| 65% |
With TurboGrignard; chloro-trimethyl-silane; phenylmagnesium chloride In tetrahydrofuran at 0 - 10℃; for 0.0466667h; |
1-11 This embodiment provides a microchannel reaction device for preparing the key intermediate (3R, 4R, 5R)-2-(4-aminopyrrolo[2,1-f][1,2,4] The method of triazine-7-yl)-3,4-bis(benzyloxy)-5-((benzyloxy)methyl)tetrahydrofuran-2-ol is shown in Figure 1. The specific synthesis method includes the following steps :
Weigh 5.20g (20mmol, 1.0equiv) of 7-iodopyrrolo[2,1-f][1,2,4]triazine-4-amine, fully dissolve it in tetrahydrofuran solvent, and add 5.0mL TMS-Cl (40mmol, 2.0equiv), prepare a 50mL solution as material I; measure 20mL of PhMgCl2 (2M, 40mmol, 2.0equiv) in tetrahydrofuran solution, and measure 20mL of iPrMgCl2·LiCl (1M, 20mmol, 1.0equiv) in tetrahydrofuran solution, Mix the two and use it as material II; weigh 8.36g (20mmol, 1.0equiv) of 2,3,5-tri-O-benzyl-D-ribose-1,4-lactone and dissolve it in tetrahydrofuran solvent to prepare Make 50mL solution, as material III. Pump material I and material II at the same time, where the pumping flow rate of material I is 1.0 mL/min, and the pumping flow rate of material II is 0.8 mL/min. After mixing, it is transported to the first microchannel reactor for reaction, wherein the inner diameter of the pipe of the first microchannel reactor is 1.0mm, the length is 5m, the volume is 3.9mL, the residence time is 2.2min, and the reaction temperature is 10°C. Then pump the material III to mix with the above reaction solution at a flow rate of 1.0 mL/min. After mixing, it is transported to the second microchannel reactor for reaction, wherein the pipe inner diameter of the second microchannel reactor is 1.0mm, the length is 10m, the volume is 7.8mL, the residence time is 2.8min, and the reaction temperature is 0°C. The reaction was monitored by TLC. After the completion of the reaction, the effluent reaction liquid was collected. The reaction was quenched by adding 20 mL methanol, 20 mL acetic acid and 20 mL water to the reaction liquid. The reaction solvent was removed, and the organic was extracted with ethyl acetate and 1 mol/L hydrochloric acid. The obtained organic phase was washed with 10% NaHCO3 solution and saturated brine in turn, dried with anhydrous Na2SO4, and the solvent was removed by distillation under reduced pressure and recovered, and recrystallized to obtain (3R, 4R, 5R)-2-(4-aminopyrrole) And [2,1-f][1,2,4]triazin-7-yl)-3,4-bis(benzyloxy)-5-((benzyloxy)methyl)tetrahydrofuran-2-ol 7.18g, yield 65%. |
| 65% |
Stage #1: 7-iodopyrrolo-[2,1-f][1,2,4]-triazin-4-amine With chloro-trimethyl-silane In tetrahydrofuran at -10℃; for 0.166667h;
Stage #2: With TurboGrignard; methylmagnesium bromide In tetrahydrofuran; diethyl ether at -10℃; for 0.1h;
Stage #3: (3R,4R,5R)-3,4-Bis-benzyloxy-5-benzyloxymethyl-dihydro-furan-2-one With isopropylmagnesium chloride; N,O-dimethylhydroxylamine*hydrochloride In tetrahydrofuran for 3.33333h; Cooling with ice; |
17.A; 17.B; 18.A; 18.B
Step A: 7-iodopyrrolo[2,1-F][1,2,4]triazine-4-amine (1.3g, 5.0mmol) was added to anhydrous tetrahydrofuran (6mL),Add trimethylchlorosilane (1.1g, 10.0mmol, 2.0eq) at minus 10 degrees Celsius, stir for 10 minutes,Slowly add 3M methylmagnesium bromide ether solution (3.3mL, 10.0mmol, 2.0eq),After adding, stir for 20 minutes,Then add 1.3M isopropyl magnesium chloride lithium chloride tetrahydrofuran solution (5.0mL, 6.5mmol, 1.3eq),Control the reaction temperature at minus 10 degrees Celsius to 0 degrees Celsius, and stir for about 1 hour. |
