| 99% |
With toluene-4-sulfonic acid at 0 - 20℃; Inert atmosphere; |
2’,3’-O-Isopropylideneadenosine (S1)
p-Toluenesulfonic acid (19 g, 110.2 mmol) was added to a solution of adenosine (3 g, 11.2 mmol) in acetone (300 mL) at 0 °C. The reaction mixture was stirred at room temperature overnight. While cooling in an ice bath, a saturated sodium bicarbonate solution (300 mL) was added to the reaction mixture until the pH of the solution was slightly basic. Then the acetone was evaporated using rotary evaporator and the remaining aqueous layer was extracted with ethyl acetate. The combined organicl ayers were washed with brine and dried over sodium sulfate. The product was dried under high-powered vaccum to afford compound S1 as a white solid (3.56 g, 99%). |
| 99% |
With perchloric acid for 2h; Cooling; |
|
| 99% |
With perchloric acid for 2h; Cooling with ice; |
6.A A. 2′, 3′-O-isopropylidene Adenosine (11)
A. 2', 3'-O-isopropylidene Adenosine (11) To adenosine (2.02 g, 7.56 mmol) suspended in acetone (150 ml) was added catalytic amount of perchloric acid (0.91 ml) drop-wise while under ice-bath. The milky white reaction mixture turned clear after 2 hours of stirring. The solution was then neutralized using two equivalent of ammonium hydroxide under ice-bath. The reaction mixture was then evaporated to under rotary evaporator to complete dryness and purified using flash silica gel chromatography (gradient: 0% for 4 min, 0-15% for 4-10 min and eluted at 15% MeOH:dichloromethane). The fractions containing the product were evaporated to obtain the product (2.3 g, 3.58 mmol) in 99% yield. The 1H NMR spectrum was (DMSO-d6): 1.33 (s, 3H), 1.55 (s, 3H), 3.54-3.56 (m, 2H), 4.22 (m, 1H), 4.97 (dd, 1H), 5.23 (t, 1H), 5.35 (d, 1H), 6.12 (d, 1H), 7.34 (s, 2H), 8.17 (s, 1H) and 8.35 (s, 1H). 13C-DMSO-d6: 156.60, 153.09, 149.28, 140.16, 119.57, 113.51, 90.07, 86.82, 83.68, 81.82, 62.05, 27.55 and 25.66 ppm. HRMS (ESI+) calcd for C13H18N5O4 [(M+H)+] 308.1359 found 308.1351. |
| 99% |
With toluene-4-sulfonic acid at 20℃; for 1h; |
1.1a 1a) 2',3'-O-isopropylidene-5'-O-p-toluenesulfonyladenosine
Adenosine (5.0 g, 18.7 mmol, 1.0 eq),TsOH·H2O (32.2 g, 187 mmol, 10.0 eq) was dissolved in 1 L of acetone.Stir at room temperature for 1 h. Saturated NaHCO3 solution was added to the reaction solution under ice bath.Adjust the pH ≥ 7, and remove the acetone by rotary evaporation to obtain a white solid.Namely, 8.6 g of 2',3'-O-isopropylidene adenosine, yield 99%.The above obtained 2',3'-O-isopropylidene adenosine (4.16 g, 10 mmol, 1.0 eq), TsCl (2.48 g, 13 mmol, 1.3 eq) andDMAP (1.83 g, 15 mmol, 1.5 eq) was dissolved in DCM.Stir at room temperature for 3 h.The solvent was evaporated under reduced pressure and the residue was diluted with EA.Wash with saturated NaHCO3 solution and saturated NaCl solution in turn.The organic phase was collected and dried over anhydrous Na 2 SO 4 .Silica gel column chromatography (DCM: MeOH = 50:1)The product was obtained as a white solid, 3.50 g, yield 76%. |
| 95% |
With perchloric acid In lithium hydroxide monohydrate at 0 - 20℃; for 7h; |
|
| 95% |
With toluene-4-sulfonic acid at 20℃; |
|
| 95% |
With toluene-4-sulfonic acid In methanol at 20℃; for 6h; |
((3aR,4R,6R,6aR)-6-(6-amino-9H-purin-9-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methanol (2)
