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CAS No. : | 305329-97-9 |
Formula : | C10H18BrNO2 |
M.W : | 264.16 |
SMILES Code : | BrCC1CN(C(OC(C)(C)C)=O)CC1 |
MDL No. : | MFCD06410515 |
InChI Key : | NQNGQGISAMHLST-UHFFFAOYSA-N |
Pubchem ID : | 24730280 |
GHS Pictogram: | ![]() ![]() |
Signal Word: | Danger |
Hazard Statements: | H302+H312-H314 |
Precautionary Statements: | P260-P264-P270-P280-P301+P312+P330-P301+P330+P331-P303+P361+P353-P304+P340+P310-P305+P351+P338+P310-P362+P364-P405-P501 |
Class: | 8 |
UN#: | 1760 |
Packing Group: | Ⅲ |
Num. heavy atoms | 14 |
Num. arom. heavy atoms | 0 |
Fraction Csp3 | 0.9 |
Num. rotatable bonds | 4 |
Num. H-bond acceptors | 2.0 |
Num. H-bond donors | 0.0 |
Molar Refractivity | 64.46 |
TPSA ? Topological Polar Surface Area: Calculated from | 29.54 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from | 3.0 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by | 2.26 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from | 2.26 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from | 2.15 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by | 1.8 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions | 2.29 |
Log S (ESOL):? ESOL: Topological method implemented from | -2.64 |
Solubility | 0.609 mg/ml ; 0.0023 mol/l |
Class? Solubility class: Log S scale | Soluble |
Log S (Ali)? Ali: Topological method implemented from | -2.52 |
Solubility | 0.804 mg/ml ; 0.00304 mol/l |
Class? Solubility class: Log S scale | Soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by | -2.25 |
Solubility | 1.47 mg/ml ; 0.00557 mol/l |
Class? Solubility class: Log S scale | Soluble |
GI absorption? Gatrointestinal absorption: according to the white of the BOILED-Egg | High |
BBB permeant? BBB permeation: according to the yolk of the BOILED-Egg | Yes |
P-gp substrate? P-glycoprotein substrate: SVM model built on 1033 molecules (training set) | No |
CYP1A2 inhibitor? Cytochrome P450 1A2 inhibitor: SVM model built on 9145 molecules (training set) | No |
CYP2C19 inhibitor? Cytochrome P450 2C19 inhibitor: SVM model built on 9272 molecules (training set) | No |
CYP2C9 inhibitor? Cytochrome P450 2C9 inhibitor: SVM model built on 5940 molecules (training set) | No |
CYP2D6 inhibitor? Cytochrome P450 2D6 inhibitor: SVM model built on 3664 molecules (training set) | No |
CYP3A4 inhibitor? Cytochrome P450 3A4 inhibitor: SVM model built on 7518 molecules (training set) | No |
Log Kp (skin permeation)? Skin permeation: QSPR model implemented from | -6.31 cm/s |
Lipinski? Lipinski (Pfizer) filter: implemented from | 0.0 |
Ghose? Ghose filter: implemented from | None |
Veber? Veber (GSK) filter: implemented from | 0.0 |
Egan? Egan (Pharmacia) filter: implemented from | 0.0 |
Muegge? Muegge (Bayer) filter: implemented from | 0.0 |
Bioavailability Score? Abbott Bioavailability Score: Probability of F > 10% in rat | 0.55 |
PAINS? Pan Assay Interference Structures: implemented from | 0.0 alert |
Brenk? Structural Alert: implemented from | 1.0 alert: heavy_metal |
Leadlikeness? Leadlikeness: implemented from | No; 1 violation:MW<0.0 |
Synthetic accessibility? Synthetic accessibility score: from 1 (very easy) to 10 (very difficult) | 3.13 |
* 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 |
---|---|---|
