Structure of 1049730-42-8
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CAS No. : | 1049730-42-8 |
Formula : | C11H16BF3N2O2 |
M.W : | 276.06 |
SMILES Code : | FC(F)(F)CN1N=CC(B2OC(C)(C)C(C)(C)O2)=C1 |
MDL No. : | MFCD18383264 |
InChI Key : | VWPXSWMYEMPJGB-UHFFFAOYSA-N |
Pubchem ID : | 68923586 |
GHS Pictogram: |
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Signal Word: | Warning |
Hazard Statements: | H302-H315-H319-H335 |
Precautionary Statements: | P261-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 |
---|---|---|
78% | With caesium carbonate; In N,N-dimethyl-formamide; at 20 - 100℃; for 2h; | To a stirred solution of 4-(4,4,5 ,5 -tetramethyl- 1,3 ,2-dioxaborolan-2-yl)- 1 Hpyrazole (100 mg, 0.5 15 mmol) in DMF (1 ml) were added Cs2CO3 (252 mg, 0.773mmol) and 2,2,2-trifluoroethyl trifluoromethanesulfonate (0.144 ml, 1.031 mmol) at rt. After stirring at 100 C for 2 h, the reaction mixture was evaporated to dryness, partitioned between EtOAc and water, and the layers were separated. The organic layer was dried over Na2SO4, filtered, and concentrated to afford 4-(4,4,5,5-tetramethyl-i,3,2- dioxaborolan-2-yl)- 1 -(2,2,2-trifluoroethyl)- 1 H-pyrazole (0.111 g, 78% yield). MS(ESI)m/z: 277.4 (M+H). |
76% | With caesium carbonate; In N,N-dimethyl-formamide; at 100℃; for 0.833333h; | To a solution of 4-(4, 4,5,5, -tetramethyl-1 ,3, 2-dioxaborolan-2-yl)-1 H-pyrazole (250 mg, 1.29 mmol) in N,N-dimethylformamide (4 mL) were added cesium carbonate (630 mg, 1.93 mmol) and 2,2,2-trifluoroethyl trifluoro methanesulfonate (0.37 mL, 2.58 mmol). The mixture was stirred at 100C for 50 minutes. The mixture was then poured in water (15 mL) and extracted with ethyl acetate (2x10 mL). The organic layer was washed with a saturated solution of sodium hydrogenocarbonate (10 mL), brine (10 mL), dried over sodium sulfate and concentrated in vacuo to provide 4-(4, 4,5,5,- tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 -(2,2,2-trifluoroethyl)-1 H-pyrazole (22a) (271 mg, 0.98 mmol, 76%) which was used without further purification. 1H NMR (300 MHz, CDCl3) delta 1.32 (s, 12H), 4.71 (q, J = 8.4 Hz, 2H), 7.80 (s, 1 H), 7.84 (s, 1 H). |
64% | With caesium carbonate; In N,N-dimethyl-formamide; at 0 - 20℃; for 3.5h; | 2,2,2-Trifluoroethyl trifluoromethanesulfonate (0.66 g, 2.86 mmol, 0.4 mL) was added to a mixture of 4-(4,4,5,5-tetramethyl-i ,3,2-dioxaborolan-2-yl)-i H-pyrazole (0.46 g, 2.37 mmol) and cesium carbonate (1.60 g, 4.92 mmol) in dry N,N-dimethylformamide (10.0 mL) at 0C. After stirring for 30 mm the reaction mixture was allowed to warm to room temperature. After stirring for 3 h the reaction mixture was poured out into water (200 mL) and the mixture was extracted with ethyl acetate (3x50 mL). The combined organic layers were washed with water (3x100 mL) and brine and were dried with sodium sulfate. Solvents were removed in vacuo to afford 0.42 g (1.51 mmol; 64% of theory) of the title compound.GO-MS (Method L9): R1 = 3.36 mm; m/z = 276 M |
62% | With potassium carbonate; In N,N-dimethyl-formamide; at 80℃; for 15h; | To a stirred solution of 4-(4,4,5,5-tetramethyl- I ,3,2-dioxaborolan-2-yl)-1 H-pyrazole (2.00 g, 10.3 mmcl) in DMF (20 ml) was added potassium carbonate (4.27 g, 30.9 mmol) and 2,2,2-trifluoroethyl trifluoromethanesulfonate (2.2 ml, 15 mmcl). The mixture was stirred at 80C for14 h. Further 2,2,2-trifluoroethyl trifluoromethanesulfonate (420 p1, 2.9 mmcl) was added and the mixture was stirred at 80C for 1 h. Water was added and the mixture was extracted with ethyl acetate. The organic phase was washed with half-saturated sodium chloride solution, dried (sodium sulfate), filtered and the solvent was removed in vacuum. Silicagelchromatography gave 1.76 g (62 % yield) of the title compound. 1H-NMR (400 MHz, DMSO-d6) oe [ppm]: 1.066 (1.33), 1.256 (16.00), 5.144 (0.85), 5.167 (0.81),7.701 (1.31), 8.055 (1.26). |