To a solution of adenosine (100.0 g, 374.5 mmol) in methanol and acetone (1:1, 300 ml) was dropwise added the solution of p-toluenesulfonic acid (284.6 g, 1498.1 mmol) in methanol, mixtures were stirred at room temperature for 6 h. The mixture was quenched with saturated NaHCO3 at 0 , the acetone was evaporated, the water layer was extracted with chloroform, the organic layer was washed with deionized water and saturated brine, dried with Na2SO4, filtered and evaporated. To give the compound 2 in 95% yield, white solid (109.2 g). 1H NMR (400 MHz, DMSO-d6) δ 1.38 (s, 3H), 1.65 (s, 3H), 3.80 (d, J = 12.4 Hz, 1H), 3.89 (d, J = 12.8 Hz, 1H), 4.55 (s,1H), 5.11 (d, J = 5.6 Hz, 1H), 5.19 (t, J = 5.2 Hz, 1H), 5.88 (d, J = 4.8 Hz, 1H), 7.89 (s, 1H), 8.33 (s, 1H). 13C NMR (100 MHz, DMSO-d6) δ 25.4, 27.8, 63.5, 81.8, 83.1, 86.2, 94.5, 114.2, 121.2, 140.4, 148.5, 152.6, 156.0. |
| 95% |
With perchloric acid In lithium hydroxide monohydrate at 0 - 20℃; for 2h; Inert atmosphere; |
|
| 95% |
With perchloric acid In lithium hydroxide monohydrate at 0 - 20℃; for 2h; |
To a solution of adenosine (6.68 g, 25.0 mmol) in 500 mL of acetone was treated with perchloroic add (3.0 mL, 70% in water) at 0 °C then stirred at room temperature for 2 h. The resulting solution was neutralized with Na2CO3 at 0 °C and the resulting white solid removed by filtration. The filtrate was concentrated under reduced pressure to yield acetonide (4.67 g, 95 ). (0129) 1H NMR (400 MHz, DMSO) δ 8.25 (s, 1H), 8.07 (s, 1H), 6.03 (d, J = 3.0 Hz, 1H), 5.25 (dd, J = 6.1, 3.1 Hz, 2H), 5.16 (s, 1H), 4.87 (dd, J = 6.1, 2.4 Hz, 2H), 4.12 (q, J = 4.6 Hz, 2H), 3.45 (qd, J = 11.7, 4.8 Hz, 3H), 1.45 (s, 3H), 1.23 (s, 3H). |
| 95% |
With perchloric acid In lithium hydroxide monohydrate at 0 - 20℃; for 2h; |
To a solution of adenosine (6.68 g, 25.0 mmol) in 500 mL of acetone was treated with perchloroic add (3.0 mL, 70% in water) at 0 °C then stirred at room temperature for 2 h. The resulting solution was neutralized with Na2CO3 at 0 °C and the resulting white solid removed by filtration. The filtrate was concentrated under reduced pressure to yield acetonide (4.67 g, 95 ). (0129) 1H NMR (400 MHz, DMSO) δ 8.25 (s, 1H), 8.07 (s, 1H), 6.03 (d, J = 3.0 Hz, 1H), 5.25 (dd, J = 6.1, 3.1 Hz, 2H), 5.16 (s, 1H), 4.87 (dd, J = 6.1, 2.4 Hz, 2H), 4.12 (q, J = 4.6 Hz, 2H), 3.45 (qd, J = 11.7, 4.8 Hz, 3H), 1.45 (s, 3H), 1.23 (s, 3H). |
| 93% |
Stage #1: propan-2-one; adenosine With toluene-4-sulfonic acid at 20℃; for 0.5h;
Stage #2: With orthoformic acid triethyl ester for 48h; |
A11 Pre aration of intermediate 42
A solution of adenosine (20 g, 74.8 mmol) and p-toluenesulfonic acid monohydrate (14.8 g, 77.9 mmol) in acetone (786 mL) was stirred for 30 min at r.t. and then triethyl orthoformate anhydrous (57 mL, 342.8 mmol) was added. After 2 days volatiles were evaporated and the residue was partitioned in NaHC03 aq. and CH2CI2. The solid was filtered and was washed with water and ether to give 20.2 g of intermediate 42. The filtrate was evaporated and the residue was partitioned in NaHC03 ac and CH2CI2. The separated organic layer was washed with brine, dried over MgSC^ and evaporated. The yellow solid was washed with ether to give another 1.89 g of intermediate 42 In total 22.1 g of intermediate 42 (22.1 g, 69.7 mmol, 93% yield)) is formed and isolated. |
| 93% |
With toluene-4-sulfonic acid at 20℃; for 3h; |
|
| 92% |
With perchloric acid for 2h; Inert atmosphere; |
2',3'-Isopropylidene -adenosine (1).
