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CAS No. : | 321601-48-3 | MDL No. : | MFCD12828055 |
Formula : | C7H6BrNO3 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | UGFPNFKMYRHGBG-UHFFFAOYSA-N |
M.W : | 232.03 | Pubchem ID : | 22175135 |
Synonyms : |
|
Num. heavy atoms : | 12 |
Num. arom. heavy atoms : | 6 |
Fraction Csp3 : | 0.14 |
Num. rotatable bonds : | 2 |
Num. H-bond acceptors : | 4.0 |
Num. H-bond donors : | 1.0 |
Molar Refractivity : | 45.24 |
TPSA : | 59.42 Ų |
GI absorption : | High |
BBB permeant : | Yes |
P-gp substrate : | No |
CYP1A2 inhibitor : | Yes |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -6.11 cm/s |
Log Po/w (iLOGP) : | 2.16 |
Log Po/w (XLOGP3) : | 2.26 |
Log Po/w (WLOGP) : | 1.34 |
Log Po/w (MLOGP) : | 0.51 |
Log Po/w (SILICOS-IT) : | 1.41 |
Consensus Log Po/w : | 1.53 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 0.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -2.94 |
Solubility : | 0.266 mg/ml ; 0.00115 mol/l |
Class : | Soluble |
Log S (Ali) : | -3.14 |
Solubility : | 0.166 mg/ml ; 0.000717 mol/l |
Class : | Soluble |
Log S (SILICOS-IT) : | -2.39 |
Solubility : | 0.954 mg/ml ; 0.00411 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 1.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.97 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H302-H315-H319 | Packing Group: | N/A |
GHS Pictogram: |
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* 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.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With potassium carbonate In N,N-dimethyl-formamide at 25℃; for 3 h; | A mixture of methyl 6-bromo-3-hydroxypicolinate (4 g, 17.2 mmol), CH3I (7.15 g, 34.5 mmol) and K2C03 (4.76 g, 34.5 mmol) in DMF (50 mL) was stirred at RT for 3 hours. After concentrated, the mixture was diluted with H20 and extracted with EtOAc (50 mL * 3). The organic layer was dried over Na2S04 and concentrated to give crude methyl 6-bromo-3- methoxypicolinate (4 g, yield: 90percent). 1H- MR (CDC13 , 400 MHz) δ 7.56 (d, J= 8.0 Hz, 1H), 7.25 (d, J= 8.0 Hz, 1H), 3.94 (s, 3H), 3.90 (s, 3H). MS (M+H)+: 256 / 258. |
78% | With potassium carbonate In acetone for 3 h; Reflux | [0183] Methyl 6-bromo-3-hydroxypicolinate (5.07 g, 21.85 mmol) was dissolved in acetone (75 mL). To the resulting solution were added dropwise potassium carbonate (K2CO3) (4.83 g, 34.96 mmol) and iodomethane (CH3I) (1.77 mL, 28.41 mmol) and the solution was refluxed with heat for 3 hrs. The solution was evaporated under reduced pressure to concentrate, diluted with EtOAc, 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 (4.18 g, 78 percent). 1H NMR (600 MHz, CDCl3) δ 7.57 (d, J = 9.0 Hz, 1H), 7.26 (d, J = 9.0 Hz, 1H), 3.95 (s, 3H), 3.92 (s, 3H). |
76% | With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 4 h; | (step 3 ); A solution of the compound obtained in step 2 (9.42 g) , methyl iodide (2.78 mL) and potassium carbonate (7.29 g) in DMF (80 mL) was stirred at room temperature for 4 hrs, and poured into cold water. The mixture was extracted twice with ethyl acetate, and 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; 20-25percent ethyl acetate/hexane) and <n="86"/>crystallized from ethyl acetate/hexane to give methyl 6-bromo-3-methoxypyridine-2-carboxylate (7.57 g, 76percent) as white crystals, |
42% | With potassium carbonate In N,N-dimethyl-formamide at 20℃; | A mixture of methyl 6-bromo-3-hydroxypicolinate (10.0 g, 43.10 mmol), Mel (12.3 g, 86.66 mmol) and K2C03 (12.0 g, 86.83 mmol) in DMF (100 mL) was stirred at RT overnight. Then the reaction mixture was concentrated, diluted with water and extracted with EtOAc. The organic layer was dried over a2S04 and concentrated to give methyl 6-bromo-3- methoxypicolinate (4.5 g, yield 42percent). XH-NMR (CDC13, 400 MHz) δ 7.55 (d, J = 8.8 Hz, 1H), 7.24 (d, J = 8.8 Hz, 1H), 3.94 (s, 3H), 3.90 (s, 3H). MS (M+H)+: 246 / 248. |
42% | With potassium carbonate In N,N-dimethyl-formamide at 25℃; | A mixture of methyl 6-bromo-3-hydroxypicolinate (10.0 g, 43.10 mmol), Mel (12.3 g, 86.66 mmol) and K2C03 (12.0 g, 86.83 mmol) in DMF (100 mL) was stirred at RT overnight. Then the reaction mixture was concentrated, diluted with water and extracted with EtOAc. The organic layer was dried over Na2SO4 and concentrated to give methyl 6-bromo-3-methoxypicolinate (4.5 g,yield 42percent). ‘H-NMR (CDC13, 400 MHz) 7.55 (d, J = 8.8 Hz, 1H), 7.24 (d, J = 8.8 Hz, 1H), 3.94(s, 3H), 3.90 (s, 3H). MS (M+H): 246 / 248. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
A stirred mixture of methyl 6-BROMO-3-HYDROXYPYRIDINE-2-CARBOXYLATE (6.15 g, 26.5 mmol), 8-sultam (described in WO 02/30931-A2, Merck & Co. , Inc. , 2002) (3. 98 g, 29.4 mmol) and copper (I) oxide (5.75 g, 40.2 mmol) in anhydrous pyridine (100 mL) was heated at 130 C, under argon, for 6 h. The mixture was cooled, and the pyridine removed under reduced pressure. The residue was treated with CH2C12 (400 mL) and EDTA (0.35 M in H20, 300 ML, 105 mmol) and air was bubbled into the mixture for 18 h. The mixture was filtered through a pad of celite and the aqueous layer was saturated with solid NACI and extracted with CH2CLZ (4 x 250 mL). The combined organic extracts were dried (NA2S04), filtered, and concentrated in vacuo to afford a crude oil. The oil was dissolved in MEOH (400 mL) and conc. H2S04 (2 ML) and heated to reflux for 18 h, then allowed to cool to ambient temperature. Most of the solvent was removed in vacuo and the residual mixture was partitioned between CHZCLX (400 mL) and saturated NAHCO3 (400 mL). The aqueous layer was extracted further with CH2Cl2 (2 x 250 mL) and the combined organic extracts were dried (NA2S04), filtered, and concentrated in vacuo to afford a crude sample of the product. This crude product was partially purified by silica gel chromatography, eluting with a gradient of CH2C12 : MEOH-100 : 0 to 95: 5 to give a yellow solid that was crystallized from MEOH to afford the title compound as a pale yellow solid of sufficient purity for use in the next step. MS: FALZ = 287 (M + 1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | 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. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In methanol; diethyl ether at 0℃; for 2h; | c A solution of diazomethane in diethyl ether (about 0.4 M) is added in excess to a solution of 2.3 mmol of methyl 6-bromo-3-hydroxypyridine-2-carboxylate [321601-48-3] in 30 ml of methanol at 0°C. The mixture is stirred at 0°C for 2 hours, then quenched with magnesium sulphate, filtered and evaporated. The crude title compound is identified by means of the Rf. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With potassium carbonate In N,N-dimethyl-formamide at 25℃; for 3h; | 19.3; 20.3 Synthesis of methyl 6-bromo-3-methox icolinate A mixture of methyl 6-bromo-3-hydroxypicolinate (4 g, 17.2 mmol), CH3I (7.15 g, 34.5 mmol) and K2C03 (4.76 g, 34.5 mmol) in DMF (50 mL) was stirred at RT for 3 hours. After concentrated, the mixture was diluted with H20 and extracted with EtOAc (50 mL * 3). The organic layer was dried over Na2S04 and concentrated to give crude methyl 6-bromo-3- methoxypicolinate (4 g, yield: 90%). 1H- MR (CDC13 , 400 MHz) δ 7.56 (d, J= 8.0 Hz, 1H), 7.25 (d, J= 8.0 Hz, 1H), 3.94 (s, 3H), 3.90 (s, 3H). MS (M+H)+: 256 / 258. |
81% | With potassium carbonate In acetone at 38℃; for 2h; | 22 Intermediate 66: methyl 6-bromo-3-methoxypicolinate To a solution of methyl 6-bromo-3-hydroxypicolinate (21 g, 91 mmol) in Acetone (400 mL) was added iodomethane (38.5 g, 272 mmol) at rt. The mixture was stired for 2 h at 38 °C. The precipitate was filtered, washed with water and dried in vacuo to provide the desired product methyl 6-bromo-3-methoxypicolinate (18g, 73.2 mmol, 81 % yield), m/z: [M + H]+ Calcd for C8H8BrN03 246.0; Found 246.0 |
