adjusted at 8.5 withan aqueous solution of saturated NaHCO3 and solid NaHCO3. Theaqueous layer was extracted with EtOAc and the combined organiclayer was washed with brine, dried over MgSO4 and concentrated underreduced pressure to give 2 as a white solid (10.9 g, 99percent). Rf=0.3(Petroleum ether/EtOAc 1/1, v/v). m.p. = 74 °C. 1H NMR (300 MHz,CDCl3): δ (ppm)=4.06 (s, 3H), 7.34 (dd, J=3.9, 8.4 Hz, 1H), 7.38(dd, J=1.5, 8.4 Hz, 1H), 8.38 (dd, J=1.5, 3.9 Hz, 1H), 10.64 (s, 1H).13C NMR (75 MHz, CDCl3): δ=53.2, 126.3, 129.8, 130.2, 141.6, 158.9,169.9. MS (ESI+): m/z (percent): 154 (100) [M+H]+.
93.1%
for 24 h; Inert atmosphere; Reflux
To a stirred mixture of 3-thydroxypicolinic acid (10 g, 71.9 mmol) in 350 mL CH3OH and 5 mL H2SO4 was added several drops benzene as dehydrate; the resulting mixture was refluxed for another 24 h under the protection of nitrogen. After cooled to room temperature (rt), the mixture was poured into brine and extracted with ethyl acetate (EA). The organic layer was washed with brine for three times and then dried over anhydrous Na2SO4. After removal of the solvent, the intermediate (2) was gained as a white solid (11.0 g, 93.1percent). 1H NMR (CDCl3, 400 MHz), δ (ppm): 7.68-7.62 (m, 2H), 7.52-7.50 (d, J=7.92 Hz, 2H), 7.45-7.43 (d, J=7.92 Hz, 2H), 4.28-4.25 (t, J=12.4 Hz, 2H), 3.94 (s, 3H), 1.94-1.89 (m, 4H), 1.62-1.57 (m, 2H), 1.25-1.04 (m, 14H), 0.84-0.81 (t, J=11.8 Hz, 3H), 0.59-0.58 (m, 4H).
85%
at 83℃;
To a solution of compound 20A (100.0 g, 0.719 mol, 1.0 eq) in methanol (1.5 L) was added cone, sulfuric acid (120 mL, 2.157 mol, 3.0 eq) and the reaction mixture was heated to reflux (83 °C) overnight. The solvent was removed in vacuo, and the residue was diluted with water (1.5 L), and adjusted to pH 8.5 with solid K2CO3, then extracted with DCM (3 x 1 L). The organic phases were dried over sodium sulfate and concentrated under reduced pressure to give compound 20B (94 g, 85percent) as a slightly blue solid. JH NMR (400 MHz, CDCI3) δ 10.61 (s, 1H), 8.28 (dd, / = 4.1, 1.4 Hz, 1H), 7.42 (dd, / = 8.5, 4.2 Hz, 1H), 7.37 (dd, / = 8.5, 1.5 Hz, 1H), 4.05 (s, 3H)
83%
at 0℃; for 24 h; Reflux
3-Hydroxypicolinic acid (5.0 g, 35.94 mmol) was dissolved in methanol (120 mL). To the resulting solution was slowly added dropwise sulfuric acid (5.75 mL, 107.83 mmol) at 0 °C and the solution was refluxed with heat for 24 hrs, cooled to room temperature, and evaporated under reduced pressure. The resulting residue was diluted with dichloromethane and distilled water, neutralized with 6N sodium hydroxide, and extracted with dichloromethane. The organic solvent was dried over anhydrous magnesium sulfate (MgSO4) to concentrate. The resulting residue was isolated and purified by silica gel column chromatography (hexane/ethylacetate = 1/1) to give the white title compound (4.62 g, 83 percent). 1H NMR (600 MHz, CDCl3) δ 8.28 (dd, J = 1.2, 2.4 Hz, 1H), 7.43 (dd, J = 4.2, 4.2 Hz, 1H), 7.38, (dd, J = 1.2, 7.2 Hz, 1H), 4.06 (s, 3H).
82.8%
at 80℃;
A solution of 3-hydroxypicolinic acid (30 g, 0.22 mol) in CH3OH (300 mL) was stirred at RT and cone. H2S04 (30 mL) was added dropwise. The resulting mixture was stirred at 80 °C overnight. After the pH was adjusted to 7 with solid Na2C03, the mixture was filtrated and the precipitate was thoroughly washed with EtOAc several times. The filtrate was concentrated to give crude methyl 3-hydroxypicolinate (27 g, yield: 82.8 percent). 1H- MR (CDC13, 400 MHz) δ 10.57 (s, 1H), 8.22-8.20 (m, 1H), 7.32-7.29 (m, 1H), 3.93 (s, 3H). MS (M+H)+: 154.
