Structure of 856250-60-7
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CAS No. : | 856250-60-7 |
Formula : | C6H7BFNO3 |
M.W : | 170.93 |
SMILES Code : | COC1=C(F)C=C(B(O)O)C=N1 |
MDL No. : | MFCD04112520 |
InChI Key : | OCWTXKZPAZAQQW-UHFFFAOYSA-N |
Pubchem ID : | 44717400 |
GHS Pictogram: |
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Signal Word: | Warning |
Hazard Statements: | H302 |
Precautionary Statements: | P280-P305+P351+P338 |
* 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 |
---|---|---|
A mixture of 3-(l-(4-methoxybenzyl)-lH-pyrazol-4-yl)-4,5,7,8-tetrahydro-lH-oxepino[4,5-c]pyrazole (1.006 g, 3.10 mmol), (5-fluoro-6-methoxypyridin-3-yl)boronic acid (0.585g, 3.42 mmol), CuOAc (0.563 g, 3.10 mmol) and DMAP (0.758 g, 6.20 mmol) in MeCN (30 ml.) was stirred at room temperature overnight, open to the air. The reaction mixture was treated with a 5% by weight aqueous solution of DM EDA (30 mL) and paritioned with EtOAc (30 mL). The aqueous layer was re- extracted with EtOAc (30 mL) and the combined organic layer passed through a hydrophobic frit then concentrated under reduced pressure to give crude product. The crude product was purified by silica column chromatography, eluting with a 30 to 60% gradient of EtOAc in cyclohexane to afford a mixture of the title compounds (1.2 q). LCMS (Method C) Rt = 1.11 min and 1.14 min, MH+ = 450. The partially purified mixture of compounds was taken forward into the next reaction step. Intermediate 60. l-(5-Fluoro-6-methoxypyridin-3-yl)-3-(lH-pyrazol-4-yl)-4,5,7,8- tetrahydro-lH-oxepinor4,5-clpyrazole and 2-(5-fluoro-6-methoxypyridin-3-yl)-3-(lW- pyrazol-4-yl)-4,5,7,8-tetrahydro-2H-oxepinor4,5-clpyrazole A solution of a mixture of l-(5-fluoro-6-methoxypyridin-3-yl)-3-(l-(4-methoxybenzyl)-lH-pyrazol-4- yl)-4,5,7,8-tetrahydro-lH-oxepino[4,5-c]pyrazole and 2-(5-fluoro-6-methoxypyridin-3-yl)-3-(l-(4- methoxybenzyl)-lH-pyrazol-4-yl)-4,5,7,8-tetrahydro-2H-oxepino[4,5-c]pyrazole (1.2 g, 2.67 mmol) in DCM (8 mL) was treated with TFA (8.00 mL) and heated using a microwave for 3 h at 70 C. The reaction mixture was treated with a saturated aqueous solution of sodium bicarbonate (20 mL) and stirred at room temperature for 1 h. The mixture was partitioned using DCM (30 mL) and the organic layer isolated. The aqueous layer was re-extracted with DCM (5 x 20 mL) and the combined organic layer passed through a hydrophobic frit and concentrated under reduced pressure to afford the crude mixture of products. The crude product was purified by silica column chromatography, eluting with a 0 to 50 % gradient of a 3: 1 solution of EtOAc in EtOH and cyclohexane to afford a mixture of the title compounds (698 mg). LCMS (Method C) Rt = 0.79 min and 0.83 min, MH+ = 330. The mixture of compounds was taken forward into the next reaction step. Intermediate 61. tert-Butyl 3-((4-(l-(5-fluoro-6-methoxypyridin-3-yl)-4,5.7,8- tetrahydro-lW-oxepinor4,5-c1pyrazol-3-yl)-lH-pyrazol-l-yl)methyl)pyrrolidine-l- car boxy late and tert-butyl 3-((4-(2-(5-fluoro-6-methoxypyridin-3-yl)-4.5.7.8- tetrahydro-2W-oxepinor4.5-c1pyrazol-3-yl)-lH-pyrazol-l-yl)methyl)pyrrolidine-l- car boxy late Prepared using the general alkylation procedure from a mixture of l-(5-fluoro-6-methoxypyridin-3- yl)-3-(lH-pyrazol-4-yl)-4,5,7,8-tetrahydro-lH-oxepino[4,5-c]pyrazole and 2-(5-fluoro-6- methoxypyridin-3-yl)-3-(lH-pyrazol-4-yl)-4,5,7,8-tetrahydro-2W-oxepino[4,5-c]pyrazole (461 mg), NaH (112 mg, 60% dispersion on mineral oils), DMF (10 mL), and tert-butyl 3- (bromomethyl)pyrrolidine-l-carboxylate (924 mg, 3.50 mmol), except the crude material was purified by silica column chromatography using a gradient of 0 to 100% EtOAc in cyclohexane to give a mixture of the title compounds as a white solid (658 mg). LCMS (Method C) Rt = 1.17 min and 1.19 min, MH+ = 513. The mixture of compounds was taken forward into the next reaction step. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