78% | With potassium carbonate In acetone for 3h; Reflux; | 3-3 Preparation Example 3-3 : Preparation of methyl 6-bromo-3-methoxypicolinate (LXVII) [0183] Methyl 6-bromo-3-hydroxypicolinate (5.07 g, 21.85 mmol) was dissolved in acetone (75 mL). To the resulting solution were added dropwise potassium carbonate (K2CO3) (4.83 g, 34.96 mmol) and iodomethane (CH3I) (1.77 mL, 28.41 mmol) and the solution was refluxed with heat for 3 hrs. The solution was evaporated under reduced pressure to concentrate, diluted with EtOAc, 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 (4.18 g, 78 %). 1H NMR (600 MHz, CDCl3) δ 7.57 (d, J = 9.0 Hz, 1H), 7.26 (d, J = 9.0 Hz, 1H), 3.95 (s, 3H), 3.92 (s, 3H). |
76% | With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 4h; | 3.3 (step 3 ); A solution of the compound obtained in step 2 (9.42 g) , methyl iodide (2.78 mL) and potassium carbonate (7.29 g) in DMF (80 mL) was stirred at room temperature for 4 hrs, and poured into cold water. The mixture was extracted twice with ethyl acetate, and 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; 20-»25% ethyl acetate/hexane) and crystallized from ethyl acetate/hexane to give methyl 6-bromo-3-methoxypyridine-2-carboxylate (7.57 g, 76%) as white crystals, |
42% | With potassium carbonate In N,N-dimethyl-formamide at 20℃; | 10.1 Step 1 - Synthesis of methyl 6-bromo-3-methoxypicolinate A mixture of methyl 6-bromo-3-hydroxypicolinate (10.0 g, 43.10 mmol), Mel (12.3 g, 86.66 mmol) and K2C03 (12.0 g, 86.83 mmol) in DMF (100 mL) was stirred at RT overnight. Then the reaction mixture was concentrated, diluted with water and extracted with EtOAc. The organic layer was dried over a2S04 and concentrated to give methyl 6-bromo-3- methoxypicolinate (4.5 g, yield 42%). XH-NMR (CDC13, 400 MHz) δ 7.55 (d, J = 8.8 Hz, 1H), 7.24 (d, J = 8.8 Hz, 1H), 3.94 (s, 3H), 3.90 (s, 3H). MS (M+H)+: 246 / 248. |
42% | With potassium carbonate In N,N-dimethyl-formamide at 25℃; | 10.1 Synthesis of methyl 6-bromo-3-methoxypicolinate A mixture of methyl 6-bromo-3-hydroxypicolinate (10.0 g, 43.10 mmol), Mel (12.3 g, 86.66 mmol) and K2C03 (12.0 g, 86.83 mmol) in DMF (100 mL) was stirred at RT overnight. Then the reaction mixture was concentrated, diluted with water and extracted with EtOAc. The organic layer was dried over Na2SO4 and concentrated to give methyl 6-bromo-3-methoxypicolinate (4.5 g,yield 42%). ‘H-NMR (CDC13, 400 MHz) 7.55 (d, J = 8.8 Hz, 1H), 7.24 (d, J = 8.8 Hz, 1H), 3.94(s, 3H), 3.90 (s, 3H). MS (M+H): 246 / 248. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60% | With sodium hydride In ISOPROPYLAMIDE at 90℃; for 3h; | 67.a a) 6-Bromo-3-(3-phenoxy-propoxy)-pyridine-2-carboxylic acid methyl esterA mixture of -bromo-3-hydroxypicolinic acid methyl ester (lOOmg, 0.43 mmol), sodium hydride (60% dispersion in mineral oil) (17.3mg, 0.43 mmol), 3-phenoxypropyl bromide(68 μL, 0.43 mmol), in dimethyl acetamide (1.5 mL) was heated at 9O0C for 3 hours. The reaction was allowed to cool, poured onto water and then extracted with ethyl acetate (2 x3mL). The organic layer was dried (MgSO4) and concentrated in vacuo. The resulting residue was purified by silica chromatography eluting with 100% petroleum ether to 30% ethyl acetate/petroleum ether to obtain a white solid (95mg, 60%). 1H NMR (300 MHz,CDCl3) δ: 7.48 (IH, d), 7.24-7.21 (3H, m), 6.91-6.86 (3H, m), 4.19 (2H, t), 4.15 (2H, t),3.88 (3H, s), 2.30-2.22 (2H, m). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
31% | With tetrabutylammomium bromide; caesium carbonate In 1,4-dioxane; water at 100℃; for 1.5h; Microwave irradiation; | 68.a a) 3-Hydroxy-6-(8-Oxo-5,6,7,8-tetrahydro-naphthalen-2-yl)-pyridine-2-carboxylic acid methyl esterA mixture of methyl 6-bromo-3-hydroxypicolinate (lOOmg, 0.43 mmol), 7-pinacloatoborane-tetralone (129mg, 0.47 mmol), PdCl2(PPh3)2 (7.5mg, 2.5 mol%), tetrabutylammonium bromide (14mg, 0.043 mmol), caesium fluoride (145mg, 0.95 mmol) in dioxane:H2O (2:1, mL) was heated at 1000C under microwave irradiation for 90 minutes. The reaction was cooled, diluted with ethyl acetate and poured onto water. The aqueous phase was extracted with ethyl acetate (2 x 3mL), the organic layer was dried (MgSO4) and concentrated in vacuo. The residue was triturated with diethyl ether and the solid was filtered to afford an off-white solid (40mg, 31%). 1H NMR (d6-DMSO) δ: 10.55 (IH, bs), 8.42 (IH, d), 8.13 (IH, dd), 8.07 (IH, dd), 7.48 (IH, d), 7.43 (IH, d), 3.90 (3H, s), 2.96 (2H, t), 2.61 (2H, t), 2.07-2.01 (2H, m). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
56% | Stage #1: methyl 6-bromo-3-hydroxypyridine-2-carboxylate With lithium aluminium tetrahydride In tetrahydrofuran at 20℃; for 2h; Stage #2: With sodium hydroxide; water In tetrahydrofuran for 1h; | 133.17a To a solution of methyl 6-bromo-3-hydroxypyridine-2-carboxylate (2g, 8.6 mmol, prepared according to procedures in WO2005009962) in THF (30 mL), was added LAH (34 mL, 34.4 mmol, 1 M in TBDF). The solution was stirred at rt for 2 h. To the solution was then added water (1.3 mL), 10% aqueous NaOH (1.3 mL), and water (3.9 mL). After stirring for 1 h, the solution was filtered and the solids washed with EtOAc. The organics were then washed with IN HCl and brine, dried over sodium sulfate, filtered and concentrated in vacuo to yield intermediate 17A (0.99g, 56%). 1H-NMR (CD3OD) δ 7.3 (d, J = 8.4 Hz, IH), 7.09 (d, J = 8.4 Hz, IH), 4.67 (s, 2 H); MS (ESI+): 204.1 (M+H). |
With lithium aluminium tetrahydride In tetrahydrofuran at 20℃; for 0.5h; | 10.B Step B: 6-bromo-2-(hvdroxymethyl)pyridin-3-ol To a THF (8 mL) solution of methyl 6-bromo-3-hydroxypicolinate (500 mg, 2.15 mmol) was added a LAH solution (1M in THF, 4 ml, 8.0 mmol. After 30 minutes at room temp, the reaction was quenched by the sequential addition of water (0.30 mL), 15% NaOH (0.30 mL), and water (0.90 mL). The mixture was then stirred vigorously as a white precipitate formed. The resulting mixture was filtered and concentrated to give the title compound. 1H NMR (500 MHz, CDCI3): δ 7.31 (d, 1H), 7.10 (d, 1H), 4.65 (s, 2H), 3.30 (br, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate In N,N-dimethyl-formamide at 20℃; | 46 Methyl 6-bromo-3-hydroxy-2-pyridinecarboxylate D45 (0.200 g, 0.862 mmol), K2CO3 (0.596 g, 4.31 mmol) and iodoethane (0.139 ml, 1.724 mmol) were dissolved DMF (3 ml). The mixture was left stirring at room temperature overnight. To the solution were added H2O and DCM. The two layers were separated. The aqueous one was extracted several times with DCM. The organic layers were washed with brine/ice, filtered through a phase separator and evaporated. The crude was purified by flash chromatography on silica gel (Flash Master Personal, 20 g cartridge eluting from Cy 100 % to Cy 90 %: EtOAc 10 %). The fractions were collected obtaining the title compound D46 (0.200 g). MS: (ES/+) m/z: 260 (M+l). C9H10BrNO3 requires 259. 