Adenosine (0,5 g; 1,9 mmoli) was suspended in 15 mL of acetone under Ar obtaining a white suspension. After the addition of 0.4 mL of HClO4 the solution became clear. After 2 h the solution was treated with NH3 until pH 7 and evaporated. The residue was purified by flash chromatography (eluent: CH2Cl2/MeOH 96/4 v/v) to afford desiderated compound 1 (yield 92%). 1H-NMR (400 MHz, DMSO-d6) d: 1.3 (3H, s, (CH3)2C), 1.5 (3H, s, (CH3)2C), 3.5 (2H, m, H-5, H-5’), 4.2 (1H, m, H-4), 5.0 (1H, dd, H-3), 5.6 (1H, dd, H-2), 6.0 (1H, d, H-1), 8.1 (1H, s, H-8). ESI MS: m/z 310.2 Da [M+H]+, C13H19N5O4 Mol. Wt. 309.32. |
| 92% |
With toluene-4-sulfonic acid; orthoformic acid triethyl ester at 20℃; for 16h; |
1 Synthesis of compound 9a
((3aR,4R,6R,6aR)-6-(6-amino-9H-purin-9-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4- yl)methanol (1).19 To a solution of adenosine (10.0 g, 37.4 mmol, 1 equiv.) in acetone (1 L), was added CH(OEt)3 (31.1 mL, 187 mmol, 5 equiv.) and pTsOH (35.6 g, 187 mmol, 5 equiv.) . The mixture was stirred at rt for 16 h, then quenched with aqueous saturated NaHCO3, concentrated until a precipitate was obtained. The precipitate was dissolved in MeOH/CH2Cl2, filtered and evaporated to give the final product (10.5 g, 34.4 mmol, 92%) as a white solid. 1H NMR (500 MHz, DMSO-d6) d 8.33 (s, 1H), 8.15 (s, 1H), 7.33 (s, 2H), 6.11 (d, J = 3.1 Hz, 1H), 5.33 (dd, J = 6.2, 3.1 Hz, 1H), 5.29 (d, J = 21.9 Hz, 1H), 4.96 (dd, J = 6.2, 2.5 Hz, 1H), 4.20 (td, J = 4.8, 2.5 Hz, 1H), 3.59 - 3.48 (m, 2H), 1.53 (d, J = 0.7 Hz, 3H), 1.31 (d, J = 0.8 Hz, 3H). 13C NMR (101 MHz, DMSO) d 156.1, 152.5, 148.8, 139.6, 119.0, 113.0, 89.5, 86.3, 83.2, 81.3, 61.5, 27.0, 25.1. Rf : 0.31 (4 % MeOH in CH2Cl2; + 2 % NH37 M in MeOH). HRMS (ESI): calcd. for C13H17N5O4 [M+H ]+: 308.13 found: 308.13 |
| 92% |
With toluene-4-sulfonic acid; orthoformic acid triethyl ester In lithium hydroxide monohydrate at 20℃; |
|
| 91% |
With thionyl chloride; orthoformic acid triethyl ester at 20℃; |
|
| 87% |
With toluene-4-sulfonic acid |
|
| 86% |
With toluene-4-sulfonic acid at 20℃; for 3h; Inert atmosphere; |
S.1.1 ((3aR,4R,6R,6aR)-6-(6-amino-9H-purin-9-yl)-2,2- dimethyltetrahydrofuro[3,4-d][1 ,3]dioxol-4-yl)methanol (3)
Adenosine (2.0 g, 7.5 mmol) was stirred in acetone (400 mL) with para- toluene sulfonic acid monohydrate (14.3 g, 75 mmol) for three hours at room temperature under nitrogen. Upon completion, the reaction was basified with saturated sodium bicarbonate (400 mL) until the pH was slightly basic via litmus paper detection. The acetone was concentrated and the product was extracted from the aqueous layer using ethyl acetate (5 x 200 mL washes). The organic layer was washed with brine, dried over sodium sulfate and solvent removed in vacuo to yield a white solid (1.91 g, 86%).1H NMR (400 MHz, CD30D) δ 8.31 (s, 1H), 8.18 (s, 1H), 6.16-6.12 (d, J = 2.5 Hz, 1H), 5.29-5.24 (m, 1H), 5.05-5.01 (m, 1H), 4.39-4.34 (br, 1H), 3.81-3.75 (dd, J = 12.2 Hz, 2.5 Hz, 1H), 3.74-3.67 (dd, J = 12.2 Hz, 2.8 Hz, 1H), 1.61 (s, 3H), 1.37 (s, 3H); 13C NMR (100 MHz, CD30D) δ 155.9, 152.2, 148.5, 140.2, 119.1, 113.7, 91.3, 86.5, 83.7, 81.4, 62.0, 26.0, 24.0; LRMS (ESI): m/z [M+Na]+ calc'd for C13H17N5Na04+ 330.12, found 330.13. |
| 86% |
With toluene-4-sulfonic acid at 20℃; for 3h; Inert atmosphere; |