A mixture of 3-(l-(4-methoxybenzyl)-lH-pyrazol-4-yl)-4,5,7,8-tetrahydro-lH-oxepino[4,5-c]pyrazole (1.006 g, 3.10 mmol), (5-fluoro-6-methoxypyridin-3-yl)boronic acid (0.585g, 3.42 mmol), CuOAc (0.563 g, 3.10 mmol) and DMAP (0.758 g, 6.20 mmol) in MeCN (30 ml.) was stirred at room temperature overnight, open to the air. The reaction mixture was treated with a 5% by weight aqueous solution of DM EDA (30 mL) and paritioned with EtOAc (30 mL). The aqueous layer was re- extracted with EtOAc (30 mL) and the combined organic layer passed through a hydrophobic frit then concentrated under reduced pressure to give crude product. The crude product was purified by silica column chromatography, eluting with a 30 to 60% gradient of EtOAc in cyclohexane to afford a mixture of the title compounds (1.2 q). LCMS (Method C) Rt = 1.11 min and 1.14 min, MH+ = 450. The partially purified mixture of compounds was taken forward into the next reaction step. Intermediate 60. l-(5-Fluoro-6-methoxypyridin-3-yl)-3-(lH-pyrazol-4-yl)-4,5,7,8- tetrahydro-lH-oxepinor4,5-clpyrazole and 2-(5-fluoro-6-methoxypyridin-3-yl)-3-(lW- pyrazol-4-yl)-4,5,7,8-tetrahydro-2H-oxepinor4,5-clpyrazole A solution of a mixture of l-(5-fluoro-6-methoxypyridin-3-yl)-3-(l-(4-methoxybenzyl)-lH-pyrazol-4- yl)-4,5,7,8-tetrahydro-lH-oxepino[4,5-c]pyrazole and 2-(5-fluoro-6-methoxypyridin-3-yl)-3-(l-(4- methoxybenzyl)-lH-pyrazol-4-yl)-4,5,7,8-tetrahydro-2H-oxepino[4,5-c]pyrazole (1.2 g, 2.67 mmol) in DCM (8 mL) was treated with TFA (8.00 mL) and heated using a microwave for 3 h at 70 C. The reaction mixture was treated with a saturated aqueous solution of sodium bicarbonate (20 mL) and stirred at room temperature for 1 h. The mixture was partitioned using DCM (30 mL) and the organic layer isolated. The aqueous layer was re-extracted with DCM (5 x 20 mL) and the combined organic layer passed through a hydrophobic frit and concentrated under reduced pressure to afford the crude mixture of products. The crude product was purified by silica column chromatography, eluting with a 0 to 50 % gradient of a 3: 1 solution of EtOAc in EtOH and cyclohexane to afford a mixture of the title compounds (698 mg). LCMS (Method C) Rt = 0.79 min and 0.83 min, MH+ = 330. The mixture of compounds was taken forward into the next reaction step. Intermediate 61. tert-Butyl 3-((4-(l-(5-fluoro-6-methoxypyridin-3-yl)-4,5.7,8- tetrahydro-lW-oxepinor4,5-c1pyrazol-3-yl)-lH-pyrazol-l-yl)methyl)pyrrolidine-l- car boxy late and tert-butyl 3-((4-(2-(5-fluoro-6-methoxypyridin-3-yl)-4.5.7.8- tetrahydro-2W-oxepinor4.5-c1pyrazol-3-yl)-lH-pyrazol-l-yl)methyl)pyrrolidine-l- car boxy late Prepared using the general alkylation procedure from a mixture of l-(5-fluoro-6-methoxypyridin-3- yl)-3-(lH-pyrazol-4-yl)-4,5,7,8-tetrahydro-lH-oxepino[4,5-c]pyrazole and 2-(5-fluoro-6- methoxypyridin-3-yl)-3-(lH-pyrazol-4-yl)-4,5,7,8-tetrahydro-2W-oxepino[4,5-c]pyrazole (461 mg), NaH (112 mg, 60% dispersion on mineral oils), DMF (10 mL), and tert-butyl 3- (bromomethyl)pyrrolidine-l-carboxylate (924 mg, 3.50 mmol), except the crude material was purified by silica column chromatography using a gradient of 0 to 100% EtOAc in cyclohexane to give a mixture of the