80%
Stage #1: for 24 h; Reflux Stage #2: With potassium carbonate In water
H2SO4 (1.8 mL, 3 equiv) was added dropwise to a suspension of 3-hydroxypicolinic acid 7 (1.5 g, 10.5 mmol) in MeOH (24 mL). The mixture was refluxed for 24 h. Then, the mixture was basified with a solution of K2CO3 (pH 8.5). The aqueous layer was extracted with EtOAc, and the organic layer was dried over MgSO4 and concentrated under reduced pressure to give desired methyl ester 8 (1.28 g, 80percent) as a white solid. 1H and 13C NMR data were in agreement with those given in the literature.refPreviewPlaceHolder18 L. Louise-Leriche, E. Punescu, G. Saint-Andre, R. Baati, A. Romieu, A. Wagner and P.-Y. Renard. Chem.-Eur. J., 16 (2010), pp. 3510-3523. 18
79%
for 18 h; Reflux
A mixture of 3-hydroxypicolinic acid (2 g, 14.1 mmol) in MeOH (100 mL) containing concentrated H2SO4 (4 mL) was refluxed for 18 h. The mixture was concentrated to about 40 mL, diluted with water (150 mL), adjusted to pH around 6 with Na2CO3, and then extracted with CHCl3 (100 mL.x.3). The combined organic extracts were washed with water, brine and dried over Na2SO4, filtered, and the filtrate was concentrated to give 1.71 g (79percent) of methyl 3-hydroxy-2-pyridinecarboxylate as off-white crystals. 1H NMR (400 MHz, CDCl3): δ 10.63 (s, 1H), 8.30-8.25 (m, 1H), 7.50-7.35 (m, 2H), 4.06 (s, 3H); LRMS (ESI), m/z 154 (M+H).
65%
With sulfuric acid; water In benzene for 24 h; Inert atmosphere; Reflux
In 500mL single-neck flask fitted with a water separator, were added sequentially 4. 17g namely 0. 03mol 3-hydroxy-2-pyridine carboxylic acid, 350mL of anhydrous methanol, and then slowly added dropwise 6mL of concentrated sulfuric acid and 10mL benzene, under a nitrogen blanket reflux 24h. The reaction was stopped, cooled to room temperature, spin most methanol, with sodium hydroxide solution 2mol / L pH is adjusted to 4. 0~5. 0, extracted three times with 30mL dichloromethane and the combined organic phase was dried over anhydrous magnesium dried overnight, filtered, and the solvent under reduced pressure to spin, to give an off-white solid was dried in vacuo to give product 3. 0g, 65percent yield
64%
Stage #1: for 120 h; Heating / reflux Stage #2: With potassium carbonate In methanol; water
Reference Example 3; 4- (6-formγl-5-methoxγpγridin-2-γl) benzonitrile; (step 1); A solution of 3-hydroxypicolinic acid (50.9 g) and cone, sulfuric acid (40 iαL) in methanol (500 mL) was heated under reflux for 5 days. The reaction mixture was concentrated under reduced pressure, and the residue was poured into cold water. The mixture was basified with potassium carbonate, and extracted twice with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (solvent gradient; 0-50percent ethyl acetate/hexane) and crystallized from ethyl acetate/hexane to give methyl 3-hydroxypyridine-2- carboxylate (35.5 g, 64percent) as white crystals.
45%
for 6 h; Heating / reflux
A mixture of 3-hydroxypicolic acid (1.39 g, 10.0 mmol) and HCl (2 M in methanol, 60 ml) was refluxed for 6 hours. The solvent was removed under reduced pressure and the residue was neutralized with saturated aqueous NaHCO3 solution, extracted with ethyl acetate, dried (MgSO4) and evaporated under reduced pressure to give methyl 3- hydroxypicolinate (687 mg, 45 percent, colorless solid).
32%
at 64℃; for 24 h;
In a 500 ml_ round-bottorned flask fitted with a condenser-and a magnetic stirrer were placed MeOH (250 mL), S-hydroxypyridine^-carboxylic acid 1 (10.0 g, 72 mmol) and concentrated H^SO4 (3 mL). The reaction mix was heated to 64°C for 24 hours. The reaction mix was cooled to room temperature. The solvent was removed under reduced pressure; the residue was partitioned between ethyl acetate (150 mL) and water (20 mL). Solid sodium carbonate was added to adjust the pH to 6. The organic layer was separated, dried over Na2SO4, and concentrated to give crude 3.5 g of intermediate 2 (32percent yield).
23%
Inert atmosphere; Reflux
3-hydroxy picolinic acid (1.0 g, 7.19 mmol) in methanol (15 ml) solution was added dropwise concentrated sulfuric acid (200 μl). Under an argon atmosphere, and stirred under reflux conditions overnight. After completion of the reaction, concentrated to dryness. Saturated saline, a saturated aqueous solution of sodium hydrogen carbonate was added, and the mixture was extracted with chloroform. Dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. To give the title compound (250 mg, 23percent).