With caesium carbonate; In N,N-dimethyl-formamide; at 0 - 20℃; for 2.5h;Inert atmosphere; | Intermediate 14: 4-(4,4,5,5-Tetramethyl-1 , 3,2-dioxaborolan-2-yl)-1 -(2,2,2- trif luoroethyl)-1 H-pyrazole; 2,2,2-Trifluoroethyl trifluoromethanesulfonate (28.7g, 124mmol) (Apollo Scientific) was added to a mixture of 4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H- pyrazole (20g, 103mmol) (Aldrich) and cesium carbonate (67.2g, 206mmol) in N,N- Dimethylformamide (DMF) (150ml) at 0C under nitrogen . The mixture was stirred for 30 min at 0C then allowed to warm to room temperature and stirred for a further 2h. The mixture was quenched with water (200ml) and extracted with EtOAc (200ml). The organic layer was washed with water (200ml), dried and evaporated to give a brown oil. This was dissolved in DCM (30ml), the fine precipitate was filtered off and the filtrate loaded onto a 330g silica column, then eluted with 0-50% EtOAc/cyclohexane. Appropriate fractions were combined and evaporated to give the title compound as a colourless oil (14.7g)1 H NMR (CDCI3) 7.86ppm (1 H, s, CH); 7.82ppm (1 H, s, CH); 4.73ppm ( 2H, q, CH2); 1.34ppm (12H, s, 4xCH3). | |
14.7 g | With caesium carbonate; In N,N-dimethyl-formamide; at 0 - 20℃;Inert atmosphere; | Intermediate 14: 4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-1-(2,2,2-trifluoroethyl)-1H-pyrazole 2,2,2-Trifluoroethyl trifluoromethanesulfonate (28.7 g, 124 mmol) (Apollo Scientific) was added to a mixture of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (20 g, 103 mmol) (Aldrich) and cesium carbonate (67.2 g, 206 mmol) in N,N-Dimethylformamide (DMF) (150 ml) at 0 C. under nitrogen. The mixture was stirred for 30 min at 0 C. then allowed to warm to room temperature and stirred for a further 2 h. The mixture was quenched with water (200 ml) and extracted with EtOAc (200 ml). The organic layer was washed with water (200 ml), dried and evaporated to give a brown oil. This was dissolved in DCM (30 ml), the fine precipitate was filtered off and the filtrate loaded onto a 330 g silica column, then eluted with 0-50% EtOAc/cyclohexane. Appropriate fractions were combined and evaporated to give the title compound as a colourless oil (14.7 g) 1H NMR (CDCl3) 7.86 ppm (1H, s, CH); 7.82 ppm (1H, s, CH); 4.73 ppm (2H, q, CH2); 1.34 ppm (12H, s, 4*CH3). |
The following Preparations were prepared according to Method H (Preparation 122) using 4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H-pyrazole and the appropriate alkyl electrophile. | ||
With sodium hydride; In N,N-dimethyl-formamide; at 0 - 20℃; for 12h; | . Sodium hydride (61.8 mg, 1.55 mmol) was added to a solution of 4-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)-lH-pyrazole (150 mg, 0.77 mmol) and 2,2,2-trifluoroethyl trifluoromethanesulfonate (269 mg, 1.16 mmol) in DMF (5 ml) at 0C and the mixture was stirred at 20C for 12 h. The mixture was quenched with aqueous saturated ammonium chloride (6 mL) and extracted with ethyl acetate (3 x 8 mL). The combined organic fractions were washed with brine, dried over sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to give 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l-(2,2,2-trifluoroethyl)- lH-pyrazole. MS (ESI) calc'd for (C11H17BF3N2O2) [M+H]+, 277 ; found, 277 | |
With caesium carbonate; In 1,4-dioxane; at 20℃; for 3.5h; | [00771] Compound 50 was prepared in 2 steps according to the following procedures: 4-(4,4,5,5- tetramethyl- 1 ,3,2-dioxaborolan-2-yl)- 1H-pyrazole (2.6 mmol, 1.0 equiv) and cesium carbonate (2.0 equiv) were suspended in dioxane (10 mL). Trifluoroethyltriflate (1.24 equiv) was added and the reaction was stirred at room temperature for 3 .5h after which the mixture partionned between water and brine and extracted with ethyl acetate. The combined organics were concentrated onto silica gel (4g) and purified using flash silica gel chromatography (Silicycle Si-40g, gradient 10-100% ethyl acetate/hexanes) to provide pinacol ester 49. | |
Step 1: 4-(4,4, 5,5-Tetramethyl- 1 ,3,2-dioxaborolan-2-yl)- 1 -(2 ,2,2-trifl uoroethyl)- 1 H-pyrazole Cesium carbonate (3.36 g, 10.31 mmol) was added to a stirred solution of 4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1.0 g, 5.15 mmol) in dry DMF (12 ml).After stirring at RT for 10 mm 2,2,2-trifluoroethyl trifluoromethanesulfonate (1.11 ml, 7.73 mmol) was added. The reaction was stirred for 2 days at RT then the solvent was removed and the residue was partitioned between diethyl ether and water. The organic extract was separated, dried over MgSO4 and the solvent removed to give an oil;LCMS: Rt 1.00 mins; MS MS mlz 277.4 [M+H]+; Method 2minLCvOO3 | ||
