| 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. |
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