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CAS No. : | 73-03-0 | MDL No. : | |
Formula : | C10H13N5O3 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | OFEZSBMBBKLLBJ-BAJZRUMYSA-N |
M.W : | 251.24 | Pubchem ID : | 6303 |
Synonyms : |
3'-Deoxyadenosine;NSC 63984;9(3DeoxyDribofuranosyl)adenine;3Deoxyadenosine;NSC 401022
|
Num. heavy atoms : | 18 |
Num. arom. heavy atoms : | 9 |
Fraction Csp3 : | 0.5 |
Num. rotatable bonds : | 2 |
Num. H-bond acceptors : | 6.0 |
Num. H-bond donors : | 3.0 |
Molar Refractivity : | 61.51 |
TPSA : | 119.31 Ų |
GI absorption : | High |
BBB permeant : | No |
P-gp substrate : | No |
CYP1A2 inhibitor : | No |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -8.27 cm/s |
Log Po/w (iLOGP) : | 1.07 |
Log Po/w (XLOGP3) : | -0.61 |
Log Po/w (WLOGP) : | -1.27 |
Log Po/w (MLOGP) : | -1.94 |
Log Po/w (SILICOS-IT) : | -1.48 |
Consensus Log Po/w : | -0.85 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 0.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -1.25 |
Solubility : | 14.1 mg/ml ; 0.0561 mol/l |
Class : | Very soluble |
Log S (Ali) : | -1.42 |
Solubility : | 9.47 mg/ml ; 0.0377 mol/l |
Class : | Very soluble |
Log S (SILICOS-IT) : | -0.4 |
Solubility : | 100.0 mg/ml ; 0.398 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 0.0 |
Synthetic accessibility : | 3.67 |
Signal Word: | Danger | Class: | 6.1 |
Precautionary Statements: | P261-P264-P270-P271-P280-P301+P310-P302+P352-P304+P340-P305+P351+P338-P312-P330-P362+P364-P403+P233-P405-P501 | UN#: | 2811 |
Hazard Statements: | H301-H315-H319-H335 | Packing Group: | Ⅲ |
GHS Pictogram: |
* 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 |
---|---|---|
With acetate buffer; Diaion WK-20 resin <Na(1+) form>; calcium chloride 1.) H2O, CHCl3, 45 deg C, 6 h, pH 5.6, 2.) CHCl3, MeOH, H2O; Yield given. Multistep reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | With pyridine; at 80℃; for 4h; | Example 22; Preparation of (2R,3R,5tS')-2-[6-amino-2-(cyclopentylamino)-9H-purin-9-yll-5-(hvdroxymethyl)tetrahydrofuran-3 -ol 21; Scheme 21; To a solution of 3'-deoxy adenosine (506mg, 2.01mmol) in pyridine (15mL) was added benzoyl chloride (1.5mL, 12.93mmol) and the resulting solution was refiuxed at 8O0C for 4h. This procedure was then repeated on the same scale and both batches were combined and the solvents were removed in vacuo. The residue was dissolved in EtOAc (10OmL) and washed with 0.2M aq. HCl (5OmL), aq. NaHCO3 (5OmL) and brine (5OmL), and the organic phase dried over MgSO4. Crystallisation from DCM/ethanol afforded 29 as a white crystalline solid (2.38g, 88%, >97% purity by HPLC). |
With pyridine; at 65℃; for 4h;Heating / reflux; | To a solution of 3'-deoxy-adenosine (leq) in pyridine was added benzoyl chloride (6eq) and the resulting solution was refluxed at 65C for 4h. The solvents were removed in vacuo and the residue dissolved in EtOAc and washed with water (x3) and brine, and the organic phase dried over MgS04. Purification using silica gel column chromatography afforded 3'-deoxy-tetrabenzoyl adenosine |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With 1H-imidazole; In dichloromethane; at 25℃; for 9h; | Compound 363l-(3-((((2S,4R,5R)-5-(6-amino-9H-purin-9-yl)-4-hydroxytetrahydrofuran-2- yl)methyl)(isopropyl)amino)propyl)-3-(4-(tert-butyl)phenyl)ureaStep I. Preparation (2R,3R,5S)-2-(6-amino-9H-purin-9-yl)-5-(((tert- butyldimethylsilyl)oxy)methyl)tetrahydrofuran-3-ol To a solution (2R,3R,5S)-2-(6-amino-9H-purin-9-yl)-5- (hydroxymethyl)tetrahydrofuran-3-ol (1.5 g, 6 mmol) and imidazole (680 mg, 10 mmol) in dried DMF (8 mL) was added TBSC1 (1.5 g, 10 mmol) and the solution was stirred at 25 C for 9 h. The reaction mixture was diluted with EA (100 mL) and washed with water (3 x 40 mL). The organic phase was dried over Na2S04 and concentrated to afford the title compound (1.48 g, yield: 74 ) as a white solid, which was used directly in the next step without further purification. 1H NMR (500 MHz, CDC13) delta 8.31 (s, 1H), 8.28 (s, 1H), 5.96 (d, J = 2.5 Hz, 1H), 5.88 (br s, 2H), 4.65-4.60 (m, 2H), 4.05-4.02 (m, 1H), 3.73 (dd, J = 2.5 Hz, 11.5 Hz, 1H), 2.34-2.30 (m, 1H), 2.11-2.08 (m, 1H), 0.89 (s, 9H), 0.11 (s, 6H); LC-MS (m/z): 366.2 [M+l]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | (2) Basic deacylation: To a 250 mL reaction flask, 15.0 g of Compound 5-1, 150 mL of methanol and 3.9 g of sodium hydroxide solid were added, and the reaction was stirred at 25 C for 1 h.5.4 g of solid ammonium chloride was added, stirred for 30 min, filtered, and the filtrate was spun dry and recrystallized to give 9.8 g of Compound 1 crystals, yield 87%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With 1H-imidazole; In N,N-dimethyl-formamide; at 20℃; for 4h;Cooling; | A 50 mL round-bottomed flask was charged with29c (0.430 g, 1.00 mmol) and dry EtOH (10 mL) and the mixture was cooled to -20 C. Then, a solutionof NH3 in MeOH (10 mL, 7 N) was added and the mixture was stirred for 48 h. After removalof all the volatiles in vacuo, the resulting crude residue was purified by silica gel chromatographyCH2Cl2/MeOH (7:3) to afford product 3'-deoxyadenosine (0.250 g) as a white solid in quantitative yield.1H-NMR (600 MHz, D2O): delta 8.26 (s, 1H, H-2), 8.14 (s, 1H, H-8), 6.01 (d, 1H, J = 2.2 Hz, H-1'), 4.76 (m, 2H,H-2', H-4'), 3.91 (dd, 2H, J = 12.6, 2.7 Hz, H-5), 3.71 (dd, 1H, J = 12.6, 4.5 Hz, H-5?), 2.28 (ddd, 1H,J = 13.6, 8.7, 5.7 Hz, H-3'), 2.20 (ddd, 1H, J = 13.6, 6.6, 3.2 Hz, H-3?); 13C-NMR (150MHz, D2O): delta 155.3 (6-C), 152.3 (2-C), 148.0 (4-C), 139.6 (8-C), 118.6 (5-CH), 90.8 (1'-CH), 81.1 (4'-CH), 74.8 (2'-CH),62.6 (5'-CH2), 32.9 (3'-CH2); HRMS for C10H13N5O3 [M + H+]+ Calc.: 252.1091, found: 252.1085.To a stirred mixture of 3'-deoxyadenosine (0.05 g, 0.25 mmol) and imidazole (0.070 g, 1.0 mmol) inanhydrous DMF (5 mL) was added TBDPSCl (0.275 g, 1.0 mmol) at -50 C. The reaction mixture wasallowed to warm to room temperature and stirred for 4 h. It was then diluted with EtOAc (100 mL) andwashed with water and brine. The organic layer was dried over Na2SO4, filtered, and concentratedin vacuo. The crude residue was then purified by silica gel column chromatography (EtOAc) toafford compound 30d (0.112 g, 92%) as a white solid. 1H-NMR (600 MHz, MeOD): delta 8.32 (s, 1H, H-2),8.18 (s, 1H, H-8), 7.67-7.32 (m, 10H, ArH), 6.02 (d, 1H, J = 1.5 Hz, H-1'), 4.71 (dt, 1H, J = 5.5, 1.6 Hz,H-2'), 4.57 (dddd, 1H, J = 8.9, 3.9, 2.8, 2.1 Hz, H-4'), 4.05 (dd, 1H, J = 11.6, 2.8 Hz, H-5'), 3.78 (dd, 1H,J = 11.7, 3.9 Hz, H-5?), 2.46 (ddd, 1H, J = 14.4, 8.9, 5.5 Hz, H-3'), 2.01 (ddd, 1H, J = 14.4, 5.6, 2.1 Hz, H-3?),1.28 (s, 9H, 3 CH3); 13C-NMR (150 MHz, MeOD): delta 157.3 (6-C), 153.8 (2-C), 150.0 (4-C), 140.3 (8-C),136.7 (ArC), 136.6 (ArC), 134.2 (ArC), 134.0 (ArC), 131.0 (ArC), 131.0 (ArC), 128.8 (ArC), 120.4 (5-CH),93.2 (10-CH), 82.7 (4'-CH), 77.0 (2'-CH), 66.0 (5'-CH2), 34.4 (3'-CH2), 31.6 (CCH3)3), 27.4 (CH3); HRMSfor C26H31N5O3Si1 [M + H+]+ Calc.: 490.2268, found: 490.2273. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With hydrogenchloride; adenosine deaminase In water at 45℃; for 5h; pH 6; | ||
With Sav2595 from Steptomyces avermitilis MA-4680; water at 30℃; for 16h; Enzymatic reaction; | ||
With mammalian adenosine deaminase Enzymatic reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With 1-butyl-3-methylimidazolium Tetrafluoroborate; at 50℃; for 6h;Sonication; Enzymatic reaction; | General procedure: A typical enzymatic acylation reaction was conducted in 20 mL of ILs with a specified aw value containing 4.0 mmol (1.0 g) of <strong>[73-03-0]cordycepin</strong>, 40.0 mmol of vinyl esters, and 3000 U of Novozym 435 at 50 ± 1 C under ultrasonic irradiation or shaking. Aliquots (20 lL) were withdrawn at specified time intervals from the reaction mixture, filtered through a 0.45-mum syringe filter to remove the biocatalyst, and then diluted 100 times with methanol prior to HPLC analysis. The HPLC analysis was conducted according to a method reported previously [8]. The retention times for <strong>[73-03-0]cordycepin</strong> and 50-acetyl <strong>[73-03-0]cordycepin</strong> were 2.81 and 5.69 min, respectively (ESI Figs. S1and S2). In the control reaction, which was performed using the above procedure without the enzyme, no chemical acylation reaction was detectable. All of the experiments were performed at least in triplicate, and the results are reported as the mean ± standard deviation. ;_ESI Table S1 ). 5'-acetyl <strong>[73-03-0]cordycepin</strong>: 1H NMR: H-2 (8.14, s, 1H), H-8 (8.27, s, 1H), -NH2 (7.28, s, 2H), 1'-H (5.90, d, J = 2.2 Hz, 1H), 2'-H (4.52, m, 1H), 2'-OH (5.77, d, J = 4.1 Hz, 1H), 3'-H (2.01, m, 1H; 2.29, m, 1H), 4'-H (2.06, m, 1H), 5'-H (4.27, m, 1H; 4.68, m, 1H); Acetyl: -CH3, 1.98, s, 3H. 13C NMR: C-2 152.4, C4 148.9, C 5 118.9, C6 156.0, C8 138.9, C1' 90.7, C2' 74.3, C 3' 34.7, C4' 77.4, C5' 65.0. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1: 90 percent / imidazole / dimethylformamide / 20 °C 2: 92 percent / dimethylformamide / 20 °C 3: 63 percent / (n-Bu)3SnH; AIBN / toluene / Heating 4: 94 percent / CF3CO2H / tetrahydrofuran / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