With caesium carbonate; In acetonitrile; at 60℃; for 2h; | Intermediate D1 4-(4,4,5,5-Tetramethyl-1,3,2-dioxoborolan-2-yl)-1-(2,2,2-trifluoroethyl)-1 H-pyrazoleA stirred mixture of 4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H-pyrazole (0.56 g, 2.89 mmol), 2,2,2-trifluoroethyl trifluoromethanesulfonate (0.633 ml, 4.39 mmol) and cesium carbonate (2.81 g, 8.62 mmol) in acetonitrile (20 ml) was heated at 60C. After 2h the solvent was removed under reduced pressure and the residue was partitioned between EtOAc and water. The organic extract was dried over MgS04 and the solvent was removed under reduced pressure to afford the title compound as a gum;LCMS: Rt 1.00 mins; MS m/z 277.4 [M+H]+; Method 2minl_C_v0031H NMR (400MHz, CDCI3) delta 7.88 (1 H, s), 7.82 (1 H, s), 4.73 (2H, q), 1.35 (12H, s). | |
With caesium carbonate; In N,N-dimethyl-formamide; at 100℃; for 2h; | Intermediate 255A: 4-(4,4,5,5-tetramethyl-l ,3,2-dioxaborolan-2-yl)-l -(2,2,2- trifluoroethyl)- lH-pyrazole To a stirred solution of 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH- pyrazole (400 mg, 2.06 mmol) in DMF (2 mL) was added CS2CO3 (1.0 g mg, 3.1 mmol) and 2,2,2-trifluoroethyl triflate (0.58 mL, 4.1 mmol). The mixture was heated at 100 C for 2 hours. After cooling, the mixture was concentrated to dryness then partitioned between EtOAc and water. The layers were separated and the organic layer was dried over Na2S04, filtered, and concentrated to afford the crude product which was used directly in the next step. NMR (400 MHz, CHLOROFORM-^ delta 7.85 (s, 1 H) 7.80 (s; 1 H) 4.64-4.76 (m, 2 H), 1.32 (s, 12 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99 mg | Example 3 N-[(3S)-3-fluoro-3-piperidinyl]methyl}-7-[1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl]pyrido[3,4-b]pyrazin-5-amine To a solution of 1,1-dimethylethyl (3R)-3-[(7-chloropyrido[3,4-b]pyrazin-5-yl)amino]methyl}-3-fluoro-1-piperidinecarboxylate (120 mg, 0.303 mmol) in 1,4-Dioxane (2 ml) was added <strong>[1049730-42-8]4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-(2,2,2-trifluoroethyl)-1H-pyrazole</strong> (84 mg, 0.303 mmol), caesium carbonate (198 mg, 0.606 mmol) and water. Nitrogen was bubbled through for 1 min before adding tetrakis(triphenylphosphine)palladium (0) (10.51 mg, 9.09 mumol). This was heated in a microwave at 130 C. for 1.5 h. The reaction had gone to completion and so was partitioned between ethyl acetate and aqueous ammonium chloride. The aqueous was re-extracted with ethyl acetate and the combined organics were washed with brine, passed through a hydrophobic frit and concentrated in vacuo to give the crude product as a bright yellow gum (140 mg). This was dissolved in DCM (2 ml) and to it was added trifluoroacetic acid (2 ml) and the reaction was stirred at room temperature for 1 h. The mixture was concentrated in vacuo and the residue was dissolved in methanol and purified through an SCX cartridge (10 g) washing with methanol (3 column volumes). The product was eluted as the free base with 2M ammonia in methanol. This was concentrated in vacuo to give the title compound as a bright yellow gum (99 mg). LCMS (Method C): Rt=0.67 min, MH+=409.8 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With caesium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; water; at 130℃; for 1.5h;Inert atmosphere; microwave irradiation; | Example 3: N-t K3S)-3-f luoro-3-piperidinyl1methyl V7-M -(2.2.2-trifluoroethvn-1 H- pyrazol-4-vnpyridor3,4-/3lpyrazin-5-amine; To a solution of 1 , 1-dimethylethyl (3f~)-3-[(7-chloropyrido[3,4-b]pyrazin-5- yl)amino]methyl}-3-fluoro-1-piperidinecarboxylate (120mg, 0.303mmol) in 1 ,4- Dioxane (2ml) was added 4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1-(2,2,2- trifluoroethyl)-1 H-pyrazole (84mg, 