Reference：
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2
[ 874-24-8 ]
[ 62733-99-7 ]
Yield
Reaction Conditions
Operation in experiment
64%
With sulfuric acid In methanol
Step 1 Production of Methyl 3-hydroxypicolinate 3-Hydroxypicolinic acid (1.0 g) was suspended in methanol (10 ml) and concentrated sulfuric acid (1.0 ml) was added. The mixture was refluxed under heating for 5 hr. The reaction mixture was ice-cooled, neutralized with saturated aqueous sodium hydrogencarbonate, and extracted with chloroform. The organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give the title compound (711 mg, yield 64percent). 1H-NMR (300 MHz, CDCl3): 10.63 (1H, s), 8.28 (1H, dd, J=3.7, 1.8 Hz), 7.47-7.35 (2H, m), 4.06 (3H, s).
With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 18 h;
In a 50 mL round-bottomed flask fitted with a magnetic stirrer were placed intermediate 2 (3.5 g, 22.8 mmol), potassium carbonate (3.46 g, 25.0 mmol), methyl iodide (4.87 g, 34.3 mmol) and DMF (20 mL). The reaction mix was stirred for 18 h at room temperature under nitrogen. The reaction mix was diluted with ethyl acetate (30 mL) and water (10 mL). The organic layer was separated and aqueous layer was extracted with ethyl acetate. The combined organic extracts were dried over Na2SO4 and concentrated to give crude product, which was then purified by column chromatography using 30percent ethyl acetate in hexane, to give 2.1 g of intermediate 3 (54percent yield).
2.1 g
With potassium carbonate In N,N-dimethyl-formamide for 18 h; Inert atmosphere
In a 50 mL round-bottom flask fitted with magnetic stirrer were placed 3-hydroxypyridine-2-carboxylic acid methyl ester (3.5 g, 22.80 mmol), K2CO3 (3.46 g, 25.0 mmol), MeI (4.87 g, 34.3 mmol) and DMF (20 mL). The reaction mixture was stirred for 18 h at it under nitrogen. The reaction mixture was diluted with EtOAc (30 mL) and water (10 mL). The organic layer was separated and aqueous layer was extracted with EtOAc. The combined organic extracts were dried over Na2SO4 and concentrated to give the crude product. The crude product was purified by column chromatography using 30percent EtOAc in hexane to give 2.1 g of 3-methoxypyridine-2-carboxylic acid methyl ester (54percent).
At room temperature, Br2 (2.7 mL, 3 equiv) was added to a suspension of methyl ester 8 (2.7 g, 6.5 mmol) in water (200 mL). The mixture was stirred for 20 h at room temperature. The solution was extracted with dichloromethane, and the organic layer was washed with an aqueous solution of sodium thiosulfate, with brine, dried over MgSO4, and concentrated under reduced pressure to give desired compound 9 (4.0 g, 76percent) as a white powder. 1H NMR (300 MHz, CDCl3) δ (ppm) 4.06 (s, 3H), 7.86 (s, 1H), 11.35 (br s, 1H). 13C NMR (75 MHz, CDCl3) δ 53.9, 124.7, 129.9, 130.2, 136.9, 156.0, 168.8. MS (ESI-) m/z: 312 (40), 310 (100), 308 (45).
With bromine In water at 0℃; regioselective reaction;
2.2.2. Synthesis of methyl 3-hydroxy-6-bromopicolinate (Compound 3)
To a solution of methyl 3-hydroxypicolinate 2 (10 g, 65.36 mmol) inosmosed water (0.1 M) with crushed ice at 0 °C, was added portionwisebromine (4×1.02 mL every 30 min, 78.4 mmol, 1.2 equiv) under vigorousstirring. The mixture was vigorously stirred at 0 °C for 1-2 h. Thesolution was extracted by dichloromethane and the combined organiclayers were washed with brine, dried over MgSO4 and concentratedunder reduced pressure to give 3 as a white-off solid (15.1 g, 99%).Rf=0.3 (Petroleum ether/EtOAc 3/2, v/v). 1H NMR (300 MHz, CDCl3)δ (ppm)=4.07 (s, 3H), 7.29 (d, J=8.7 Hz, 1H), 7.58 (dd, J=0.3,8.7 Hz, 1H), 10.72 (br s, 1H). 13C NMR (75 MHz, CDCl3) δ(ppm)=53.5, 129.5, 130.0, 130.7, 134.5, 158.5, 169.1. MS (ESI+): m/z (%): 234 (85) and 232 (100) [M+H]+ .
99%
With bromine In water at 0℃;
1 Methyl 6-bromo-3-hydroxypicolinate - 9a
To a solution of methyl 3-hydroxypicolinate 8 (10 g, 65.36 mmol) in osmosed water (0.1 M) with crushed ice at 0 °C, was added portionwise bromine (4 x 1.02 mL every 30 min, 78.4 mmol, 1.2 equiv.) under vigorous stirring. The mixture was vigorously stirred at 0 °C for 1-2 h. The solution was extracted by dichloromethane and the combined organic layers were washed with brine, dried over magnesium sulfate and concentrated under reduced pressure to give 9a as a white-off solid (15.08 g, 99%). Rf = 0.3 (Petroleum ether/EtOAc 6/4, v/v). 1H NMR (300 MHz, CDCl3) δ (ppm) 4.07 (s, 3H), 7.29 (d, J = 8.7 Hz, 1H), 7.58 (dd, J = 0.3, 8.7 Hz, 1H), 10.72 (br s, 1H). 13C NMR (75 MHz, CDCl3): δ (ppm) 53.5, 129.5, 130.0, 130.7, 134.5, 158.5, 169.1. MS (ESI+): m/z (%): 234 (85) and 232 (100) [M+H]+.