title compounds as a white solid (658 mg). LCMS (Method C) Rt = 1.17 min and 1.19 min, MH+ = 513. The mixture of compounds was taken forward into the next reaction step. Intermediate 63. l-(5-Fluoro-6-methoxypyridin-3-yl)-3-(l-(pyrrolidin-3-ylmethyl)-lH- Dvrazol-4-vl^-4.5.7.8-tetrahvdro-lH-oxepinor4.5-clPvrazole and. 2-f5-fluoro-6- methoxypyridin-3-yl)-3-(l-(pyrrolidin-3-ylmethyl)-lH-pyrazol-4-yl)-4,5.7.8-tetrahydro- 2H-oxepinor4,5-cl Prepared using the general Boc-deprotection procedure from a mixture of iert-butyl 3-((4-(l-(5-fluoro- 6-methoxypyridin-3-yl)-4,5,7,8-tetrahydro-lH-oxepino[4,5-c]pyrazol-3-yl)-lH-pyrazol-l- yl)methyl)pyrrolidine-l-carboxylate and te/t-butyl 3-((4-(2-(5-fluoro-6-methoxypyridin-3-yl)-4,5,7,8- tetrahydro-2H-oxepino[4,5-c]pyrazol-3-yl)-lH-pyrazol-l-yl)methyl)pyrrolidine-l-carboxylate (658 mg), DCM (7 mL) and TFA (3.96 mL), except the reaction was left for 3 h. A mixture of the title compounds was isolated as a pale yellow glassy solid (483 mg). LCMS (Method C) Rt = 0.84 min and 0.91 min, MH+ = 413. The crude mixture of compounds was taken forward into the next reaction step without further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
33% | A mixture of 3-(l-(4-methoxybenzyl)-lH-pyrazol-4-yl)-4,5,7,8-tetrahydro-lH-oxepino[4,5-c]pyrazole (1.006 g, 3.10 mmol), (5-fluoro-6-methoxypyridin-3-yl)boronic acid (0.585g, 3.42 mmol), CuOAc (0.563 g, 3.10 mmol) and DMAP (0.758 g, 6.20 mmol) in MeCN (30 ml.) was stirred at room temperature overnight, open to the air. The reaction mixture was treated with a 5% by weight aqueous solution of DM EDA (30 mL) and paritioned with EtOAc (30 mL). The aqueous layer was re- extracted with EtOAc (30 mL) and the combined organic layer passed through a hydrophobic frit then concentrated under reduced pressure to give crude product. The crude product was purified by silica column chromatography, eluting with a 30 to 60% gradient of EtOAc in cyclohexane to afford a mixture of the title compounds (1.2 q). LCMS (Method C) Rt = 1.11 min and 1.14 min, MH+ = 450. The partially purified mixture of compounds was taken forward into the next reaction step. Intermediate 60. l-(5-Fluoro-6-methoxypyridin-3-yl)-3-(lH-pyrazol-4-yl)-4,5,7,8- tetrahydro-lH-oxepinor4,5-clpyrazole and 2-(5-fluoro-6-methoxypyridin-3-yl)-3-(lW- pyrazol-4-yl)-4,5,7,8-tetrahydro-2H-oxepinor4,5-clpyrazole A solution of a mixture of l-(5-fluoro-6-methoxypyridin-3-yl)-3-(l-(4-methoxybenzyl)-lH-pyrazol-4- yl)-4,5,7,8-tetrahydro-lH-oxepino[4,5-c]pyrazole and 2-(5-fluoro-6-methoxypyridin-3-yl)-3-(l-(4- methoxybenzyl)-lH-pyrazol-4-yl)-4,5,7,8-tetrahydro-2H-oxepino[4,5-c]pyrazole (1.2 g, 2.67 mmol) in DCM (8 mL) was treated with TFA (8.00 mL) and heated using a microwave for 3 h at 70 C. The reaction mixture was treated with a saturated aqueous solution of sodium bicarbonate (20 mL) and stirred at room temperature for 1 h. The mixture was partitioned using DCM (30 mL) and the organic layer isolated. The aqueous layer was re-extracted with DCM (5 x 20 mL) and the combined organic layer passed through a hydrophobic frit and concentrated under reduced pressure to afford the crude mixture of products. The crude product was purified by silica column chromatography, eluting with a 0 to 50 % gradient of a 3: 1 solution of EtOAc in EtOH and cyclohexane to afford a mixture of the title compounds (698 mg). LCMS (Method C) Rt = 0.79 min and 0.83 min, MH+ = 330. The mixture of compounds was taken forward into the next reaction step. Intermediate 61. tert-Butyl 