0.303mmol), caesium carbonate (198mg, 0.606mmol) and water. Nitrogen was bubbled through for 1 min before adding tetrakis(triphenylphosphine)palladium (0) (10.51 mg, 9.09muetaiotaomicronIota). This was heated in a microwave at 130C for 1.5h. The reaction had gone to completion and so was partitioned between ethyl acetate and aqueous ammonium chloride. The aqueous was re-extracted with ethyl acetate and the combined organics were washed with brine, passed through a hydrophobic frit and concentrated in vacuo to give the crude product as a bright yellow gum (140mg). This was dissolved in DCM (2ml) and to it was added trifluoroacetic acid (2ml) and the reaction was stirred at room temperature for 1 h. The mixture was concentrated in vacuo and the residue was dissolved in methanol and purified through an SCX cartridge (10g) washing with methanol (3 column volumes). The product was eluted as the free base with 2M ammonia in methanol. This was concentrated in vacuo to give the title compound as a bright yellow gum (99mg).LCMS (Method C): Rt = 0.67min, MH+ = 409.8 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With lithium hydroxide monohydrate;tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; water; at 140℃; for 3h;microwave irradiation; | Intermediate 19: 1.1 -Dimethylethyl (3S)-3-r(f7-ri-(2.2.2-trifluoroethvn-1H- pyrazol-4-vnpyridor3,4-/3lpyrazin-5-yl)oxy)methvn-1 -piperidinecarboxylate; 4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1-(2,2,2-trifluoroethyl)-1 H-pyrazole (1312mg, 4.75mmol), 1 , 1-dimethylethyl (3S)-3-[(7-chloropyrido[3,4-b]pyrazin-5- yl)oxy]methyl}-1-piperidinecarboxylate (600mg, 1.584mmol), lithium hydroxide, monohydrate (198mg, 4.75mmol) and tetrakis(triphenylphosphine)palladium (0) (183mg, 0.158mmol) were combined and dissolved in 1 ,4-dioxane (3ml) and water (2ml). The reaction was heated in the microwave at 140C for 3h. The reaction was partitioned between ethyl acetate (100ml) and water (100 ml). The organic layer was washed with brine (100ml) and the solvent was evaporated. The residue was dissolved in DCM and loaded on to a 50g silica column and purified on the SP4 eluting with 10-90% ethyl acetate/cyclohexane gradient. Appropriate fractions were combined and evaporated to give the title compound as a brown oil which was dried under high vacuum overnight (174.6mg). LCMS (Method B): Rt = 1.2min, MKT 493 | |
174.6 mg | With tetrakis(triphenylphosphine) palladium(0); lithium hydroxide monohydrate; In 1,4-dioxane; water; at 140℃; for 3h;Microwave irradiation; | Intermediate 19: 1,1-Dimethylethyl (3S)-3-[({7-[1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl]pyrido[3,4-b]pyrazin-5-yl}oxy)methyl]-1-piperidinecarboxylate <strong>[1049730-42-8]4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-(2,2,2-trifluoroethyl)-1H-pyrazole</strong> (1312 mg, 4.75 mmol), 1,1-dimethylethyl (3S)-3-[(7-chloropyrido[3,4-b]pyrazin-5-yl)oxy]methyl}-1-piperidinecarboxylate (600 mg, 1.584 mmol), lithium hydroxide.monohydrate (198 mg, 4.75 mmol) and tetrakis(triphenylphosphine)palladium (0) (183 mg, 0.158 mmol) were combined and dissolved in 1,4-dioxane (3 ml) and water (2 ml). The reaction was heated in the microwave at 140 C. for 3 h. The reaction was partitioned between ethyl acetate (100 ml) and water (100 ml). The organic layer was washed with brine (100 ml) and the solvent was evaporated. The residue was dissolved in DCM and loaded on to a 50 g silica column and purified on the SP4 eluting with 10-90% ethyl acetate/cyclohexane gradient. Appropriate fractions were combined and evaporated to give the title compound as a brown oil which was dried under high vacuum overnight (174.6 mg). LCMS (Method B): Rt=1.2 min, MH+ 493 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate; In 1,4-dioxane; at 80℃; for 18h;Inert atmosphere; | PdC12(dppf) (11 mg, 0.014 mmol) was added to a mixture of 4-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)-l-(2,2,2-trifluoroethyl)-lH-pyrazole (50 mg, 0.18 mmol), Intermediate VI (77 mg, 0.18 mmol) and K2CO3 (62.6 mg, 0.453 mmol) in dioxane (5 ml) at room temperature and the mixture was stirred at 80 C under N2 for 18 h. The mixture was quenched with aqueous saturated ammonium chloride ( 6 mL) and extracted with ethyl acetate (3 x 6 mL). The combined organic fractions were washed with brine, dried over sodium sulfate, filtered, and the solvent was evaporated under reduced pressure. The residue was purified by preparative Reverse phase HPLC (C-18), eluting with Acetonitrile/Water + 0.05% NH3, to give 3-37. 