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CAS No. : | 937046-98-5 | MDL No. : | MFCD09033848 |
Formula : | C6H5BrN4 | Boiling Point : | No data available |
Linear Structure Formula : | - | InChI Key : | YGCJBESZJIGDMP-UHFFFAOYSA-N |
M.W : | 213.04 | Pubchem ID : | 42281383 |
Synonyms : |
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Signal Word: | Warning | Class: | |
Precautionary Statements: | P261-P280-P305+P351+P338 | UN#: | |
Hazard Statements: | H302-H315-H319-H332-H335 | Packing Group: | |
GHS Pictogram: |
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* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | To a stirred suspension of Intermediate B (1.30 g, 6.08 mmol) in THF (31 mL) was added chlorotrimethylsilane (1.54 mL, 12.15 mmol), dropwise. The mixture was stirred at rt for 3 h and 2-propylmagnesium chloride (2M in THF; 12.76 mL, 25.52 mmol) was added dropwise. The suspension immediately went into solution. The mixture was stirred at rt for 2 h and te/-butyl 3-[methoxy(methyl)carbamoyl]azetidine-1-carboxylate (1.93 g, 7.90 mmol) was added in one portion. The reaction was stirred at rt for 16 h. The reaction was poured over a mixture of ice and saturated, aqueous ammonium chloride (200 mL). The mixture was allowed to warm to rt and was extracted with EtOAc (3 x 100 mL). The combined organics were washed with brine, dried (Na2SO4), and concentrated to dryness. The crude residue was purified by ISCO chromatography using a gradient of 50 to 75% ethyl acetate in hexanes to afford 1.6 g (83%) of the desired product. ES-MS m/z 318.14 [M+H]+, HPLC RT (min) 2.58. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | A 1 L, 3-neck RB flask was fitted with a mechanical stirrer, a nitrogen inlet, thermocouple and thermocontroller, and a water cooling bath. In the flask 7-bromopyrrolo[2,1- f][1 ,2,4]triazin-4-amine (175 g, 352mmol) was suspended in tetrahydrofuran (100 ml_) and treated with chlorotrimethylsilane (7.65g, 70.4 mmol). The mixture was allowed to stir 3 h at rt. A solution of isopropylmagnesium bromide in THF (2M, 70.4 mL, 141 mmol) was added slowly over 20 min taking care that the internal temperature never rose above 40 0C. After 1 h a sample quenched in MeOH and analyzed by RP-HPLC indicated that the metallation was > 90percent complete. The water bath was replaced with an ice-acetone bath and stirring was continued until the internal temperature fell to -10 0C. 2-Chloro-N- methoxy-N-methylacetamide (7.3 g, 53 mmol) was added as a solid, and the reaction allowed to warm to rt over 30 min. The reaction was quenched with MeOH and diluted with EtOAc (200 mL) and 500 mL of citrate buffer (pH 4). The mixture was stirred for 15 min, during which time a thick tan precipitate formed. This was filtered off to provide the desired compound as a tan solid (2g, 27percent). The organic layer was separated, dried with sodium sulfate and filtered through a silica plug. Removal of the solvent in vacuo and trituration of the residue with EtOAc gave a second batch of the desired product (4.3 g, 58percent). The 2 batches were combined to provide the desired product as a tan powder (6.25 g, 84percent). 1H-NMR (DMSO): delta 7.88 (bs, 1 H), 7.80 (s, 1 H), 7.08 (d, 1 H, J = 5 Hz), 6.70 (d, 1H, J = 5 Hz), 4.82 (s, 2H), 3.06 (bs, 1); MS: LC/MS (+esi): m/z=211.2 [MH]+ ;LC/MS rt = 1.69 min. | |
76% | To a stirred suspension of Intermediate B (3.00 g, 14.08 mmol) in THF (50 ml_) was added chlorotrimethylsilane (3.57 mL, 28.16 mmol). The mixture was stirred at rt for 3 h. The mixture was placed in a water ice bath and 2-propylmagnesium chloride (2M in THF; 29.6 mL, 59.14 mmol) was added dropwise. The suspension immediately went into solution. The ice bath was removed and the mixture was stirred at rt for 3 h. The mixture was placed in an ice bath and 2- chloro-AA-methoxy-AA-methylacetamide (2.91 g, 21.12 mmol) was added in one portion. The ice bath was once again removed and the reaction was stirred at rt for 16 h. The reaction was poured over a mixture of ice and saturated, aqueous ammonium chloride (250 mL). The mixture was allowed to warm to rt and EtOAc (200 mL) was added. The undissolved solid was collected by filtration to afford 636 mg (21percent) of the desired product. The layers of the filtrate were separated and and the aqueous phase was extracted with EtOAc (2 x 100 mL). The combined organic layers were washed with brine, dried (Na2SO4), and concentrated to dryness. The crude solid was triturated with EtOAc to provide an additional 1.62 g (55percent) of the desired product, for a combined yield of 2.26 g (76percent). ES-MS m/z 211.47 [M+H]+, HPLC RT (min) 1.67. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60% | To a suspension of N-methyltetrahydro-2H-pyran-4-amine (541 mg, 4.69 mmol) and <strong>[51323-43-4](3-(bromomethyl)phenyl)boronic acid</strong> (756 mg, 3.52 mmol) in acetonitrile (8 mL) was added K2C03 (973 mg, 7.04 mmol) under anhydrous conditions. After stirring at room temperature for 10 h, the reaction mixture was concentrated, phosphoric acid,potassium salt (1.50 g, 2.35 mmol), 7-bromopyrrolo[2,1-f][1,2,4]triazin-4-amine (500 mg, 2.347 mmol), dioxane (8 mL) and water (4 mL) were added. The reaction vessel was evacuated, backfilled with N2 and then degassed by bubbling N2 with sonication. Tetrakis triphenylphosphine (271 mg, 0.235 mol) was added and the degassing process was repeated. The resulting reaction mixture was heated at 140 C in a microwave for 45mm. The reaction complex was cooled, filtered, and washed with water. The filtrate was extracted with ethyl acetate (10 mL x 3). The organic layers were combined, dried and concentrated. The crude mixture was dissolved in DMF, and purified by preparative LC Method C to obtain 7-(3 -((methyl(tetrahydro-2H-pyran-4-yl)amino)methyl)phenyl) pyrrolo[2,1-f][1,2,4]triazin-4-amine, TFA (636 mg, 60% yield). LC/MS (M+H) =338.30. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
62% | With [1,1?-bis(di-cyclohexylphosphino)ferrocene]dichloropalladium (II); sodium carbonate; In water; tert-butyl alcohol; at 110℃; for 2.0h;Inert atmosphere; | Step 1: 7-(1-Acetyl-1,2,3,6-tetrahydropyridin-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine A mixture of <strong>[1227068-67-8]1-acetyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridine</strong> (from Combi-Blocks, 500 mg, 1.99 mmol), 7-bromopyrrolo[2,1-f][1,2,4]triazin-4-amine (from J & W Pharm Lab, 424 mg, 1.99 mmol), sodium carbonate (700 mg, 6.6 mmol), and [1,1'-bis(di-cyclohexylphosphino)ferrocene]dichloropalladium (II) (199 mg, 0.26 mmol) in tert-butyl alcohol (6.0 mL) and water (2.2 mL) was degassed with nitrogen, then stirred and heated at 110 C. for 2 h. The mixture was diluted with ethyl acetate, washed with saturated NaHCO3, water, dried over Na2SO4, filtered and concentrated. The product was purified by Biotage silica gel chromatography (20 g column, 0 to 30% MeOH in EtOAc) to give the desired product as brown solid (317 mg, 62%). LCMS calcd for C13H16N5O (M+H)+: m/z=258.1. Found: 258.1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium phosphate; (chloro(2-dicyclohexylphosphino-2?,4?,6?-triisopropyl-1,1?-biphenyl)[2-(2?-amino-1,1?-biphenyl)]palladium(II)); In 1,4-dioxane; water; at 80℃; for 1h;Inert atmosphere; Sealed tube; | Step 1: 7-(1-Methyl-1,2,3,6-tetrahydropyridin-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine The mixture of 7-bromopyrrolo[2,1-f][1,2,4]triazin-4-amine (from J & W Pharm Lab, 208 mg, 0.97 mmol), <strong>[454482-11-2]1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridine</strong> (from Aldrich, 250 mg, 1.12 mmol), potassium phosphate (0.61 g, 2.9 mmol) in 1,4-dioxane (3.4 mL) and water (1.1 mL) was degassed, refilled with nitrogen, followed by addition of dicyclohexyl(2',4',6'-triisopropylbiphenyl-2-yl)phosphine-(2'-aminobiphenyl-2-yl)(chloro)palladium (1:1) (110 mg, 0.14 mmol). The reaction mixture was degassed again, refilled with nitrogen and was then sealed and heated at 80° C. for 1 h. The reaction mixture was allowed to cool to rt, diluted with ethyl acetate, washed with brine, dried over sodium sulfate, filtered, and concentrated under vacuum to give the crude product, which was used directly in the next step. LCMS calcd for C12H16N5(M+H)+: m/z=230.1. Found: 230.1. |
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