99%
With bromine In water at 0℃;
1 Methyl 6-bromo-3-hydroxypicolinate - 9a
To a solution of methyl 3-hydroxypicolinate 8 (10 g, 65.36 mmol) in osmosed water (0.1 M) with crushed ice at 0 °C, was added portionwise bromine (4 x 1.02 mL every 30 min, 78.4 mmol, 1.2 equiv.) under vigorous stirring. The mixture was vigorously stirred at 0 °C for 1-2 h. The solution was extracted by dichloromethane and the combined organic layers were washed with brine, dried over magnesium sulfate and concentrated under reduced pressure to give 9a as a white-off solid (15.08 g, 99%). Rf = 0.3 (Petroleum ether/EtOAc 6/4, v/v). 1H NMR (300 MHz, CDCl3) δ (ppm) 4.07 (s, 3H), 7.29 (d, J = 8.7 Hz, 1H), 7.58 (dd, J = 0.3, 8.7 Hz, 1H), 10.72 (br s, 1H). 13C NMR (75 MHz, CDCl3): δ (ppm) 53.5, 129.5, 130.0, 130.7, 134.5, 158.5, 169.1. MS (ESI+): m/z (%): 234 (85) and 232 (100) [M+H]+.
82%
With bromine In water at 20℃; for 3h;
135.2 Methyl 3-[(1-[(1-methylethyl)oxy]carbonyl}-4-piperidinyl)methyl]oxy}-6-[4-(methylsulfonyl)phenyl]-2-pyridinecarboxylate
A stirred solution of methyl 3-hydroxy-2-pyridinecarboxylate (1.69 g, 11.0 mmol) in water (75 mL) at ambient temperature was treated dropwise with bromine (2.39 g, 15.0 mmol). The reaction mixture was stirred at ambient temperature for 3 h, during which time a fine white precipitate formed. The mixture was extracted with CH2Cl2 (100 mL×2). The combined organic extracts were washed with water, brine and dried over Na2SO4, filtered, and the filtrate was concentrated to give 2.11 g (82%) of methyl 6-bromo-3-hydroxy-2-pyridinecarboxylate as an off-white solid. 1H NMR (400 MHz, CDCl3): δ 10.69 (s, 1H), 7.55 (d, 1H, J=8.8 Hz), 7.27 (d, 1H, J=8.8 Hz), 4.04 (s, 3H); LRMS (APCI), m/z 232/234 (M+H).
80.7%
With bromine In water at 25℃;
19.2; 20.2 Synthesis of methyl 6-bromo-3-hydroxypicolinate
A solution of methyl 3-hydroxypicolinate (5 g, 32.65 mmol) in 60 mL of H20 was stirred at RT and Br2 (5.22 g, 32.65 mmol) was added dropwise. The mixture was stirred at RT overnight, and the resulting solid was collected and washed with water to afford methyl 6- bromo-3-hydroxypicolinate. Then the filtrate was basified with Na2C03 until pH reached 7, and after extracted with EtOAc, the organic layer was concentrated to give the 2nd part of methyl 6- bromo-3-hydroxypicolinate (6.1 g total, yield: 80.7%). 1H- MR (CDC13 , 400 MHz) δ 10.67 (s, 1H), 7.54 (t, J= 8.0 Hz, 1H), 7.24 (d, J= 4.0 Hz, 1H), 4.02 (s, 3H). MS (M+H)+: 232 / 234.
80.7%
With bromine In water at 20℃;
1.1 Step 1 - Synthesis of methyl 6-bromo-3-hydroxypicolinate
A mixture of methyl 3-hydroxypicolinate (5.0 g, 32.65 mmol) in H2O was stirred at RT and then Br2 (5.2 g, 32.65 mmol) was added dropwise. After the mixture was stirred at RT overnight, the mixture was filtered and the precipitate was washed with water and dried to give methyl 6-bromo-3-hydroxypicolinate (6.1 g, yield 80.7%). XH-NMR (DMSO, 400 MHz) δ 10.71 (s, 1H), 7.69 (d, J= 8.4 Hz, 1H), 7.41 (d, J= 8.4 Hz, 1H), 3.87 (s, 3H). MS (M+H)+: 232 / 234.
80.7%
With bromine In water at 25℃;
1.1 Synthesis of methyl 6-bromo-3-hydroxypicolinate
A mixture of methyl 3-hydroxypicolinate (5.0 g, 32.65 mmol) in H20 was stirred at RT and then Br2 (5.2 g, 32.65 mmol) was added dropwise. After the mixture was stirred at RT overnight, the mixture was filtered and the precipitate was washed with water and dried to give methyl 6-bromo-3-hydroxypicolinate (6.1 g, yield 80.7%). ‘H-NMR (DMSO, 400 MHz) 10.71 (s, 1H), 7.69 (d, J= 8.4 Hz, 1H), 7.41 (d, J= 8.4 Hz, 1H), 3.87 (s, 3H). MS (M+H): 232 / 234.