1H NMR (400 MHz, CD3OD): delta 8.46 (s, 1H), 8.33 (m, 1H), 8.17 (s, 1H), 5.13 (q, / = 8.8 Hz, 2H), 5.05 - 4.90 (m, 1H), 4.48 - 4.42 (m, 2H), 4.21 - 3.60 (m, 4H), 2.52 - 2.05 (m, 2H), 1.95 - 1.70 (m, 1H), 1.45 (t, / = 8.8 Hz, 3H), 0.95 - 0.75 (m, 4H). MS (ESI) calc'd for (C2oH24F3N80) [M+H]+, 449 ; found, 449 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
45% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate; In water; acetonitrile; at 140℃; for 0.416667h;Inert atmosphere; Microwave irradiation; | A mixture of 3-bromo-6-(3,5- dimethyltriazol-4-yl)-l-[(l,4,4-trifluorocyclohexyl)methyl]pyrrolo[3,2-b]pyridine (29, 63 mg, 0.142 mmol), 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l-(2,2,2-trifluoroethyl)pyrazole (90 mg, 0.33 mmol) and [l ,l'-bis(diphenylphosphino) ferrocene] dichloropalladium(II) (16 mg, 0.021 mmol) in acetonitrile (2 ml) was purged with nitrogen gas then 0.43 mL of 1M aqueous degassed potassium carbonate was added. The resulting mixture was irradiated in a microwave vessel at 140C for 25 minutes. The resulting mixture was cooled & filtered through a pad of celite, concentrated down and purified by flash chromatography eluting with 50-90% ethyl acetate in hexane to provide product (P-0372, 33 mg, 45%) MS (ESI) [M+H+]+ = 512.3. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
37.4% | With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In 1,4-dioxane; water; at 60℃; for 5h; | To 6-bromo-l-[(4,4- difluorocyclohexyl)methyl]-3-iodo-pyrrolo[3,2-b]pyridine (41, 1 g, 2.2 mmol), 4-(4,4,5,5-tetramethyl- l,3,2-dioxaborolan-2-yl)-l-(2,2,2-trifluoroethyl)pyrazole (0.64 g, 2.31 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.22 g, 0.19 mmol) in 1,4 dioxane (20 ml) was added 1M aqueous potassium carbonate (4.5 ml). The reaction was allowed to stir at 60C for 5 hours. The reaction mixture was partitioned between ethyl acetate and water, washed with brine, and dried over sodium sulfate. After removal of drying agent and solvent, the residue was purified by flash chromatography (0- 30% ethyl acetate in hexane). Desired fractions were collected and concentrated to afford product as a yellow solid (42, 392 mg, 37.4%) MS (ESI) [M+H+]+ = 478.9. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
39.2% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate; In water; acetonitrile; at 75℃; for 5h;Microwave irradiation; | To a 10 mL microwave vial charged with 4-[3-iodo- l-[l,2,2,2-tetradeuterio-l- (2,3,4,5, 6-pentadeuteriophenyl)ethyl]pyrrolo[3,2-b]pyridin-6-yl]-3,5-dimethyl-isoxazole (47, 0.06 g, 0.12 mmol) in acetonitrile (6 ml) was added 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)- l -(2,2,2- trifluoroethyl)pyrazole (0.04 g, 0.16 mmol), 1M aqueous potassium carbonate in water (3 ml), and [Iota, Gamma- bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.01 g, 0.01 mmol). The reaction mixture was heated at 75 C for 5 hrs. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with water, brine, dried over magnesium sulfate, filtered and the volatiles were removed under reduced pressure. The product was purified by silica gel flash chromatography eluting with 20- 100% ethyl acetate in hexane. Fractions that contained product were combined and further purified by RP-HPLC to provide pure product after lyophilization (P-0606, 23 mg, 39.2%) MS (ESI) [M+H+]+ = 474.9. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With caesium carbonate; In N,N-dimethyl-formamide; at 100℃; for 1h;Inert atmosphere; Microwave irradiation; Sealed tube; | Step 1: 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l-(2,2,2-trifluoroethyl)-lH- pyrazole [00249] A 25 mL teflon cap tube was charged with 4-pyrazoleboronic acid pinacol ester (0.94 g, 4.87 mmol), cesium carbonate (2.58 g, 7.31 mmol), 2,2,2 trifluoroethyl methanesulfonate (1.30 g, 0.86 mL, 7.31 mmol) and anhydrous DMF (8 mL). The reagents were capped under N2 and heated at 100 C under microwave irradiation for 1 h. After this time the reaction mixture was cooled to rt and partitioned with EtOAc (60 mL) and water (100 mL). Organic layers were extracted, washed with brine (2 x 65 mL), then dried and filtered (phase separator) to give a pale yellow oil. The crude product was purified by flash silica column chromatography (gradient elution /so-hexane to 33% EtOAc in i'so-hexane) to give the title compound as a colorless oil (0.37 g, 35% - mixture of target material and 2,2,2 trifluoroethyl methanesulfonate 1:2). MS (ES+) consistent with target (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With bis-triphenylphosphine-palladium(II) chloride; sodium carbonate; In 1,2-dimethoxyethane; ethanol; at 120℃; for 0.5h;Microwave irradiation; | Step 2: 3-(5-Amino-6-(1 -(2,2,2-trifluoroethyl)-1 H-pyrazol-4-yl)pyrazin-2-yl)-N-(3-hydroxy-3-methylbutyl)-4-methyl benzenesulfonamide A mixture of 4-(4,4, 5, 5-tetramethyl- 1, 3,2-dioxaborolan-2-yl)- 1 -(2 ,2,2-trifl uoroethyl)- 1 Hpyrazole (step 1) (115 mg, 0.417 mmol), 3-(5-Amino-6-chloropyrazin-2-yl)-N-(3-hydroxy-3- methylbutyl)-4-methyl benzenesulfonamide (Intermediate D3) (150 mg, 0.390 mmol),bis(triphenylphosphine) palladium dichloride (14 mg, 0.020 mmol) in sodium carbonate 2M aqueous solution (0.6 mL, 1.200 mmol), Ethanol (1.2 ml) and DME (1.8 mL) was heated to 120 C for 30 minutes in the microwave, then partitioned between DCM/water, separated using a phase separator and organics evaporated under reduced pressure. The crude product was purified by flash column chromatography (12g silica, 0-5% methanol in TBME).The product fractions were combined and evaporated, triturated with a mixture of ethylacetate/diethyl ether and solid collected by filtration, washed with cold dry diethyl ether anddried in the vacuum oven overnight to give pale yellow solid;1H NMR (400MHz, DMSO-d6) O 8.49 (1H, 5); 8.16 (1H, 5); 8.13 (1H, 5); 7.83 (1H, d, -2Hz);7.68 (1H, dd, -8 and 2Hz); 7.53 (1H, d, -8Hz); 7.42 (1H, t); 6.37 (2H, 5); 5.21 (2H, q); 4.27(1H, 5); 2.83 (2H, m); 2.48 (3H, s, partially overlapping with solvent); 1.51 (2H, m); 1.01 (6H,5). LC-MS: Rt 0.92mm; MS mlz 499.2 [M+H]+; Method: 2minLowpH |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
58% | With bis-triphenylphosphine-palladium(II) chloride; sodium carbonate; In ethanol; toluene; at 90℃; for 3h; | Intermediate C1 (2881) 5-Bromo-3-[1-(2,2,2-trifluoro-ethyl)-1H-pyrazol-4-yl]-pyridin-2-ylamine (2882) (2883) Sodium carbonate (2.76 ml of a 2M solution, 5.52 mmol) was added to a mixture of 5-bromo- 3-iodopyridin-2-amine (0.55 g, 1.84 mmol), 4-(4,4,5,5-tetramethyl-1 ,3,2-dioxoborolan-2-yl)-1- (2,2,2-trifluoroethyl)-1 H-pyrazole (0.61 g, 2.21 mmol) (Intermediate D1) and Pd(PPh3)2CI2 (0.065 g, 0.092 mmol) in toluene (7 ml) and ethanol (3.5 ml). The mixture was heated at 90C. After 3h the reaction was complete by LCMS. The reaction mixture was diluted with EtOAc and washed with brine. The organic extract was dried over MgS04 and the crude product absorbed on silica. Chromatography on silica, eluting with EtOAc, gave the product as a grey solid (0.36 g, 58 %); (2884) LCMS: Rt 1.00 mins; MS m/z 321.3 [M+H]+ ; Method 2minLC_v003 (2885) 1H NMR (400MHz, CDCI3) 8.15 (1 H, br s), 7.82 (1 H, s), 7.78 (1 H, s), 7.55 (1 H, s), 4.7 (2H, m) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
13.16% | With caesium carbonate; In N,N-dimethyl-formamide; at 100℃; for 3h; | To a solution of 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazole (5.0 g, 25.8 mmol) in Nu,Nu-Dimethylformamide (DMF) (50 mL) and was added Cs2C03 (16.79 g, 51.5 mmol) at RT and 2,2,2-trifluoroethyl trifluoromethanesulfonate (4.45 mL, 30.9 mmol) added drop wise at RT.The reaction mixture was stirred at 100 C for 3 hr. The reaction mixture was diluted with water(100 mL) and extracted with EtOAc (2 X 100 mL), the combined organics were washed with cold water(3 X 100ml) and brine solution (100ml) and dried over Na2S04,filtered and evaporated under vacuo to get 4-(4,4,5,5-tetramethyl- l,3,2-dioxaborolan-2-yl)-l-(2,2,2-trifluoroethyl)-lH-pyrazole (1.8 g, 3.39 mmol, 13.16 % yield) as an off white gummy liquid |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