1H-NMR (400 MHz, CDCl3) δ ppm: 7.55-7.53 (d, 1 H), 7.25-7.23 (d, 1 H), 4.18-4.10 (m, 2 H), 3.96 (s, 3 H), 1.50-1.43 (m, 3 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: potassium carbonate / acetone / 15 h / Reflux 2: copper(l) iodide; tetrakis(triphenylphosphine) palladium(0); triethylamine / tetrahydrofuran / 15 h / 20 °C / Inert atmosphere |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1: potassium carbonate / acetone / 15 h / Reflux 2: copper(l) iodide; tetrakis(triphenylphosphine) palladium(0); triethylamine / tetrahydrofuran / 15 h / 20 °C / Inert atmosphere 3: hydrogen; palladium(II) hydroxide / ethyl acetate / 15 h / 20 °C / 760.05 Torr |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 6 steps 1: potassium carbonate / acetone / 15 h / Reflux 2: copper(l) iodide; tetrakis(triphenylphosphine) palladium(0); triethylamine / tetrahydrofuran / 15 h / 20 °C / Inert atmosphere 3: hydrogen; palladium(II) hydroxide / ethyl acetate / 15 h / 20 °C / 760.05 Torr 4: 1H-imidazole / N,N-dimethyl-formamide / 2 h / 20 °C / Inert atmosphere 5: diisobutylaluminium hydride / dichloromethane / 0.17 h / -78 °C 6: tetrabutyl ammonium fluoride / tetrahydrofuran / 0.5 h / 0 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1: potassium carbonate / acetone / 15 h / Reflux 2: copper(l) iodide; tetrakis(triphenylphosphine) palladium(0); triethylamine / tetrahydrofuran / 15 h / 20 °C / Inert atmosphere 3: hydrogen; palladium(II) hydroxide / ethyl acetate / 15 h / 20 °C / 760.05 Torr 4: 1H-imidazole / N,N-dimethyl-formamide / 2 h / 20 °C / Inert atmosphere |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 7 steps 1: potassium carbonate / acetone / 15 h / Reflux 2: copper(l) iodide; tetrakis(triphenylphosphine) palladium(0); triethylamine / tetrahydrofuran / 15 h / 20 °C / Inert atmosphere 3: hydrogen; palladium(II) hydroxide / ethyl acetate / 15 h / 20 °C / 760.05 Torr 4: 1H-imidazole / N,N-dimethyl-formamide / 2 h / 20 °C / Inert atmosphere 5: diisobutylaluminium hydride / dichloromethane / 0.17 h / -78 °C 6: tetrabutyl ammonium fluoride / tetrahydrofuran / 0.5 h / 0 °C 7: hydroxylamine hydrochloride; sodium acetate / ethanol / 20 °C / Inert atmosphere |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: potassium carbonate / acetone / 15 h / Reflux 2: copper(l) iodide; tetrakis(triphenylphosphine) palladium(0); triethylamine / tetrahydrofuran / 15 h / 20 °C / Inert atmosphere |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1: potassium carbonate / acetone / 15 h / Reflux 2: copper(l) iodide; tetrakis(triphenylphosphine) palladium(0); triethylamine / tetrahydrofuran / 15 h / 20 °C / Inert atmosphere 3: hydrogen; palladium(II) hydroxide / ethyl acetate / 15 h / 20 °C / 760.05 Torr |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1: potassium carbonate / acetone / 15 h / Reflux 2: copper(l) iodide; tetrakis(triphenylphosphine) palladium(0); triethylamine / tetrahydrofuran / 15 h / 20 °C / Inert atmosphere 3: hydrogen; palladium(II) hydroxide / ethyl acetate / 15 h / 20 °C / 760.05 Torr 4: 1H-imidazole; tert-butyldimethylsilyl chloride / N,N-dimethyl-formamide / 2 h / 20 °C / Inert atmosphere |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 6 steps 1: potassium carbonate / acetone / 15 h / Reflux 2: copper(l) iodide; tetrakis(triphenylphosphine) palladium(0); triethylamine / tetrahydrofuran / 15 h / 20 °C / Inert atmosphere 3: hydrogen; palladium(II) hydroxide / ethyl acetate / 15 h / 20 °C / 760.05 Torr 4: diisobutylaluminium hydride / dichloromethane / 0.17 h / -78 °C 5: tetrabutyl ammonium fluoride / tetrahydrofuran / 0.5 h / 0 °C 6: hydroxylamine hydrochloride; sodium acetate / ethanol / 20 °C / Inert atmosphere |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 5 steps 1: potassium carbonate / acetone / 15 h / Reflux 2: copper(l) iodide; tetrakis(triphenylphosphine) palladium(0); triethylamine / tetrahydrofuran / 15 h / 20 °C / Inert atmosphere 3: hydrogen; palladium(II) hydroxide / ethyl acetate / 15 h / 20 °C / 760.05 Torr 4: diisobutylaluminium hydride / dichloromethane / 0.17 h / -78 °C 5: tetrabutyl ammonium fluoride / tetrahydrofuran / 0.5 h / 0 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 5 steps 1: potassium carbonate / acetone / 15 h / Reflux 2: copper(l) iodide; tetrakis(triphenylphosphine) palladium(0); triethylamine / tetrahydrofuran / 15 h / 20 °C / Inert atmosphere 3: hydrogen; palladium(II) hydroxide / ethyl acetate / 15 h / 20 °C / 760.05 Torr 4: 1H-imidazole / N,N-dimethyl-formamide / 2 h / 20 °C / Inert atmosphere 5: diisobutylaluminium hydride / dichloromethane / 0.17 h / -78 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1: potassium carbonate / acetone / 15 h / Reflux 2: copper(l) iodide; tetrakis(triphenylphosphine) palladium(0); triethylamine / tetrahydrofuran / 15 h / 20 °C / Inert atmosphere 3: hydrogen; palladium(II) hydroxide / ethyl acetate / 15 h / 20 °C / 760.05 Torr 4: diisobutylaluminium hydride / dichloromethane / 0.17 h / -78 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With potassium carbonate In acetone Reflux; | 2.2.3. Synthesis of methyl 3-(benzyloxy)-6-bromopicolinate (Compound 4) To a solution of methyl 3-hydroxy-6-bromopicolinate 3 (11.6 g,49.8 mmol), in acetone (200 mL, 0.25 M) was added successively K2CO3(21 g, 149 mmol, 3 equiv) and benzyl bromide (12 mL, 100 mmol, 2.0equiv). The heterogeneous reaction mixture was reflux overnight. Saltswere removed by filtration and the crude product was concentratedunder reduced pressure. Purification by flash chromatography (Petroleum ether/EtOAc 95/5 to 3/2, v/v) afforded the desired product4 as a white solid (15.2 g, 95%). Rf=0.4 (Petroleum ether/EtOAc 8/2,v/v). 1H NMR (300 MHz, CDCl3): δ (ppm)=3.97 (s, 3H), 5.21 (s, 2H),7.24 (d, J=8.7 Hz, 1H), 7.47-7.34 (m, 5H), 7.51 (d, J=8.7 Hz, 1H).13C NMR (75 MHz, CDCl3): δ (ppm)=52.9, 71.2, 125.0, 126.9, 128.4,128.8, 131.2, 131.4, 135.2, 139.8, 154.0, 164.0. MS (ESI+): m/z (%):324 (85) and 322 (100) [M+H]+. |
95% | With potassium carbonate In acetone Reflux; | 1 Methyl 3-(benzyloxy)-6-bromopicolinate - 4a To a solution of methyl 3-hydroxy-6-bromopicolinate 9a (11.6 g, 49.8 mmol), in acetone (200 mL, 0.25 M) was added successively potassium carbonate (21 g, 149 mmol, 3 equiv.) and benzyl bromide (12 mL, 100 mmol, 2.0 equiv.). The heterogeneous reaction mixture was reflux overnight. Salts were removed by filtration and the crude product was concentrated under reduced pressure. Purification by flash chromatography on silica gel (Petroleum ether/EtOAc 95/5 to 60/40, v/v) afforded the desired product 4a as a white solid (15.2 g, 95%). Rf = 0.4 (Petroleum ether/EtOAc 8/2, v/v). 1H NMR (300 MHz, CDCl3): δ (ppm) 3.97 (s, 3H), 5.21 (s, 2H), 7.24 (d, J = 8.7 Hz, 1H), 7.47-7.34 (m, 5H), 7.51 (d, J = 8.7 Hz, 1H). 13C NMR (75 MHz, CDCl3): δ (ppm) 52.9, 71.2, 125.0, 126.9, 128.4, 128.8, 131.2, 131.4, 135.2, 139.8, 154.0, 164.0. MS (ESI+): m/z (%): 324 (85) and 322 (100) [M+H] +. |
95% | With potassium carbonate In acetone Reflux; | 1 Methyl 3-(benzyloxy)-6-bromopicolinate - 4a To a solution of methyl 3-hydroxy-6-bromopicolinate 9a (11.6 g, 49.8 mmol), in acetone (200 mL, 0.25 M) was added successively potassium carbonate (21 g, 149 mmol, 3 equiv.) and benzyl bromide (12 mL, 100 mmol, 2.0 equiv.). The heterogeneous reaction mixture was reflux overnight. Salts were removed by filtration and the crude product was concentrated under reduced pressure. Purification by flash chromatography on silica gel (Petroleum ether/EtOAc 95/5 to 60/40, v/v) afforded the desired product 4a as a white solid (15.2 g, 95%). Rf = 0.4 (Petroleum ether/EtOAc 8/2, v/v). 1H NMR (300 MHz, CDCl3): δ (ppm) 3.97 (s, 3H), 5.21 (s, 2H), 7.24 (d, J = 8.7 Hz, 1H), 7.47-7.34 (m, 5H), 7.51 (d, J = 8.7 Hz, 1H). 13C NMR (75 MHz, CDCl3): δ (ppm) 52.9, 71.2, 125.0, 126.9, 128.4, 128.8, 131.2, 131.4, 135.2, 139.8, 154.0, 164.0. MS (ESI+): m/z (%): 324 (85) and 322 (100) [M+H] +. |
93% | With potassium carbonate In acetone for 15h; Reflux; | |
93% | With potassium carbonate In acetone for 15h; Reflux; | |