55% | With carbon tetrabromide; triphenylphosphine; In dichloromethane; at 20℃; for 18h; | To a solution of 1 ,1 -dimethylethyl 3-(hydroxymethyl)-1 - pyrrolidinecarboxylate (0.56 g, 2.8 mmol) with carbon tetrabromide (1.39 g, 4.2 mmol) in methylene chloride (10 ml_) was added drop wise a solution of triphenyl phosphine (0.73 g, 2.8 mmol in 5 mL of methylene chloride). Upon completion the mixture was stirred 18 h at room temperature. The solvent was removed at reduced pressure and the residue stirred in 10% ethyl acetate 90% hexane. The <n="54"/>mixture was filtered and the resulting solution chromatographed on silica eluting with a gradient of 0 - 25% EtOAc in hexane to afford the desired compound (0.41 g, 55%). MS (ES+) m/z 264 (M+H)+. |
55% | With carbon tetrabromide; triphenylphosphine; In dichloromethane; at 20℃; for 18h; | To a solution of 1 ,1-dimethylethyl 3-(hydroxymethyl)-1-pyrrolidinecarboxylate (0.56 g, 2.8 mmol) with carbon tetrabromide (1.39 g, 4.2 mmol) in methylene chloride (10 ml.) was added drop wise a solution of triphenyl phosphine (0.73 g, 2.8 mmol in 5 ml. of methylene chloride). Upon completion the mixture was stirred 18 h at room temperature. The solvent was removed at reduced pressure and the residue stirred in 10% ethyl acetate 90% hexane. The mixture was filtered and the resulting solution chromatographed on silica eluting with a gradient of 0 - 25% EtOAc in hexane to afford the desired compound (0.41 g, 55%). MS (ES+) m/z 264 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
69% | A mixture consisting of intermediate VII (100 mg, 0.35mmol) in DMF (2 mL) with cesium carbonate (290 mg, 0.9 mmol) and the compound of Example 5(a) (290 mg, 1.1 mmol) was stirred at room temperature for 24 h. The mixture was poured into rapidly stirring ice water (7 mL) and stirring continued for 10 min. To this was added cyclohexane (7 mL) and stirring continued for an additional 20 min. The solid was collected by filtration then washed with cyclohexane and dried in vacuo to afford the desired compound (111 mg, 69%). MS (ES+) m/z 464 (M+H)+. | |
69% | With caesium carbonate; In cyclohexane; N,N-dimethyl-formamide; at 0 - 20℃; for 44.5h; | A mixture consisting of intermediate VII (100 mg, 0.35mmol) in DMF (2 ml.) with cesium carbonate (290 mg, 0.9 mmol) and the compound of Example 5(a) (290 mg, 1.1 mmol) was stirred at room temperature for 44 h. The mixture was poured into rapidly stirring ice water (7 ml.) and stirring continued for 10 min. To this was added cyclohexane (7 ml.) and stirring continued for an additional 20 min. The solid was <n="48"/>collected by filtration then washed with cyclohexane and dried in vacuo to afford the desired compound (11 1 mg, 69%). MS (ES+) m/z 464 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Step 1 DMPU (225ml), FeCl3(0.75 g) and CuCl (0.3 g) are added to N-Boc-3-bromomethylpyrrole (24.75g, 0.138mol), and then Et2Zn (106.8ml) is slowly dropped at 40~45 C for 45 minutes to obtain a zinc-reagent. THF (810ml) and PdCl2(dppf) (5.09g) are added to 4-chloro-2-(4-chlorophenyl) -thieno [2,3-d] pyridazinyl-7-ethyl formate (30g), and then the zinc-reagent is added to the THF solution at 45C for 4h. The reaction mixture is poured into a saturated brine, filtrated after stirring for 15 minutes and placed for layer separation. The aqueous phase is extracted with THF (500 ml, 2 times). The organic phase is combined together, washed with a saturated brine (500ml, 3 times) and dried with anhydrous Na2SO4, ands evaporated under reduced pressure