29.8% | To a degassed solution of (4,S)-N-(4-bromopyridin-2-yl)-7-(2-methylpyridin-4-yl)-3,4- dihydro-l,4-methanopyrido[2,3-^][l,4]diazepine-5(2H)-carboxamide (450 mg, 0.997 mmol), in 1,4-Dioxane (50 mL) and Water (10 mL) under argon, was added K3P04 (635 mg, 2.99 mmol) 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l-(2,2,2-trifluoroethyl)- lH-pyrazole (358 mg, 1.296 mmol) and stirred at RT for 10 min. then added PdCl2(dppf)- CH2C12 adduct (81 mg, 0.100 mmol) and stirred at 80 C for 3 h. (TLC system: 10% methanol in DCM, Rf value: 0.4). Water (100 mL) was added to the reaction mixture and extracted with ethylacetate (3x100 mL). Combined extracts were washed with brine solution (100 mL), dried over anhydrous Na2S04, filtered and filtrate was evaporated to get crude compound. Crude product was purified by preparative HPLC (Column: XBridge C-18 (150* 19)iotaetaiotaeta,5mu; Mobile phase-A: 0.1% Formic acid; Mobile phase-B: Acetonitrile; Flow: 15 mL/min; Method: 0.1/37, 1/37,10/37; Solubility: Acetonitrile+THF+MeOH) to afford (4^-7-(2-methylpyridin-4-yl)-N-(4-(l-(2,2,2-trifluoroethyl)-lH-pyrazol-4- yl)pyridin-2-yl)-3,4-dihydro-l,4-methanopyrido[2,3-^][l,4]diazepine-5(2H)-carboxamide (155 mg, 0.297 mmol, 29.8% yield) as an off white solid. LCMS (m/z): 521.22 [M+H]+, Rt =1.74 min.1H NMR (400 MHz, CDC13): delta ppm 13.61 (s, 1 H), 8.63 (d, J=5.48 Hz, 1 H), 8.41 (s, 1 H), 8.35 (d, J=5.04 Hz, 1 H), 8.21 (s, 1 H), 8.00 (s, 1 H), 7.96 (s, 1 H), 7.73 (br d, J=4.38 Hz, 1 H), 7.63 (d, J=7.89 Hz, 1 H), 7.49 (d, J=7.89 Hz, 1 H), 7.13 (d, J=3.95 Hz, 1 H), 5.71 (dd, J=5.70, 3.07 Hz, 1 H), 4.75 (q, J=8.26 Hz, 2 H), 3.36 - 3.12 (m, 3 H), 3.03 (dd, J=12.06, 3.07 Hz, 1 H), 2.75 (s, 3 H), 2.36 (qd, J=9.83, 4.49 Hz, 1 H), 2.11 (dt, J=14.20, 7.26 Hz, 1 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
170 mg | With chloro(2-dicyclohexylphosphino-2?,4?,6?-triisopropyl-1,1?-biphenyl)[2-(2?-amino-1,1?-biphenyl?)]palladium(II); potassium carbonate; In water; N,N-dimethyl-formamide; at 100℃; for 3h;Inert atmosphere; Sealed tube; | Intermediate 255B: 2-Chloro-N-isopropyl-5-(l -(2,2,2-trifluoroethyl)-lH-pyrazol-4-yl) pyridin-4-amine To a stirred solution of 5-bromo-2-chloro-N-isopropylpyridin-4-amine (300 mg, 1.202 mmol) in DMF (10 mL) and water (1 mL) was added 4-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)-l-(2,2,2-trifluoroethyl)-lH-pyrazole (498 mg, 1.8 mmol) and K2CO3 (498 mg, 3.6 mmol). The mixture was degassed by bubbling nitrogen for 2mins. 2nd generation Xphos precatalyst (95 mg, 0.12 mmol) was added and the mixture was further degassed for 2 min. The mixture was sealed and heated at 100 C for 3 hours. After cooling, the mixture was concentrated to dryness then partitioned between EtOAc (150 mL) and ice water (20 mL). The layers were separated and the organic layer washed again with cold water. The organic layer was dried over Na2S04, filtered, and concentrated. The product was purified via column chromatography (30% EtO Ac/pet ether) to afford 2-chloro-N-isopropyl-5-(l-(2,2,2-trifluoroethyl)-lH-pyrazol-4-yl)pyridin- 4-amine (170 mg, 44 % yield). LCMS: 319.3 (M+H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
66% | With dicyclohexyl-(2',6'-dimethoxybiphenyl-2-yl)-phosphane; caesium carbonate; In 1,2-dimethoxyethane; water; at 130℃; for 2h;Microwave irradiation; | To a solution of 6 (305 mg, 1.44 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1- (2,2,2-trifluoroethyl)-1H-pyrazole (477 mg, 1.73 mmol), Cs2CO3 (1.17 g, 3.60 mmol) and dicyclohexyl(2',6'-dimethoxy-[1,1'-biphenyl]-2-yl)phosphine (Sphos, 59.1 mg, 0.14 mmol) in DME (4 mL) and water (0.80 mL) was added Sphos precatalyst (104 mg, 0.14 mmol) at rt. The mixture was stirred at 130 C for 2 h under microwave irradiation. The mixture was filtered through Celite, and the filtrate was treated with water and extracted with EtOAc. The organic layer was separated, washed with brine, dried over MgSO4, and concentrated under vacuum. The residue was purified by column chromatography (silica gel, eluted with 10-100% EtOAc/hexane) to yield 8e (310 mg, 66%) as a yellow oil. MS (API): m/z 325.9 (M + H)+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