With potassium carbonate In tetrahydrofuran at 20℃; for 3h; | 1.2 Step 2 - Synthesis of methyl 3-(benzyloxy)-6-bromopicolinate A mixture of methyl 6-bromo-3-hydroxypicolinate (500 mg, 2.15 mmol), BnBr (443 mg, 3.25 mmol) and K2C03 (595 mg, 4.31 mmol) in THF (5 mL) was stirred at RT for 3 h. Then water was added and the mixture was extracted with EtOAc (20 mL * 3). The organic layer was dried over Na2S04 and concentrated to give crude methyl 3-(benzyloxy)-6- bromopicolinate (500 mg, yield 72%), which was used for the next step without further purification. MS (M+H)+: 322 / 324. | |
With potassium carbonate In tetrahydrofuran at 25℃; for 3h; | 1.2 Synthesis of methyl 3-(benzyloxy)-6-bromopicolinate A mixture of methyl 6-bromo-3-hydroxypicolinate (500 mg, 2.15 mmol), BnBr (443 mg, 3.25 mmol) and K2C03 (595 mg, 4.31 mmol) in THF (5 mL) was stirred at RT for 3 h. Then water was added and the mixture was extracted with EtOAc (20 mL * 3). The organic layer was dried over Na2504 and concentrated to give crude methyl 3-(benzyloxy)-6-bromopicolinate (500 mg, yield 72%), which was used for the next step without further purification. MS (M+H): 322 / 324. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1: pyridine; copper(II) oxide / 130 °C 2: N-Bromosuccinimide; methylene chloride / 80 °C 3: toluene / Reflux | ||
Multi-step reaction with 4 steps 1.1: pyridine / copper(I) oxide / 6 h / 130 °C 1.2: 18 h / Heating / reflux 2.1: N-Bromosuccinimide / chloroform / 3 h / Heating / reflux 3.1: sodium hydroxide; water / tetrahydrofuran / 18 h / 20 °C 3.2: pH 3 4.1: benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride / DMF (N,N-dimethyl-formamide) / 0.02 h / 20 °C 4.2: 2 h |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: pyridine; copper(II) oxide / 130 °C 2: N-Bromosuccinimide; methylene chloride / 80 °C | ||
Multi-step reaction with 2 steps 1.1: pyridine / copper(I) oxide / 6 h / 130 °C 1.2: 18 h / Heating / reflux 2.1: N-Bromosuccinimide / chloroform / 3 h / Heating / reflux |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With N-ethyl-N,N-diisopropylamine In chloroform at 0 - 20℃; for 1.08333h; Inert atmosphere; | 21.21.1 Reference Example 21(1) methyl 6-bromo-3-(methoxymethoxy)picolinate Diisopropylethylamine (1.46 mL) was added to a chloroform (20 mL) solution of methyl 6-bromo-3-hydroxypyridine-2-carboxylate (970 mg) and placed in a nitrogen atmosphere. Next, the reaction mixture was cooled to 0° C., and chloromethoxymethane (0.38 mL) was added thereto. The reaction mixture was stirred at 0° C. for 5 minutes, and then stirred at room temperature for 1 hour. The reaction mixture was cooled to 0° C., diluted with water, and extracted with chloroform. The combined organic layer was washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (hexane:ethyl acetate) to give the desired product (1.22 g, yield: 100%) as a colorless oil. 1H-NMR (CDCl3) δ: 7.54 (1H, d, J=8.8 Hz), 7.51 (1H, d, J=8.8 Hz), 5.26 (2H, s), 3.96 (3H, s), 3.51 (3H, s). ESI-MS m/z 276,278 (MH+) |
100% | With N-ethyl-N,N-diisopropylamine In chloroform at 0 - 20℃; for 1.08333h; Inert atmosphere; | 21.1 Reference Example 21(1) methyl 6-bromo-3-(methoxymethoxy)picolinate Reference Example 21 Reference Example 21(1) methyl 6-bromo-3-(methoxymethoxy)picolinate Diisopropylethylamine (1.46 mL) was added to a chloroform (20 mL) solution of methyl 6-bromo-3-hydroxypyridine-2-carboxylate (970 mg) and placed in a nitrogen atmosphere. Next, the reaction mixture was cooled to 0°C, and chloromethoxymethane (0.38 mL) was added thereto. The reaction mixture was stirred at 0°C for 5 minutes, and then stirred at room temperature for 1 hour. The reaction mixture was cooled to 0°C, diluted with water, and extracted with chloroform. The combined organic layer was washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (hexane:ethyl acetate) to give the desired product (1.22 g, yield: 100%) as a colorless oil. 1H-NMR (CDCl3) δ: 7.54 (1H, d, J = 8.8 Hz), 7.51 (1H, d, J = 8.8 Hz), 5.26 (2H, s), 3.96 (3H, s), 3.51 (3H, s). ESI-MS m/z 276,278(MH+) |
95% | Stage #1: methyl 6-bromo-3-hydroxypyridine-2-carboxylate; chloromethyl methyl ether With potassium carbonate at 0℃; Inert atmosphere; Reflux; Stage #2: With sodium hydride at 0℃; for 1h; Inert atmosphere; | 1 Methyl 6-bromo-3-(methoxymethoxy)picolinate - 4b To a solution of 9a (4.84 g, 20.87 mmol) in acetone (100 mL) was slowly added potassium carbonate (5.8 g, 2 equiv.) and MOMCl (20 mL, 41.74 mmol, 2 equiv.) under argon at 0 °C. The mixture was stirred heated to reflux overnight. Salts were removed by filtration and the crude was concentrated under vacuum. The desired product was obtained after purification by flash chromatography on silica gel (Petroleum ether/EtOAc, 60/40, v/v) as a colourless oil (1.70 g, 94%). (0229) To a solution of 9a (1 g, 6.5 mmol) in DMF (65 mL) was slowly added NaH (230 mg, 9.75 mmol, 1.2 equiv.) and MOMCl (3 mL, 6.5 mmol, 1.0 equiv.) under argon at 0 °C. The mixture was stirred 1 h and quenched with aq. NH4Cl. The cooled reaction mixture was washed extracted with dichloromethane, washed with water, dried under magnesium sulfate and concentrated under reduced pressure. The desired product was obtained without further purification as a colourless oil (5.18 g, 95%). Rf = 0.25 (Petroleum ether/EtOAc 60/40, v/v). 1H NMR (300 MHz, CDCl3) δ (ppm) 7.53 (d, J = 8.8 Hz, 1H), 7.49 (d, J = 8.8 Hz, 1H), 5.25 (s, 2H), 3.95 (s, 3H), 3.50 (s, 3H). 13C NMR (75 MHz, CDCl3) δ (ppm) 52.7, 56.6, 95.1, 127.1, 131.3, 132.1, 140.1, 152.4, 163.9. MS (ESI+): m/z (%): 276 (85) [M+H]+ and 278 (100). |
95% | Stage #1: methyl 6-bromo-3-hydroxypyridine-2-carboxylate; chloromethyl methyl ether With potassium carbonate at 0℃; Inert atmosphere; Reflux; Stage #2: With sodium hydride at 0℃; for 1h; Inert atmosphere; | 1 Methyl 6-bromo-3-(methoxymethoxy)picolinate - 4b To a solution of 9a (4.84 g, 20.87 mmol) in acetone (100 mL) was slowly added potassium carbonate (5.8 g, 2 equiv.) and MOMCl (20 mL, 41.74 mmol, 2 equiv.) under argon at 0 °C. The mixture was stirred heated to reflux overnight. Salts were removed by filtration and the crude was concentrated under vacuum. The desired product was obtained after purification by flash chromatography on silica gel (Petroleum ether/EtOAc, 60/40, v/v) as a colourless oil (1.70 g, 94%). (0229) To a solution of 9a (1 g, 6.5 mmol) in DMF (65 mL) was slowly added NaH (230 mg, 9.75 mmol, 1.2 equiv.) and MOMCl (3 mL, 6.5 mmol, 1.0 equiv.) under argon at 0 °C. The mixture was stirred 1 h and quenched with aq. NH4Cl. The cooled reaction mixture was washed extracted with dichloromethane, washed with water, dried under magnesium sulfate and concentrated under reduced pressure. The desired product was obtained without further purification as a colourless oil (5.18 g, 95%). Rf = 0.25 (Petroleum ether/EtOAc 60/40, v/v). 1H NMR (300 MHz, CDCl3) δ (ppm) 7.53 (d, J = 8.8 Hz, 1H), 7.49 (d, J = 8.8 Hz, 1H), 5.25 (s, 2H), 3.95 (s, 3H), 3.50 (s, 3H). 13C NMR (75 MHz, CDCl3) δ (ppm) 52.7, 56.6, 95.1, 127.1, 131.3, 132.1, 140.1, 152.4, 163.9. MS (ESI+): m/z (%): 276 (85) [M+H]+ and 278 (100). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: sulfuric acid / 24 h / Reflux 2: bromine / water / 17 h / 0 - 20 °C | ||
Multi-step reaction with 2 steps 1: sulfuric acid / 80 °C 2: bromine / water / 25 °C | ||
Multi-step reaction with 2 steps 1: sulfuric acid / 24 h / 0 °C / Reflux 2: bromine / water / 4 h / 20 °C |
Multi-step reaction with 2 steps 1: sulfuric acid / 6 h / 0 °C / Reflux 2: bromine / water / 0 °C | ||
Multi-step reaction with 2 steps 1: sulfuric acid / 72 h / 70 °C / Inert atmosphere 2: bromine / water / 2 h / 20 °C | ||
Multi-step reaction with 2 steps 1: sulfuric acid / methanol / 16 h / 0 - 80 °C 2: bromine / water / 6 h / 20 °C | ||
Multi-step reaction with 2 steps 1: sulfuric acid / 72 h / 20 °C / Reflux 2: bromine / water / 3 h / 20 °C | ||