to remove solvent to obtain 2-(4-chlorophenyl)-4-(N-Boc-3-tetrahydropyrrolemethyl)-thieno[2,3-d] pyridazinyl -7-ethyl formate (25g). MS (ESI): 502(M+1) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Intermediate 25 :N-methyl-N-(pyrrolidin-3-ylmethyl)-5-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-5,8- diazas iro[2.5]octane-8-sulfonamide4-(4-Methylsulfamoyl-4,7-diaza-spiro[2.5]oct-7-yl)-pyrrolo[2,3-d]pyrimidine-7- carboxylic acid tert-butyl ester (intermediate 4) (0.71 mmol) was dissolved in dry DMF (0.5 ml.) and added Cs2C03 (1.42 mmol) and tert-butyl 3-(bromomethyl)pyrrolidine-l- carboxylate (0.85 mmol). Stirred at 45C for 16h and then added H20 (2 ml_). Extracted with EtOAc (3 x 2 ml.) and the combined organic phases were concentrated in vacuo. The residual oil was treated with a mixture of l,l,l,3,3,3-hexafluoro-2- propanol : 2,2,2-trifluoroethanol (3 : 1, 4 ml.) at 150C for 2h. The crude reaction mixture was concentrated on celite in vacuo and purified by standard column chromatography using methanol in DCM as eluent. The obtained compound was recrystallized in methanol : EtOAc affording the title compound as solid.LC-MS: 1.59 min, ES (+), m/z: 406.202 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | With potassium carbonate; In N,N-dimethyl acetamide; water; at 85℃; for 3h; | [00316] A suspension of 3-iodo-lH-pyrazolo[3,4-d]pyrimidin-4-amine (4.5 g, 17.24 mmol, 1.0 equiv), tert-butyl 3 -(bromomethyl)pyrrolidine-l -carboxylate (4.78 g, 18.10 mmol, 1.05 equiv) and K2CO3 (7.15 g, 51.72 mmol, 3.0 equiv) in DMA (40 mL) was heated to 85 C. The reaction was stirred at 85 C for 3 h, at which point the solution was cooled to room temperature. Then, H2O (80 mL) was added to the reaction, and a solid precipitated out. The mixture was filtered, and the solid cake was washed with H2O (2 x 40 mL), and then dried under reduced pressure to give tert-butyl 3-((4-amino-3-iodo-lH-pyrazolo[3,4-d]pyrimidin-l- yl) methyl)pyrrolidine-l -carboxylate (6 g, 78% yield) as a yellow solid. LCMS (ESI) m/z: [M + H] calcd for C15H21IN6O2: 445.08; found: 445.1. |
78% | With potassium carbonate; In N,N-dimethyl acetamide; at 85℃; for 3h; | A suspension of 3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine (4.5 g, 17.24 mmol, 1.0 equiv), <strong>[305329-97-9]tert-butyl 3-(bromomethyl)pyrrolidine-1-carboxylate</strong> (4.78 g, 18.10 mmol, 1.05 equiv) and K2CO3 (7.15 g, 51.72 mmol, 3.0 equiv) in DMA (40 mL) was heated to 85 C. The reaction was stirred at 85 C for 3 h, at which point the solution was cooled to room temperature. Then, H2O (80 mL) was added to the reaction, and a solid precipitated out. The mixture was filtered, and the solid cake was washed with H2O (2 x 40 mL), and then dried under reduced pressure to give tert-butyl 3-((4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1- yl) methyl)pyrrolidine-1-carboxylate (6 g, 78% yield) as a yellow solid. LCMS (ESI) m/z: [M + H] calcd for C15H21IN6O2: 445.08; found 445.1. |