((3aR,4R,6R,6aR)-6-(6-amino-9H-purin-9-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methanol (4)
Adenosine (2.0 g, 7.5 mmol) was stirred in acetone (400 mL) with para-toluene sulfonic acid monohydrate (14.3 g, 75 mmol) for three hours at room temperature under nitrogen. Upon completion, the reaction was basified with saturated sodium bicarbonate (400 mL) until the pH was slightly basic via litmus paper detection. The acetone was concentrated and the product was extracted from the aqueous layer using ethyl acetate (5 x 200 mL washes). The organic layer was washed with brine, dried over sodium sulfate and solvent removedin vacuoto yield a white solid (1.91 g, 86%).1H NMR (400 MHz, CD3OD) δ 1.38 (s, 3H, COC(CH3)2), 1.62 (s, 3H, COC(CH3)2), 3.71 (dd,J= 12.0 and 2.8 Hz, 1H, 5’CH2), 3.79 (dd,J= 12.3 and 2.0 Hz, 1H, 5’CH2), 4.38 (s, 1H, 4’H), 5.04 (d,J= 4.4 Hz, 1H, 3’H), 5.24-5.31 (m, 1H, 2’H), 6.15 (d,J= 2.4 Hz, 1H, 1’H), 8.19 (s, 1H, C2-H), 8.32 (s, 1H, C8-H);13C NMR (100 MHz, CD3OD) δ 25.53, 27.60, 63.57, 82.97, 85.30, 88.10, 92.85, 115.26, 120.69, 141.73, 150.03, 153.77, 157.51; LRMS (ESI): m/z [M+Na]+calc’d for C13H17N5NaO4+330.12, found 330.13. |
| 85% |
With toluene-4-sulfonic acid at 20℃; for 6h; Cooling with ice; |
3.1 Synthesis of 2′,3′-O-isopropylideneadenosine
Adenosine (1 mmol of) was dissolved in 10 ~ 30ml (preferably 20 ml) of acetone, p-toluenesulfonic acid 8 ~ 12mmol (preferably 10 mmol) was dissolved in 10 ~ 30ml (preferably 20 ml) of acetone. Under ice cooling, p-toluenesulfonic acid in acetone was slowly added dropwise to a solution of 2-amino-adenosine in acetone, stirred at room temperature 24 ~ 72 h (preferably 6H), poured into ice 4% sodium hydrogencarbonate aqueous solution, a white precipitate, suction filtration, and dried. Soxhlet extraction with chloroform and purified to give a white powder after drying. Yield 85%. |
| 81% |
With perchloric acid at 20℃; for 5h; Inert atmosphere; |
|
| 79% |
With toluene-4-sulfonic acid at 20℃; for 50h; |
Synthesis of 2',3'-O-isopropylideneadenosine (2)
A mixture of adenosine (4.96 g, 18.56 mmol), p-toluenesulfonicacid monohydrate (3.53 g, 18.56 mmol) and acetone (150 mL) wasstirred at room temperature in an open vessel. After 46 h fromstarting reaction, 5.10 g of p-toluenesulfonic acid monohydratewas added. After 2 h, 5.21 g of p-toluenesulfonic acid monohydratewas added (total 13.94 g, 73.3 mmol). After 2 h from adding theacid, the spot of compound 1 disappeared. The mixture turned intoa yellow solution. The reaction mixture was quenched by adding12.3 mL of triethylamine (88.4 mmol, 4.73 eq.). The mixture wasevaporated and purified by column chromatography (chloroform/methanol 20:1) to give compound 2 (4.50 g, 14.6 mmol, 79%). 1HNMR (300 MHz, DMSO-d6) d 1.33 and 1.55 (2s, 6H, CMe2), 3.52-3.56 (m, 2H, H50), 4.19-4.23 (m, 1H, H40), 4.95-4.98 (m, 1H, H30), 5.25 (vbs, 1H, OH), 5.33-5.36 (m, 1H, H 20), 6.11-6.12 (m,1H,H 10), 7.34 (bs, 2H, NH2), 8.15 (s, 1H, H2), 8.34 (s, 1H, H8);ESI-TOF-MS for C13H17N5O4: (MNa+) calcd: 330.12, found: 330.03. |
| 78% |
Stage #1: propan-2-one; adenosine With perchloric acid at 20℃; for 1.5h;
Stage #2: With ammonia In lithium hydroxide monohydrate at 20℃; for 3h; |
|
| 78% |
With perchloric acid at 0 - 20℃; for 21h; |
|
| 77% |
Stage #1: propan-2-one; adenosine at 20 - 30℃; for 0.0833333h;