Multi-step reaction with 2 steps 1: sulfuric acid / 6 h / 0 °C / Reflux 2: bromine / water / 0 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: potassium carbonate / acetone / 15 h / Reflux 2: triethylamine; copper(l) iodide; tetrakis(triphenylphosphine) palladium(0) / dichloromethane / 20 °C / Inert atmosphere | ||
Multi-step reaction with 2 steps 1.1: potassium carbonate / acetone / Reflux 2.1: triethylamine / dichloromethane / 0.33 h / Inert atmosphere 2.2: 20 °C / Inert atmosphere |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1: potassium carbonate / acetone / 15 h / Reflux 2: triethylamine; copper(l) iodide; tetrakis(triphenylphosphine) palladium(0) / dichloromethane / 20 °C / Inert atmosphere 3: triethylamine / dichloromethane / 4 h / Reflux | ||
Multi-step reaction with 3 steps 1.1: potassium carbonate / acetone / Reflux 2.1: triethylamine / dichloromethane / 0.33 h / Inert atmosphere 2.2: 20 °C / Inert atmosphere 3.1: triethylamine / dichloromethane / 2 h / 0 - 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide; triethylamine In tetrahydrofuran at 50℃; for 22h; Inert atmosphere; | Methyl 3-hydroxy-6-[5-(1,2,3,4-tetrahydroacridin-9-ylsulfanyl)pent-1-yn-1-yl]pyridine-2-carboxylate(48) To the degazed solution of 47 (0.75 g, 3.2 mmol, 1 equiv) in 40 mL of THF/Et3N (1/1) catalysts Pd(PPh3)2Cl2 (0.124 g, 0.18mmol, 0.05 equiv) and CuI (0.034 g, 0.18mmol, 0.05equiv) were added. After degazation the mixture was stirred at the room temperature for 5 min, then 15 mL of degazed solution of alkyne 46(1.00 g, 3.55 mmol, 1.1 equiv) was added. The reaction mixture was degased with hydrogen, then stirred during 22 h at 50 °C in Ar/H2 atmosphere. After concentration at reduced pressure the residue was purified by flash chromatography (CH2Cl2/MeOH) to give 1.26g of 48 (90% yield). 1H NMR (400 MHz, CDCl3, δ): 8.42 (1H, dd, J = 8.4, 1.2 Hz), 7.97 (1H, d, J = 8.4 Hz), 7.59-7.55 (1H, m), 7.47-7.43 (1H, m), 7.27 (1H, d, J = 8.7 Hz), 7.21 (1H, d, J = 8.7 Hz), 3.95 (3H, s), 3.16 (2H, t, J = 6.3 Hz), 3.10 (2H, t, J = 6.3 Hz), 2.92 (2H, t, J = 7.3 Hz), 2.45 (2H, t, J = 6.9 Hz), 1.93-1.80 (4H, m), 1.76-1.69 (2H, m).13C NMR (100 MHz, CDCl3, δ): 169.61, 159.18, 158.00, 146.50, 141.94, 136.14, 135.41, 133.21, 129.89, 129.07, 129.00, 126.64, 126.54, 126.07, 88.54, 80.42, 53.62, 53.41, 35.08, 34.42, 29.38, 28.74, 23.19, 22.85, 18.71. HRMS (ESI) m/z: calculated for C25H25N2O3S [M+H]+ = 433.15858, found [M+H]+ = 433.15887. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: potassium carbonate / tetrahydrofuran / 3 h / 20 °C 2: potassium phosphate tribasic trihydrate; tris-(dibenzylideneacetone)dipalladium(0); XPhos / water; 1,4-dioxane / 8 h / 80 °C / Inert atmosphere | ||
Multi-step reaction with 2 steps 1: potassium carbonate / tetrahydrofuran / 3 h / 25 °C 2: potassium phosphate tribasic trihydrate; tris-(dibenzylideneacetone)dipalladium(0); XPhos / water; 1,4-dioxane / 8 h / 80 °C / Inert atmosphere |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1: potassium carbonate / tetrahydrofuran / 3 h / 20 °C 2: potassium phosphate tribasic trihydrate; tris-(dibenzylideneacetone)dipalladium(0); XPhos / water; 1,4-dioxane / 8 h / 80 °C / Inert atmosphere 3: lithium hydroxide / water; 1,4-dioxane / 1 h / 100 °C / Inert atmosphere | ||
Multi-step reaction with 3 steps 1: potassium carbonate / tetrahydrofuran / 3 h / 25 °C 2: potassium phosphate tribasic trihydrate; tris-(dibenzylideneacetone)dipalladium(0); XPhos / water; 1,4-dioxane / 8 h / 80 °C / Inert atmosphere 3: lithium hydroxide monohydrate / water; 1,4-dioxane / 1 h / 100 °C / Inert atmosphere |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With bromine; In tetrahydrofuran; water; | 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. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 5 steps 1.1: pyridine / copper(I) oxide / 6 h / 130 °C 1.2: 18 h / Heating / reflux 2.1: N-Bromosuccinimide / chloroform / 3 h / Heating / reflux 3.1: sodium hydroxide; water / tetrahydrofuran / 18 h / 20 °C 3.2: pH 3 4.1: benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride / DMF (N,N-dimethyl-formamide) / 0.02 h / 20 °C 4.2: 2 h 5.1: triethylamine / palladium diacetate; 1,3-bis-(diphenylphosphino)propane / 18 h / 760.05 Torr / Heating / reflux |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1.1: pyridine / copper(I) oxide / 6 h / 130 °C 1.2: 18 h / Heating / reflux 2.1: N-Bromosuccinimide / chloroform / 3 h / Heating / reflux 3.1: sodium hydroxide; water / tetrahydrofuran / 18 h / 20 °C 3.2: pH 3 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
42% | Stage #1: methanol; 3-hydroxypyridine-2-carboxylic acid With diazomethyl-trimethyl-silane In dichloromethane Stage #2: With bromine In water |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: methyl 6-bromo-3-hydroxypyridine-2-carboxylate; 2-Chlorobenzeneboronic acid With tetrakis(triphenylphosphine) palladium(0); cesium fluoride In N,N-dimethyl-formamide at 100℃; Stage #2: With hydroxylamine; sodium hydroxide In 1,4-dioxane; water |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1.30 g | With tetra-(n-butyl)ammonium iodide; potassium carbonate; In N,N-dimethyl-formamide; at 80℃; for 16h;Inert atmosphere; | A 25 mL single-necked flask was charged with methyl 6-bromo-3-hydroxy-2-picolinate (1.50 g), p-toluenesulfonate-4-methyl pyran (1.92 g), potassium carbonate (2.68 g), tetrabutylammonium iodide (0.24 g) and 15 mL of dimethylformamide (DMF). The mixture was purged with nitrogen gas three times and then reacted in an oil bath at 80C for 16 h. A sample was taken, and TLC detection showed that the spots of the raw materials disappeared. 50 mL of water was added, and the resulting mixture was extracted with ethyl acetate (25 mL × 3), washed with 30 mL of saturated saline, dried over anhydrous sodium sulfate, and subjected to column chromatography (PE EA = 5 1), so as to obtain 1.30 g of methyl 6-bromo-3-((tetrahydro-2H-pyran-4-yl)methoxy)-2-picolinate. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: sodium hydride / ISOPROPYLAMIDE / 3 h / 90 °C 2: tetrabutylammomium bromide; potassium carbonate / bis-triphenylphosphine-palladium(II) chloride / 1,4-dioxane; water / 1.5 h / 100 °C / Microwave irradiation |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1: sodium hydride / ISOPROPYLAMIDE / 3 h / 90 °C 2: tetrabutylammomium bromide; potassium carbonate / bis-triphenylphosphine-palladium(II) chloride / 1,4-dioxane; water / 1.5 h / 100 °C / Microwave irradiation 3: acetic acid / 16 h / 60 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1.1: triphenylphosphine; di-isopropyl azodicarboxylate / tetrahydrofuran / 0.25 h / 0 - 20 °C 1.2: 3 h / 20 °C 2.1: tetrabutylammomium bromide; cesium fluoride; bis-triphenylphosphine-palladium(II) chloride / water; 1,4-dioxane / 2 h / 120 °C / Inert atmosphere; Microwave irradiation |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1.1: triphenylphosphine; di-isopropyl azodicarboxylate / tetrahydrofuran / 0.25 h / 0 - 20 °C 1.2: 3 h / 20 °C 2.1: tetrabutylammomium bromide; cesium fluoride; bis-triphenylphosphine-palladium(II) chloride / water; 1,4-dioxane / 2 h / 120 °C / Inert atmosphere; Microwave irradiation 3.1: lithium hydroxide / water; tetrahydrofuran / 16 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1.1: triphenylphosphine; di-isopropyl azodicarboxylate / tetrahydrofuran / 0.25 h / 0 - 20 °C 1.2: 3 h / 20 °C 2.1: tetrabutylammomium bromide; cesium fluoride; bis-triphenylphosphine-palladium(II) chloride / water; 1,4-dioxane / 2 h / 120 °C / Inert atmosphere; Microwave irradiation 3.1: lithium hydroxide / water; tetrahydrofuran / 16 h / 20 °C 4.1: ethanol / 16 h / 60 