With potassium carbonate; In N,N-dimethyl acetamide; at 85℃; for 3h; | A suspension of 3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine (4.5 g, 17.24 mmol, 1.0 equiv), <strong>[305329-97-9]tert-butyl 3-(bromomethyl)pyrrolidine-1-carboxylate</strong> (4.78 g, 18.10 mmol, 1.05 equiv) and K2CO3 (7.15 g, 51.72 mmol, 3.0 equiv) in DMA (40 mL) was heated to 85 C. The reaction was stirred at 85 C for 3 h, at which point the solution was cooled to room temperature. Then, H2O (80 mL) was added to the reaction, and a solid precipitated out. The mixture was filtered, and the solid cake was washed with H2O (2 x 40 mL), and then dried under reduced pressure to give tert-butyl 3-((4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1- yl) methyl)pyrrolidine-1-carboxylate (6 g, 78% yield) as a yellow solid. LCMS (ESI) m/z: [M + H] calcd for C15H21IN6O2: 445.08; found 445.1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
16% | With potassium carbonate; In N,N-dimethyl-formamide; at 80℃; for 4h; | General procedure: Potassium carbonate (0.145 mmol) was added to a solution of the appropriate amide (0.048 mmol) and an alkyl halide (0.058 mmol), in DMF (300 muL) and stirred at 80C for 4 h. The reaction mixture was added to water (5mL) and extracted with EtOAc (3 × 5 mL). The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by flash column chromatography to give the desired product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate; potassium iodide; In N,N-dimethyl-formamide; at 100℃; for 16h; | into a 50mL roundbottom flask, was placed a mixture of tertbuty1 3-(bromomethyi)pyrrolidine-i--carboxyiate (230 mg, 0.87 mmol, 1.00 eq.), DMF (10 mL), 9-chloro-2--methoxyacridin-3-ol (226 mg, 0.87 mmoi, I.0() eq.), potassium carbonate (240 mg, 174 mmol, 200eq.) and KI (290 mg, 1.74 mmol, 2.00 eq.). The resulting mixture was stirred at 100 C for 16 h . Themixture was diluted with water (50 mL) and extracted with ethyl acetate thirce. The combinedorganic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure.The residue was purified by column chromatography on silica gel eluted with ethyl acetate/petroleum ether (1/2) to provide tert.-butyi 3 -[[(9chioro2-.methoxyacdin.-3 yl)oxyimethyi1pyrrolidine- 1- carhoxylate as a yellow solid. LCMS ES) [M±ij m/z 4432. |
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 |
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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 |
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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 |
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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... |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
30% | With caesium carbonate; In N,N-dimethyl-formamide; at 80℃;Inert atmosphere; | 0.414 g (1.57 mmol) of te/t-butyl 3-(bromomethyl)pyrrolidine-1 -carboxylate in 1 mL of DMF were added under nitrogen atmosphere to a solution of 0.219 g (1.99 mmol) of catechol (Sigma-Aldrich, Cat. No. 135011 ) and 0.649 g (1.99 mmol) of Cs2C03 in 3 mL of dry DMF. The reaction mixture was stirred overnight at 80C. The reaction solution was then diluted with brine and the product was extracted with EtOAc. The combined organic phases were dried over Na2S04, the solvent was removed and the crude mixture was purified by flash chromatography on silica gel (hexane/acetone, 0% to 10% of acetone (by volume)) to give 0.1 12 g of tert-butyl 3-[(2- hydroxyphenoxy)methyl]pyrrolidine-1-carboxylate (yield: 30%). 1H NMR (CDCb) delta (ppm): 6.98-6.83 (m, 4 H), 5.55 (s, 1 H), 4.07-3.98 (m, 2 H), 3.66-3.58 (m, 1 H), 3.55-3.47 (m, 1 H), 3.45-3.35 (m, 1 H), 3.27-3.18 (m, 1 H), 2.78-2.67 (m, 1 H), 2.17-2.05 (m, 1 H), 1.88-1.74 (m, 1 H), 1.48 (s, 9 H); MS (ESI): m/z: 238 [M-56+H]+. |
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