Stage #2: With perchloric acid at 20 - 30℃; for 1h; |
1 Example 1 : Acetonide protection
Adenosine 1 (100 g) and acetone (4 L, 40 v/w) were stirred for 5 minutes at 20-30 °C for 5 minutes. Perchloric acid (40 mL, 0.4 v/w) was added to the reaction mixture and stirred at 20-30 °C for 1 h, monitoring by UPLC. The reaction mass was quenched with 7 % sodium bicarbonate solution (1 L, 10 v/w) at 20-30 °C and cooled to -5 °C to 5 °C. The reaction mass was stirred for 1 hour. The obtained product was filtered, the filter cake was washed with acetone (200 mL, 2.0 v/w) and dried under vacuum for 8 h to yield compound 2.Yield: 89 g, 77 %HPLC purity: 97.96 % |
| 75% |
With toluene-4-sulfonic acid at 20℃; for 3h; |
|
| 73% |
With toluene-4-sulfonic acid Inert atmosphere; |
|
| 72% |
With toluene-4-sulfonic acid; orthoformic acid triethyl ester |
I.2
Preparation of adenosine 2',3'-Isopropylidene(Nucleic Acid Chemistry, part 2, Editors Townsend, Tipson, Wiley Interscience, John Wiley & Sons p. 768, (1978))Ethyl orthoformate (12.44 ml, 74.8 mmol) is added dropwise, under argon, to a suspension of adenosine (5 g, 18.7 mmol) in acetone (10 ml) containing APTS (para-toluene-sulfonic acid) (3.9 g, 20.6 mmol). After reaction overnight, 110 ml of water containing 1.86 ml of aqueous ammonia at 27% are added. After stirring for 30 minutes, the reaction mixture is evaporated until white crystals appear. After 12 h at +40° C., a white precipitate is obtained which is recrystallized in water. 4.17 g (13.5 mmol, 72%) of product is obtained in the form of a white powder. This intermediate was characterized by proton NMR. |
| 70.1% |
With Trimethyl orthoacetate; thionyl chloride at 20℃; for 6h; |
Synthesis of 2',3'-O-isopropylideneadenosine (14)
In a 250 mL, three-neck round-bottom flask were placedadenosine 2 (4.01 g, 15 mmol) and acetone (40 mL). Trimethylorthoacetate (6 mL) was added to the reactionmixture upon stirring and thionyl chloride (SOCl2, 3.3 mL)was added dropwise to the solution for acidification. Afteraddition of thionyl chloride, the mixture was stirred atroom temperature for another 6 h. After reaction completion,the mixture was filtered and the residue was addedinto saturated sodium bicarbonate solution to adjust the pHvalue to 7 or 8. After 30 min of standing, the crude productwas obtained by filtration and was dried at 50 C in avacuum drying oven. Recrystallization from water affordedpure 14 as a light yellow solid (3.23 g, 70.1%) with thepurity of 98.7% (HPLC). 1H NMR (500 MHz, DMSO-d6)d 8.35 (s, 1H, 2-H), 8.16 (s, 1H, 8-H), 7.40 (s, 2H, -NH2),6.13 (d, J = 3.1 Hz, 1H, 10-H), 5.35 (dd, J = 6.2, 3.1 Hz,1H, 20-H), 5.25 (s, 1H, 50-OH), 4.97 (dd, J = 6.2, 2.5 Hz,1H, 30-H), 4.23-4.21 (m, 1H, 40-H), 3.58-3.51 (m, 2H, 50-H), 1.55 (s, 3H, -CH3), 1.33 (s, 3H, -CH3).13C NMR(101 MHz, DMSO) d 156.60 (6-C), 153.10 (2-C), 149.25(4-C), 140.17 (8-C), 119.56 (5-C), 113.49 (quaternarycarbon), 90.09 (10-C), 86.80 (40-C), 83.67 (20-C), 81.82 (30-C), 62.05 (50-C), 27.54 (-CH3), 25.64 (-CH3). |
| 69% |
With perchloric acid; 4 A molecular sieve for 2h; Ambient temperature; |
|
|
unter Zusatz von ZnCl2; |
|
|
With DL-10-camphorsulphonic acid |
|
|
Stage #1: propan-2-one; adenosine With methanesulfonyl chloride for 0.5h;