80%
With bromine In water at 20℃; for 3h;
79%
With bromine In water
74%
With bromine In water at 20℃; for 4h;
3.2
(step 2); To a solution of the compound obtained in step 1(9.19 g) in water (150 mL) was added bromine (3.23 mL) at room temperature and the mixture was stirred for 4 hrs . The reaction mixture was extracted with a mixture of ethyl acetate/THF, and the organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated. The residue was crystallized from ethyl acetate/hexane to give methyl 6-bromo-3- hydroxypyridine-2-carboxylate (10.3 g, 74%) as brown crystals,
72%
With bromine In water at 20℃; for 4h;
3-2 Preparation Example 3-2 : Preparation of methyl 6-bromo-3-hydroxypicolinate (LXVI)
[0182] Methyl 3-hydroxypicolinate (4.62 g, 30.17 mmol) was dissolved in distilled water (200 mL). To the resulting solution was slowly added dropwise bromine water (1.7 mL, 33.18 mmol) and the solution was stirred at room temperature for 4 hrs. The solution was diluted with ethylacetate and washed with water. The washed organic solvent was dried over anhydrous magnesium sulfate (MgSO4) to concentrate. The resulting residue was isolated and purified by silica gel column chromatography (hexane/ethylacetate = 3/1) to give the white title compound (5.07 g, 72 %). 1H NMR (600 MHz, CDCl3) δ 7.55 (d, J = 9.0 Hz, 1H), 7.27 (d, J = 9.0 Hz, 1H), 4.04 (s, 3H).
66%
With bromine In water at 20℃; for 2h;
22 Intermediate 65: methyl 6-bromo-3-hydroxypicolinate
A solution of methyl 3-hydroxypicolinate (21 g, 137 mmol) in Water (500 mL) was stired at rt for 2 h. The precipitate was filtered, washed with water and dried in vacuo to provide the desired product methyl 6-bromo-3-hydroxypicolinate (21 g, 91 mmol, 66.0 % yield), m/z: [M + H]+ Calcd for C7H6BrN03 232.0; Found 232
53%
With bromine In water at 0 - 20℃; for 17h;
53%
With bromine In water at 0 - 20℃; for 17h;
52.8%
With bromine In water at 0℃; for 2h;
Step-2 synthesis of methyl 6-bromo-3-hydroxypicolinate (Intermediate AA198-4)
To a solution of Intermediate AA198-3 (5.0 g, 32.67 mmol) in water (50 mL) at 0° C. was added slowly dropwise bromine (2.0 mL, 39.20 mmol, 1.2 eq). After stirring for 2 h, the reaction mixture was extracted with DCM (3×80 mL). The combined organic extracts were washed with brine (250 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to afford Intermediate AA198-4 (4.0 g, 52.80%), MS (ES): m/z 232.9 [M+H]+
With bromine In water
6-BROMO-3-HYDROXYPICOLINIC ACID (17).
6-BROMO-3-HYDROXYPICOLINIC ACID (17). To a mechanically stirred solution of methyl 3-hydroxypicolinate (30.6 g) in water (800 mL) was slowly added bromine (32 g) over a 30 minute period. After the addition was complete, stirring was continued for an additional hour. Ether (300 mL) was added and stirring continued until all the solids had dissolved. The organic layer was separated and the aqueous phase extracted with ether (200 mL). The organic phases were combined, dried (MgSO4) and the solvent evaporated to give 32.8 g of methyl 6-bromo-3-hydroxypicolinate as an off-white solid. Recrystallization from methanol/water gave an analytical sample, m.p. 115-117° C.
With bromine In water at 20℃;
45
To a stirred solution of methyl 3-hydroxy-2-pyridinecarboxylate D44 (0.100 g) in water (5 ml), Br2 (0.045 ml, 0.882 mmol) was added dropwise and the solution was left stirring at room temperature. A precipitate occurred. The mixture was left stirring for 30 minutes, then DCM was added and the two phases were separated. The aqueous one was extracted with DCM. The organic layers were filtered through a phase separator and evaporated. The crude was purified by flash chromatography on silica gel (Flash Master Personal, 1O g cartridge eluting with Cy 90% EtOAc 10%). The fractions were collected and the solvent removed in vacuo obtaining the title compound D45 (0.100 g). MS: (ES/+) m/z: 233 (M+l). C7H6BrNO3 requires 232. 1H-NMR (400 MHz, CDCl3) δ ppm: 10.69 (s, 1 H), 7.61-7.51 (d, 1 H), 7.32-7.25 (d, 1 H), 4.06 (s, 3 H).