3-((4-(l-(5-fluoro-6-methoxypyridin-3-yl)-4,5.7,8- tetrahydro-lW-oxepinor4,5-c1pyrazol-3-yl)-lH-pyrazol-l-yl)methyl)pyrrolidine-l- car boxy late and tert-butyl 3-((4-(2-(5-fluoro-6-methoxypyridin-3-yl)-4.5.7.8- tetrahydro-2W-oxepinor4.5-c1pyrazol-3-yl)-lH-pyrazol-l-yl)methyl)pyrrolidine-l- car boxy late Prepared using the general alkylation procedure from a mixture of l-(5-fluoro-6-methoxypyridin-3- yl)-3-(lH-pyrazol-4-yl)-4,5,7,8-tetrahydro-lH-oxepino[4,5-c]pyrazole and 2-(5-fluoro-6- methoxypyridin-3-yl)-3-(lH-pyrazol-4-yl)-4,5,7,8-tetrahydro-2W-oxepino[4,5-c]pyrazole (461 mg), NaH (112 mg, 60% dispersion on mineral oils), DMF (10 mL), and tert-butyl 3- (bromomethyl)pyrrolidine-l-carboxylate (924 mg, 3.50 mmol), except the crude material was purified by silica column chromatography using a gradient of 0 to 100% EtOAc in cyclohexane to give a mixture of the title compounds as a white solid (658 mg). LCMS (Method C) Rt = 1.17 min and 1.19 min, MH+ = 513. The mixture of compounds was taken forward into the next reaction step. Intermediate 63. l-(5-Fluoro-6-methoxypyridin-3-yl)-3-(l-(pyrrolidin-3-ylmethyl)-lH- Dvrazol-4-vl^-4.5.7.8-tetrahvdro-lH-oxepinor4.5-clPvrazole and. 2-f5-fluoro-6- methoxypyridin-3-yl)-3-(l-(pyrrolidin-3-ylmethyl)-lH-pyrazol-4-yl)-4,5.7.8-tetrahydro- 2H-oxepinor4,5-cl Prepared using the general Boc-deprotection procedure from a mixture of iert-butyl 3-((4-(l-(5-fluoro- 6-methoxypyridin-3-yl)-4,5,7,8-tetrahydro-lH-oxepino[4,5-c]pyrazol-3-yl)-lH-pyrazol-l- yl)methyl)pyrrolidine-l-carboxylate and te/t-butyl 3-((4-(2-(5-fluoro-6-methoxypyridin-3-yl)-4,5,7,8- tetrahydro-2H-oxepino[4,5-c]pyrazol-3-yl)-lH-pyrazol-l-yl)methyl)pyrrolidine-l-carboxylate (658 mg), DCM (7 mL) and TFA (3.96 mL), except the reaction was left for 3 h. A mixture of the title compounds was isolated as a pale yellow glassy solid (483 mg). LCMS (Method C) Rt = 0.84 min and 0.91 min, MH+ = 413. The crude mixture of compounds was taken forward into the next reaction step without further purification. Example 37. l-(3-((4-(l-(5-Fluoro-6-methoxypyridin-3-yl)-4.5.7.8-tetrahydro-lH- oxepinor4,5-c1pyrazol-3-yl)-lH-pyrazol-l-yl)methyl)pyrrolidin-l-yl)-2-methylpropan-2- ol A solution of a mixture of l-(5-fluoro-6-methoxypyridin-3-yl)-3-(l-(pyrrolidin-3-ylmethyl)-lW-pyrazol- 4-yl)-4,5,7,8-tetrahydro-lH-oxepino[4,5-c]pyrazole and 2-(5-fluoro-6-methoxypyridin-3-yl)-3-(l- (pyrrolidin-3-ylmethyl)-lH-pyrazol-4-yl)-4,5,7,8-tetrahydro-2H-oxepino[4,5-c]pyrazole (100 mg), 2,2- dimethyloxirane (0.065 mL, 0.727 mmol), DIPEA (0.085 ml_, 0.485 mmol) in EtOH (2 mL) was heated using a microwave at 70 C for 1 h. The reaction mixture was treated with MeOH (1 m), co... |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
36 mg | A mixture of 3-(l-(4-methoxybenzyl)-lH-pyrazol-4-yl)-4,5,7,8-tetrahydro-lH-oxepino[4,5-c]pyrazole (1.006 g, 3.10 mmol), (5-fluoro-6-methoxypyridin-3-yl)boronic acid (0.585g, 3.42 mmol), CuOAc (0.563 g, 3.10 mmol) and DMAP (0.758 g, 6.20 mmol) in MeCN (30 ml.) was stirred at room temperature overnight, open to the air. The reaction mixture was treated with a 5% by weight aqueous solution of DM EDA (30 mL) and paritioned with EtOAc (30 mL). The aqueous layer was re- extracted with EtOAc (30 mL) and the combined organic layer passed through a hydrophobic frit then concentrated under reduced pressure to give crude product. The crude product was purified by silica column chromatography, eluting with a 30 to 60% gradient of EtOAc in cyclohexane to afford a mixture of the title compounds (1.2 q). LCMS (Method C) Rt = 1.11 min and 1.14 min, MH+ = 450. The partially purified mixture of