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Chemical Structure| 1191237-68-9 Chemical Structure| 1191237-68-9

Structure of 1191237-68-9

Chemical Structure| 1191237-68-9

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Product Details of [ 1191237-68-9 ]

CAS No. :1191237-68-9
Formula : C33H31N5O4
M.W : 561.63
SMILES Code : N#CC1(C2=CC=C3C(N)=NC=NN32)O[C@H](COCC4=CC=CC=C4)[C@@H](OCC5=CC=CC=C5)[C@H]1OCC6=CC=CC=C6
English Name :(3R,4R,5R)-2-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-3,4-bis(benzyloxy)-5-((benzyloxy)methyl)tetrahydrofuran-2-carbonitrile

Safety of [ 1191237-68-9 ]

Application In Synthesis of [ 1191237-68-9 ]

* 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.

  • Downstream synthetic route of [ 1191237-68-9 ]

[ 1191237-68-9 ] Synthesis Path-Downstream   1~2

  • 1
  • [ 7677-24-9 ]
  • [ 1355049-94-3 ]
  • [ 1191237-68-9 ]
YieldReaction ConditionsOperation in experiment
86.3% With trimethylsilyl trifluoropmethanesulfonate In dichloromethane at 0 - 15℃; for 5.5h; Inert atmosphere; 2 Example 2 Preparation of compound C-2 nitrile base Compound C-1 hydroxy compound (40g, 0.0724mmol, 1.0eq) was added to the 5L reaction flask, dichloromethane (1.2L) was added and stirred to dissolve, argon was replaced three times, the temperature was lowered to 0°C, TMSCN (28.74g, 0.2897 mol, 4.0eq), stirred for 30 minutes, added TMSOTf (33.8g, 0.1521mol, 2.1eq) dropwise, reacted at 0°C for 2 hours, added TMSOTf (33.8g, 0.1521mol, 2.1eq) and reacted for 1 hour, heated up React at 15°C for 2 hours, cool down to 0°C, add 2.4L to dilute, pour the reaction solution into 3.6L of saturated NaHCO3solution to quench the reaction, and extract the aqueous phase with 2L of dichloromethane again.The organic phases were combined, washed once with saturated brine, and concentrated to obtain the crude product, which was crystallized with isopropanol and n-heptane to obtain a white solid C-2 nitrile (35.1 g, yield: 86.3%).
80% Stage #1: trimethylsilanecarbonitrile; (3R,4R,5R)-2-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-3,4-bis(benzyloxy)-5-((benzyloxy)methyl)tetrahydrofuran-2-ol In dichloromethane at 0℃; for 0.166667h; Inert atmosphere; Stage #2: With trimethylsilyl trifluoropmethanesulfonate In dichloromethane at -78℃; for 1h; Stage #3: With Sodium hydrogenocarbonate In dichloromethane; lithium hydroxide monohydrate for 0.166667h; The hydroxy nucleoside (1.1 g, 2.0 mmol) was dissolved in anhydrous CH2CI2 (40 mL) and the solution cooled with stirring to 0 °C under N2(g).TMSCN (0.931 mL, 7 mmol) was added and the mixture stirred for a further 10 min. TMSOTf (1.63 mL, 9.0 mmol) was slowly added to the reaction and the mixture stirred for 1 h. The reaction mixture was then diluted with CH2CI2 (120 mL) and aqueous NaHC03 (120 mL) was added to quench the reaction. The reaction mixture was stirred for a further 10 min and the organic layer separated. The aqueous layer was extracted with CH2CI2 (150 mL) and the combined organic extracts dried over anhydrous MgS04, filtered and concentrated under reduced pressure. The residue was dissolved in a minimal amount of CH2CI2 and subjected to silica gel chromatography eluting with a gradient of 0-75% EtOAc and hexanes to provide the tribenzyl cyano nucleoside as a mixture of anomers.(0.9 g, 80%).'H MR (300 MHz, CD3CN) δ 7.94 (s, 0.5H), 7.88 (s, 0.5H), 7.29-7.43 (m, 13H), 7.11-7.19 (m, 1H), 6.82-6.88 (m,lH), 6.70-6.76 (m, 1H), 6.41 (bs, 2H), 5.10 (d, J = 3.9 Hz, 0.5H), 4.96 (d, J = 5.1 Hz, 0.5H), 4.31-4.85 (m, 7H), 4.09-4.18 (m, 2H), 3.61-3.90 (m, 2H).LCMS m/z 562 [M+H].