941 mg | With bis-triphenylphosphine-palladium(II) chloride; potassium carbonate; triphenylphosphine; In propan-1-ol; for 2h;Reflux; | To a stirred solution of 4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 -(2,2,2-trifluoroethyl)- 1H-pyrazole (1.76 g, 6.06 mmol) in 1-propanol (42 ml) was added potassium carbonatesolution (7.0 ml, 2.0 M, 14 mmol), 4-bromo-2-nitroaniline (1.01 g, 4.66 mmol), triphenylphosphine (61.1 mg, 233 pmol) and PdCI2(PPh3)2 (164 mg, 233 pmol). The mixture was heated to reflux for 2 h. Water was added and the mixture was extracted with ethyl acetate. The organic phase was dried (sodium sulfate), filtered and the solvent was removed in vacuum. Aminophase-silicagel chromatography gave 941 mg of the title compound.LC-MS (Method 2): R = 1.00 mm; MS (ESIpos): m/z = 287 [M+H]1H..NMR (400 MHz, DMSO-d6) [ppm]: 1.066 (0.59), 1.172 (0.65), 1.987 (1.19), 2.518 (2.95),2.523 (2.06), 5.090 (3.14), 5.113 (9.09), 5.136 (8.48), 5.159 (2.55), 7.045 (9.54), 7.067 (9.88),7.471 (12.23), 7.671 (5.50), 7.676 (5.37), 7.693 (4.69), 7.698 (5.06), 8.004 (15.43), 8.006(16.00), 8.132 (10.24), 8.137 (10.07), 8.253 (13.82). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75 mg | With bis(di-tert-?butyl(4-?dimethylaminophenyl)?phosphine)?dichloropalladium(II); sodium carbonate; In 1,2-dimethoxyethane; water; at 110℃; for 1h;Microwave irradiation; | A mixture of 1, 5-anhydro-3- (6- ( (6-chloropyridin-3- yl)methyl) -7, 8-dimethyl-4-oxoquinazolin-3 (4H) -yl) -2, 3-dideoxy- L-threo-pentitol (140 mg) , 4- (4, 4, 5, 5-tetramethyl-l, 3, 2- dioxaborolan-2-yl) -1- (2, 2, 2-trifluoroethyl) -lH-pyrazole (145 mg) , PdCl2(Amphos)2 (23.55 mg) , 2 M aqueous sodium carbonate solution (0.525 mL) and DME (4 mL) was subjected to microwave irradiation at 110C for 1 hr. To the mixture was added water at room temperature, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by HPLC (L-Column 2 ODS, mobile phase: water/acetonitrile (containing 0.1% TFA) ) . The obtained fraction was filtered through Stratospheres SPE (PL-HC03 MP-Resin) and concentrated under reduced pressure. The obtained solid was crystallized from ethyl acetate/hexane to give the title compound (75 mg) . (1563) 1H N R (300 MHz, DMSO-d6) delta 1.72-1.72 (1H, m) , 2.08-2.34 (4H, m), 2.53 (3H, s) , 3.11 (1H, t, J = 10.2 Hz), 3.42 (1H, t, J = 11.0 Hz), 3.93 (2H, dt, J = 10.9, 5.3 Hz), 4.03-4.14 (1H, m) , 4.18 (2H, s), 4.44-4.61 (1H, m) , 5.13-5.28 (3H, m) , 7.49 (1H, dd, J = 8.3, 2.3 Hz), 7.62 (1H, d, J = 7.9 Hz), 7.82 (1H, s) , 8.11 (1H, s), 8.36-8.45 (3H, m) . |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate; In ethanol; at 120℃; for 0.333333h; | 1-(S)-( 1-(2-chloropyridin-4-yl)- 1H-indazol-6-yl)spiro[2.2lpentane- 1 -carbonitrile (32.1 mg, 0.1mmol), 4-(4,4,5 ,5 -tetramethyl- 1,3 ,2-dioxaborolan-2-yl)- 1 -(2,2,2-trifluoroethyl)- 1 H-pyrazole(41.4 mg, 0.150 mmol), Si-DPP-Pd (80 mg, 0.020 mmol), potassium carbonate (100 jil, 0.200 mmol), and ethanol (1000 jil) were added to a microwave vial. The contents of the vial were microwaved at 120 C for 20 minutes. The reaction mixture was filtered and the resulting material was further purified via reverse phase prep-HPLC [method Al. This providedi -(S)-( 1- (2-( 1-(2,2,2-trifluoroethyl)- 1H-pyrazol-4-yl)pyridin-4-yl)- 1H-indazol-6-yl)spiro[2.2lpentane- 1-carbonitrile, TFA (13.4). MS (ESI) mlz calc?d for C23H17F3N6 [M+Hl + 435 found 435. 1HNMR (499 MHz, DMSO-d6) 8.74 (d, J = 5.7 Hz, 1H), 8.62 (s, 1H), 8.58 (s, 1H), 8.34 (s, 1H),8.24 (d, J = 1.8 Hz, 1H), 8.00 (d, J = 8.4 Hz, 1H), 7.94 (s, 1H), 7.79 (dd, J = 5.7, 2.0 Hz, 1H),7.32 (dd, J = 8.4, 1.4 Hz, 1H), 5.26 (q, J = 9.0 Hz, 2H), 2.37 (d, J = 5.2 Hz, 1H), 2.21 (d, J = 5.2Hz, 1H), 1.31 - 1.20 (m, 3H), 1.14 - 1.08 (m, 1H). |