compounds was taken forward into the next reaction step. Intermediate 60. l-(5-Fluoro-6-methoxypyridin-3-yl)-3-(lH-pyrazol-4-yl)-4,5,7,8- tetrahydro-lH-oxepinor4,5-clpyrazole and 2-(5-fluoro-6-methoxypyridin-3-yl)-3-(lW- pyrazol-4-yl)-4,5,7,8-tetrahydro-2H-oxepinor4,5-clpyrazole A solution of a mixture of l-(5-fluoro-6-methoxypyridin-3-yl)-3-(l-(4-methoxybenzyl)-lH-pyrazol-4- yl)-4,5,7,8-tetrahydro-lH-oxepino[4,5-c]pyrazole and 2-(5-fluoro-6-methoxypyridin-3-yl)-3-(l-(4- methoxybenzyl)-lH-pyrazol-4-yl)-4,5,7,8-tetrahydro-2H-oxepino[4,5-c]pyrazole (1.2 g, 2.67 mmol) in DCM (8 mL) was treated with TFA (8.00 mL) and heated using a microwave for 3 h at 70 C. The reaction mixture was treated with a saturated aqueous solution of sodium bicarbonate (20 mL) and stirred at room temperature for 1 h. The mixture was partitioned using DCM (30 mL) and the organic layer isolated. The aqueous layer was re-extracted with DCM (5 x 20 mL) and the combined organic layer passed through a hydrophobic frit and concentrated under reduced pressure to afford the crude mixture of products. The crude product was purified by silica column chromatography, eluting with a 0 to 50 % gradient of a 3: 1 solution of EtOAc in EtOH and cyclohexane to afford a mixture of the title compounds (698 mg). LCMS (Method C) Rt = 0.79 min and 0.83 min, MH+ = 330. The mixture of compounds was taken forward into the next reaction step. Intermediate 61. tert-Butyl 3-((4-(l-(5-fluoro-6-methoxypyridin-3-yl)-4,5.7,8- tetrahydro-lW-oxepinor4,5-c1pyrazol-3-yl)-lH-pyrazol-l-yl)methyl)pyrrolidine-l- car boxy late and tert-butyl 3-((4-(2-(5-fluoro-6-methoxypyridin-3-yl)-4.5.7.8- tetrahydro-2W-oxepinor4.5-c1pyrazol-3-yl)-lH-pyrazol-l-yl)methyl)pyrrolidine-l- car boxy late Prepared using the general alkylation procedure from a mixture of l-(5-fluoro-6-methoxypyridin-3- yl)-3-(lH-pyrazol-4-yl)-4,5,7,8-tetrahydro-lH-oxepino[4,5-c]pyrazole and 2-(5-fluoro-6- methoxypyridin-3-yl)-3-(lH-pyrazol-4-yl)-4,5,7,8-tetrahydro-2W-oxepino[4,5-c]pyrazole (461 mg), NaH (112 mg, 60% dispersion on mineral oils), DMF (10 mL), and tert-butyl 3- (bromomethyl)pyrrolidine-l-carboxylate (924 mg, 3.50 mmol), except the crude material was purified by silica column chromatography using a gradient of 0 to 100% EtOAc in cyclohexane to give a mixture of the title compounds as a white solid (658 mg). LCMS (Method C) Rt = 1.17 min and 1.19 min, MH+ = 513. The mixture of compounds was taken forward into the next reaction step. Intermediate 63. l-(5-Fluoro-6-methoxypyridin-3-yl)-3-(l-(pyrrolidin-3-ylmethyl)-lH- Dvrazol-4-vl^-4.5.7.8-tetrahvdro-lH-oxepinor4.5-clPvrazole and. 2-f5-fluoro-6- methoxypyridin-3-yl)-3-(l-(pyrrolidin-3-ylmethyl)-lH-pyrazol-4-yl)-4,5.7.8-tetrahydro- 2H-oxepinor4,5-cl Prepared using the general Boc-deprotection procedure from a mixture of iert-butyl 3-((4-(l-(5-fluoro- 6-methoxypyridin-3-yl)-4,5,7,8-tetrahydro-lH-oxepino[4,5-c]pyrazol-3-yl)-lH-pyrazol-l- yl)methyl)pyrrolidine-l-carboxylate and te/t-butyl 3-((4-(2-(5-fluoro-6-methoxypyridin-3-yl)-4,5,7,8- tetrahydro-2H-oxepino[4,5-c]pyrazol-3-yl)-lH-pyrazol-l-yl)methyl)pyrrolidine-l-carboxylate (658 mg), DCM (7 mL) and TFA (3.96 mL), except the reaction was left for 3 h. A mixture of the title compounds was isolated as a pale yellow glassy solid (483 mg). LCMS (Method C) Rt = 0.84 min and 0.91 min, MH+ = 413. The crude mixture of compounds was taken forward into the next reaction step without further purification. Example 44. (2R)-l-C3-((4-(l-C5-Fluoro-6-methoxypyridin-3-Yl)-4,5,7,8-tetrahYdro-lH- oxepinor4,5-c1pyrazol-3-yl)-lH-pyrazol-l-yl)methyl)pyrrolidin-l-yl)propan-2-ol