| 64% |
Stage #1: 7-iodopyrrolo-[2,1-f][1,2,4]-triazin-4-amine With chloro-trimethyl-silane In tetrahydrofuran at 20℃; for 0.166667h;
Stage #2: With phenylmagnesium chloride In tetrahydrofuran at 0℃; for 0.333333h;
Stage #3: (3R,4R,5R)-3,4-Bis-benzyloxy-5-benzyloxymethyl-dihydro-furan-2-one Further stages; |
4-amino-1-hydroxy-7-(2,3,5-tri-O-benzyl-α/β-D-ribofuranosyl)-pyrrolo[2,1-f][1,2,4]triazine5 (37)
Compound 36 (5.9 g, 22.7 mmol, 1.0 eq.) was suspended in THF (120 mL). TMS-Cl (5.76 g, 45.4 mmol, 2.0 eq.) was added, and the resulting mixture stirred for 10 minutes at room temperature before it was cooled to 0 °C. PhMgCl (2 M in THF, 22.7 mL, 45.4 mmol, 2.0 eq.) was added dropwise (3 mL/min). when addition was complete, the mixture was stirred for another 20 minutes after which iPrMgCl.LiCl (1.3M in THF, 19.2 mL, 25.0 mmol, 1.1 eq.) was added slowly. After 15 minutes, the reaction was cooled to - 15 °C, and a solution of 2,3,5-tri-O-benzyl-D-ribono-1,4-lactone (9.51 g, 22.7 mmol, 1.0 eq.) in THF (30 mL), previously dried over 4 molecular sieves, was added slowly. After 1h , the reaction mixture was warmed to 0 °C, and then quenched with MeOH (20 mL), followed by acetic acid (20 mL) and water (20 mL). The resulting mixture was warmed to room temperature and concentrated in vacuo. The residue was partitioned between EtOAc (200 mL) and aq. 1M HCl (200 mL). The phases were separated, and the organic layer washed with aq. 10% NaHCO3 solution (200 mL) and brine (200 mL), dried over Na2SO4 and concentrated in vacuo. The residue was purified via flash column chromatography (0 10% MeOH in EtOAc) to afford 38 (8.02 g, 14.5 mmol, 64% yield) as a light yellow foam. HRMS (ESI): calculated for C32H33N4O5 ([M+H]+): 553.2451, found: 553.2395. Spectral data were in accordance with literature values.5 |
| 60% |
Stage #1: (3R,4R,5R)-3,4-Bis-benzyloxy-5-benzyloxymethyl-dihydro-furan-2-one With isopropylmagnesium chloride; N,O-dimethylhydroxylamine*hydrochloride In tetrahydrofuran at 0℃; Inert atmosphere;
Stage #2: 7-iodopyrrolo-[2,1-f][1,2,4]-triazin-4-amine With chloro-trimethyl-silane In tetrahydrofuran at -10℃; for 0.00333333h; Inert atmosphere; Further stages; |
|
| 59.2% |
Stage #1: 7-iodopyrrolo-[2,1-f][1,2,4]-triazin-4-amine With N,N,N,N,-tetramethylethylenediamine In tetrahydrofuran; water at 20℃; for 0.166667h; Industrial scale;
Stage #2: With chloro-trimethyl-silane In tetrahydrofuran; water at 10℃; for 0.5h; Industrial scale;
Stage #3: (3R,4R,5R)-3,4-Bis-benzyloxy-5-benzyloxymethyl-dihydro-furan-2-one Industrial scale; Further stages; |
1.S-5.S4
Weigh 7-iodopyrrolo[2,1-f][1,2,4]triazine-4-amine (1300g, 5mol) into the reaction kettle, add 15L of tetrahydrofuran (water content of 135ppm), Stir at room temperature to dissolve it, then add tetramethylethylenediamine (1624g, 14mol) to it, stir at room temperature for about 15min, then cool to 10°C, add trimethylchlorosilane (972g, 9mol) to react for 30 minutes, Replace the air under reduced pressure, slowly lower the temperature to -40°C, slowly add 2mol/L phenylmagnesium chloride (5.5L, 11mol) dropwise, and continue to stir and react for 15 minutes;S2. Add 1.3mol/L isopropyl magnesium chloride lithium chloride complex (3.46L, 4.5mol) to the system and