Stage #2: With anhydrous sodium carbonate In lithium hydroxide monohydrate for 0.5h; |
1 2',3' isoproylidene adenosine
2',3' isoproylidene adenosine A 250 ml round bottom flask was charged with 10 gm adenosine and to it was added 100 ml acetone. Methanesulfonyl chloride (10 ml) was then added drop-wise to the above solution. The solution was stirred for 30 minutes, after which time 100 ml of 1M Na2CO3 was carefully added. This sample was stirred for another 30 minutes and the solution filtered. The filtrate was taken up in dichloromethane, washed with water, and dried. The organic solvent was removed to afford the 4.45 grams pure 2',3' isopropylidene adenosine as the product. |
|
With thionyl chloride; trimethyl orthoformate |
|
|
Stage #1: propan-2-one; adenosine With toluene-4-sulfonic acid In lithium hydroxide monohydrate
Stage #2: With orthoformic acid triethyl ester for 1h;
Stage #3: With potassium carbonate |
2
9 (3aR,4R,6R,6aR)-6-(aminomethyl)-2,2-dimethyltetrahydrofuro[3,4-d][l,3]dioxol-4- yl)-9H-purin-6-amineStep 1. Preparation of ((3aR,4R,6R,6aR)-6-(6-amino-9H-purin-9-yl)-2,2- dimethyltetrahydrofuro[3,4-d][l,3]dioxol-4-yl)methanol(2R,3R,4S,5R)-2-(6-amino-9H-purin-9-yl)-5-(hydroxymethyl)tetrahydrofuran-3,4- diol (200 g, 748 mmol) was suspended in dried acetone (5 L) containing p-toluenesulfonic acid monohydrate (400 g, 2 mol). Triethyl orthoformate (400 ml, 2.4mol) was then added over a period of 1 h at ambient temperature with vigorous stirring to give a clear solution and then a white solid formed after a while. The mixture was stirred overnight. The mixture was adjusted pH = 8 with saturated aqueous potassium carbonate. The precipitate was filtered off, the filtrate was evaporated and the residue was extracted with EA (1000 ml x 12). The combined organic phase was washed with saturated aqueous potassium carbonate (100 ml x 2) and water (200 ml), dried and concentrated. The crude was triturated (PE : EA = 10 : 1) to afford the target (190 g, yield: 85%) as a white solid. |
|
With thionyl chloride; trimethyl orthoformate |
It was prepared according to Scheme 1. To a suspension of adenosine (8.03 g, 30 mmol) in 100 mL dry acetone was added trimethyl orthoformate (2.4 mL), followed by SOCl2 (6.75 mL, 90 mmol) dropwise. After stirring overnight, the solid was filtered, dissolved in saturated NaHCO3, and neutralized to pH 7. The solid was collected by filtration, washed with ether (20 mL), and dried in vacuo to give 2′,3′-isopropylidene-N6-methyl-adenosine, to which (3.07 g, 10 mmol) in dry THF (20 mL) were added phthalimide (1.62 g, 11 mmol) and PPh3 (2.88 g, 11 mmol), followed by diisopropyl azodicarboxylate (DIAD, 1.08 g, 11 mmol). After 2.5 h, the white solid was filtered, washed with 20 mL of cold Et2O. The crude Mitsunobu product and hydrazine hydrate (2.4 mL, 50 mmol) were refluxed overnight in ethanol (20 mL). After cooling, the reaction mixture was filtered and the filtrate evaporated to dryness. To the product (612 mg, 2.0 mmol) in THF (5 mL) were added Et3N (0.9 mL, 6.4 mmol) and ethyl bromoacetate (0.28 mL, 2.5 mmol). After stirring overnight, the resulting mixture was filtered and evaporated to dryness. The residue oil thus obtained was dissolved in THF (10 mL) and cooled to -20° C., followed by addition of LiAlH4 (166 mg, 4.4 mmol). The reaction was allowed to warm to room temperature over 2.5 h, quenched with saturated NaHCO3, and the product was extracted with 50 mL of EtOAc, washed successively with saturated NaHCO3, water, and saturated NaCl. |
