Structure of 1366482-32-7
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CAS No. : | 1366482-32-7 |
Formula : | C5H4BClFNO2 |
M.W : | 175.35 |
SMILES Code : | FC1=C(Cl)C=C(B(O)O)C=N1 |
MDL No. : | MFCD18257900 |
InChI Key : | YYFMQBOVWLWZQO-UHFFFAOYSA-N |
Pubchem ID : | 71305234 |
GHS Pictogram: |
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Signal Word: | Warning |
Hazard Statements: | H302-H315-H319-H335 |
Precautionary Statements: | P261-P264-P270-P271-P280-P301+P312+P330-P302+P352-P304+P340+P312-P305+P351+P338-P332+P313-P337+P313-P362-P403+P233-P405-P501 |
* 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 |
---|---|---|
48% | STEP 2: 4-(5-CHLORO-6-FLUOROPYRIDIN-3-YL)-N-(METHYLSULFONYL)-3- (OXETAN-3-YLOXY)BENZAMIDE[00231 ] To a flask charged with 4-bromo-N-(methylsulfonyl)-3 -(oxetan-3 - yloxy)benzamide (4.76 g, 13.59 mmol), <strong>[1366482-32-7](5-chloro-6-fluoropyridin-3-yl)boronic acid</strong> (2.384 g, 13.59 mmol), Pd(Ph3P)4(0.785 g, 0.680 mmol) was added 1,4-dioxane (54.4 ml) and Na2C03(2M) (34.0 ml, 68.0 mmol). The mixture was purged with nitrogen for 5 mins then heated to 110 C overnight affording about 75% conversion. To the mixture was added additional 5- chloro-6-fluoropyridin-3-yl)boronic acid (0.5 eq, 1.2g) and Pd(PPh3)4(0.025 eq, 392 mg) and heating continued at 110 C for 2 hrs affording complete conversion according to LC-MS. The mixture was cooled in an ice water bath and brought to pH 2S04, filtered and dried under reduced pressure. The aqueous layer still contained product and was dried under reduced pressure and combined with the organic extracted material. The mixture was adsorbed onto silica gel and purified with chromatography using a lOOg ultra snap column ramping EtOAc in heptane (0 - 100%, then DCM:MeOH (90:10) in DCM (0 - 100%) to affording the product (2.61 g, 48%). 1H NMR (400MHz, DMSO-d6) δ 8.43 - 8.51 (m, 2H), 7.67 - 7.73 (m, 1H), 7.59 - 7.67 (m, 1H), 7.25 (s, 1H), 5.45 (t, J= 5.28 Hz, 1H), 4.95 (t, J= 6.60 Hz, 2H), 4.47 - 4.61 (m, 2H), 3.38 (s, 3H). MS m/z: [M+l]+= 401.1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
62.8% | With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In 1,4-dioxane; at 110℃;Inert atmosphere; | STEP 2: 4-(5-CHLORO-6-FLUOROPYRIDIN-3-YL)-3-(DIFLUOROMETHOXY)-N- (METHYLSULFONYL)BENZAMIDE[00234] To a flask charged with 4-bromo-3 -(difluoromethoxy)-N- (methylsulfonyl)benzamide (6.45 g, 18.74 mmol), <strong>[1366482-32-7](5-chloro-6-fluoropyridin-3-yl)boronic acid</strong> (3.29 g, 18.74 mmol), Pd(Ph3P)4(1.083 g, 0.937 mmol) was added 1,4-dioxane (75.0 ml) and Na2C03(2M) (46.9 ml, 94 mmol) and the mixture purged with nitrogen for 5 mins then heated overnight at 110 C affording conversion to the desired product as the major species. The mixture was cooled in an ice water bath and the pH adjusted to 3- yl)-3-(difluoromethoxy)-N-(methylsulfonyl)benzamide (4.65 g, 11.78 mmol, 62.8 % yield) with an aromatic impurity present. The filtrate and this solid were combined and repurified using the following conditions: System: Prep SFC-3, Whelk-O, 2 x 25 cm column, 20% methanol, 80 mL/min (column backpressure = 52 bar), 100 bar BPR, 254nm, Dissolution: 200 mL 3:2 MeOH:DCM, Test Injections: 0.1, 0.25, 0.5, 1.0, 2.0, and 4.0 mL, Sample processed with 4.0 mL injections and 3.3 minute cycle time. The product was obtained as a yellow solid4- (5-chloro-6-fluoropyridin-3-yl)-3-(difluoromethoxy)-N-(methylsulfonyl)benzamide (4.65 g,11.78 mmol, 62.8 % yield) with about 85% purity. 1H NMR (400MHz, DMSO-d6) δ = 1H NMR (400 MHz, DMSO-de) δ 8.40 - 8.46 (m, 1H), 8.35 - 8.40 (m, 1H), 7.94 (d, J= 7.73 Hz, 1H), 7.88 (s, 1H), 7.76 (d, J= 8.12 Hz, 1H), 7.21 (t, J= 71 Hz, 1 H), 3.41 (s, 3H). MS m/z: [M+l]+= 395.1 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
36% | With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; caesium carbonate; In 1,4-dioxane; water; at 100℃; for 12.0h;Inert atmosphere; | A mixture of methyl (4-chloropyrimidin-2-yl)carbamate (75 mg, 0.400 mmol), <strong>[1366482-32-7](5-chloro-6-fluoropyridin-3-yl)boronic acid</strong> (70.1 mg, 0.400 mmol), PdCl2(dppf)-CH2Cl2 adduct (16.33 mg, 0.020 mmol) and Cs2C03 (391 mg, 1.199 mmol) in 1,4-dioxane (2.5 mL)-water (02 mL) was purged with nitrogen and heated at 100 C for 12 h. The solution cooled to room temperature and was concentrated under reduced pressure. Water (50 mL) was added and the solution was extracted with EtOAc (2 x 50 mL). The combined organic extracts were washed with water (50 mL) and brine (50 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (EtOAc in hexanes) to afford methyl (4-(5-chloro-6-fluoropyridin-3-yl)pyrimidin-2- yl)carbamate (55 mg, 0.144 mmol, 36% yield) as a brown solid. LCMS (ESI) m/e 283.0 [(M+H)+, calcd for CnH9ClFN402 283.0]; LC/MS retention time (Method Al): fe = 2.01 min. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