stir for 30min, control the temperature of the reaction system below -40, and add 2,3,5-in batches Tribenzyloxy-D-ribonic acid-1,4-lactone (1607.2g, 4mol), continue the reaction for 2h;S3. TLC (Thin Layer Chromatography) detects the reaction. After the reaction is over, 1.3L of acetic acid is added to the reaction system to quench, and the reaction solution is taken out and collected, and 10L of water and 15L of ethyl acrylate are added to the reaction system for extraction. Collect the organic phase and the aqueous phase separately. The aqueous phase is back-extracted with 5L of ethyl acrylate once, the organic phases obtained from the two extractions are combined, and the combined organic phase is washed with 1mol/L hydrochloric acid 18L, separated and treated with water. The phase is back-extracted once with 5L of ethyl acrylate, and it is combined with the organic phase obtained from the previous liquid separation;S4. Wash the obtained organic phase with saturated sodium carbonate solution and saturated brine in turn, concentrate under reduced pressure, and pass through the column twice after mixing the sample. The solvent used in the first mixing and passing through the column is a molar ratio of 2: 1 is a mixed solution of petroleum ether and ethyl acrylate, the solvent used for the second sample mixing is a mixed solution of dichloromethane and methanol with a molar ratio of 20:1, and dried to obtain (3R, 4R, 5R)-2 -(4-Aminopyrrole[2,1-f][1,2,4]triazine-7-yl)-3,4-bis(benzyloxy)-5-((benzyloxy)methyl ) Tetrahydrofuran-2-ol) 1636g, the molar yield is 59.2%. |
|
Stage #1: 7-iodopyrrolo-[2,1-f][1,2,4]-triazin-4-amine With chloro-trimethyl-silane In tetrahydrofuran at 0℃; for 0.5h;
Stage #2: With phenylmagnesium chloride In tetrahydrofuran at 0 - 5℃; for 0.583333h;
Stage #3: (3R,4R,5R)-3,4-Bis-benzyloxy-5-benzyloxymethyl-dihydro-furan-2-one Further stages; |
4 Example 4
[0185] A solution of 7-iodopyrrolo[2,l-fJ[l,2,4]triazin-4-amine (7.5 g, 28.8 mmol, 1.0 equiv) was prepared in THF (67 mL). The solution was cooled to about 0 °C, and TMSC1 (3.3 mL, 30.3 mmol, 1.05 equiv) was added. The reaction mixture was stirred for about 30 min, and then PhMgCI (2 M in THF; 28 mL, 56.8 mmol, 1.97 equiv) was added while maintaining an internal temperature below 5 °C. The reaction mixture was agitated at about 0 °C for about 35 min, and then cooled to about -15 °C. /PrMgCI (2 M in THF, 14 mL, 30.2 mmol, 1.05 equiv) was then added while maintaining an internal temperature below about -10 °C. After approximately 15 minutes at about -15 °C, LaCl3-2LiCl (0.6 M in THF, 50 mL, 14.4 mmol, 0.5 equiv) was added while maintaining an internal temperature below about -15 °C. The reaction mixture was agitated for about 25 min at about -20 °C. [0186] In a separate flask, a solution of (3R,4R,5R)-3,4-bis(benzyloxy)-5- ((benzyloxy)methyl)dmydrofuran-2(3H)-one (10.0 g, 23.9 mmol, 0.83 equiv) was prepared in THF (45 mL). The solution was cooled to about -20 °C, and then transferred to the Grignard solution while maintaining an internal temperature below about -15 °C. The resulting reaction mixture was agitated at about -20 °C for about 30 min. The reaction was quenched with 2 M HC1 (53 mL), and the mixture warmed to about 15 °C. fPrOAc (38 mL) was added, and the organic and aqueous phases were separated. The bottom aqueous layer was discharged, and the upper organic