80% Stage #1: trimethylsilanecarbonitrile; (3R,4R,5R)-2-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-3,4-bis(benzyloxy)-5-((benzyloxy)methyl)tetrahydrofuran-2-ol In dichloromethane at 0℃; for 0.166667h; Inert atmosphere; Stage #2: With trimethylsilyl trifluoropmethanesulfonate In dichloromethane at 0℃; for 1h; 4 The hydroxy nucleoside (1.1 g, 2.0 mmol) was dissolved in anhydrous CH2Cl2 (40 mL) and the solution cooled with stirring to 0° C. under N2(g). TMSCN (0.931 mL, 7 mmol) was added and the mixture stirred for a further 10 min. TMSOTf (1.63 mL, 9.0 mmol) was slowly added to the reaction and the mixture stirred for 1 h. The reaction mixture was then diluted with CH2Cl2 (120 mL) and aqueous NaHCO3 (120 mL) was added to quench the reaction. The reaction mixture was stirred for a further 10 min and the organic layer separated. The aqueous layer was extracted with CH2Cl2 (150 mL) and the combined organic extracts dried over anhydrous MgSO4, filtered and concentrated under reduced pressure. The residue was dissolved in a minimal amount of CH2Cl2 and subjected to silica gel chromatography eluting with a gradient of 0-75% EtOAc and hexanes to provide the tribenzyl cyano nucleoside as a mixture of anomers. (0.9 g, 80%). 1H NMR (300 MHz, CD3CN) δ 7.94 (s, 0.5H), 7.88 (s, 0.5H), 7.29-7.43 (m, 13H), 7.11-7.19 (m, 1H), 6.82-6.88 (m, 1H), 6.70-6.76 (m, 1H), 6.41 (bs, 2H), 5.10 (d, J=3.9 Hz, 0.5H), 4.96 (d, J=5.1 Hz, 0.5H), 4.31-4.85 (m, 7H), 4.09-4.18 (m, 2H), 3.61-3.90 (m, 2H). LCMS m/z 562 [M+H].
54% Stage #1: trimethylsilanecarbonitrile; (3R,4R,5R)-2-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-3,4-bis(benzyloxy)-5-((benzyloxy)methyl)tetrahydrofuran-2-ol In dichloromethane at 0℃; for 10h; Inert atmosphere; Stage #2: With trimethylsilyl trifluoropmethanesulfonate In dichloromethane at 0℃; for 2h; Inert atmosphere; C Step C. (3R,4R,5R)-2-(4-aminopyrrolo[2,l-f][l ,2,4]triazin-7-yl)-3,4-bis(benzyloxy)- 5-((benzyloxy)methyl)tetrahydrofuran-2-carbonitrile. To a solution of (3R,4R,5R)-2-(4-aminopyrrolo[2, 1 -f] [1 ,2,4]triazin-7-yl)-3 ,4-bis(benzyloxy)-5 - ((benzyloxy)methyl)tetrahydrofuran-2-ol (2.2 g, 3.98 mmol, 1.00 equiv) in DCM (80 mL) under inert atmosphere, was added trimethylsilanecarbonitrile (1.86 mL, 3.50 equiv) dropwise at 0 °C. The resulting solution was stirred for 10 mm. To this was added trimethylsilyl trifluoromethanesulfonate (3.26 mL, 4.50 equiv) dropwise at 0 °C. The resulting solution was stirred for 2 h at 0°C. then quenched by the addition of 200 mL of sat. sodium bicarbonate (aq.). The resulting solution was extracted with 200 mL of DCM and the organic layers combined and dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified on silica gel column with ethyl acetate/petroleum ether (1:10-2:1). This resulted in 1.2 g (54%) of the title compound as a yellow solid. MS mlz [M+H] (ESI): 562.
Stage #1: trimethylsilanecarbonitrile; (3R,4R,5R)-2-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-3,4-bis(benzyloxy)-5-((benzyloxy)methyl)tetrahydrofuran-2-ol In dichloromethane at -78℃; for 0.166667h; Inert atmosphere; Stage #2: With trimethylsilyl trifluoropmethanesulfonate In dichloromethane at -78℃; for 1h; Inert atmosphere; 4 Example 4 [0183] The hydroxy nucleoside (1.1 g, 2.0 mmol) was dissolved in anhydrous CH2CI2 (40 mL) and the solution cooled with stirring to about -78 °C under N2 (g). TMSCN (0.931 mL, 7 mmol) was added and the mixture stirred for a further 10 min. TMSOTf (1.63 mL, 9.0 mmol) was slowly added to the reaction and the mixture stirred for 1 h. The reaction mixture was then diluted with CH2CI2 (120 mL) and aqueous NaHCC>3 (120 mL) was added to quench the reaction. The reaction mixture was stirred for a further 10 min and the organic layer separated. The aqueous layer was extracted with CH2C12 (150 mL) and the combined organic extracts dried over anhydrous MgSO-j, filtered and concentrated under reduced pressure. The residue was dissolved in a minimal amount of CH2CI2 and subjected to silica gel chromatography eluting with a gradient of 0-75% EtOAc and hexanes to provide the tribenzyl cyano nucleoside as a mixture of anomers. 