37% | With acetic acid; In ethanol; water;Heating / reflux; | A solution of <strong>[73-03-0]Cordycepin</strong> (leq), and thiol 1a-9a (3-4eq) 0.1 ml of aqueous formaldehyde' (37% w/v, 2. 8-3.6eq.) and glacial acetic acid in ethanol was heated under reflux for overnight. The products were concentrated under reduced pressure and 'chromatographed on a silica gel . AND ELUTED with CH2Cl2/Methanol (8. 5: 1.5 v/v). Evaporation of the appropriate fractions afforded <strong>[73-03-0]Cordycepin</strong> PRODRUG compounds lb-9b' as white power. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
12% | With 1-methyl-1H-imidazole; In tetrahydrofuran; at 20℃; for 16h; | Using General Procedure 1 above, N-methylimidazole (240 mu., 3.0 mmol) and a solution of (2,S)-benzyl 2-((chloro(naphthalen-l-yloxy)phosphoryl)amino)propanoate (727 mg, 1.8 mmol) in anhydrous THF (10 mL) were added dropwisely to a suspension of 3'-deoxyadenosine (150 mg, 0.6 mmol) in anhydrous THF and the reaction mixture was stirred at room temperature during a period of 16 hours. Purification by column chromatography (eluent system CH30H/CH2C12 0/100 to 6/94) and preparative TLC (2000 muMu, eluent system CH30H/CH2C12 5/95) afforded the desired compound as white solid (45 mg, 12%). MS (ES+) m/z: Found: 619.2 (M + H+), 641.2 (M + Na+), 1259.4 (2M + Na+) C30H31N6O7P required: (M) 618.58. 31P NMR (202 MHz, CH3OD): deltaRho 4 3 (s), 4 1 (s) NMR (500 MHz, CH3OD): deltaEta 8.24 (s, 0.5H, H8), 8.22 (s, 0.5H, H8), 8.20 (s, 0.5H, H2), 8.19 (s, 0.5H, H2), 8.14-8.09 (m, 1H, Ar), 7.89-7.85 (m, 1H, Ar), 7.70-7.67 (m, 1H, Ar), 7.53- 7.42 (m, 3H, Ar), 7.39-7.34 (m, 1H, Ar), 7.31-7.25 (m, 5H, Ar), 5.99 (d, J = 2.0 Hz, 0.5H, HI'), 5.98 (d, J = 2.0 Hz, 0.5H, HI'), 5.10-5.01 (m, 2H, CH2Ph), 4.72-4.61 (m, 2H, H2', H4'), 4.47- 4.40 (m, 1H, H5'), 4.33-4.24 (m, 1H, H5'), 4.09-3.98 (m, 1H, CH ala) 2.35-2.26 (m, 1H, H3'), 2.07-1.98 (m, 1H, H3'), 1.30-1.24 (m, 3H, CH3). 13C NMR (125 MHz, CH3OD): 6C 174.85 (d, 3Jc-p = 3.7 Hz, C=0), 174.56 (d, 3Jc-p = 3.7 Hz, C=0), 157.33 (C6), 157.31 (C6), 153.87 (C2), 153.85 (C2), 150.24 (C4), 150.23 (C4), 147.91 (d, 3Jc-p = 7.5 Hz, 'ipso' Nap), 147.95, (d, 3Jc-p = 7.5 Hz, 'ipso' Nap), 140.56 (C8), 140.50 (C8), 137.22 (C-Ar), 137.17 (C-Ar), 136.28 (C-Ar), 129.55 (CH-Ar), 129.53 (CH-Ar), 129.30 (CH- Ar), 129.25 (CH-Ar), 128.88 (CH-Ar), 128.82 (CH-Ar), 127.91 (d, 2Jc-p = 6.25 Hz, C-Ar), 127.83 (d, 2JC-p = 6.25 Hz, C-Ar), 127.77 (CH-Ar), 127.75 (CH-Ar), 127.49 (CH-Ar), 127.45 (CH-Ar), 126.48 (CH-Ar), 126.47 (CH-Ar), 126.02 (CH-Ar), 125.97 (CH-Ar), 122.77 (CH-Ar), 122.63 (CH-Ar), 120.58 (C5), 120.53 (C5), 116.35 (d, 3Jc-p = 3.75 Hz, CH-Ar), 116.15 (d, 3Jc-p = 3.75 Hz, CH-Ar), 93.22 (CI '), 93.20 (CI '), 80.30 (d, 3Jc-p = 2.75 Hz, C4'), 80.24 (d, 3Jc-p = 2.75 Hz, C4'), 76.51 (C2'), 76.44 (C2'), 68.87 (d, 2Jc-p = 5.2 Hz, C5'), 68.64 (d, 2Jc-p = 5.2 Hz, C5'), 67.93 (OCH2Ph), 51.82 (CH ala), 51.73 (CH ala), 35.01 (C-3'), 34.76 (C3'), 20.41 (d, 3Jc-p = 6.7 Hz, CH3 ala), 20.22 (d, 3JC-p = 6.7, CH3 ala). HPLC Reverse-phase HPLC eluting with H20/CH3CN from 100/10 to 0/100 in 30 minutes, lml/min, 1 = 200 nm, showed two peaks of the diastereoisomers with tR 16.36 min. and tR 16.60 min. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
11% | With tert-butylmagnesium chloride; In tetrahydrofuran; at 20℃; for 16h; | Using General Procedure 3 above, <strong>[73-03-0]3'-Deoxyadenosine</strong> (50 mg, 0.20 mmol) was suspended in anhydrous THF (5 mL) and TiuMgCl (1.0 M solution in THF, 0.3 mL, 0.3 mmol) was added dropwisely at room temperature. A solution of (2,S)-benzyl 2-((chloro(naphthalen-l- yloxy)phosphoryl)amino)propanoate (323 mg, 0.8 mmol) in anhydrous THF (2 mL) was added dropwisely and the reaction mixture was stirred at room temperature during a period of 16 hours. Purification by column chromatography (eluent system CH30H/CH2C12 0/100 to 6/94) and preparative TLC (500 muMu, eluent system CH30H/CH2C12 5/95) afforded the desired compound as a white solid (14 mg, 11 %). (ES+) m/z, found: 619.2 (M + H+), 641.2 (M + Na+), 1259.4 (2M + Na+). C30H31N6O7P required: (M) 618.20. 31P NMR (202 MHz, CH3OD): deltaRho 3 27 (s), 2 75 (s) NMR (500 MHz, CH3OD): deltaEta 8.37 (s, 1H, H8), 8.18 (s, 1H, H8), 8.14 (s, 1H, H2), 8.13- 8.11 (m, 0.5 H, Nap) 8.11 (s, 1H, H2), 7.94-7.90 (m, 0.5 H, Ar), 7.90-7.87 (m, 0.5 H, Ar), 7.86- 7.82 (m, 0.5 H, Ar), 7.74-7.70 (m, 0.5 H, Ar), 7.66-7.61 (m, 0.5 H, Ar), 7.57-7.47 (m, 1.5 H, Ar), 7.46-7.37 (m, 2.5 H, Ar), 7.34-7.27 (m, 4 H, Ar), 7.25-7.17 (m, 1 H, Ar), 6.19 (d, J = 2.4 Hz, 0.5H, HI'), 6.04 (d, J = 2.4 Hz, 0.5H, HI '), 5.60-5.54 (m, 0.5H, H2'), 5.50-5.42 (m, 0.5H, H2'), 5.16-4.99 (m, 2H, OCH2Ph), 4.46-4.40 (m, 0.5H, H4'), 4.36-4.30 (m, 0.5H, H4'), 4.13-4.04 (m, 1H, CH ala), 3.90-3.83 (m, 1H, H5'), 3.64-3.56 (m, 1H, H5'), 2.61-2.54 (m, 0.5H, H3'), 2.49- 2.41 (m, 0.5H, H3'), 2.35-2.27 (m, 0.5H, H3'), 2.22-2.16 (m, 0.5H, H3'), 1.35-1.24 (m, 3H, CH3 ala). 13C NMR (125 MHz, CH3OH): 6C 174.52 (C=0), 174.49 (C=0), 157.27 (C6), 153.58 (C2), 149.97 (C4), 149.93 (C-4), 147.70 (d, 3Jc-p = 7.5, 'ipso' Nap), 147.48 (d, 3Jc-p = 7.5, 'ipso' Nap), 141.36 (C8), 141.19 (C8), 137.25 (C-Ar), 137.05 (C-Ar), 136.31 (C-Ar), 136.20 (C-Ar), 129.58 (CH-Ar), 129.48 (CH-Ar), 129.37 (CH-Ar), 129.26 (CH-Ar), 129.22 (CH-Ar), 128.88 (CH-Ar), 127.84 (CH-Ar), 127.75 (CH-Ar), 127.49 (CH-Ar), 127.44 (CH-Ar), 126.48 (CH-Ar), 126.39 (CH-Ar), 126.26 (CH-Ar), 126.05 (CH-Ar), 122.76 (CH-Ar), 122.38 (CH-Ar), 120.68 (C5), 120.61 (C5), 116.64 (d, 3Jc-p = 3.75 Hz, CH-Ar), 116.13 (d, 3Jc-p = 3.75, CH-Ar), 91.60 (d, 3Jc-p = 7.5 Hz, CI '), 91.43 (d, 3Jc-p = 7.5 Hz, CI '), 82.74 (C4'), 82.27 (C4'), 81.99 (d, 2Jc-p = 5.5 Hz, C2'), 81.12 (d, 2JC-p = 5.5 Hz, C2'), 67.97 (OCH2Ph), 67.94 (OCH2Ph), 64.16 (C5'), 63.51 (C5'), 51.96 (CH ala), 51.89 (CH ala), 33.89 (d, 3Jc-p = 7.5 Hz, CH3 ala), 33.63 (d, 3Jc-p = 7.5 Hz, CH3 ala). HPLC Reverse-phase HPLC eluting with H20/CH3OH from 100/10 to 0/100 in 30 minutes, lml/min, 1 = 200 nm, showed two peaks of the diastereoisomers with tR 24.84 min. and tR 25.43 min. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
19% | With 1-methyl-1H-imidazole; In tetrahydrofuran; at 20℃; for 16h; | Using General Procedure 1 above, /V-methylimidazole (80 muL, 1.0 mmol) and a solution of benzyl 2-((chloro(phenoxy)phosphoryl)amino)acetate (204 mg, 0.6 mmol) in anhydrous THF (2 mL) were added dropwisely to a suspension of 3'-deoxyadenosine (50 mg, 0.20 mmol) in anhydrous THF and the reaction mixture was stirred at room temperature for 16 hours. Purification by column chromatography (eluent system CH3OH/CH2CI2 0/100 to 6/94) and preparative TLC (500 muMu, eluent system CH3OH/CH2CI2 5/95) afforded the desired compound as a white solid (21 mg, 19 %). (ES+) m/z, found: 555.2 (M + H+), 577.2 (M + Na+), 1131.4 (2M + Na+). C25H27N6O7P required: (M) 554.2. 31P NMR (202 MHz, CH3OD) delta 5 1, 4 9 *H NMR (500 MHz, CH3OD) delta 8.27 (s, 0.5H, H8), 8.24 (s, 0.5H, H8), 8.22 (s, 0.5H, H2), 8.21 (s, 0.5H, H2), 7.37-7.26 (m, 7H, Ph), 7.22-7.13 (m, 3H, Ph), 6.02 (d, J= 1.8 Hz, 0.5H, HI '), 6.00 (d, J = 1.8 Hz, 0.5H, HI '), 5.14-5.11 (m, 2H, OCH2Ph), 4.73-4.64 (m, 2H, H2', H4'), 4.50-4.39 (m, 1H, H5'), 4.36-4.24 (m, 1H, H5'), 3.53-3.71 (m, 2H, CH2 gly), 2.39-2.25 (m, 1H, H3'), 2.13- 2.02 (m, 1H, H3'). 13C NMR (125 MHz, CH3OD) delta 172.30 (d, 5JC-p = 5.0 Hz, C=0), 172.27 (d, 5JC-p = 5.0 Hz, C=0), 157.34 (C6), 157.32 (C6), 153.88 (C2), 153.87 (C2), 152.08 (d, 5JC-p = 7.5 Hz, C-Ar), 152.05 (d, 5JC-p = 7.5 Hz, C-Ar), 150.20 (C4), 150.19 (C4), 140.52 (C8), 140.42 (C8), 137.15 (C- Ar), 130.79 (CH-Ar), 129.57 (CH-Ar), 129.55 (CH-Ar), 129.35 (CH-Ar), 129.34 (CH-Ar), 129.33 (CH-Ar), 126.22 (CH-Ar), 121.44 (d, Jc-p = 3.7 Hz, CH-Ar), 121.40 (d, Jc-p = 3.7 Hz, CH-Ar), 120.51 (C5), 120.49 (C5), 93.19, 93.14 (CI '), 80.46 (d, 3Jc-p = 4.60 Hz, C4'), 80.39 (d, 3Jc-p = 4.60, C4'), 76.66 (C2'), 68.68 (d, 2Jc-p = 5.42 Hz, C5'), 68.24 (d, 2Jc-p = 5.42 Hz, C5'), 67.95 (OCH2Ph), 67.93 (OCH2Ph), 43.90 (CH2 gly), 43.83 (CH2 gly), 34.83 (C3'), 34.54 (C3'). HPLC Reverse-phase HPLC eluting with H2O/CH3CN from 100/10 to 0/100 in 30 minutes, lml/min, 1 = 200 nm, showed two peaks of the diastereoisomers with tR 13.63 min. and tR 13.41 min. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
22% | With 1-methyl-1H-imidazole; In tetrahydrofuran; at 20℃; for 16h; | Using General Procedure 1 above, N-methylimidazole (76 mu^, 0.95 mmol) and a solution of (2,S)-pentyl 2-((chloro(naphthalen-l-yloxy)phosphoryl)amino)-4-methylpentanoate (250 mg, 0.6 mmol) in anhydrous THF (1 mL) were added dropwisely to a suspension of 3 '-deoxy adenosine (48 mg, 19 mmol) in anhydrous THF (5 mL) and the reaction mixture was stirred at room temperature during a period of 16 hours. Purification by column chromatography (eluent system CH3OH/CH2CI2 0/100 to 5/95) and preparative TLC (1000 muMu, eluent system CH3OH/CH2CI2 4/96) afforded the desired compound as a white solid (27 mg, 22 %). MS (ES+) m/z: Found: 641.3 (M + H+), 663.3 (M + Na+), 1303.6 (2M + Na+) C31H41N6O7P required: (M) 640.3. 31P NMR (202 MHz, CH3OD) delta 4 64, 4 37 JH NMR (500 MHz, CH3OD) delta 8.28 (s, 0.5H, H-8), 8.25 (s, 0.5H, H-8), 8.21 (s, 0.5H, H-2), 8.20 (s, 0.5H, H-2), 8.17-8.12 (m, 1H, Nap), 7.88-7.83 (m, 1H, Nap), 7.69-7.66 (m, 1H, Nap), 7.54-7.42 (m, 3H, Nap), 7.40-7.35 (m, 1H, Nap), 7.31-7.26 (m, 5H, Ar), 6.01 (d, J = 2.1 Hz, 0.5H, HI '), 6.00 (d, J = 2.1 Hz, 0.5H, HI '), 4.47-4.67 (m, 2H, H2', H4'), 4.55-4.44 (m, 1H, H5'), 4.43-4.31 (m, 1H, H5'), 4.00-3.87 (m, 3H, CH leu, CH2 Pen), 2.44-2.30 (m, 1H, H3'), 2.14-2.04 (m, 1H, H3'), 1.66-1.39 (m, 5H, CH2CH leu, CH2 Pen), 1.1.28-1.21 (m, 4H, CH2CH2 Pen), 0.86-0.81 (m, 3H, CH3 Pen), 0.81-0.68 (m, 6H, (CH3)2 leu). 13C NMR (125 MHz, CH3OD) delta 175.42 (d, 3Jc-p = 2.5 Hz, C=0), 175.04 (d, 3Jc-p = 2.5 Hz, C=0), 157.32 (C6), 153.87 (C2), 153.86 (C2), 150.23 (C4), 147.97 (d, 3Jc-p = 6.2 Hz, 'ipso' Nap), 140.55 (C8), 136.30 (C-Ar), 136.29 (C-Ar), 128.89 (CH-Ar), 128.84 (CH-Ar), 127.95 (C- Ar), 127.91 (C-Ar), 127.84 (C-Ar), 127.78 (CH-Ar), 127.76 (CH-Ar), 127.46 (CH-Ar), 126.50 (C-Ar), 126.48 (C-Ar), 126.46 (C-Ar), 126.01 (CH-Ar), 125.91 (CH-Ar), 122.80 (CH-Ar), 122.70 (CH-Ar), 120.58 (C5), 120.56 (C5), 1 16.40 (d, 3Jc-p = 3.7 Hz, CH-Ar), 1 16.01 (d, 3Jc-p = 3.7 Hz, CH-Ar), 93.31 (CI '), 93.27 (CI '), 80.35 (d, 3Jc-p = 3.5 Hz, C4'), 80.29 (d, 3Jc-p = 3.5 Hz, C4'), 76.54 (C2'), 76.50 (C2'), 69.07 (d, 2Jc-p = 5.5 Hz, C5'), 68.85 (d, 2Jc-p = 5.5 Hz, C5'), 66.33 (CH2 Pent), 66.32 (CH2 Pent), 54.81 (CH leu), 54.71 (CH leu), 44.22 (d, 3Jc-p = 7.6 Hz, CH2 leu), 43.93 (d, 3Jc-p = 7.6 Hz, CH2 leu), 35.15 (C3 '), 34.86 (C3 '), 29.32 (CH2 pent), 29.30 (CH2 Pent), 29.1 1 (CH2 pent), 25.67 (CH leu), 25.45 (CH leu), 23.30 (CH2 pent), 23.12 (CH3 leu), 23.02 (CH3 leu), 22.04 (CH3 leu), 21.78 (CH3 leu), 14.28 (CH3 pent). HPLC Reverse-phase HPLC eluting with H20/CH3CN from 100/10 to 0/100 in 30 minutes, lml/min, 1 = 200 nm, showed one peak of the two overlapping diastereoisomers with tR 20.84 min. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