layer was washed sequentially with 2.5 wt% NaHC03 (53 mL), 2.5 wt% NaHC03 (53 mL), and 10 wt% NaCl (53 mL). [0187] The organic phase was concentrated to about 45 mL, and then diluted with iPrOAc (75 mL). The solution was concentrated again to about 45 mL, and then diluted with z'PrOAc (23 mL). The solution was concentrated to about 45 mL, and then filtered over a pad of Celite. The filtered solution was concentrated to about 26 mL, and then diluted with MTBE (75 mL). After 2h, heptane (23 mL) was slowly added and the slurry was stirred at about 25 °C for about 2 h, and was then cooled to about -5 °C over about 8 h. The solids were isolated by filtration, and the filter cake was washed with MTBE/heptane (4:1, 23 mL). The solids were dried in a vacuum oven at no more than about 35 °C to afford (3R,4R,5R)-2-(4-aminopyirolo[2,I-fJ[l ,2,4]triazin- 7-yl)-3,4-bis(benzyloxy)-5-((benzyloxy)methyl)tetrahydrofuran-2-ol. |
|
Stage #1: 7-iodopyrrolo-[2,1-f][1,2,4]-triazin-4-amine With chloro-trimethyl-silane; phenylmagnesium chloride In tetrahydrofuran at 0 - 5℃; for 0.5h; Inert atmosphere;
Stage #2: With TurboGrignard In tetrahydrofuran at -15 - -12℃; for 0.166667h;
Stage #3: (3R,4R,5R)-3,4-Bis-benzyloxy-5-benzyloxymethyl-dihydro-furan-2-one In tetrahydrofuran at -20℃; for 1h; |
35 Preparation (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 via (4-amino-7-iodopyrrolo[2,1-f][1,2,4]triazine)
To a reactor under a nitrogen atmosphere was charged iodobase 2 (81 g) and THF (1.6 LV). The resulting solution was cooled to about 5° C., and TMSCl (68 g) was charged. PhMgCl (345 mL, 1.8 M in THF) was then charged slowly while maintaining an internal temperature at about ≦5° C. The reaction mixture was stirred at about 0° C. for 30 min, and then cooled to about -15° C. iPrMgCl-LiCl (311 mL, 1.1 M in THF) was charged slowly while maintaining an internal temperature below about -12° C. After about 10 minutes of stirring at about -15° C., the reaction mixture was cooled to about -20° C., and a solution of lactone 1 (130 g) in THF (400 mL) was charged. The reaction mixture was then agitated at about -20° C. for about 1 h and quenched with AcOH (57 mL). The reaction mixture was warmed to about 0° C. and adjusted to pH 7-8 with aqueous NaHCO3 (5 wt %, 1300 mL). The reaction mixture was then diluted with EtOAc (1300 mL), and the organic and aqueous layers were separated. The organic layer was washed with 1N HCl (1300 mL), aqueous NaHCO3 (5 wt %, 1300 mL), and brine (1300 mL), and then dried over anhydrous Na2SO4 and concentrated to dryness. Purification by silica gel column chromatography using a gradient consisting of a mixture of MeOH and EtOAc afforded the product. |
|
Stage #1: 7-iodopyrrolo-[2,1-f][1,2,4]-triazin-4-amine With chloro-trimethyl-silane; phenylmagnesium chloride In tetrahydrofuran at 0 - 5℃; for 0.5h; Inert atmosphere;
Stage #2: With TurboGrignard In tetrahydrofuran at -15 - -12℃; for 0.166667h; Inert atmosphere;
Stage #3: (3R,4R,5R)-3,4-Bis-benzyloxy-5-benzyloxymethyl-dihydro-furan-2-one In tetrahydrofuran at 20℃; for 1h; Inert atmosphere; |
5 Preparation (3R,4R,5R)-2-(4-aminopyrrolor2, l-firi,2,41triazin-7-yl)-3,4-bis(benzyloxy)-5- ((benzyloxy)methyl)tetrahvdrofuran-2-ol via (4-amino-7-iodopyrrolor2,l-fl ri,2,41triazine)