With bromine In water for 0.5h;
10.A Step A: methyl 6-bromo-3-hydroxypicolinate
To a water (20 mL) solution of methyl 3-hydroxypicolinate (500 mg, 3.27 mmol) was added dropwise bromine (225 μ, 4.37 mmol). A precipitate formed. After 30 min, the reaction was extracted with DCM (2 x 20 mL). The combined organic layers were dried (Na2SC"4), filtered and concentrated to give the title compound. 1H NMR (500 MHz, CDC13): δ 10.71 (s, 1H), 7.59 (d, 1H), 7.25 (d, 1H), 4.04 (s, 3H).
With bromine In water at 20℃; for 3h;
B Step B. Methyl 6-BROMO-3-HYDRYPYRIDINE-2-CARBOXYLATE
To a stirred solution of methyl 3-hydroxypyridine-2-carboxylate (9.03 g, 59.0 mmol) in H20 (400 mL), at ambient temperature, was added dropwise bromine (12.8 g, 4.10 ML, 80.0 mmol). The mixture was stirred for 3 h, during which time a fine white precipitate formed. The aqueous mixture was extracted with CH2C12 (2 x 500 mL) and the combined organic extracts were dried (NA2SO4), filtered, and concentrated IN VACUO TO afford the title compound as a white solid of sufficient purity for use in the next step. MS: m/z = 232 (M + 1).
3.5 g
With bromine In water at 20℃; for 6h;
39.39.2 39.2 Methyl 6-bromo-3-hydroxy-2-picolinate
A 250 mL single-necked flask was charged with methyl 3-hydroxy-2-picolinate (3.00 g), bromine (4.70 g) and 80 mL of water, which were reacted at room temperature for 6 h. A sample was taken, and TLC detection showed that the spots of the raw materials disappeared. The mixture was extracted with ethyl acetate (50 mL × 3), washed with 100 mL of saturated saline, dried over anhydrous sodium sulfate, concentrated, and subjected to column chromatography (PE : EA = 7 : 1), so as to obtain 3.5 g of methyl 6-bromo-3-hydroxy-2-picolinate.
To a solution of compound 601-B (30 g, 196 mmol) in H2O (1500 mL) was added Br2 (94 g, 590 mmol) slowly.The mixture was stirred at 30 C for overnight. Then the mixture was extracted with DCM (500 mL2), washed with brine(500 mL), dried, filtered and concentrated to afford 601-C (methyl 4,6-dibromo-3-hydroxypicolinate, 49 g, yield: 81%)as a white solid.1H NMR (300 MHz, CDCl3) delta 11.35 (s, 1H), 7.87 (s, 1H), 4.07 (s, 3H).
76%
With bromine; In water; at 20℃; for 20h;
At room temperature, Br2 (2.7 mL, 3 equiv) was added to a suspension of methyl ester 8 (2.7 g, 6.5 mmol) in water (200 mL). The mixture was stirred for 20 h at room temperature. The solution was extracted with dichloromethane, and the organic layer was washed with an aqueous solution of sodium thiosulfate, with brine, dried over MgSO4, and concentrated under reduced pressure to give desired compound 9 (4.0 g, 76%) as a white powder. 1H NMR (300 MHz, CDCl3) delta (ppm) 4.06 (s, 3H), 7.86 (s, 1H), 11.35 (br s, 1H). 13C NMR (75 MHz, CDCl3) delta 53.9, 124.7, 129.9, 130.2, 136.9, 156.0, 168.8. MS (ESI-) m/z: 312 (40), 310 (100), 308 (45).
With bromine; sodium carbonate; In water;
a. PREPARATION OF METHYL 4,6-DIBROMO-3-HYDROXYPYRIDINE-2-CARBOXYLATE (14). To a 2 L, 3-necked flask equipped with a dropping funnel and a mechanical stirrer, was added water (800 mL) and methyl 3-hydroxypyridine-2-carboxylate (15.3 g). To this stirred solution was slowly added bromine (32 g). As the reaction progressed, a solid separated from solution and the reaction mixture became difficult to stir. After the addition was complete, the mixture was vigorously stirred until the bromine color disappeared. 1H-NMR (CDCl3) of a small sample of the crude product showed that it was about a 3:1 mixture of mono to dibrominated product. Sodium carbonate (31.8 g) was carefully added to the reaction mixture and then additional bromine (12 g) was added dropwise. After the bromine color had disappeared, the reaction mixture was adjusted to approximately pH 5 with conc. HCl, and the resulting mixture was extracted with CH2Cl2 (3*150 mL). The organic extracts were combined, dried (MgSO4) and concentrated to give an orange solid (14 g). This material could be recrystallized from methylcyclohexane (after charcoal treatment) to give 14 as a white solid, m.p. 181-183 C.