6% | With 1-methyl-1H-imidazole; In tetrahydrofuran; at 20℃; for 16h; | Using General Procedure 1 above, N-methylimidazole (24 pL, 3.0 mmol) and a solution of methyl 2-((chloro(naphthalen-l-yloxy)phosphoryl)amino)-2-methylpropanoate (612 mg, 1.8 mmol) in anhydrous THF (1 mL) were added dropwisely to a suspension of 3 '-deoxy adenosine (150 mg, 0.6 mmol) in anhydrous THF (15 mL) and the reaction mixture was stirred at room temperature during a period of 16 hours. Purification by column chromatography (eluent system CH30H/CH2C12 0/100 to 7/93) and preparative TLC (1000 muMu, eluent system CH30H/CH2C12 4/96) afforded the desired compound as a white solid (20 mg, 6%). MS (ES+) m/z: Found: 557.2 (M + H+), 579.2 (M + Na+), 1 135.4 (2M + Na+) C25H29N6O7P required: (M) 556.51. 31P NMR (202 MHz, CH3OD) delta 2 73 NMR (500 MHz, CH3OD) delta 8.28 (s, 0.5H, H8), 8.25 (s, 0.5H, H8), 8.21 (s, 0.5H, H2), 8.19 (s, 0.5H, H2), 8.18-8.14 (m, 1H, Nap), 7.90-7.84 (m, 1H, Nap), 7.71-7.66 (m, 1H, Nap), 7.53- 7.47 (m, 3H, Nap), 7.41-7.35 (m, 1H, Nap), 6.03 (d, J = 2. 1 Hz, 0.5H, HI '), 5.99 (d, J = 2. 1 Hz, 0.5H, HI '), 4.76-4.67 (m, 2H, H2', H4'), 4.52-4.44 (m, 1H, H5'), 4.42-4.33 (m, 1H, H5'), 3.65 (s, 1.5H, OCH3), 3.64 (s, 1.5H, OCH3), 2.48-2.41 (m, 0.5H, H3 '), 2.37-2.30 (m, 0.5H, H3'), 2.15-2.09 (m, 0.5H, H3 '), 2.08-2.02 (m, 0.5H, H3 '), 1.47-1.44 (m, 6H, CH3). 13C NMR (125 MHz, CH3OD) delta 177.25 (d, 3Jc-p = 3.7 Hz, C=0), 157.53 (C6), 157.51 (C6), 153.86 (C2), 150.28 (C4), 150.25 (C4), 148.06 (d, 3JC-P = 7.5 Hz, 'ipso' Nap), 148.04 (d, 3JC-P = 7.5, 'ipso' Nap), 140.67 (C8), 140.60 (C8), 136.28 (C-Ar), 136.27 (C-Ar), 128.82 (CH-Ar), 128.80 (CH-Ar), 127.93 (d, 2Jc-p = 6.25 Hz, C-Ar), 127.92 (d, 2 Jc-p = 6.25 Hz, C-Ar), 127.71 (CH-Ar), 127.69 (CH-Ar), 127.32 (CH-Ar), 126.44 (CH-Ar), 125.84 (CH-Ar), 122.93 (CH-Ar), 120.56 (C5), 120.50 (C5), 1 16.38 (d, 3Jc-p = 3.75 Hz, CH-Ar), 1 16.36 (d, 3Jc-p = 3.75 Hz, CH- Ar), 93.25 (CI '), 80.40 (d, 3Jc-p = 8.0 Hz, C4'), 80.33 (d, 3Jc-p = 8.0 Hz, C4'), 76.57 (C2'), 76.43 (C2'), 68.99 (d, 2Jc-p = 5.5 Hz, C5'), 68.84 (d, 2Jc-p = 5.5 Hz, C5'), 53.01 (OCH3), 35.22 (C-3'), 34.90 (C3 '), 27.85 (d, 3Jc-p = 6.0 Hz, CH3), 27.80 (d, 3Jc-p = 6.0, CH3), 27.60 (d, 3Jc-p = 6.0, CH3), 27.56 (d, 3Jc-p = 6.0, CH3). HPLC Reverse-phase HPLC eluting with H2O/CH3CN from 100/10 to 0/100 in 30 minutes, lml/min, 1 = 254 nm, showed two peaks with tR 16.51 min, tR 16.75 min. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
22% | With 1-methyl-1H-imidazole; In tetrahydrofuran; at 20℃; for 16h; | Using General Procedure 1 above, N-methylimidazole (32 mu^, 4.2 mmol) and a solution of (2,S)-benzyl 2-((chloro(2-(3-ethoxy-3-oxopropyl)phenoxy)phosphoryl)amino)propanoate (1.14 g, 2.5 mmol) in anhydrous THF (2 mL) were added dropwisely to a suspension of 3 '- deoxyadenosine (210 mg, 0.84 mmol) in anhydrous THF (10 mL) and the reaction mixture was stirred at room temperature during a period of 16 hours. Purification by column chromatography (eluent system CH3OH/CHCI3 0/100 to 8/92) and preparative TLC (1000 muMu, eluent system CH3OH/CH2CI2 5/95) afforded the desired compound as a white solid (123 mg, yield = 22%). MS (ES+) m/z: Found: 669.3 (M + H+), 691.3 (M + Na+), C31H37N6O9P required: (M) 668.63. 31P NMR (202 MHz, CH3OD): deltaRho 3 95, 3.65. NMR (500 MHz, CH3OD): deltaEta 8.25 (s, 0.5H, H8), 8.21 (s, 1H, H8, H2), 8.20 (s, 0.5H, H2), 7.35-7.29 (m, 6H, Ph), 7.25-7.21 (m, 1H, Ph), 7.16-7.07 (m, 2H, Ar), 6.00 (d, J = 1.9 Hz, 0.5H, HI '), 5.98 (d, J = 1.9 Hz, 0.5H, HI '), 5.17-5.05 (m, 2H, OCH2Ph), 4.76-4.73 (m, 0.5H, H2'), 4.70-4.59 (m, 1.5H, H2', H4'), 4.45-4.34 (m, 1H, H5'), 4.30-4.22 (m, 1H, H5'), 4.08-3.96 (m, 3H, CH2CH3, CH ala), 2.98-2.92 (m, 2H, CH2CH2), 2.62-2.56 (m, 2H, CH2CH2), 2.40-2.29 (m, 1H, H3'), 2.11-2.03 (m, 1H, H3'), 1.36 (d, J = 6.9 Hz, 1.5 H, CH3 ala), 1.33 (d, J = 6.9 Hz, 1.5 H, CH3 ala), 1.17 (t, J = 7.0 Hz, 1.5 H, CH2CH3), 1.16 (t, J = 7.0 Hz, 1.5 H, CH2CH3). 13C NMR (125 MHz, CH3OD): 6C 174.82 (d, 5JC-p = 3.7 Hz, C=0), 174.62 (C=0), 174.58 (C=0), 174.55 (d, 5JC-p = 3.7 Hz, C=0), 157.34 (C6), 157.32 (C6), 153.86 (C2), 153.84 (C2), 150.48 (d, Jc-p = 2.5 Hz, C-Ar), 150.44 (C4), 150.22 (d, Jc-p = 2.5 Hz, C-Ar), 140.49 (C8), 137.29 (C-Ar), 137.21 (C-Ar), 133.09 (d, J = 7.5 Hz, C-Ar), 132.94 (d, J = 7.5 Hz, C-Ar), 131.62 (CH-Ar), 131.59 (CH-Ar), 129.58 (CH-Ar), 129.34 (CH-Ar), 129.31 (CH-Ar), 129.28 (CH-Ar), 128.70 (d, J= 5.0 Hz, CH-Ar), 128.69 (d, J= 5.0 Hz, CH-Ar), 126.18 (CH-Ar), 121.02 (d, J = 2.5 Hz, CH-Ar), 120.49 (d, J = 2.5 Hz, CH-Ar), 120.58 (C5), 93.28 (CI '), 93.24 (CI '), 80.32 (d, 3JC-p = 8.7 Hz, C4'), 76.57 (C2'), 68.86 (d, 2Jc-p = 5.0 Hz, C5'), 68.53 (d, 2Jc-p = 5.0 Hz, C5'), 67.98 (OCH2Ph), 67.95 (OCH2Ph), 61.57 (CH2CH3), 51.76 (CH ala), 51.65 (CH ala), 35.37 (CH2CH2), 35.30 (CH2CH2), 35.08 (C3'), 34.85 (C3'), 26.77 (CH2CH2), 26.72 (CH2CH2), 20.55 (d, 3JC-p = 6.2 Hz, CH3 ala), 20.33 (d, 3Jc-p = 6.2 Hz, CH3 ala), 14.53 (CH2CH3). HPLC Reverse-phase HPLC eluting with H20/CH3CN from 100/10 to 0/100 in 30 minutes, lml/min, 1 = 245 nm, showed one peak with tR 15.99 min. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
49% | Using General Procedure 2 above, 3 '-deoxyadenosine (200 mg, 0.80 mmol) was suspended in (CH3)3P03 (5 mL), and POCl3 (75 mu., 0.80 mmol) was added dropwise at -5 C. The reaction mixture was allowed to reach room temperature and left stirring for 4 hours. A solution of (S)-l- (benzyloxy)-l-oxopropan-2-aminium 4-methylbenzenesulfonate (1.4 g, 4.0 mmol) dissolved in anhydrous CH2CI2 (5 mL) was added followed by diisopropyl ethyl amine (1.4 mL, 8.0 mmol) at -78 C. After stirring at room temperature for 20 hours, water was added and the layers were separated. The aqueous phase was extracted with dichloromethane and the organic phase washed with brine. The combined organic layers were dried over Na2S04 and concentrated. The residue was purified by column chromatography (gradient elution of CH2Cl2/MeOH= 100/0 to 93/7) to give a white foam (256 mg, 49%). MS (ES+) m/z: Found: 654.2 (M + H+), 676.2 (M + Na+), 1329.5 (2M + Na+) C30H36N7O8P required: (M) 653.62. 31P NMR (202 MHz, CH3OD) 6 13 9 *H NMR (500 MHz, CH3OD) delta 8.28 (s, 1H, H8), 8.22 (s, 1H, H2), 7.37-7.26 (m, 10H, Ph), 6.00 (d, J = 1.9 Hz, 1H, HI '), 5.15-5.05 (m, 4H, OCH2Ph), 4.74-4.70 (m, 1H, H2'), 4.63-4.56 (m, 1H, H4'), 4.24-4.18 (m, 1H, H5'), 4.1 1-4.05 (m, 1H, H5'), 3.97-3.87 (m, 1H, CH ala), 2.35- 2.27 (m, 1H, H3'), 2.07-2.01 (m, 1H, H3'), 1.34-1.27 (m, 3H, CH3 ala). 13C NMR (125 MHz, CH3OD) delta 175.40 (d, 5JC-p = 5.0 Hz, C=0), 175.36 (d, 5JC-p = 5.0 Hz, C=0), 157.36 (C6), 153.91 (C2), 150.25 (C4), 140.64 (C8), 137.33 (C-Ar), 137.29 (C-Ar), 129.58 (CH-Ar), 129.57 (CH-Ar), 129.33 (CH-Ar), 129.31 (CH-Ar), 129.29 (CH-Ar), 120.55 (C5), 93.18 (CI '), 80.67 (d, 3Jc-p = 8.4 Hz, C4'), 76.59 (C2'), 67.90 (OCH2Ph), 67.47 (d, 2Jc-p = 5.2 Hz, C5'), 51.14 (d, 2Jc-p = 1.7 Hz, CH ala), 51.1 1 (d, 2Jc-p = 1.7 Hz, CH ala), 35.08 (C3 '), 20.77 (d, 3JC-p = 6.5 Hz, CH3 ala), 20.59 (d, 3Jc-p = 6.5 Hz, CH3 ala). HPLC Reverse-phase HPLC eluting with H20/CH3CN from 90/10 to 0/100 in 30 minutes, lml/min, 1 = 254 nm, showed one peak with tR 13.87 min |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
13% | With 1-methyl-1H-imidazole; In tetrahydrofuran; at 20℃; for 16h; | N-methylimidazole (240 muL, 5 mmol) and a solution of (2,S)-isopropyl 2- ((chloro(phenoxy)phosphoryl)amino)propanoate (546 mg, 3 mmol) in anhydrous TFIF (5 mL) were added dropwisely to a suspension of (2R,3R,5,S)-2-(6-amino-9H-purin-9-yl)-5- (hydroxymethyl)tetrahydrofuran-3-ol (150 mg, 0.6 mmol) in anhydrous TFIF (3 mL) and the reaction mixture was stirred at room temperature during a period of 16 hours. Purification by column chromatography (eluent system CH3OH/CH2CI2 0/100 to 6/94) and preparative TLC (2000 muGammaomicroneta, eluent system CH3OH/CH2CI2 5/95) afforded the desired compound as white solid (40 mg, 13%). MS (ES+) m/z: Found: 521.2 (M + H+), 543.3 (M + Na+), 1063.4 (2M + Na+) C31H33N6O8P required: 520.18(M). 31P NMR (202 MHz, CD3OD): deltaRho 3 99 (s), 3 82 (s) NMR (500 MHz, CD3OD): deltaEta 8.16 (s, 0.5H, H8), 8.15 (s, 0.5H, H8), 8.11 (s, 1H, H-2) 7.23-7.20 (m, 2H, Ph), 7.11-7.03 (m, 3H, Ph), 5.91 (d J = 2.0Hz, 0.5H, HI '), 5.90 (d J = 2.0Hz, 0.5H, HI '), 4.85-4.79 (m, 1H, CH(CH3)2, 4.64-4.63 (m, 1H, H4'), 4.60-6.57 (m, 1H, H2'), 4.37- 4.33 (m, 1H, H5'), 4.31-4.28 (m, 1H, H5'), 3.74-4.22-4.17 (m, 1H, H5'), 3.70 (m, 1H, CH ala), 2.02-1.97 (m, 1H, H3'), 2.04-2.01 (m, 1H, H3'), 1.18-1.14 (m, 3H, CH3), 1.24 (m,6H, CH(CH3)2) HPLC Reverse-phase HPLC eluting with H2O/CH3CN from 100/10 to 0/100 in 30 minutes, F =lml/min, lambda = 200 nm, showed two peaks of the diastereoisomers with tR 11.58 min. and tR 11.92 min. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