To a reactor under a nitrogen atmosphere was charged iodobase 2 (81 g) and THF (1.6 LV). The resulting solution was cooled to about 5 °C, and TMSC1 (68 g) was charged. PhMgCl (345mL, 1.8 M in THF) was then charged slowly while maintaining an internal temperature at about < 5°C. The reaction mixture was stirred at about 0°C for 30 min, and then cooled to about -15 °C. z'PrMgCl-LiCl (311 mL, 1.1 M in THF) was charged slowly while maintaining an internal temperature below about -12 °C. After about 10 minutes of stirring at about -15 °C, the reaction mixture was cooled to about -20 °C, and a solution of lactone 1 (130 g) in THF (400 mL) was charged. The reaction mixture was then agitated at about -20 °C for about 1 h and quenched with AcOH (57 mL). The reaction mixture was warmed to about 0 °C and adjusted to pH 7-8 with aqueous NaHCC>3 (5 wt%, 1300 mL). The reaction mixture was then diluted with EtOAc (1300 mL), and the organic and aqueous layers were separated. The organic layer was washed with IN HC1 (1300 mL), aqueous NaHCC>3 (5 wt%, 1300 mL), and brine (1300 mL), and then dried over anhydrous Na2S04 and concentrated to dryness. Purification by silica gel column chromatography using a gradient consisting of a mixture of MeOH and EtOAc afforded the product. |
|
Stage #1: 7-iodopyrrolo-[2,1-f][1,2,4]-triazin-4-amine With chloro-trimethyl-silane In tetrahydrofuran at 20℃; for 0.166667h;
Stage #2: With phenylmagnesium chloride In tetrahydrofuran at 0℃; for 0.333333h;
Stage #3: (3R,4R,5R)-3,4-Bis-benzyloxy-5-benzyloxymethyl-dihydro-furan-2-one Further stages; |
|
| 17.6 g |
With chloro-trimethyl-silane; isopropyl magnesium chloride - lithium chloride complex; phenylmagnesium chloride In tetrahydrofuran at -20 - 20℃; for 1.5h; Inert atmosphere; |
2 Example 2 (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
Dissolve 7-iodopyrrolo[2,1-f][1,2,4]triazine-4-amine (32.2g, 76.9mmol) in tetrahydrofuran (480mL),Under the protection of nitrogen, trimethylchlorosilane (16.87g, 153.8mmol, 2eq.) was added dropwise,After stirring for 10 minutes at room temperature, place in an ice water bath.When cooled to about 0,Slowly add phenylmagnesium chloride (2M, 77mL, 2eq.) dropwise.Continue to stir for 20 minutes after the addition is complete,Then slowly add isopropyl magnesium chloride-lithium chloride (1.3M, 62mL, 1.05eq.),Keep the internal temperature below 5°C during the dropping process.After the addition is complete, the reaction mixture is cooled to about -20°C,And added (3R, 4R, 5R)-3,4-bis(benzyloxy)-5-((benzyloxy)methyl)dihydrofuran-2(3H)-one (20g, 76.9mmol, 1eq. ) In tetrahydrofuran (97ml),At the same time, the internal reaction temperature is maintained at about -20°C.Continue to react for 1 hour after the addition is complete,Then the temperature was raised to 0°C, and then quenched with methanol (64 mL),Then add acetic acid (64mL) and water (64mL),The resulting mixture was warmed to room temperature, and then concentrated under reduced pressure.The resulting concentrate was partitioned between ethyl acetate (800 mL) and aqueous hydrochloric acid (1M, 800 mL).The organic layer was separated and washed with saturated aqueous sodium bicarbonate (800 mL) and saturated brine (800 mL), respectively,Dry over anhydrous sodium sulfate, and concentrate under reduced pressure.Separated by silica gel column, eluted with a gradient of 0-5% methanol and dichloromethane,17.6 g of light yellow solid was obtained. |
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