With bromine; sodium carbonate; In water;
a. PREPARATION OF METHYL 4,6-DIBROMO-3-HYDROXYPYRIDINE-2-CARBOXYLATE (14). To a 2 L, 3-necked flask equipped with a dropping funnel and a mechanical stirrer, was added water (800 mL) and methyl 3-hydroxypyridine-2-carboxylate (15.3 g). To this stirred solution was slowly added bromine (32 g). As the reaction progressed, a solid separated from solution and the reaction mixture became difficult to stir. After the addition was complete, the mixture was vigorously stirred until the bromine color disappeared. 1H-NMR (CDCl3) of a small sample of the crude product showed that it was about a 3:1 mixture of mono to dibrominated product. Sodium carbonate (31.8 g) was carefully added to the reaction mixture and then additional bromine (12 g) was added dropwise. After the bromine color had disappeared, the reaction mixture was adjusted to approximately pH 5 with conc. HCl, and the resulting mixture was extracted with CH2Cl2 (3x150 mL). The organic extracts were combined, dried (MgSO4) and concentrated to give an orange solid (14 g). This material could be recrystallized from methylcyclohexane (after charcoal treatment) to give 14 as a white solid, m.p. 181-183 C.
With bromine; In water; at 10 - 20℃;
To a solution of compound 20B (114 g, 0.745 mol, 1.0 eq) in water (8 L) at 10C was added bromine (114.6 mL, 2.235 mol, 3.0 eq). The reaction mixture was stirred at rt overnight. The reaction mixture was extracted with DCM (2 x 8 L). The organic phase was separated, and dried over sodium sulfate, and concentrated to give crude compound 20C (186 g, 81%) as a slightly yellow solid. JH NMR (400 MHz, CDC13) delta 11.35 (s, 1H), 7.56 (s, 1H), 4.06 (s, 3H).
With bromine; In water; at 15℃; for 5h;
To a mixture of in compound Int-20a (50 g, 327 mmol) in H20 (5.0 L) stirred at 15C, was add bromine (157 g, 979 mmol). The mixture was stirred at 15C for 5 hours. The resulting mixture was filtered,the filter cake was washed with water and driedunder vacuum to give compound Int-20b. The crude material was used in the next reaction without further purification. 1H NMR (400 MHz, CDC13) delta 11.37 (s, 1H), 7.87 (s, 1H), 4.07 (s, 3H).
With bromine; In water; at 15℃; for 5h;
To a mixture of compound Int-la (50 g, 327 mmol) in water (5.0 L) stirred at l5C, was added bromine (157 g, 979 mmol). The mixture was stirred at l5C for 5 hours. The resulting mixture was filtered, and the filter cake was washed with water and dried under vacuum to give compound Int-lb. The crude material was used in the next reaction without further purification. NMR (400 MHz, CDCb) d 11.37 (s, 1H), 7.87 (s, 1H), 4.07 (s, 3H).
With bromine; In water; at 15℃; for 5h;
To a mixture of compound int-1 a (50 g, 327 mmol) in water (5.0 L) stirred at l5C, bromine (157 g, 979 mmol) was added. The mixture was stirred at l5C for 5 hours. The resulting mixture was filtered, and the filter cake was washed with water and dried under vacuum to give compound int-lb. The crude material was used in the next reaction without further purification. NMR (400 MHz, CDCb) d 11.37 (s, 1H); 7.87 (s, 1H); 4.07 (s, 3H).
Preparation of methyl 3-(4,6-dimethoxy-2-pyrimidinyloxy)-2-pyridinecarboxylate 1.75 g (10 mmol) of <strong>[13223-25-1]2-<strong>[13223-25-1]chloro-4,6-dimethoxypyrimidine</strong></strong>, 1.53 g (10 mmol) of methyl 3-hydroxy-2-pyridinecarboxylate and 0.104 g (1.0 mmol) of sodium methanesulfinate were heated in the presence of 2.17 g (15 mmol) of potassium carbonate in 6 ml of N,N-dimethylformamide to 100 C. with stirring. After 5 hours, the solvent was removed in a rotary evaporator at 60 C./20 mbar. The residue was purified by chromatography on a silica gel column (eluent hexane/ethyl acetate 4:1). The title product was obtained from the product fraction in the form of a yellowish oil in a yield of 1.94 g (61 percent of theory) (GC content 92.3 percent). Other data concerning the title compound was: 1 H NMR (DMSO, MHz 400)delta=8.58 (1 H, d); 7.90 (1 H, d); 7.74 (1 H, dd); 6.01 (1 H, s); 3.75 (6 H, s); 3.68 (3 H, s).
With potassium iodide; potassium carbonate; In N-methyl-acetamide;
EXAMPLE 1 Preparation of methyl 3-(4,6-dimethoxypyrimidin-2-yl)oxy picolinate (Compound No. 1) To a solution of 30.0 g of methyl 3-hydroxypicolinate in 250 ml of dimethylformamide, 42.7 g of 4,6-dimethoxy-2-methylsulfonylpyrimidine, 32.5 g of potassium carbonate and 16.3 g of potassium iodide, were added, and the mixture was heated and stirred at a reaction temperature of from 100 to 110 C. for 1.5 hours. After cooling, the reaction solution was poured into water, and extracted with ethyl acetate. The extract was washed with water, and dried over magnesium sulfate. Ethyl acetate was distilled off under reduced pressure, and the residue was recrystallized from a solvent mixture of hexane, diisopropyl ether and toluene, to obtain 37.2 g of methyl 3-(4,6-dimethoxypyrimidin-2-yl)oxy picolinate. (Yield: 65%, white crystal, melting point: 65-66 C.)