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1.1: triphenylphosphine; di-isopropyl azodicarboxylate / tetrahydrofuran / 0.25 h / 0 - 20 °C 1.2: 3 h / 20 °C 2.1: tetrabutylammomium bromide; cesium fluoride; bis-triphenylphosphine-palladium(II) chloride / water; 1,4-dioxane / 2 h / 120 °C / Inert atmosphere; Microwave irradiation 3.1: lithium hydroxide / water; tetrahydrofuran / 16 h / 20 °C 4.1: ethanol / 16 h / 60 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1.1: triphenylphosphine; di-isopropyl azodicarboxylate / tetrahydrofuran / 0.25 h / 0 - 20 °C 1.2: 3 h / 20 °C 2.1: tetrabutylammomium bromide; cesium fluoride; bis-triphenylphosphine-palladium(II) chloride / water; 1,4-dioxane / 2 h / 120 °C / Inert atmosphere; Microwave irradiation 3.1: lithium hydroxide / water; tetrahydrofuran / 16 h / 20 °C 4.1: ethanol / 16 h / 60 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1.1: triphenylphosphine; di-isopropyl azodicarboxylate / tetrahydrofuran / 0.25 h / 0 - 20 °C 1.2: 3 h / 20 °C 2.1: tetrabutylammomium bromide; cesium fluoride; bis-triphenylphosphine-palladium(II) chloride / water; 1,4-dioxane / 2 h / 120 °C / Inert atmosphere; Microwave irradiation 3.1: lithium hydroxide / water; tetrahydrofuran / 16 h / 20 °C 4.1: ethanol / 16 h / 60 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1.1: triphenylphosphine; di-isopropyl azodicarboxylate / tetrahydrofuran / 0.25 h / 0 - 20 °C 1.2: 3 h / 20 °C 2.1: tetrabutylammomium bromide; cesium fluoride; bis-triphenylphosphine-palladium(II) chloride / water; 1,4-dioxane / 2 h / 120 °C / Inert atmosphere; Microwave irradiation 3.1: lithium hydroxide / water; tetrahydrofuran / 16 h / 20 °C 4.1: ethanol / 16 h / 60 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1.1: triphenylphosphine; di-isopropyl azodicarboxylate / tetrahydrofuran / 0.25 h / 0 - 20 °C 1.2: 3 h / 20 °C 2.1: tetrabutylammomium bromide; cesium fluoride; bis-triphenylphosphine-palladium(II) chloride / water; 1,4-dioxane / 2 h / 120 °C / Inert atmosphere; Microwave irradiation 3.1: lithium hydroxide / water; tetrahydrofuran / 16 h / 20 °C 4.1: ethanol / 16 h / 60 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1.1: triphenylphosphine; di-isopropyl azodicarboxylate / tetrahydrofuran / 0.25 h / 0 - 20 °C 1.2: 3 h / 20 °C 2.1: tetrabutylammomium bromide; cesium fluoride; bis-triphenylphosphine-palladium(II) chloride / water; 1,4-dioxane / 2 h / 120 °C / Inert atmosphere; Microwave irradiation 3.1: lithium hydroxide / water; tetrahydrofuran / 16 h / 20 °C 4.1: ethanol / 16 h / 60 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1.1: triphenylphosphine; di-isopropyl azodicarboxylate / tetrahydrofuran / 0.25 h / 0 - 20 °C 1.2: 3 h / 20 °C 2.1: tetrabutylammomium bromide; cesium fluoride; bis-triphenylphosphine-palladium(II) chloride / water; 1,4-dioxane / 2 h / 120 °C / Inert atmosphere; Microwave irradiation 3.1: lithium hydroxide / water; tetrahydrofuran / 16 h / 20 °C 4.1: ethanol / 16 h / 60 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1.1: triphenylphosphine; di-isopropyl azodicarboxylate / tetrahydrofuran / 0.25 h / 0 - 20 °C 1.2: 3 h / 20 °C 2.1: tetrabutylammomium bromide; cesium fluoride; bis-triphenylphosphine-palladium(II) chloride / water; 1,4-dioxane / 2 h / 120 °C / Inert atmosphere; Microwave irradiation 3.1: lithium hydroxide / water; tetrahydrofuran / 16 h / 20 °C 4.1: ethanol / 16 h / 60 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1.1: triphenylphosphine; di-isopropyl azodicarboxylate / tetrahydrofuran / 0.25 h / 0 - 20 °C 1.2: 3 h / 20 °C 2.1: tetrabutylammomium bromide; cesium fluoride; bis-triphenylphosphine-palladium(II) chloride / water; 1,4-dioxane / 2 h / 120 °C / Inert atmosphere; Microwave irradiation 3.1: lithium hydroxide / water; tetrahydrofuran / 16 h / 20 °C 4.1: ethanol / 16 h / 60 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1.1: triphenylphosphine; di-isopropyl azodicarboxylate / tetrahydrofuran / 0.25 h / 0 - 20 °C 1.2: 3 h / 20 °C 2.1: tetrabutylammomium bromide; cesium fluoride; bis-triphenylphosphine-palladium(II) chloride / water; 1,4-dioxane / 2 h / 120 °C / Inert atmosphere; Microwave irradiation 3.1: lithium hydroxide / water; tetrahydrofuran / 16 h / 20 °C 4.1: ethanol / 16 h / 60 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1.1: triphenylphosphine; di-isopropyl azodicarboxylate / tetrahydrofuran / 0.25 h / 0 - 20 °C 1.2: 3 h / 20 °C 2.1: tetrabutylammomium bromide; cesium fluoride; bis-triphenylphosphine-palladium(II) chloride / water; 1,4-dioxane / 2 h / 120 °C / Inert atmosphere; Microwave irradiation 3.1: lithium hydroxide / water; tetrahydrofuran / 16 h / 20 °C 4.1: ethanol / 16 h / 60 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1.1: triphenylphosphine; di-isopropyl azodicarboxylate / tetrahydrofuran / 0.25 h / 0 - 20 °C 1.2: 3 h / 20 °C 2.1: tetrabutylammomium bromide; cesium fluoride; bis-triphenylphosphine-palladium(II) chloride / water; 1,4-dioxane / 2 h / 120 °C / Inert atmosphere; Microwave irradiation 3.1: lithium hydroxide / water; tetrahydrofuran / 16 h / 20 °C 4.1: ethanol / 16 h / 60 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1.1: triphenylphosphine; di-isopropyl azodicarboxylate / tetrahydrofuran / 0.25 h / 0 - 20 °C 1.2: 3 h / 20 °C 2.1: tetrabutylammomium bromide; cesium fluoride; bis-triphenylphosphine-palladium(II) chloride / water; 1,4-dioxane / 2 h / 120 °C / Inert atmosphere; Microwave irradiation 3.1: lithium hydroxide / water; tetrahydrofuran / 16 h / 20 °C 4.1: ethanol / 16 h / 60 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1.1: triphenylphosphine; di-isopropyl azodicarboxylate / tetrahydrofuran / 0.25 h / 0 - 20 °C 1.2: 3 h / 20 °C 2.1: tetrabutylammomium bromide; cesium fluoride; bis-triphenylphosphine-palladium(II) chloride / water; 1,4-dioxane / 2 h / 120 °C / Inert atmosphere; Microwave irradiation 3.1: lithium hydroxide / water; tetrahydrofuran / 16 h / 20 °C 4.1: ethanol / 16 h / 60 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1.1: triphenylphosphine; di-isopropyl azodicarboxylate / tetrahydrofuran / 0.25 h / 0 - 20 °C 1.2: 3 h / 20 °C 2.1: tetrabutylammomium bromide; cesium fluoride; bis-triphenylphosphine-palladium(II) chloride / water; 1,4-dioxane / 2 h / 120 °C / Inert atmosphere; Microwave irradiation 3.1: lithium hydroxide / water; tetrahydrofuran / 16 h / 20 °C 4.1: ethanol / 16 h / 60 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1.1: triphenylphosphine; di-isopropyl azodicarboxylate / tetrahydrofuran / 0.25 h / 0 - 20 °C 1.2: 3 h / 20 °C 2.1: tetrabutylammomium bromide; cesium fluoride; bis-triphenylphosphine-palladium(II) chloride / water; 1,4-dioxane / 2 h / 120 °C / Inert atmosphere; Microwave irradiation 3.1: lithium hydroxide / water; tetrahydrofuran / 16 h / 20 °C 4.1: ethanol / 16 h / 60 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1.1: triphenylphosphine; di-isopropyl azodicarboxylate / tetrahydrofuran / 0.25 h / 0 - 20 °C 1.2: 3 h / 20 °C 2.1: tetrabutylammomium bromide; cesium fluoride; bis-triphenylphosphine-palladium(II) chloride / water; 1,4-dioxane / 2 h / 120 °C / Inert atmosphere; Microwave irradiation 3.1: lithium hydroxide / water; tetrahydrofuran / 16 h / 20 °C 4.1: ethanol / 16 h / 60 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1.1: triphenylphosphine; di-isopropyl azodicarboxylate / tetrahydrofuran / 0.25 h / 0 - 20 °C 1.2: 3 h / 20 °C 2.1: tetrabutylammomium bromide; cesium fluoride; bis-triphenylphosphine-palladium(II) chloride / water; 1,4-dioxane / 2 h / 120 °C / Inert atmosphere; Microwave irradiation 3.1: lithium hydroxide / water; tetrahydrofuran / 16 h / 20 °C 4.1: ethanol / 16 h / 60 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1.1: triphenylphosphine; di-isopropyl azodicarboxylate / tetrahydrofuran / 0.25 h / 0 - 20 °C 1.2: 3 h / 20 °C 2.1: tetrabutylammomium bromide; cesium fluoride; bis-triphenylphosphine-palladium(II) chloride / water; 1,4-dioxane / 2 h / 120 °C / Inert atmosphere; Microwave irradiation 3.1: lithium hydroxide / water; tetrahydrofuran / 16 h / 20 °C 4.1: ethanol / 16 h / 60 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1.1: triphenylphosphine; di-isopropyl azodicarboxylate / tetrahydrofuran / 0.25 h / 0 - 20 °C 1.2: 3 h / 20 °C 2.1: tetrabutylammomium bromide; cesium fluoride; bis-triphenylphosphine-palladium(II) chloride / water; 1,4-dioxane / 2 h / 120 °C / Inert atmosphere; Microwave irradiation 3.1: lithium hydroxide / water; tetrahydrofuran / 16 h / 20 °C 4.1: ethanol / 16 h / 60 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1.1: triphenylphosphine; di-isopropyl azodicarboxylate / tetrahydrofuran / 0.25 h / 0 - 20 °C 1.2: 3 h / 20 °C 2.1: tetrabutylammomium bromide; cesium fluoride; bis-triphenylphosphine-palladium(II) chloride / water; 1,4-dioxane / 2 h / 120 °C / Inert atmosphere; Microwave irradiation 3.1: lithium hydroxide / water; tetrahydrofuran / 16 h / 20 °C 4.1: ethanol / 16 h / 60 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1.1: triphenylphosphine; di-isopropyl azodicarboxylate / tetrahydrofuran / 0.25 h / 0 - 20 °C 1.2: 3 h / 20 °C 2.1: tetrabutylammomium bromide; cesium fluoride; bis-triphenylphosphine-palladium(II) chloride / water; 1,4-dioxane / 2 h / 120 °C / Inert atmosphere; Microwave irradiation 3.1: lithium hydroxide / water; tetrahydrofuran / 16 h / 20 °C 4.1: ethanol / 16 h / 60 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79% | Stage #1: methyl 6-bromo-3-hydroxypyridine-2-carboxylate With di-isopropyl azodicarboxylate; triphenylphosphine In tetrahydrofuran at 0 - 20℃; for 0.25h; Stage #2: 2-phenylethanol In tetrahydrofuran at 20℃; for 3h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With potassium carbonate at 100℃; for 2h; | Step-2 Synthesis of methyl6-bromo-3-(2,2-difluoroethoxy)picolinate (Intermediate AA211-3) To a solution of Intermediate AA198-4 (1.5 g, 46.55 mmol) in DMF (15 mL) were added potassium carbonate (2.6 g, 39.65 mmol, 3 eq) and dropwise Intermediate-Intermediate AA211-2 (1.98 g, 40.55 mmol, 0.3 eq). After stirring at 100° C. and for 2 h, the reaction mixture was quenched with water (300 mL) and extracted by EtOAc (2×100). The combined organic layer was washed with brine (100 mL), passed through a Na2SO4, and concentrated under reduced pressure. The residue was purified by column chromatography (5-10% gradient with ethyl acetate in hexane) to afford Intermediate AA211-3 (1.2 g, 98%), MS (ES): m/z 295 [M+1]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
3.21 g | With 1H-imidazole In dichloromethane at 20℃; for 18h; | Step 1: methyl 6-bromo-3-((tert-butyldimethylsilyl)oxy)picolinate (Intermediate AB84-2) A mixture of methyl-6-bromo-3-hydroxypyridine-2-carboxylate (Intermediate AB84-1) (2.50 g, 10 77 mmol), TBDMSCl (2.44 g, 16.16 mmol) and imidazole (1.10 g, 16.16 mmol) in DCM (30 mL) was stirred at RT for 18 h. The reaction was diluted with DCM and washed with water. The organic solution was washed with brine, dried over Na2SO4, and concentrated in vacuo to leave the title compound (Intermediate AB84-2) (3.21 g, 9.27 mmol) as a pale yellow oil which was used crude in subsequent reactions. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
67.2% | With potassium carbonate In N,N-dimethyl-formamide at 90℃; for 16h; | Step-3 Synthesis of methyl (R)-6-bromo-3-((THF-3-yl)oxy)picolinate (Intermediate AA198-5) To a solution of Intermediate AA198-4 (4.0 g, 17.24 mmol) and Intermediate AA198-2 (5.4 g, 22.41 mmol, 1.5 eq) in DMF (20 mL) was added potassium carbonate (7.1 g, 51.72 mmol, 3.0 eq). After stirring at 90° C. for 16 h, the reaction was diluted with ice cold water (250 mL) and extracted into ethyl acetate (3×80 mL). The combined organic layer was washed with brine, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 17% ethyl acetate in hexane to afford Intermediate AA198-5 (3.5 g, 67.20%) as a yellow oil. MS (ES): m/z 302.9 [M+H]+. |
Tags: 321601-48-3 synthesis path| 321601-48-3 SDS| 321601-48-3 COA| 321601-48-3 purity| 321601-48-3 application| 321601-48-3 NMR| 321601-48-3 COA| 321601-48-3 structure
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Precautionary Statements-General | |
Code | Phrase |
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P103 | Read label before use |
Prevention | |
Code | Phrase |
P201 | Obtain special instructions before use. |
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P221 | Take any precaution to avoid mixing with combustibles |
P222 | Do not allow contact with air. |
P223 | Keep away from any possible contact with water, because of violent reaction and possible flash fire. |
P230 | Keep wetted |
P231 | Handle under inert gas. |
P232 | Protect from moisture. |
P233 | Keep container tightly closed. |
P234 | Keep only in original container. |
P235 | Keep cool |
P240 | Ground/bond container and receiving equipment. |
P241 | Use explosion-proof electrical/ventilating/lighting/equipment. |
P242 | Use only non-sparking tools. |
P243 | Take precautionary measures against static discharge. |
P244 | Keep reduction valves free from grease and oil. |
P250 | Do not subject to grinding/shock/friction. |
P251 | Pressurized container: Do not pierce or burn, even after use. |
P260 | Do not breathe dust/fume/gas/mist/vapours/spray. |
P261 | Avoid breathing dust/fume/gas/mist/vapours/spray. |
P262 | Do not get in eyes, on skin, or on clothing. |
P263 | Avoid contact during pregnancy/while nursing. |
P264 | Wash hands thoroughly after handling. |
P265 | Wash skin thouroughly after handling. |
P270 | Do not eat, drink or smoke when using this product. |
P271 | Use only outdoors or in a well-ventilated area. |
P272 | Contaminated work clothing should not be allowed out of the workplace. |
P273 | Avoid release to the environment. |
P280 | Wear protective gloves/protective clothing/eye protection/face protection. |
P281 | Use personal protective equipment as required. |
P282 | Wear cold insulating gloves/face shield/eye protection. |
P283 | Wear fire/flame resistant/retardant clothing. |
P284 | Wear respiratory protection. |
P285 | In case of inadequate ventilation wear respiratory protection. |
P231 + P232 | Handle under inert gas. Protect from moisture. |
P235 + P410 | Keep cool. Protect from sunlight. |
Response | |
Code | Phrase |
P301 | IF SWALLOWED: |
P304 | IF INHALED: |
P305 | IF IN EYES: |
P306 | IF ON CLOTHING: |
P307 | IF exposed: |
P308 | IF exposed or concerned: |
P309 | IF exposed or if you feel unwell: |
P310 | Immediately call a POISON CENTER or doctor/physician. |
P311 | Call a POISON CENTER or doctor/physician. |
P312 | Call a POISON CENTER or doctor/physician if you feel unwell. |
P313 | Get medical advice/attention. |
P314 | Get medical advice/attention if you feel unwell. |
P315 | Get immediate medical advice/attention. |
P320 | |
P302 + P352 | IF ON SKIN: wash with plenty of soap and water. |
P321 | |
P322 | |
P330 | Rinse mouth. |
P331 | Do NOT induce vomiting. |
P332 | IF SKIN irritation occurs: |
P333 | If skin irritation or rash occurs: |
P334 | Immerse in cool water/wrap n wet bandages. |
P335 | Brush off loose particles from skin. |
P336 | Thaw frosted parts with lukewarm water. Do not rub affected area. |
P337 | If eye irritation persists: |
P338 | Remove contact lenses, if present and easy to do. Continue rinsing. |
P340 | Remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P341 | If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P342 | If experiencing respiratory symptoms: |