28% | With 1-methyl-1H-imidazole; In tetrahydrofuran; at 20℃; for 16h; | General procedure 1 (For compounds A-F and L-U) N-methylimidazole (1.0 mmol) and a solution of the appropriate phosphorochloridate (0.6 mmol) in anhydrous TFIF (2 mL) were added dropwisely to a suspension of 3'-deoxyadenosine (0.20 mmol), or of the substituted 3'-deoxyadenosine, in anhydrous TFIF (10 mL) and the reaction mixture was stirred at room temperature during a period of 16 hours. Purification by column chromatography and preparative TLC afforded the desired compound as a white solid.Compound A was prepared according to the General Procedure 1 using 3'-deoxyadenosine (50 mg, 0.20 mmol), N-methylimidazole (80 L, 1.0 mmol) and phenyl(benzyloxy-L-alaninyl) phosphorochloridate (212 mg, 0.6 mmol). Purification by column chromatography (eluent system CH30H/CH2C12 0/100 to 7/93) with gradient of CH2Cl2/MeOH (100% to 95:5%) and preparative TLC (1000 mupiiota, eluent system CH30H/CH2C12 5/95) afforded the title compound as a white solid (31 mg, 28 %). NMR (500 MHz, CD3OD): deltaEta 8.26 (s, 0.5H, H8), 8.24 (s, 0.5H, H8), 8.22 (s, 0.5H, H2), 8.21 (s, 0.5H, H2), 7.34-7.25 (m, 7H, Ar), 7.21-7.13 (m, 3H, Ar), 6.01 (d, J = 2.9 Hz, 1H, HI '), 6.00 (d, J = 2.9 Hz, 1H, HI'), 5.15-5.04 (m, 2H, OCftPh), 4.73-4.63 (m, 2H, H2', H4'), 4.43- 4.35 (m, 1H, H5'), 4.27-4.20 (m, 1H, H5'), 4.03-3.91 (m, 1H, CHCH3), 2.35-2.28 (m, 1H, H3'), 2.09-2.02 (m, 1H, H3'), 1.32 (d, J= 7.4 Hz, 1.5 H, CHC%), 1.28 (d, J= 7.4 Hz, 1.5 H, CHC%). 13C NMR (125 MHz, CD3OD): 6C 174.84 (d, 3Jc-p = 4.5 Hz, C=0), 174.63 (d, 3Jc-p = 4.5 Hz, C=0), 157.32 (C6), 157.31 (C6), 153.86 (C2), 153.84 (C2), 152.13 (C4), 152.07 (C4), 150.20 (C-Ar), 150.18 (C-Ar), 140.47 (C8), 137.26 (C-Ar), 137.19 (C-Ar), 130.76 (CH-Ar), 130.74 (CH-Ar), 129.57 (CH-Ar), 129.32 (CH-Ar), 129.31 (CH-Ar), 129.29 (CH-Ar), 129.26 (CH-Ar), 126.16 (CH-Ar), 126.14 (CH-Ar), 121.46 (d, 3Jc-e = 4.7 Hz, CH-Ar), 121.38 (d, 3Jc-p = 4.7 Hz, CH-Ar) 120.54 (C5), 120.53 (C5), 93.24 (CI '), 93.18 (CI '), 80.43 (d, 3Jc-p = 3.6 Hz, C4'), 80.36 (d, 3JC-p = 3.6 Hz, C4'), 76.62 (C2'), 68.62 (d, 2Jc-p = 5.3 Hz, C5'), 68.30 (d, 2Jc-p = 5.3 Hz, C5'), 67.95 (OCHiPh), 67.92 (OCH2Ph), 51.74 ( HCH3), 51.60 ( HCH3), 34.91 (C3'), 34.70 (C3'), 20.45 (d, 3JC-p = 7.0 Hz, CHCH3), 20.28 (d, 3Jc-p = 7.0 Hz, CHCH3). 31P NMR (202 MHz, CD3OD): deltaRho 3 9, 3 7 MS (ES+) m/z: Found: 569.2 (M + H+), 591.2 (M + Na+), 1159.4 (2M + Na+) C26H29N6O7P required: (M) 568.2. HPLC Reverse-phase HPLC eluting with H20/CH3CN from 100/10 to 0/100 in 30 minutes, lml/min, 1 = 254 nm, showed two peaks of the diastereoisomers with tR 14.02 min. and tR 14.26 min. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
5% | With tert-butylmagnesium chloride; In tetrahydrofuran; at 20℃; for 16h; | Using General Procedure 3 above, 3'-deoxyadenosine (50 mg, 0.20 mmol) was suspended in anhydrous THF (5 mL) and 'BuMgCl (1.0 M solution in THF, 0.22 mL, 0.22 mmol) was added dropwisely at room temperature. A solution of (2,S)-benzyl 2- ((chloro(phenoxy)phosphoryl)amino)propanoate (212 mg, 0.6 mmol) in anhydrous THF (2 mL) was added dropwisely and the reaction mixture was stirred at room temperature during a period of 16 hours. Purification by column chromatography (eluent system CH3OH/CH2CI2 0/100 to 8/92) and preparative TLC (500 muMu, eluent system CH3OH/CH2CI2 = 5/95) afforded the desired compound as a white solid (6 mg, 5%). MS (ES+) m/z: Found: 569.2 (M + H+), 591.2 (M + Na+), 1159.4 (2M + Na+) C26H29N6O7P required: (M) 568.2. 31P NMR (202 MHz, CH3OD): deltaRho 2 44 (s), 2 92 (s) JH NMR (500 MHz, CH3OD): deltaEta 8.41 (s, 0.5 H, H8), 8.28 (s, 0.5 H, H8), 8.19 (s, 0.5H, H2), 8.18 (s, 0.5H, H2), 7.39-7.30 (m, 4H, Ar), 7.28-7.18 (m, 4H, Ar), 7.17-7.11 (m, 1H, Ar), 7.08- 7.03 (m, 1H, Ar), 6.23 (d, J = 2.0 Hz, 0.5H, HI'), 6.08 (d, J = 3.4 Hz, 0.5H, HI '), 5.52-5.43 (m, 1H, C2'), 5.19-5.12 (m, 1H, CH2Ph), 5.07-4.95 (m, 1H, CH2Ph), 4.48-4.42 (m, 1H, H4'), 4.05- 3.97 (m, 1H, CH ala), 3.95-3.87 (m, 1H, H5'), 3.69-3.61 (m, 1H, H5'), 2.59-2.45 (m, 1H, H3'), 2.31-2.23 (m, 1H, H3'), 1.36-1.27 (m, 3H, CH3 ala). 13C NMR (125 MHz, CH3OH): 6C 174.76 (d, 3Jc-p = 5.0 Hz, C=0), 174.52 (d, 3Jc-p = 5.0 Hz, C=0), 157.44 (C6), 153.76 (C2), 151.93 (C4), 150.06 (C-Ar), 149.93 (C-Ar), 141.38 (C8), 141.18 (C8), 137.33 (C-Ar), 137.10 (C-Ar), 130.69 (CH-Ar), 130.79 (CH-Ar), 129.61 (CH-Ar), 129.51 (CH-Ar), 129.40 (CH-Ar), 129.30 (CH-Ar), 129.23 (CH-Ar), 126.33 (CH-Ar), 126.16 (CH-Ar), 121.53 (d, 3Jc-p = 4.5 Hz, CH-Ar), 121.20 (d, 3Jc-p = 4.5 H, CH-Ar), 120.76 (C5), 91.56 (d, 3JC-p = 7.7 Hz, CI '), 91.45 (d, 3Jc-p = 7.7 Hz, CI '), 82.78 (C4'), 82.28 (C4'), 81.83 (d, 2Jc-p = 4.7 Hz, C2'), 80.96 (2 x d, 2Jc-p = 4.7 Hz, C2'), 67.95 (OCH2Ph), 67.92 (OCH2Ph), 64.13 (C5'), 63.59 (C5'), 51.88 (CH ala), 51.75 (CH ala), 33.75 (d, 3Jc-p = 3.0 Hz, C3'), 33.59 (d, 3Jc-p = 3.0 Hz, C3'), 20.33 (d, 3JC-p = 7.1 CH3 ala), 20.18 (d, 3JC-p = 7.1 CH3 ala). HPLC Reverse-phase HPLC eluting with H20/CH3OH from 90/10 to 0/100 in 30 minutes, lml/min, 1 = 254 nm, showed two peaks of the diastereoisomers with tR 22.16 min. and tR 22.43 min |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
11% | With tert-butylmagnesium chloride; In tetrahydrofuran; at 20℃; for 16h; | Using General Procedure 3 above, 3'-deoxyadenosine (50 mg, 0.20 mmol) was suspended in anhydrous THF (5 mL) and TiuMgCl (1.0 M solution in THF, 0.22 mL, 0.22 mmol) was added dropwisely at room temperature. A solution of (2,S)-benzyl 2- ((chloro(phenoxy)phosphoryl)amino)propanoate (212 mg, 0.6 mmol) in anhydrous THF (2 mL) was added dropwisely and the reaction mixture was stirred at room temperature during a period of 16 hours. Purification by column chromatography (eluent system CH3OH/CH2CI2 0/100 to 8/92) and preparative TLC (500 muMu, eluent system CH3OH/CH2CI2 5/95) afforded the desired compound as a white solid (19 mg, yield = 11%). MS (ES+) m/z, found: 886.3 (M + H+), 1771.6 (2M + H+), 751.2 (molecule without nucleobase M). C42H45N7O11P2 required: (M+) 885.3. 31P NMR (202 MHz, CH3OD): deltaRho 3.98, 3.88, 3.59, 3.12, 3.05, 2.45, 2.32. NMR (500 MHz, CH3OD): deltaEta 8.24-8.13 (m, 2H, H8, H2), 7.39-7.08 (m, 20H, Ph), 6.27- 6.23 (m, 0.5H, HI '), 6.16-6.13 (m, 0.5H, HI '), 5.61-5.48 (m, 1H, H2'), 5.17-4.91 (m, 4H, CH2Ph), 4.57-4.49 (m, 1H, H4'), 4.41-4.29 (m, 1H, H5'), 4.25-4.15 (m, 1H, H5'), 4.10-4.01 (m, 1H, CH ala), 3.99-3.89 (m, 1H, CH ala), 2.57-2.41 (m, 1H, H3'), 2.28-2.17 (m, 1H, H3'), 1.38- 1.23 (m, 6H, CH3 ala). 13C NMR (125 MHz, CH3OD): 6C 174.88 (C=0), 174.83 (C=0), 174.79 (C=0), 174.73 (C=0), 174.61 (C=0), 174.57 (C=0), 174.53 (C=0), 157.36 (C6), 157.34 (C6), 157.32(C6), 157.29 (C6), 154.04 (C2), 154.01 (C2), 153.97 (C2), 153.94 (C2), 152.09 (C4), 152.04 (C4), 152.02 (C4), 151.97 (C4), 150.31 (C-Ar), 150.29 (C-Ar), 150.16 (C-Ar), 140.98 (C8), 140.91 (C8), 140.81 (C8), 137.31 (C-Ar), 137.28 (C-Ar), 137.22 (C-Ar), 137.09 (C-Ar), 130.86 (CH- Ar), 130.78 (CH-Ar), 130.77 (CH-Ar), 129.65 (CH-Ar), 129.61 (CH-Ar), 129.58 (CH-Ar), 129.55 (CH-Ar), 129.44 (CH-Ar), 129.42 (CH-Ar), 129.38 (CH-Ar), 129.34 (CH-Ar), 129.32 (CH-Ar), 129.30 (CH-Ar), 129.28 (CH-Ar), 129.23 (CH-Ar), 129.21 (CH-Ar), 12.42 (CH-Ar), 126.23 (CH-Ar), 126.20 (CH-Ar), 126.17 (CH-Ar), 121.65 (CH-Ar), 121.63 (CH-Ar), 121.61 (CH-Ar), 121.59 (CH-Ar), 121.52 (CH-Ar), 121.50 (CH-Ar), 121.47 (CH-Ar), 121.46 (CH-Ar), 121.40 (CH-Ar), 121.39 (CH-Ar), 121.36 (CH-Ar), 121.35 (CH-Ar), 121.30 (CH-Ar), 121.28 (CH-Ar), 121.26 (CH-Ar), 121.24 (CH-Ar), 120.61 (C5), 120.57 (C5), 120.56 (C5), 120.54 (C5), 91.56 (CI '), 91.51 (CI '), 91.45 (CI '), 91.25 (CI '), 91.20 (CI '), 81.84 (C2'), 81.82 (C2'), 81.79 (C2'), 81.27 (C2'), 81.22 (C2'), 81.18 (C2'), 80.49 (C4'), 80.43 (C4'), 80.06 (C4'), 79.99 (C4'), 68.29 (C5', OCH2Ph), 68.25 (C5', OCH2Ph), 68.00 (C5', OCH2Ph), 67.96 (C5', OCH2Ph), 67.94 (C5', OCH2Ph), 67.90 (C5', OCH2Ph), 67.71 (C5', OCH2Ph), 67.67 (C5', OCH2Ph), 51.91 (CH ala), 51.74 (CH ala), 51.70 (CH ala), 51.59 (CH ala), 34.22 (C3'), 34.20 (C3'), 34.16 (C3'), 33.97 (C3'), 33.94 (C3'), 33.91 (C3'), 20.44 (CH3 ala), 20.43 (CH3 ala), 20.39 (CH3 ala), 20.29 (CH3 ala), 20.27 (CH3 ala), 20.24 (CH3 ala), 20.21 (CH3 ala), 20.19 (CH3 ala). HPLC Reverse-phase HPLC eluting with H20/CH3CN from 100/10 to 0/100 in 30 minutes, lml/min, 1 = 254 nm, showed one broad peak with tR 15.97 min. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