With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 18h;
In a 50 mL round-bottomed flask fitted with a magnetic stirrer were placed intermediate 2 (3.5 g, 22.8 mmol), potassium carbonate (3.46 g, 25.0 mmol), methyl iodide (4.87 g, 34.3 mmol) and DMF (20 mL). The reaction mix was stirred for 18 h at room temperature under nitrogen. The reaction mix was diluted with ethyl acetate (30 mL) and water (10 mL). The organic layer was separated and aqueous layer was extracted with ethyl acetate. The combined organic extracts were dried over Na2SO4 and concentrated to give crude product, which was then purified by column chromatography using 30% ethyl acetate in hexane, to give 2.1 g of intermediate 3 (54% yield).
2.1 g
With potassium carbonate; In N,N-dimethyl-formamide; for 18h;Inert atmosphere;
In a 50 mL round-bottom flask fitted with magnetic stirrer were placed 3-hydroxypyridine-2-carboxylic acid methyl ester (3.5 g, 22.80 mmol), K2CO3 (3.46 g, 25.0 mmol), MeI (4.87 g, 34.3 mmol) and DMF (20 mL). The reaction mixture was stirred for 18 h at it under nitrogen. The reaction mixture was diluted with EtOAc (30 mL) and water (10 mL). The organic layer was separated and aqueous layer was extracted with EtOAc. The combined organic extracts were dried over Na2SO4 and concentrated to give the crude product. The crude product was purified by column chromatography using 30% EtOAc in hexane to give 2.1 g of 3-methoxypyridine-2-carboxylic acid methyl ester (54%).
With caesium carbonate; In N,N-dimethyl-formamide; at 20℃;
To the solution of methyl 3-hydroxypicoiinate (885 mg, 5.78 mmol) in 25 mL of DMF were added CS2CO3 (2.07 6.36 mmol) and. methyl iodide (396 uL, 6.36 mmoi). The reaction was stirred overnight at room temperature. The completion of the reaction was monitored by HPLC. Upon completion, solvent was removed in vacuo, H2O was added to the crude residue and the reaction mixture was extracted with QCfVL The combined organic layers were washed with saturated aqueous NaHC03, brine and dried over asSO^. Filtration and removal of the solvent provided 546 mg (57%) of the title compound as a light brown oil which was used without further purification; rH NMR (400 MHz, CDCI3) delta - 8.29 (dd, J = 1.3, 4Lambda Hz, 1 H), 7.46 - 7.41 (m, 1 H), 7.37 (dd, J ~ 1 ,3, 8.8 Hz, 1 H), 3.98 (s, 3 H), 3.94 (s, 3 H).
Multi-step reaction with 2 steps
1.1: sodium hydride / N,N-dimethyl-formamide; mineral oil / 22 °C
1.2: 2 h / 0 - 22 °C
2.1: water; lithium hydroxide / methanol / 2 h / 22 °C
Multi-step reaction with 2 steps
1.1: sodium hydride / N,N-dimethyl-formamide; mineral oil / 22 °C
1.2: 2 h / 0 - 22 °C
2.1: water; lithium hydroxide / methanol / 2 h / 22 °C
Multi-step reaction with 2 steps
1.1: sodium hydride / N,N-dimethyl-formamide / 22 °C
1.2: 2 h / 0 - 22 °C
2.1: water; lithium hydroxide / methanol / 2 h / 22 °C
Multi-step reaction with 2 steps
1.1: sodium hydride / N,N-dimethyl-formamide; mineral oil / 22 °C
1.2: 2 h / 0 - 22 °C
2.1: water; lithium hydroxide / methanol / 2 h / 22 °C
6-BROMO-3-HYDROXYPICOLINIC ACID (17). To a mechanically stirred solution of methyl 3-hydroxypicolinate (30.6 g) in water (800 mL) was slowly added bromine (32 g) over a 30 minute period. After the addition was complete, stirring was continued for an additional hour. Ether (300mL) was added and stirring continued until all the solids had dissolved. The organic layer was separated and the aqueous phase extracted with ether (200mL). The organic phases were combined, dried (MgSO4) and the solvent evaporated to give 32.8 g of methyl 6-bromo-3-hydroxypicolinate as an off-white solid. Recrystallization from methanol/water gave an analytical sample, m.p. 115-117 C. To a stirred solution of this ester (2.32 g) in THF (15 mL) was added all at once a solution of LiOH.H2O (1 g) in water (7 mL). The resulting mixture was stirred for 2 hours at room temperature then poured into water (100 mL). The pH was adjusted to approximately 3 with 1N HCl, then the mixture was extracted with CH2Cl2 (3 x 100 mL). The organic extract was dried (MgSO4), filtered and concentrated to give 2.0 g of a white solid, whose 1H-NMR and MS were consistent with the desired title acid 17.
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