P350 | Gently wash with plenty of soap and water. |
P351 | Rinse cautiously with water for several minutes. |
P352 | Wash with plenty of soap and water. |
P353 | Rinse skin with water/shower. |
P360 | Rinse immediately contaminated clothing and skin with plenty of water before removing clothes. |
P361 | Remove/Take off immediately all contaminated clothing. |
P362 | Take off contaminated clothing and wash before reuse. |
P363 | Wash contaminated clothing before reuse. |
P370 | In case of fire: |
P371 | In case of major fire and large quantities: |
P372 | Explosion risk in case of fire. |
P373 | DO NOT fight fire when fire reaches explosives. |
P374 | Fight fire with normal precautions from a reasonable distance. |
P376 | Stop leak if safe to do so. Oxidising gases (section 2.4) 1 |
P377 | Leaking gas fire: Do not extinguish, unless leak can be stopped safely. |
P378 | |
P380 | Evacuate area. |
P381 | Eliminate all ignition sources if safe to do so. |
P390 | Absorb spillage to prevent material damage. |
P391 | Collect spillage. Hazardous to the aquatic environment |
P301 + P310 | IF SWALLOWED: Immediately call a POISON CENTER or doctor/physician. |
P301 + P312 | IF SWALLOWED: call a POISON CENTER or doctor/physician IF you feel unwell. |
P301 + P330 + P331 | IF SWALLOWED: Rinse mouth. Do NOT induce vomiting. |
P302 + P334 | IF ON SKIN: Immerse in cool water/wrap in wet bandages. |
P302 + P350 | IF ON SKIN: Gently wash with plenty of soap and water. |
P303 + P361 + P353 | IF ON SKIN (or hair): Remove/Take off Immediately all contaminated clothing. Rinse SKIN with water/shower. |
P304 + P312 | IF INHALED: Call a POISON CENTER or doctor/physician if you feel unwell. |
P304 + P340 | IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing. |
P304 + P341 | IF INHALED: If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P305 + P351 + P338 | IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing. |
P306 + P360 | IF ON CLOTHING: Rinse Immediately contaminated CLOTHING and SKIN with plenty of water before removing clothes. |
P307 + P311 | IF exposed: call a POISON CENTER or doctor/physician. |
P308 + P313 | IF exposed or concerned: Get medical advice/attention. |
P309 + P311 | IF exposed or if you feel unwell: call a POISON CENTER or doctor/physician. |
P332 + P313 | IF SKIN irritation occurs: Get medical advice/attention. |
P333 + P313 | IF SKIN irritation or rash occurs: Get medical advice/attention. |
P335 + P334 | Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages. |
P337 + P313 | IF eye irritation persists: Get medical advice/attention. |
P342 + P311 | IF experiencing respiratory symptoms: call a POISON CENTER or doctor/physician. |
P370 + P376 | In case of fire: Stop leak if safe to Do so. |
P370 + P378 | In case of fire: |
P370 + P380 | In case of fire: Evacuate area. |
P370 + P380 + P375 | In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion. |
P371 + P380 + P375 | In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion. |
Storage | |
Code | Phrase |
P401 | |
P402 | Store in a dry place. |
P403 | Store in a well-ventilated place. |
P404 | Store in a closed container. |
P405 | Store locked up. |
P406 | Store in corrosive resistant/ container with a resistant inner liner. |
P407 | Maintain air gap between stacks/pallets. |
P410 | Protect from sunlight. |
P411 | |
P412 | Do not expose to temperatures exceeding 50 oC/ 122 oF. |
P413 | |
P420 | Store away from other materials. |
P422 | |
P402 + P404 | Store in a dry place. Store in a closed container. |
P403 + P233 | Store in a well-ventilated place. Keep container tightly closed. |
P403 + P235 | Store in a well-ventilated place. Keep cool. |
P410 + P403 | Protect from sunlight. Store in a well-ventilated place. |
P410 + P412 | Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF. |
P411 + P235 | Keep cool. |
Disposal | |
Code | Phrase |
P501 | Dispose of contents/container to ... |
P502 | Refer to manufacturer/supplier for information on recovery/recycling |
Physical hazards | |
Code | Phrase |
H200 | Unstable explosive |
H201 | Explosive; mass explosion hazard |
H202 | Explosive; severe projection hazard |
H203 | Explosive; fire, blast or projection hazard |
H204 | Fire or projection hazard |
H205 | May mass explode in fire |
H220 | Extremely flammable gas |
H221 | Flammable gas |
H222 | Extremely flammable aerosol |
H223 | Flammable aerosol |
H224 | Extremely flammable liquid and vapour |
H225 | Highly flammable liquid and vapour |
H226 | Flammable liquid and vapour |
H227 | Combustible liquid |
H228 | Flammable solid |
H229 | Pressurized container: may burst if heated |
H230 | May react explosively even in the absence of air |
H231 | May react explosively even in the absence of air at elevated pressure and/or temperature |
H240 | Heating may cause an explosion |
H241 | Heating may cause a fire or explosion |
H242 | Heating may cause a fire |
H250 | Catches fire spontaneously if exposed to air |
H251 | Self-heating; may catch fire |
H252 | Self-heating in large quantities; may catch fire |
H260 | In contact with water releases flammable gases which may ignite spontaneously |
H261 | In contact with water releases flammable gas |
H270 | May cause or intensify fire; oxidizer |
H271 | May cause fire or explosion; strong oxidizer |
H272 | May intensify fire; oxidizer |
H280 | Contains gas under pressure; may explode if heated |
H281 | Contains refrigerated gas; may cause cryogenic burns or injury |
H290 | May be corrosive to metals |
Health hazards | |
Code | Phrase |
H300 | Fatal if swallowed |
H301 | Toxic if swallowed |
H302 | Harmful if swallowed |
H303 | May be harmful if swallowed |
H304 | May be fatal if swallowed and enters airways |
H305 | May be harmful if swallowed and enters airways |
H310 | Fatal in contact with skin |
H311 | Toxic in contact with skin |
H312 | Harmful in contact with skin |
H313 | May be harmful in contact with skin |
H314 | Causes severe skin burns and eye damage |
H315 | Causes skin irritation |
H316 | Causes mild skin irritation |
H317 | May cause an allergic skin reaction |
H318 | Causes serious eye damage |
H319 | Causes serious eye irritation |
H320 | Causes eye irritation |
H330 | Fatal if inhaled |
H331 | Toxic if inhaled |
H332 | Harmful if inhaled |
H333 | May be harmful if inhaled |
H334 | May cause allergy or asthma symptoms or breathing difficulties if inhaled |
H335 | May cause respiratory irritation |
H336 | May cause drowsiness or dizziness |
H340 | May cause genetic defects |
H341 | Suspected of causing genetic defects |
H350 | May cause cancer |
H351 | Suspected of causing cancer |
H360 | May damage fertility or the unborn child |
H361 | Suspected of damaging fertility or the unborn child |
H361d | Suspected of damaging the unborn child |
H362 | May cause harm to breast-fed children |
H370 | Causes damage to organs |
H371 | May cause damage to organs |
H372 | Causes damage to organs through prolonged or repeated exposure |
H373 | May cause damage to organs through prolonged or repeated exposure |
Environmental hazards | |
Code | Phrase |
H400 | Very toxic to aquatic life |
H401 | Toxic to aquatic life |
H402 | Harmful to aquatic life |
H410 | Very toxic to aquatic life with long-lasting effects |
H411 | Toxic to aquatic life with long-lasting effects |
H412 | Harmful to aquatic life with long-lasting effects |
H413 | May cause long-lasting harmful effects to aquatic life |
H420 | Harms public health and the environment by destroying ozone in the upper atmosphere |
Sorry,this product has been discontinued.
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