77% | With lithium triethylborohydride; In tetrahydrofuran; dimethyl sulfoxide; at 4 - 20℃; for 17h;Inert atmosphere; | General Procedure 5 (for preparing 3' -deoxy adenosine and 3'-deoxy-2-chloroadenosine employed in the examples): A solution of H2O/CH3CN 1 :9 and then a-AIBBr (4.0 mol/eq) were added sequentially to a suspension of dried adenosine or 2-chloroadenosine in anhydrous CH3CN and stirring was continued at room temperature (20 C). After 1 h, a saturated solution of NaHC03 was added cautiously and the solution was extracted with EtOAc. The combined organic phase was washed with brine. The aqueous phase was extracted with EtOAc and the combined organic phase was dried over Na2S04, filtered and evaporated to give a white gum. The crude mixture was dissolved in anhydrous MeOH and stirred for 1 h with Amberlite (2 x OH") resin previously washed well with anhydrous MeOH. The solution was then filtered and the resin carefully washed with anhydrous methanol. Evaporation of the combined filtrate afforded 2',3'- dehydroadenosine or 2',3'-dehydro-2-chloroadenosine as a white solid. A solution of LiEt3BH (1M solution in THF 4-4.3 mol/eq) was added dropwise to a cold (4 C) solution of 2',3'-dehydroadenosine or 2',3'-dehydro-2-chloroadenosine (1 mol/eq) in anhydrous DMSO/THF (1/10) under an argon atmosphere. Stirring was continued at 4 C for 1 h and at room temperature overnight (16 h). The reaction mixture was carefully acidified (5% AcOH/H20), purged with N2 for 1 h (under the fume hood) to remove pyrophoric triethylborane, and evaporated. The residue was chromatographed to give 3'-deoxyadenosine or 3'-deoxy-2- chloroadenosine as a white powder. 3'-Deoxyadenosine was prepared from the 9.12 g (36.6 mmol) of 2',3'-dehydroadenosine and 159 mL (159 mmol) of LiEt3BH/THF 1M, in anhydrous DMSO/THF (1/10, 50 mL). Purification by column chromatography on silica gel (eluent system 3-18% MeOH in DCM) gave 3'-deoxyadenosine as a white powder (7.12 g, 77%). NMR (500 MHz, OMSO-d6) delta 8.37 (s, 1H, H8), 8.17 (s, 1H, H2), 7.29 (br s, 2H, H2), 5.89 (d, J= 2.5 Hz, 1H, HI '), 5.68 (d, J= 4.5 Hz, 1H, OH-2'), 5.19 (t, J= 6.0 Hz, 1H, OH-5'), 4.63 - 4.58 (m, 1H, H2'), 4.40 - 4.34 (m, 1H, H4'), 3.71 (ddd, J= 12.0, 6.0, 3.0 Hz, 1H, H5'), 3.53-3.49 (ddd, J= 12.0, 6.0, 4.0 Hz, 1H, H5'), 2.30-2.23 (m, 1H, H3'), 1.98-1.90 (m, 1H, H3'). 13C NMR (125 MHz, OMSO-d6) delta 156.00 (C6), 152.41 (C2), 148.82 (C4), 139.09 (C8), 119.06 (C5), 90.79 (CI '), 80.66 (C4'), 74.56 (C2'), 62.61 (C5'), 34.02 (C3'). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With palladium on activated charcoal; hydrogen; In methanol; at 25℃; under 37503.8 Torr; for 8h; | In 2000ml pressure equipment,3-deoxy-3-chloro-2,5-di (O-acetyl) adenosine 5 g,Add methanol 200ml,Palladium carbon 0.2 g,Open the stir,Room temperature with nitrogen replacement pressure equipment inside the air 3 times,And then at a temperature of ? 25 C,Slow access to hydrogen,Keep the pressure ?5MPa,Stirring reaction for 8 hours,The reaction solution was filtered to remove palladium carbon,Recovery solvent,Chloroform extraction,Swing to organic solvents,The target product,After refining,To give the final target product as a white solid, 3.07 g,The reaction yield was 95% |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
To a suspension of 3'-deoxyadenosine (2.5g, lOmmol) in pyridine (40mL) at 0C was added chlorotrimethylsilane (5.43g, 50.0mmol). The mixture was stirred at rt for 30min. Then, the reaction mixture was cooled to 0C, and benzoyl chloride (2.1 lg, 15.0mmol) was added dropwise. The reaction mixture was stirred at rt for 6h. Then, water (lOmL) and H4OH (ca 29%, 20mL) were added, and the mixture was stirred at rt for 15min. It was concentrated and purified by silica gel column chromatography using 0-10% MeOH in CH2CI2 to give the product. LCMS (ES, m/z): 354.0 [M - H]". 1H- MR (400MHz, OMSO-d6): delta 11.21 (s, 1H), 8.77 (s, 1H), 8.75 (s, 1H), 8.13-8.00 (m, 2H), 7.66 (t, J = 7.3Hz, 1H), 7.56 (t, J = 7.6Hz, 2H), 6.06 (d, J = 1.9Hz, 1H), 5.79 (d, J = 4.1Hz, 1H), 5.11 (t, J = 5.4Hz, 1H), 4.67 (dp, J = 5.1, 2.6Hz, 1H), 4.43 (ddt, J = 9.5, 6.8, 3.7Hz, 1H), 3.75 (ddd, J = 12.0, 5.4, 3.3Hz, 1H), 3.57 (ddd, J = 12.1, 5.5, 3.9Hz, 1H), 2.31 (ddd, J = 13.2, 9.2, 5.6Hz, 1H), 1.96 (ddd, J = 13.1, 6.1, 2.6Hz, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
62% | With recombinant E. coli purine nucleoside phosphorylase; In aq. phosphate buffer; dimethyl sulfoxide; at 40℃; for 120h;pH 7.0;Enzymatic reaction; | 2-Fluoroadenine (23 mg, 0.15 mmol) and cordycepin 7c (1, 42 mg, 0.167 mmol) were dissolved in DMSO (1 mL) and the solution was added to potassium sodium phosphate buffer (50 mM, 5 mL, pH 7.0); PNP (300 IU) was added and the mixture was kept at 40 C for 5 d [TLC monitoring, CHCl3/sat. NH3 in MeOH (10:1)]. The mixture was cooled and filtered, silica gel (1 mL) was added to the filtrate, and the mixture was evaporated to dryness. The residue was co-evaporated with EtOH (2 × 5 mL) and the silica gel with products was put on top of a silica gel column (1.5 × 10 cm) that was eluted with CHCl3/MeOH (10:1). Fractions containing 2-fluoro-3?-deoxyadenosine (3) were combined and evaporated to dryness to afford the desired compound as a white solid; yield: 25 mg (62%); 99.3% purity. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With acetic acid; In methanol; dichloromethane; at 20℃; for 4h;pH Ca. 4; | 5'-O-triphenylmethyl-3'-deoxyadenosine 20 (2.47 g,5 mmol) was dissolved in a mixture of dichloromethane(30 mL) and methanol (20 mL), and the pH of the reactionmixture was adjusted to *4 using acetic acid. After stirringthe reaction mixture at room temperature for 4 h, thepH of the reaction mixture was adjusted to 7-8 by additionof a 1 M methanolic CH3ONa solution. After removal ofall solvents in vacuo, the residue was purified by columnchromatography on silica gel using a gradient of dichloromethane/methanol (15:1-8:1) as eluents to afford thetarget product 1 (1.13 g, 90.0%, 35.9% overall yield) as awhite solid with the purity of 99.1% (HPLC). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
31.3%; 4.8% | N-acetyl-2',5'-O-diacetyl-3'-iodo-3'-deoxyadenosine 12(2.52 g, 5 mmol), toluene (40 mL) and 2,2-azobisisobutyronitrile(AIBN, 0.1 g, 0.6 mmol) were placed in a 100 mLround-bottom flask. Lithium aluminum hydride in anhydrousTHF (LiAlH4/THF, 1 M, 20 mL) was slowly droppedto the solution. The stirred reaction mixtures were thenheated to reflux for 12 h. After reaction completion, thereaction mixture was cooled to room temperature and wasthen poured into petroleum ether. The resulting precipitatewas collected by filtration and further washed with petroleumether. The residue was used directly in the next step.The residue was added into a 1 M methanolic MeONasolution (25 mL) and the mixture was stirred for 6 h at60 C. After reaction completion, the reaction mixture wascooled to room temperature and concentrated in vacuo. Thecrude product was purified by flash chromatography onsilica gel using dichloromethane/methanol (10:1) as eluentsto afford pure 1 (0.39 g, 31.3%, 13.5% overall yield) as awhite solid with the purity of 99.1% (HPLC). 1H NMR(500 MHz, DMSO-d6) d 8.37 (s, 1H, 8-H), 8.15 (s, 1H,2-H), 7.32 (s, 2H, -NH2), 5.87 (d, J = 2.4 Hz, 1H, 10-H),5.67 (d, J = 4.3 Hz, 1H, 20-OH), 5.17 (s, 1H, 50-OH),4.59-4.57 (m, 1H, 20-H), 4.37-4.34 (m, 1H, 40-H),3.71-3.68 (m, 1H, 50-H), 3.52 (d, J = 12.1 Hz, 1H, 50-H),2.28-2.23 (m, 1H, 30-H), 1.94-1.90 (m, 1H, 30-H). 13CNMR (101 MHz, DMSO) d 156.49 (6-C), 152.88 (2-C),149.29 (4-C), 139.52 (8-C), 119.52 (5-C), 91.24 (10-C),81.14 (40-C), 75.05 (20-C), 63.06 (50-C), 34.50 (30-C). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With selenium(IV) oxide; water; at 20℃; | Weigh 22.1 mg of selenium dioxide, 10 ml deionized water were dissolved, was added 50 mg <strong>[73-03-0]cordycepin</strong>, stir at room temperature. The solvent was removed freeze-dried, to obtain selenious acid <strong>[73-03-0]cordycepin</strong>It can also be recrystallized from water/ethanol to give crystals. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With selenium(IV) oxide; water; at 20℃; | Weigh 22.1 mg of selenium dioxide, add 10 ml of deionized water, and add 100 mg of <strong>[73-03-0]cordycepin</strong>. stir at room temperature. Freeze-drying to remove the solvent di-cordyceps selenite , It can also be recrystallized from water/ethanol to give crystal |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With selenium(IV) oxide; water; at 20℃; | Weigh 22.1 mg of selenium dioxide, add 10 ml of deionized water, add 50 mg of <strong>[73-03-0]cordycepin</strong> and stir at room temperature. Freeze-drying to remove the solventget <strong>[73-03-0]cordycepin</strong> selenate, It can also be recrystallized from water/ethanol to give crystals. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With selenium(IV) oxide; water; at 20℃; | Weigh 22.1 mg of selenium dioxide, add 10 ml of deionized water, and add 100 mg of <strong>[73-03-0]cordycepin</strong>.Stir at room temperature. freeze-drying to remove the solvent di-<strong>[73-03-0]cordycepin</strong> Selenate , It can also be recrystallized from water/ethanol to give crystals. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With ammonia; In methanol; ethanol; at -20℃; for 48h; | A 50 mL round-bottomed flask was charged with29c (0.430 g, 1.00 mmol) and dry EtOH (10 mL) and the mixture was cooled to -20 C. Then, a solutionof NH3 in MeOH (10 mL, 7 N) was added and the mixture was stirred for 48 h. After removalof all the volatiles in vacuo, the resulting crude residue was purified by silica gel chromatographyCH2Cl2/MeOH (7:3) to afford product 3'-deoxyadenosine (0.250 g) as a white solid in quantitative yield.1H-NMR (600 MHz, D2O): delta 8.26 (s, 1H, H-2), 8.14 (s, 1H, H-8), 6.01 (d, 1H, J = 2.2 Hz, H-1'), 4.76 (m, 2H,H-2', H-4'), 3.91 (dd, 2H, J = 12.6, 2.7 Hz, H-5), 3.71 (dd, 1H, J = 12.6, 4.5 Hz, H-5?), 2.28 (ddd, 1H,J = 13.6, 8.7, 5.7 Hz, H-3'), 2.20 (ddd, 1H, J = 13.6, 6.6, 3.2 Hz, H-3?); 13C-NMR (150MHz, D2O): delta 155.3 (6-C), 152.3 (2-C), 148.0 (4-C), 139.6 (8-C), 118.6 (5-CH), 90.8 (1'-CH), 81.1 (4'-CH), 74.8 (2'-CH),62.6 (5'-CH2), 32.9 (3'-CH2); HRMS for C10H13N5O3 [M + H+]+ Calc.: 252.1091, found: 252.1085.To a stirred mixture of 3'-deoxyadenosine (0.05 g, 0.25 mmol) and imidazole (0.070 g, 1.0 mmol) inanhydrous DMF (5 mL) was added TBDPSCl (0.275 g, 1.0 mmol) at -50 C. The reaction mixture wasallowed to warm to room temperature and stirred for 4 h. It was then diluted with EtOAc (100 mL) andwashed with water and brine. The organic layer was dried over Na2SO4, filtered, and concentratedin vacuo. The crude residue was then purified by silica gel column chromatography (EtOAc) toafford compound 30d (0.112 g, 92%) as a white solid. 1H-NMR (600 MHz, MeOD): delta 8.32 (s, 1H, H-2),8.18 (s, 1H, H-8), 7.67-7.32 (m, 10H, ArH), 6.02 (d, 1H, J = 1.5 Hz, H-1'), 4.71 (dt, 1H, J = 5.5, 1.6 Hz,H-2'), 4.57 (dddd, 1H, J = 8.9, 3.9, 2.8, 2.1 Hz, H-4'), 4.05 (dd, 1H, J = 11.6, 2.8 Hz, H-5'), 3.78 (dd, 1H,J = 11.7, 3.9 Hz, H-5?), 2.46 (ddd, 1H, J = 14.4, 8.9, 5.5 Hz, H-3'), 2.01 (ddd, 1H, J = 14.4, 5.6, 2.1 Hz, H-3?),1.28 (s, 9H, 3 CH3); 13C-NMR (150 MHz, MeOD): delta 157.3 (6-C), 153.8 (2-C), 150.0 (4-C), 140.3 (8-C),136.7 (ArC), 136.6 (ArC), 134.2 (ArC), 134.0 (ArC), 131.0 (ArC), 131.0 (ArC), 128.8 (ArC), 120.4 (5-CH),93.2 (10-CH), 82.7 (4'-CH), 77.0 (2'-CH), 66.0 (5'-CH2), 34.4 (3'-CH2), 31.6 (CCH3)3), 27.4 (CH3); HRMSfor C26H31N5O3Si1 [M + H+]+ Calc.: 490.2268, found: 490.2273. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With pyridine; In N,N-dimethyl-formamide; at 0 - 20℃;Inert atmosphere; | To a stirred solution of 3'-deoxyadenosine(0.251 g, 1.00 mmol) in dry pyridine (30 mL), o-toluoyl chloride (0.539 g, 0.453 mL, 3.50 mmol) wasadded at 0 C under an inert atmosphere and stirred overnight at room temperature. The mixturewas diluted with EtOAc (100 mL) and washed with water (100 mL) and brine (100 mL). The organiclayer was dried over Na2SO4, filtered, and evaporated in vacuo. The crude residue was purified bycolumn chromatography (EtOAc:hexane 3:7) to afford 32 as a colorless oil (0.600 g, 99%). 1H-NMR(600 MHz, CDCl3): delta 8.49 (s, 1H, H-2), 8.10 (s, 1H, H-8), 7.99-7.19 (m, 12H, ArH), 6.26 (d, 1H, J = 1.3 Hz,H-1'), 6.07 (dt, 1H, J = 6.0, 1.3 Hz, H-2'), 4.85 (dddd, 1H, J = 9.2, 5.6, 5.4, 3.1 Hz, H-4'), 4.68 (dd, 1H,J = 12.1, 3.1 Hz, H-5'), 4.53 (dd, 1H, J = 12.1, 5.4 Hz, H-5?), 3.18 (s, 3H, ArCH3), 2.98 (ddd, 1H,J = 12.9, 9.2, 6.0 Hz, H-3'), 2.60 (s, 3H, ArCH3), 2.56 (s, 3H, ArCH3), 2.46 (ddd, 1H, J = 12.9, 5.6, 1.3 Hz,H-3?); 13C-NMR (150 MHz, CDCl3):delta 171.1 (NHCO), 166.9 (CO), 166.3 (CO), 161.0 (6-C), 152.2 (2-C),151.0 (4-C), 141.1 (8-C), 140.8 (ArC), 140.4 (ArC), 132.7 (ArC), 131.9 (ArC), 131.7 (ArC), 130.8 (ArC),130.4 (ArC), 128.6 (ArC), 128.0 (ArC), 125.8 (ArC), 125.7 (ArC), 122.1 (5-CH), 90.4 (1'-CH), 78.9 (4'-CH),78.1 (2'-CH), 64.6 (5'-CH2), 33.4 (3'-CH2), 21.9 (CH3), 21.8 (CH3), 21.6 (CH3). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | With formic acid; palladium 10% on activated carbon; In methanol; at 40℃; for 24h; | Preparation of cordycepin (Compound 1)20 g of compound 4-1, 2 g of 10% wet Pd/C and 250 mL of methanol were added to a 500 mL three-necked flask.The temperature was raised to 40 C, 14 mL of formic acid was slowly added dropwise over 12 hours, and reacted at 40 C for 12 h.Filter by suction, wash the filter cake with methanol, spin dry the filtrate and recrystallize.9.1 g of Compound 1 Cordycepin were obtained in a yield of 75%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With 5% palladium on barium sulphate; hydrogen; triethylamine; In methanol; under 2280.15 Torr; | A solution of 19 (Y=NH2, Z=H, 380 mg, 1 mmol) in methanol (75 mL) is shaken in an atmosphere of hydrogen in the presence of 5% Pd/BaSO4 catalyst (100 mg) and triethylamine (1 mL) at the initial pressure of 3 atm overnight. After removal of the catalyst, the solvent is evaporated in vacuo, and the residue is crystallized from methanol to give 3'-deoxyadenosine 20 (Y=NH2, Z=H), 200 mg (80%). The 1H NMR spectrum of this sample is identical with that of cordycepin. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
52% | With pyridine; at 70℃; for 5h;Inert atmosphere; | Step 1. Weigh the <strong>[73-03-0]cordycepin</strong> bulk drug and anhydrous pyridine according to a certain ratio of material to liquid, and add the weighed raw material of the <strong>[73-03-0]cordycepin</strong> to the anhydrous pyridine, stir and dissolve to obtain a mixed solution, and use;Step 2, the mixed solution obtained in the step 1, under the conditions of nitrogen protection, magnetic heating and stirring, slowly adding a certain amount of thiophene chloride to carry out the reaction, the reaction process is monitored by thin layer chromatography, and the reaction liquid is obtained after the reaction. ;Step 3, the reaction liquid obtained in the step 2 is subjected to distillation under reduced pressure to obtain a paste product, which is ready for use;Step 4, the paste product obtained in the step 3 is dissolved in distilled water, and extracted with ethyl acetate three times, and the organic phase solution is combined and used;Step 5, the organic phase solution obtained in the step 4 is distilled off under reduced pressure to remove the organic solvent, and the solid powder mixture is mixed with the column chromatography silica gel, and the column chromatography is carried out by dry-loading to obtain 5'-thiophene-formyl ester- 3'-deoxyadenosine.In the method for synthesizing 5'-thiophenecarboxylate-3'-deoxyadenosine according to the present embodiment, the ratio of the solution of the <strong>[73-03-0]cordycepin</strong> bulk drug and the anhydrous pyridine in the step 1 is 1 g: 50 ml.The method for synthesizing 5'-thiophenecarboxylate-3'-deoxyadenosine according to the embodiment, wherein the mass ratio of the thiophene chloride in the step 2 to the <strong>[73-03-0]cordycepin</strong> drug in the step 1 is 0.6:1, and the heating is a water bath method. Heating, heating temperature was 70 C, reaction time 5 h.The method for synthesizing 5'-thiophenecarboxylate-3'-deoxyadenosine according to the embodiment, wherein the thin layer chromatography solvent in step 2 is a mixed solvent of methanol and dichloromethane, wherein the volume ratio of methanol to dichloromethane At 1:10, the thin layer plate was observed under an ultraviolet analyzer, the material point disappeared, and the reaction was completed.The method for synthesizing 5'-thiophenecarboxylate-3'-deoxyadenosine according to the present embodiment is subjected to vacuum distillation at 80 C in a rotary evaporator in step 3, and the distillation time is 15 min.In the method for synthesizing 5'-thiophenecarboxylate-3'-deoxyadenosine according to the embodiment, the temperature of the distilled water added in the step 4 is 60 C, and the volume ratio of the volume of the distilled water to the ethyl acetate is 10 ml: 30ml.a method for synthesizing 5'-thiophenecarboxylate-3'-deoxyadenosine according to the embodiment, wherein the solvent for column chromatography is a mixed solvent of methanol and dichloromethane, and the methanol is as described above. The volume ratio of methylene chloride is 1:15, the upper silica gel column is a 2×75 cm glass column, and the silica gel is a 200-300 mesh column chromatography silica gel.In the method for synthesizing 5'-thiophenecarboxylate-3'-deoxyadenosine according to the present embodiment, when the <strong>[73-03-0]cordycepin</strong> drug substance is 1 g, 1.337 g of a solid mixture powder is obtained in the step 5, and the color of the solid mixture powder is white. Finally, 0.751 g of the 5'-thiophenecarboxylate-3'-deoxyadenosine was obtained, and the resulting 5'-thiophenecarboxylate-3'-deoxyadenosine 1.44 g was obtained in a yield of 52.0%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