A mixture of l-(5-fluoro-6-methoxypyridin-3-yl)-3-(l-(pyrrolidin-3-ylmethyl)-lH-pyrazol-4-yl)-4,5,7,8- tetrahydro-lH-oxepino[4,5-c]pyrazole and 2-(5-fluoro-6-methoxypyridin-3-yl)-3-(l-(pyrrolidin-3- ylmethyl)-lH-pyrazol-4-yl)-4,5,7,8-tetrahydro-2H-oxepino[4,5-c]pyrazole (100 mg), (R)-2- methyloxirane (42.2 mg, 0.727 mmol), DIPEA (0.085 mL, 0.485 mmol) in EtOH (2 mL) was heated at 70 C for 1 h using a microwave. The reaction mixture was treated with MeOH (1 mL), concentrated under red... |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
36 mg | A mixture of 3-(l-(4-methoxybenzyl)-lH-pyrazol-4-yl)-4,5,7,8-tetrahydro-lH-oxepino[4,5-c]pyrazole (1.006 g, 3.10 mmol), (5-fluoro-6-methoxypyridin-3-yl)boronic acid (0.585g, 3.42 mmol), CuOAc (0.563 g, 3.10 mmol) and DMAP (0.758 g, 6.20 mmol) in MeCN (30 ml.) was stirred at room temperature overnight, open to the air. The reaction mixture was treated with a 5% by weight aqueous solution of DM EDA (30 mL) and paritioned with EtOAc (30 mL). The aqueous layer was re- extracted with EtOAc (30 mL) and the combined organic layer passed through a hydrophobic frit then concentrated under reduced pressure to give crude product. The crude product was purified by silica column chromatography, eluting with a 30 to 60% gradient of EtOAc in cyclohexane to afford a mixture of the title compounds (1.2 q). LCMS (Method C) Rt = 1.11 min and 1.14 min, MH+ = 450. The partially purified mixture of compounds was taken forward into the next reaction step. Intermediate 60. l-(5-Fluoro-6-methoxypyridin-3-yl)-3-(lH-pyrazol-4-yl)-4,5,7,8- tetrahydro-lH-oxepinor4,5-clpyrazole and 2-(5-fluoro-6-methoxypyridin-3-yl)-3-(lW- pyrazol-4-yl)-4,5,7,8-tetrahydro-2H-oxepinor4,5-clpyrazole A solution of a mixture of l-(5-fluoro-6-methoxypyridin-3-yl)-3-(l-(4-methoxybenzyl)-lH-pyrazol-4- yl)-4,5,7,8-tetrahydro-lH-oxepino[4,5-c]pyrazole and 2-(5-fluoro-6-methoxypyridin-3-yl)-3-(l-(4- methoxybenzyl)-lH-pyrazol-4-yl)-4,5,7,8-tetrahydro-2H-oxepino[4,5-c]pyrazole (1.2 g, 2.67 mmol) in DCM (8 mL) was treated with TFA (8.00 mL) and heated using a microwave for 3 h at 70 C. The reaction mixture was treated with a saturated aqueous solution of sodium bicarbonate (20 mL) and stirred at room temperature for 1 h. The mixture was partitioned using DCM (30 mL) and the organic layer isolated. The aqueous layer was re-extracted with DCM (5 x 20 mL) and the combined organic layer passed through a hydrophobic frit and concentrated under reduced pressure to afford the crude mixture of products. The crude product was purified by silica column chromatography, eluting with a 0 to 50 % gradient of a 3: 1 solution of EtOAc in EtOH and cyclohexane to afford a mixture of the title compounds (698 mg). LCMS (Method C) Rt = 0.79 min and 0.83 min, MH+ = 330. The mixture of compounds was taken forward into the next reaction step. Intermediate 61. tert-Butyl 3-((4-(l-(5-fluoro-6-methoxypyridin-3-yl)-4,5.7,8- tetrahydro-lW-oxepinor4,5-c1pyrazol-3-yl)-lH-pyrazol-l-yl)methyl)pyrrolidine-l- car boxy late and tert-butyl 3-((4-(2-(5-fluoro-6-methoxypyridin-3-yl)-4.5.7.8- tetrahydro-2W-oxepinor4.5-c1pyrazol-3-yl)-lH-pyrazol-l-yl)methyl)pyrrolidine-l- car boxy late Prepared using the general alkylation procedure from a mixture of l-(5-fluoro-6-methoxypyridin-3- yl)-3-(lH-pyrazol-4-yl)-4,5,7,8-tetrahydro-lH-oxepino[4,5-c]pyrazole and 2-(5-fluoro-6- methoxypyridin-3-yl)-3-(lH-pyrazol-4-yl)-4,5,7,8-tetrahydro-2W-oxepino[4,5-c]pyrazole (461 mg), NaH (112 mg, 60% dispersion on mineral oils), DMF (10 mL), and