17% | With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; caesium carbonate; In 1,4-dioxane; at 80℃; for 3.0h; | A mixture of 5-chloro-6-fluoropyridin-3-ylboronic acid (0.037 g, 0.213 mmol), methyl (6-chloropyrimidin-4-yl)carbamate (prepared as described in Example 432) (0.04 g, 0.213 mmol), PdCl2(dppf)-CH2Cl2 adduct (0.017 g, 0.021 mmol) and CS2CO3 (0.208 g, 0.640 mmol) in 1 ,4-dioxane (3 mL) was heated at 80 C for 3 h. The reaction mixture was cooled to room temperature, concentrated under reduced pressure, diluted with brine and extracted with ethyl acetate (20 mL). The organic layer was separated, dried over Na2S04, filtered, and concentrated under reduced pressure to afford methyl (6-(5-chloro-6-fluoropyridin-3-yl)pyrimidin-4-yl)carbamate (0.03 g, 0.035 mmol, 17% yield) as an off-white solid. LCMS (ESI) m/e 281.0 [(M- H)-, calcd for C11H7CIFN4O2 281.0] ; LC/MS retention time (method D): fa = 2.1 1 min. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
29% | With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; caesium carbonate; In 1,4-dioxane; at 80℃; for 3.0h; | A mixture of <strong>[1366482-32-7](5-chloro-6-fluoropyridin-3-yl)boronic acid</strong> (0.055 g, 0.311 mmol), 4-chloro-6-methylpyrimidine (0.04 g, 0.311 mmol), PdCl2(dppf)-CH2Cl2 adduct (0.025 g, 0.031 mmol) and Cs2C03 (0.304 g, 0.933 mmol) in 1,4-dioxane (3 mL) was heated at 80 C for 3 h. The reaction mixture was cooled to room temperature then filtered through diatomaceous earth (Celite), washing the bed with ethyl acetate (100 mL). The filtrate was concentrated under reduced pressure to afford 4-(5-chloro-6-fluoropyridin-3-yl)-6-methylpyrimidine (0.035 g, 0.090 mmol, 29% yield) as a brown solid. LCMS (ESI) m/e 224.5 [(M+H) +, calcd for CioH8ClFN3 224.0]; LC/MS retention time (method B): = 0.86 min. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
44% | With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; caesium carbonate; In 1,4-dioxane; at 80℃; for 3.0h; | A mixture of <strong>[1366482-32-7](5-chloro-6-fluoropyridin-3-yl)boronic acid</strong> (0.035 g, 0.200mmol), 6-chloro-N-(tetrahydrofuran-3-yl)pyrimidin-4-ammne (0.04 g, 0.200 mmol),PdC12(dppf)-CH2C12.adduct (0.016 g, 0.020 mmol), and C52CO3 (0.196 g, 0.601 mmol) in 1,4-dioxane (3 mL) was heated at 80 C for 3 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was diluted with water (50 mL) and extracted with DCM (80 mL). The organic layer was washed with brine (40 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to afford 6-(5-chloro-6-fluoropyridin-3-yl)-N- (tetrahydrofuran-3-yl)pyrimidin-4-amine (0.07 g, 0.088 mmol, 44% yield) as a yellowish semi-solid. LCMS (ESI) m/e 293.0 [(M-H)-, calcd for C13H13C1FN4O293.11; LC/MS retention time (method D): tR = 2.24 mm. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
19% | With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; caesium carbonate; In 1,4-dioxane; water; at 85℃; for 2.0h;Inert atmosphere; | A stirred solution of 7-chloropyrazolo[1,5-ajpyrimidine (100 mg, 0.651 mmol), <strong>[1366482-32-7](5-chloro-6-fluoropyridin-3-yl)boronic acid</strong> (114 mg, 0.65 1 mmol), and cesium carbonate (424 mg, 1.302 mmol) in a mixture of 1,4-dioxane (5 mL) and water (0.5 mL) was purged with nitrogen. PdC12(dppf)-CH2C12 adduct (80 mg, 0.098mmol) was added in one portion and the reaction mixture was heated to 85 C and stirred for 2 h. The solution cooled to room temperature and was concentrated under reduced pressure. Water (50 mL) was added and the solution was extracted with EtOAc (2 x 50 mL). The combined organic extracts were washed with water (50mL) and brine (50 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (EtOAc in hexanes) to afford 7-(5-chloro-6-fluoropyridin-3-yl)pyrazolo[ 1,5 -alpyrimidine (56 mg, 0.122 mmol, 19 % yield). LCMS (ESI) m/e 249.0 [(M+H), calcd for C11H7C1FN4, 249.01; LC/MS retention time (method B) tR = 0.95 mm. |
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