1H NMR (300 MHz, CD3CN) δ 7.94 (s, 0.5H), 7.88 (s, 0.5H), 7.29-7.43 (m, 13H), 7.11-7.19 (m, 1 H), 6.82-6.88 (m,lH), 6.70-6.76 (m, 1H), 6.41 (bs, 2H), 5.10 (d, J = 3.9 Hz, 0.5H), 4.96 (d, J = 5.1 Hz, 0.5H), 4.31-4.85 (m, 7H), 4.09-4.18 (m, 2H), 3.61-3.90 (m, 2H). LCMS m/z 562 [M+H].
1.59 g Stage #1: (3R,4R,5R)-2-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-3,4-bis(benzyloxy)-5-((benzyloxy)methyl)tetrahydrofuran-2-ol With trifluorormethanesulfonic acid In dichloromethane at -78℃; for 0.166667h; Stage #2: With trimethylsilyl trifluoropmethanesulfonate In dichloromethane for 0.5h; Stage #3: trimethylsilanecarbonitrile In dichloromethane for 2h; 4-amino-1’-cyano-7-(2,3,5-tri-O-benzyl-D-ribofuranosyl)-pyrrolo[2,1-f][1,2,4]triazine5 (39) Compound 37 (2.36 g, 4.27 mmol, 1.0 eq.) was dissolved in CH2Cl2 (20 mL).The mixture was cooled to - 78 °C and TfOH (0.754 mL, 8.54 mmol, 2.0 eq.) was added. The mixture was stirred for 10 minutes, when TMSOTf (1.62 mL, 8.97 mmol, 2.1 eq) was added. After 30 more minutes, TMSCN (2.14 mL, 17.1 mmol, 4.0 eq.) was added slowly, and the mixture was stirred for 2 more hours. The reaction was quenched via the addition of triethylamine (2.5 mL) and the mixture was allowed to warm to room temperature. Aq. sat. NaHCO3 (25 mL) was added, and the mixture was stirred for 10 minutes, when it was transferred to a separation funnel. The layers were separated, and the aqueous layer extracted with CH2Cl2 (2 x 50 mL). The combined organic layers were dried over Na2SO4 and concentrated in vacuo to afford 39 (1.59 g, 2.83 mmol) as a mixture of anomers that was used as such in the next reaction. Spectral data were in accordance with literature values.5
6 g With trimethylsilyl trifluoropmethanesulfonate In dichloromethane at 2 - 5℃; for 2h; Inert atmosphere; 3.3-1 Example 3-1 Add (3R,4R,5R)-2-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-3,4-bis(benzyloxy)- 5-((Benzyloxy)methyl)tetrahydrofuran-2-ol (8.0g, 14.48mmol)Dissolve in anhydrous dichloromethane (320mL) and stir in an ice water bath under the protection of nitrogen,When the internal temperature drops to about 2,Trimethylsilyl cyanide (7.18g, 72.4mmol, 5eq.) was added dropwise.Stir for another 10 minutes after the addition is complete,Then add dropwise trimethylsilyl trifluoromethanesulfonate (16.14g, 72.4mmol, 5eq.),Control the internal temperature below 5°C.Continue to react for 2 hours in an ice water bath.After the completion of the reaction, 300 mL of saturated sodium bicarbonate aqueous solution was added for quenching.After the reaction mixture continued to stir for 10 minutes,The organic phase was separated, and the aqueous phase was extracted three times with dichloromethane (100mL×3),After the collected organic phase was dried over anhydrous sodium sulfate, it was concentrated under reduced pressure.Separated by silica gel column, eluted with a gradient of 0-5% methanol and dichloromethane,The specific gradient elution conditions are as follows,

  • 2
  • [ 1191237-68-9 ]
  • [ 1911578-74-9 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1.1: boron trichloride / dichloromethane / 1 h / -78 - -20 °C / Inert atmosphere 2.1: trimethyl phosphite 2.2: -10 - 10 °C
 

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