tert-butyl 3- (bromomethyl)pyrrolidine-l-carboxylate (924 mg, 3.50 mmol), except the crude material was purified by silica column chromatography using a gradient of 0 to 100% EtOAc in cyclohexane to give a mixture of the title compounds as a white solid (658 mg). LCMS (Method C) Rt = 1.17 min and 1.19 min, MH+ = 513. The mixture of compounds was taken forward into the next reaction step. Intermediate 63. l-(5-Fluoro-6-methoxypyridin-3-yl)-3-(l-(pyrrolidin-3-ylmethyl)-lH- Dvrazol-4-vl^-4.5.7.8-tetrahvdro-lH-oxepinor4.5-clPvrazole and. 2-f5-fluoro-6- methoxypyridin-3-yl)-3-(l-(pyrrolidin-3-ylmethyl)-lH-pyrazol-4-yl)-4,5.7.8-tetrahydro- 2H-oxepinor4,5-cl Prepared using the general Boc-deprotection procedure from a mixture of iert-butyl 3-((4-(l-(5-fluoro- 6-methoxypyridin-3-yl)-4,5,7,8-tetrahydro-lH-oxepino[4,5-c]pyrazol-3-yl)-lH-pyrazol-l- yl)methyl)pyrrolidine-l-carboxylate and te/t-butyl 3-((4-(2-(5-fluoro-6-methoxypyridin-3-yl)-4,5,7,8- tetrahydro-2H-oxepino[4,5-c]pyrazol-3-yl)-lH-pyrazol-l-yl)methyl)pyrrolidine-l-carboxylate (658 mg), DCM (7 mL) and TFA (3.96 mL), except the reaction was left for 3 h. A mixture of the title compounds was isolated as a pale yellow glassy solid (483 mg). LCMS (Method C) Rt = 0.84 min and 0.91 min, MH+ = 413. The crude mixture of compounds was taken forward into the next reaction step without further purification. Example 44. (2R)-l-C3-((4-(l-C5-Fluoro-6-methoxypyridin-3-Yl)-4,5,7,8-tetrahYdro-lH- oxepinor4,5-c1pyrazol-3-yl)-lH-pyrazol-l-yl)methyl)pyrrolidin-l-yl)propan-2-ol A mixture of l-(5-fluoro-6-methoxypyridin-3-yl)-3-(l-(pyrrolidin-3-ylmethyl)-lH-pyrazol-4-yl)-4,5,7,8- tetrahydro-lH-oxepino[4,5-c]pyrazole and 2-(5-fluoro-6-methoxypyridin-3-yl)-3-(l-(pyrrolidin-3- ylmethyl)-lH-pyrazol-4-yl)-4,5,7,8-tetrahydro-2H-oxepino[4,5-c]pyrazole (100 mg), (R)-2- methyloxirane (42.2 mg, 0.727 mmol), DIPEA (0.085 mL, 0.485 mmol) in EtOH (2 mL) was heated at 70 C for 1 h using a microwave. The reaction mixture was treated with MeOH (1 mL), concentrated under red... |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
34 mg | A mixture of 3-(l-(4-methoxybenzyl)-lH-pyrazol-4-yl)-4,5,7,8-tetrahydro-lH-oxepino[4,5-c]pyrazole (1.006 g, 3.10 mmol), (5-fluoro-6-methoxypyridin-3-yl)boronic acid (0.585g, 3.42 mmol), CuOAc (0.563 g, 3.10 mmol) and DMAP (0.758 g, 6.20 mmol) in MeCN (30 ml.) was stirred at room temperature overnight, open to the air. The reaction mixture was treated with a 5% by weight aqueous solution of DM EDA (30 mL) and paritioned with EtOAc (30 mL). The aqueous layer was re- extracted with EtOAc (30 mL) and the combined organic layer passed through a hydrophobic frit then concentrated under reduced pressure to give crude product. The crude product was purified by silica column chromatography, eluting with a 30 to 60% gradient of EtOAc in cyclohexane to afford a mixture of the title compounds (1.2 q). LCMS (Method C) Rt = 1.11 min and 1.14 min, MH+ = 450. The partially purified mixture of compounds was taken forward into the next reaction step. Intermediate 60. l-(5-Fluoro-6-methoxypyridin-3-yl)-3-(lH-pyrazol-4-yl)-4,5,7,8- tetrahydro-lH-oxepinor4,5-clpyrazole and 2-(5-fluoro-6-methoxypyridin-3-yl)-3-(lW- pyrazol-4-yl)-4,5,7,8-tetrahydro-2H-oxepinor4,5-clpyrazole A solution of a mixture of l-(5-fluoro-6-methoxypyridin-3-yl)-3-(l-(4-methoxybenzyl)-lH-pyrazol-4- yl)-4,5,7,8-tetrahydro-lH-oxepino[4,5-c]pyrazole and 2-(5-fluoro-6-methoxypyridin-3-yl)-3-(l-(4- methoxybenzyl)-lH-pyrazol-4-yl)-4,5,7,8-tetrahydro-2H-oxepino[4,5-c]pyrazole (1.2 g, 2.67 mmol) in DCM (8 mL) was