50.4% | With pyridine; In methanol; dichloromethane; at 70℃; for 5h;Inert atmosphere; | step 1,Weighed according to a certain ratio of material to liquid<strong>[73-03-0]Cordycepin</strong> bulk drugAnd anhydrous pyridine,The weighed <strong>[73-03-0]cordycepin</strong> raw material is added to anhydrous pyridine, stirred and dissolved to obtain a mixed solution, which is ready for use;Step 2, the mixed solution obtained in the step 1, under the conditions of nitrogen protection, magnetic heating and stirring, slowly adding a certain amount of furoyl chloride to carry out the reaction, the reaction process is monitored by thin layer chromatography, and the reaction liquid is obtained after the reaction. ;Step 3, the reaction liquid obtained in the step 2 is subjected to distillation under reduced pressure to obtain a paste product, which is ready for use;Step 4, the paste product obtained in the step 3 is dissolved in distilled water, and then extracted with ethyl acetate.Second, the organic phase solution is combined and used;Step 5, the organic phase solution obtained in the step 4 is distilled off under reduced pressure to remove the organic solvent, and the solid powder mixture is mixed with the column chromatography silica gel, and the column is chromatographed by a dry method.5'-furoyl ester-3'-deoxyadenosineIn the method for synthesizing 5'-furoyl ester-3'-deoxyadenosine according to the present embodiment, the ratio of the solution of the <strong>[73-03-0]cordycepin</strong> bulk drug and the anhydrous pyridine in the step 1 is 1 g: 50 ml.In the method for synthesizing 5'-furoyl ester-3'-deoxyadenosine according to the embodiment, the mass ratio of furoyl chloride in step 2 to the <strong>[73-03-0]cordycepin</strong> bulk drug in step 1 is 0.6:1, and heating is a water bath method. Heating, heating temperature was 70 C, reaction time 5 h.The method for synthesizing 5'-furoyl ester-3'-deoxyadenosine according to the embodiment, wherein the thin layer chromatography solvent in step 2 is a mixed solvent of methanol and dichloromethane, wherein the volume ratio of methanol to dichloromethane At 1:10, the thin layer plate was observed under an ultraviolet analyzer, the material point disappeared, and the reaction was completed.The method for synthesizing 5'-furoyl ester-3'-deoxyadenosine according to the present embodiment is subjected to vacuum distillation at 80 C in a rotary evaporator in step 3, and the distillation time is 5 to 10 minutes.In the method for synthesizing 5'-furoyl ester-3'-deoxyadenosine according to the embodiment, the temperature of the distilled water added in the step 4 is 60 C, and the volume ratio of the volume of the distilled water to the ethyl acetate is 10 ml: 30ml.a method for synthesizing 5'-furoyl ester-3'-deoxyadenosine according to the embodiment, wherein the solvent for column chromatography is a mixed solvent of methanol and dichloromethane, and the methanol is as described above. The volume ratio of methylene chloride was 1:15, the upper silica gel column was a 2×75 cm glass column, and the silica gel was a 200 mesh column chromatography silica gel.In the method for synthesizing 5'-furoyl ester-3'-deoxyadenosine according to the present embodiment, when the <strong>[73-03-0]cordycepin</strong> drug substance is 1 g, the white solid powder obtained in the step 5 is 1.4369 g, and finally the 5' is obtained. - Furanyl ester-3'-deoxyadenosine 0.695 g, theoretically produced 1.38 g of 5'-furoyl ester-3'-deoxyadenosine, yield 50.4%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60.2% | step 1,Weigh the <strong>[73-03-0]cordycepin</strong> bulk drug and anhydrous pyridine according to a certain ratio of material to liquid.The weighed amount of <strong>[73-03-0]cordycepin</strong> raw material is added to anhydrous pyridine, stirred and dissolved to obtain a mixed solution.stand-by;Step 2The mixed solution obtained in the step 1 is subjected to nitrogen protection, magnetic heating and stirring,A certain amount of 6-chloronicotinoyl chloride is added to carry out the reaction, and the reaction process is monitored by thin layer chromatography, and the reaction liquid is obtained after use;Step 3The reaction liquid obtained in the step 2 is subjected to distillation under reduced pressure to obtain a paste product, which is ready for use;Step 4,The paste product obtained in the step 3 was dissolved in distilled water, and extracted with ethyl acetate three times.Combine the organic phase solution for use;Step 5,The organic phase solution obtained in the step 4 is distilled off under reduced pressure to remove the organic solvent.The solid powder mixture is mixed with column chromatography silica gel, and the method of dry loading is carried out for column chromatography.5'-(6-chloronicotinoyl ester)-3'-deoxyadenosine was obtained.In the method for synthesizing 5'-(6-chloronicotinoyl ester)-3'-deoxyadenosine according to the present embodiment, the ratio of the solution of the <strong>[73-03-0]cordycepin</strong> bulk drug and the anhydrous pyridine in the step 1 is 1 g: 50 ml.The method for synthesizing 5'-(6-chloronicotinoyl ester)-3'-deoxyadenosine according to the present embodiment, the amount of 6-chloronicotinoyl chloride in step 2 and the amount of the <strong>[73-03-0]cordycepin</strong> bulk drug in step 1 is 1:1, the heating was heated by a water bath, the heating temperature was 80 C, and the reaction time was 6 h.The method for synthesizing 5'-(6-chloronicotinoyl ester)-3'-deoxyadenosine according to the embodiment, wherein the thin layer chromatography solvent in step 2 is a mixed solvent of methanol and dichloromethane, wherein methanol and dichloro The volume ratio of methane was 1:10, and the thin layer plate was observed under an ultraviolet analyzer, the material point disappeared, and the reaction was completed.The method for synthesizing 5'-(6-chloronicotinoyl ester)-3'-deoxyadenosine according to the present embodiment is subjected to vacuum distillation at 80 C in a rotary evaporator in step 3, and the distillation time is 10 min.The method for synthesizing 5'-(6-chloronicotinoyl ester)-3'-deoxyadenosine according to the embodiment, the temperature of the distilled water added in the step 4 is 60 C, and the volume of distilled water and the volume of ethyl acetate are added. The ratio is 10ml: 30ml.a method for synthesizing 5'-(6-chloronicotinoyl ester)-3'-deoxyadenosine according to the present embodiment,In step 5, the developing solvent for column chromatography is a mixed solvent of methanol and dichloromethane.The volume ratio of the methanol to the dichloromethane is 1:15.The upper silica gel column is a 2×75 cm glass column.The silica gel was a 300 mesh column chromatography silica gel.In the method for synthesizing 5'-(6-chloronicotinoyl ester)-3'-deoxyadenosine according to the present embodiment, when the <strong>[73-03-0]cordycepin</strong> drug substance is 1 g, the white solid mixture powder is 1.376 g in the step 5, and the final product is obtained. 5,8-(6-chloronicotinoyl ester)-3'-deoxyadenosine 0.8285 g, theoretically produced 1.556 g of the 5'-(6-chloronicotinoyl ester)-3'-deoxyadenosine,The yield was 60.2%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
6% | General procedure: To a solution of DCC (3 eq.) and nucleoside in DMF (2 mL) methylene diphosphonic acid (1.5 eq.) was added at rt and the mixture was allowed to stir at rt for 6-24 h. Samples were withdrawn at 3 - 12 h interval for LC-MS to check the disappearance of nucleosides and to monitor the formation of the desired nucleotide. On the disappearance of a nucleoside, 10 mL of cold TEAC-solution was added. The mixture was stirred at rt for 30 min followed by filtration and lyophilization of the aqueous solution. The mixture of nucleotide and dinucleotide was separated by ion-exchange chromatography on Source 15Q. Fractions containing the product were pooled and evaporated to dryness. The compound was then purified by RP-HPLC using a gradient of 10 mM triethylammonium acetate buffer - CHbCN from 80:20 to 20:80 in 40 min, suitable fractions were pooled and lyophilized to obtain the final product as glassy solid |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
40.7% | 2.00 mmol (0.5 g) of <strong>[73-03-0]cordycepin</strong> was added to a dry flask containing 10 mL of N-N dimethylformamide (DMF), and dissolved by stirring.After dissolving, add 0.10g NaH to it in a dry environment and stir at room temperature for 30min.Then 2.00 mmol (0.45 g) of 4-nitrobenzenesulfonyl chloride was added for reaction, and the reaction was followed by TLC.After the reaction, about 5 g of 200-300 mesh silica gel was added, spin-dried, and passed through a silica gel column with EA / MeOH / NH4OH (99: 10: 1).Brownish yellow powderPurine-6- (4-nitro-benzenesulfonamido) -9-N- (3'-deoxy) ribofuranoside |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
68.6% | Take 2.00mmol (0.5g) <strong>[73-03-0]cordycepin</strong>,Add to a dry flask containing 10 mL of N-N dimethylformamide,Stir to dissolve. After dissolving, add 0.10g NaH to it in a dry environment and stir at room temperature for 30min.Then 2.00 mmol (0.42 g) of 4-methoxybenzenesulfonyl chloride was added for reaction, and the reaction was followed by TLC. After the reaction is over,Add about 5g 200-300 mesh silica gel, spin dry, and pass through a silica gel column with EA / MeOH / NH4OH (99: 10: 1).Yellow powder purine-6- (4-methoxy-benzenesulfonamide) -9-N- (3'-deoxy) ribofuranoside |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
58.5% | Take 2.00mmol (0.5g) <strong>[73-03-0]cordycepin</strong>,Add to a dry flask with 10mL N-N dimethylformamide,Stir to dissolve, after dissolving,Add 0.10g NaH to it in a dry environment and stir at room temperature for 30min.Then 2.00 mmol (0.38 g) of 4-methylbenzenesulfonyl chloride was added for reaction, and the reaction was followed by TLC.After the reaction, add about 5 g of 200-300 mesh silica gel, spin dry,Pass EA / MeOH / NH4OH (99: 10: 1) through a silica gel column.Purine-6- (4-methylbenzenesulfonamido) -9-N- (3'-deoxy) ribofuranoside |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
52% | 2.00 mmol (0.5 g) of <strong>[73-03-0]cordycepin</strong> was taken, added to a dry flask containing 10 mL of N-N dimethylformamide, and dissolved by stirring.After dissolving, add 0.10g NaH to it in a dry environment,After stirring at room temperature for 30 min, 2.00 mmol (0.35 g) of benzenesulfonyl chloride was added for reaction, and the reaction was followed by TLC.After the reaction was completed, about 5 g of 200-300 mesh silica gel was added, spin-dried, and passed through a silica gel column with EA / MeOH / NH4OH (99: 10: 1) to obtain a brown solid purine-6-((4H) -benzenesulfonamide ) -9-N- (3'-deoxy) ribofuranoside |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