|
With phthalic acid dimethyl ester; toluene-4-sulfonic acid at 20℃; for 24h; Inert atmosphere; |
|
|
With sulfuric acid at 20℃; for 0.5h; |
|
|
With toluene-4-sulfonic acid at 20℃; |
|
|
With toluene-4-sulfonic acid In lithium hydroxide monohydrate at 20℃; for 1h; |
|
|
unter Zusatz von ZnCl2; |
|
|
With perchloric acid at 0℃; for 2h; |
26
To a suspension of adenosine in acetone at 0°C was added HC104 and stirring continued for 2h. Aq. NH3 was then added and the solution concentrated in vacuo. The solution was cooled to-20°C and the resulting white precipitate of 2'3'-O- isopropylidene-adenosine collected and washed with acetone |
|
With Dess-Martin periodane; toluene-4-sulfonic acid at 20℃; |
|
|
With perchloric acid |
Adenosine 5′-H-Phosphonate Synthesis
The synthesis approach for 135 can be seen in Scheme 4 (FIG. 4). First, adenosine was protected using a catalytic amount of perchloric acid in acetone to give 129. This was benzoylated at the 5′ position, as well as on the exocyclic amine, using benzoyl chloride (BzCl) in pyridine to afford 130. Here, it is also possible to form a compound with two Bz protecting groups on the exocyclic amine It was observed that this had started to form before the starting material was fully consumed, so the reaction was stopped. Varying conditions may be altered to optimize this procedure, including by moving forward with an adenosine compound obtaining three Bz protecting groups. Fully protected 130 then underwent acidic hydrolysis using dilute hydrochloric acid in dioxane to give 131. Again, this saw low crude yields. Compound 131 was selectively silylated at the 2′ position using tert-butyldimethylsilyl chloride and silver nitrate (AgNO3) in a mixture of pyridine and tetrahydrofuran. Compound 132 was then protected using dimethoxytrityl chloride in pyridine to give 133 with a crude yield of 88%, which was pushed forward to attempt the selective deprotection using 2N sodium hydroxide (NaOH) in pyridine and methanol which failed. Compound 133 should be purified before going forward to ensure a single, pure product to test the reaction with. As stated before, the scheme could be modified as in the case of guanosine to remove the need to use an isopropylidene protecting group on the 2′ and 3′ hydroxyls, which should reduce the number of steps used and increase the overall yields. |
|
With perchloric acid for 2h; Inert atmosphere; |
((3aR,4R,6R,6aR)-6-(6-amino-9H-purin-9-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methanol13 (S1)
Adenosine (1.0 g, 3.7 mmol) was suspended in 50 mL acetone under argon. Dropwise addition of 800 μL of HClO4 gavea clear solution. After 2 h the solution was treated with concentrated NH4OH until the pH was 7. The solvent was evaporated, and the product purified by flash chromatography using CH2Cl2/MeOH (95%). |
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With toluene-4-sulfonic acid; trimethyl orthoformate |
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Chemistry
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Material Science
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