treated with TFA (8.00 mL) and heated using a microwave for 3 h at 70 C. The reaction mixture was treated with a saturated aqueous solution of sodium bicarbonate (20 mL) and stirred at room temperature for 1 h. The mixture was partitioned using DCM (30 mL) and the organic layer isolated. The aqueous layer was re-extracted with DCM (5 x 20 mL) and the combined organic layer passed through a hydrophobic frit and concentrated under reduced pressure to afford the crude mixture of products. The crude product was purified by silica column chromatography, eluting with a 0 to 50 % gradient of a 3: 1 solution of EtOAc in EtOH and cyclohexane to afford a mixture of the title compounds (698 mg). LCMS (Method C) Rt = 0.79 min and 0.83 min, MH+ = 330. The mixture of compounds was taken forward into the next reaction step. Intermediate 61. tert-Butyl 3-((4-(l-(5-fluoro-6-methoxypyridin-3-yl)-4,5.7,8- tetrahydro-lW-oxepinor4,5-c1pyrazol-3-yl)-lH-pyrazol-l-yl)methyl)pyrrolidine-l- car boxy late and tert-butyl 3-((4-(2-(5-fluoro-6-methoxypyridin-3-yl)-4.5.7.8- tetrahydro-2W-oxepinor4.5-c1pyrazol-3-yl)-lH-pyrazol-l-yl)methyl)pyrrolidine-l- car boxy late Prepared using the general alkylation procedure from a mixture of l-(5-fluoro-6-methoxypyridin-3- yl)-3-(lH-pyrazol-4-yl)-4,5,7,8-tetrahydro-lH-oxepino[4,5-c]pyrazole and 2-(5-fluoro-6- methoxypyridin-3-yl)-3-(lH-pyrazol-4-yl)-4,5,7,8-tetrahydro-2W-oxepino[4,5-c]pyrazole (461 mg), NaH (112 mg, 60% dispersion on mineral oils), DMF (10 mL), and tert-butyl 3- (bromomethyl)pyrrolidine-l-carboxylate (924 mg, 3.50 mmol), except the crude material was purified by silica column chromatography using a gradient of 0 to 100% EtOAc in cyclohexane to give a mixture of the title compounds as a white solid (658 mg). LCMS (Method C) Rt = 1.17 min and 1.19 min, MH+ = 513. The mixture of compounds was taken forward into the next reaction step. Intermediate 63. l-(5-Fluoro-6-methoxypyridin-3-yl)-3-(l-(pyrrolidin-3-ylmethyl)-lH- Dvrazol-4-vl^-4.5.7.8-tetrahvdro-lH-oxepinor4.5-clPvrazole and. 2-f5-fluoro-6- methoxypyridin-3-yl)-3-(l-(pyrrolidin-3-ylmethyl)-lH-pyrazol-4-yl)-4,5.7.8-tetrahydro- 2H-oxepinor4,5-cl Prepared using the general Boc-deprotection procedure from a mixture of iert-butyl 3-((4-(l-(5-fluoro- 6-methoxypyridin-3-yl)-4,5,7,8-tetrahydro-lH-oxepino[4,5-c]pyrazol-3-yl)-lH-pyrazol-l- yl)methyl)pyrrolidine-l-carboxylate and te/t-butyl 3-((4-(2-(5-fluoro-6-methoxypyridin-3-yl)-4,5,7,8- tetrahydro-2H-oxepino[4,5-c]pyrazol-3-yl)-lH-pyrazol-l-yl)methyl)pyrrolidine-l-carboxylate (658 mg), DCM (7 mL) and TFA (3.96 mL), except the reaction was left for 3 h. A mixture of the title compounds was isolated as a pale yellow glassy solid (483 mg). LCMS (Method C) Rt = 0.84 min and 0.91 min, MH+ = 413. The crude mixture of compounds was taken forward into the next reaction step without further purification. Example 50. l-(3-((4-(l-(5-Fluoro-6-methoxypyridin-3-yl)-4.5.7.8-tetrahydro-lH- oxepinor4,5-c1pyrazol-3-yl)-lH-pyrazol-l-yl)methyl)pyrrolidin-l-yl)propan-l-one A solution of propionic acid (19.76 mg, 0.267 mmol) in DMF (1.25ml_) was treated with HATU (101 mg, 0.267 mmol) and DIPEA (0.085 mL, 0.485 mmol). The reaction mixture was stirred under an atmosphere of nitrogen at room temperature for 30 min. The reaction mixture was treated with a mixture of l-(5-fluoro-6-methoxypyridin-3-yl)-3-(l-(pyrrolidin-3-ylmethyl)-lH-pyrazol-4-yl)-4,5,7,8- tetrahydro-lH-oxepino[4,5-c]pyrazole and 2-(5-fluoro-6-methoxypyridin-3-yl)-3-(l-(pyrrolidin-3- ylmethyl)-lH... |
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