49.2% | 2.00 mmol (0.5 g) of <strong>[73-03-0]cordycepin</strong> was taken, added to a flask containing 10 mL of N-N dimethylformamide, and dissolved by stirring.After dissolving, add 0.10g NaH to it in a dry environment and stir at room temperature for 30min.Then 2.00 mmol (0.51 g) of 4-bromobenzenesulfonyl chloride was added for reaction, and the reaction was followed by TLC. After the reaction is over,Add about 5g of 200-300 mesh silica gel, spin dry, and pass through a silica gel column with EA / MeOH / NH4OH (99: 10: 1).The white powder purine-6-(4-bromo-benzenesulfonamide)-9-N-(3'-deoxy)ribofuranoside is obtained |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Take 2.00 mmol of <strong>[73-03-0]cordycepin</strong> and add it to 10 mL of N-N dimethylformamide (DMF).After stirring and dissolving at room temperature, add 0.10g NaH to it in a dry environment, and continue stirring for 30min.Then 2.00 mmol of bromoethyl 4-bromobenzenesulfonamide was added for reaction, and the reaction was followed by TLC. After the reaction is completed, add about 5g of 200-300 mesh silica gel, spin dry, first rinse the silica gel column with PE / EA (3: 2),Then elute with CH2Cl2 / MeOH (5: 1) to obtain purine-6-(4-bromo-N-(2-ethylamine)benzenesulfonamide)-9-N-(3'-deoxy)ribofuranoside. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Take 2.00 mmol of <strong>[73-03-0]cordycepin</strong>, add 10 mL of N,N-dimethylformamide (DMF), stir and dissolve at room temperature, add 0.10 g NaH to it in a dry environment, and continue stirring for 30 min. Then 2.00 mmol of bromoethyl-4-nitrobenzenesulfonamide was added for reaction, and the reaction was followed by TLC. After the reaction, add about 5g of 200-300 mesh silica gel, spin dry, rinse the silica gel column with PE/EA (3: 2), and then elute with CH2Cl2/MeOH (5:1). The yellow solid purine-6-(4-nitro-N-(2-ethylamine)benzenesulfonamido)-9-N-(3'-deoxy)ribofuranoside. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Take 2.00 mmol of <strong>[73-03-0]Cordycepin</strong>, add 10 mL of N-N dimethylformamide (DMF), stir and dissolve at room temperature, add 0.10 g NaH to it in a dry environment, and continue stirring for 30 min.Then 2.00 mmol of bromoethyl-4-methoxybenzenesulfonamide was added for reaction, and the reaction was followed by TLC.After the reaction, about 5 g of 200-300 mesh silica gel was added, and the mixture was spin-dried. The silica gel column was washed with PE / EA (3: 2), and then eluted with CH2Cl2/MeOH (5:1) to obtain the target product. White crystal purine-6-(4-methoxy-N-(2-ethylamine)benzenesulfonamido)-9-N-(3'-deoxy)ribofuranoside. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
2.00 mmol of <strong>[73-03-0]cordycepin</strong> was taken, added to 10 mL of N,N-dimethylformamide (DMF), and dissolved by stirring. After dissolving, add 0.10g NaH to it and stir at room temperature for 30min. Another 2.00 mmol of bromoethyl 2-indolone-5-sulfonamide was added and the reaction was heated to 100-120 C. The reaction was followed by TLC. After the reaction, add about 5 g of 200-300 mesh silica gel, spin dry, and pass through a silica gel column with EA/MeOH (10: 1). The red powder purine-6-(N-(2-ethylamino)-1H-2-oxoindole-5-sulfonamido)-9-N-(3'-deoxy)ribofuranoside. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Take 2.00 mmol of <strong>[73-03-0]cordycepin</strong>, add 10 mL of N,N-dimethylformamide (DMF), stir and dissolve at room temperature, add 0.10 g NaH to it in a dry environment, and continue stirring for 30 minutes. Then 2.00 mmol of bromoethyl 4-methylbenzenesulfonamide was added for reaction, and the reaction was followed by TLC. After the reaction, add about 5g of 200-300 mesh silica gel, spin dry, rinse the silica gel column with PE/EA (3: 2), and then elute with CH2Cl2/MeOH (5: 1).To obtain a pale yellow powder purine-6-(4-methyl-N-(2-ethylamine)benzenesulfonamido)-9-N-(3'-deoxy)ribofuranoside |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Take 2.00mmol of <strong>[73-03-0]cordycepin</strong>, add 10mL of N,N-dimethylformamide (DMF), stir and dissolve at room temperature, add 0.10g NaH to it in a dry environment, and continue stirring for 30min. Then 2.00 mmol of bromoethylbenzenesulfonamide was added for reaction, and the reaction was followed by TLC. After the reaction, add about 5 g of 200-300 mesh silica gel, spin dry, rinse the silica gel column with PE / EA (3: 2), and then elute with CH2Cl2/MeOH (5:1) to obtain a yellow solid purine-6-((4H)-N-(2-ethylamine)benzenesulfonamido)-9-N-(3'-deoxy)ribofuranoside. |
Precautionary Statements-General | |
Code | Phrase |
P101 | If medical advice is needed,have product container or label at hand. |
P102 | Keep out of reach of children. |
P103 | Read label before use |
Prevention | |
Code | Phrase |
P201 | Obtain special instructions before use. |
P202 | Do not handle until all safety precautions have been read and understood. |
P210 | Keep away from heat/sparks/open flames/hot surfaces. - No smoking. |
P211 | Do not spray on an open flame or other ignition source. |
P220 | Keep/Store away from clothing/combustible materials. |
P221 | Take any precaution to avoid mixing with combustibles |
P222 | Do not allow contact with air. |
P223 | Keep away from any possible contact with water, because of violent reaction and possible flash fire. |
P230 | Keep wetted |
P231 | Handle under inert gas. |
P232 | Protect from moisture. |
P233 | Keep container tightly closed. |
P234 | Keep only in original container. |
P235 | Keep cool |
P240 | Ground/bond container and receiving equipment. |
P241 | Use explosion-proof electrical/ventilating/lighting/equipment. |
P242 | Use only non-sparking tools. |
P243 | Take precautionary measures against static discharge. |
P244 | Keep reduction valves free from grease and oil. |
P250 | Do not subject to grinding/shock/friction. |
P251 | Pressurized container: Do not pierce or burn, even after use. |
P260 | Do not breathe dust/fume/gas/mist/vapours/spray. |
P261 | Avoid breathing dust/fume/gas/mist/vapours/spray. |
P262 | Do not get in eyes, on skin, or on clothing. |
P263 | Avoid contact during pregnancy/while nursing. |
P264 | Wash hands thoroughly after handling. |
P265 | Wash skin thouroughly after handling. |
P270 | Do not eat, drink or smoke when using this product. |
P271 | Use only outdoors or in a well-ventilated area. |
P272 | Contaminated work clothing should not be allowed out of the workplace. |
P273 | Avoid release to the environment. |
P280 | Wear protective gloves/protective clothing/eye protection/face protection. |
P281 | Use personal protective equipment as required. |
P282 | Wear cold insulating gloves/face shield/eye protection. |
P283 | Wear fire/flame resistant/retardant clothing. |
P284 | Wear respiratory protection. |
P285 | In case of inadequate ventilation wear respiratory protection. |
P231 + P232 | Handle under inert gas. Protect from moisture. |
P235 + P410 | Keep cool. Protect from sunlight. |
Response | |
Code | Phrase |
P301 | IF SWALLOWED: |
P304 | IF INHALED: |
P305 | IF IN EYES: |
P306 | IF ON CLOTHING: |
P307 | IF exposed: |
P308 | IF exposed or concerned: |
P309 | IF exposed or if you feel unwell: |
P310 | Immediately call a POISON CENTER or doctor/physician. |
P311 | Call a POISON CENTER or doctor/physician. |
P312 | Call a POISON CENTER or doctor/physician if you feel unwell. |
P313 | Get medical advice/attention. |
P314 | Get medical advice/attention if you feel unwell. |
P315 | Get immediate medical advice/attention. |
P320 | |
P302 + P352 | IF ON SKIN: wash with plenty of soap and water. |
P321 | |
P322 | |
P330 | Rinse mouth. |
P331 | Do NOT induce vomiting. |
P332 | IF SKIN irritation occurs: |
P333 | If skin irritation or rash occurs: |
P334 | Immerse in cool water/wrap n wet bandages. |
P335 | Brush off loose particles from skin. |
P336 | Thaw frosted parts with lukewarm water. Do not rub affected area. |
P337 | If eye irritation persists: |
P338 | Remove contact lenses, if present and easy to do. Continue rinsing. |
P340 | Remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P341 | If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P342 | If experiencing respiratory symptoms: |
P350 | Gently wash with plenty of soap and water. |
P351 | Rinse cautiously with water for several minutes. |
P352 | Wash with plenty of soap and water. |
P353 | Rinse skin with water/shower. |
P360 | Rinse immediately contaminated clothing and skin with plenty of water before removing clothes. |
P361 | Remove/Take off immediately all contaminated clothing. |
P362 | Take off contaminated clothing and wash before reuse. |
P363 | Wash contaminated clothing before reuse. |
P370 | In case of fire: |
P371 | In case of major fire and large quantities: |
P372 | Explosion risk in case of fire. |
P373 | DO NOT fight fire when fire reaches explosives. |
P374 | Fight fire with normal precautions from a reasonable distance. |
P376 | Stop leak if safe to do so. Oxidising gases (section 2.4) 1 |
P377 | Leaking gas fire: Do not extinguish, unless leak can be stopped safely. |
P378 | |
P380 | Evacuate area. |
P381 | Eliminate all ignition sources if safe to do so. |
P390 | Absorb spillage to prevent material damage. |
P391 | Collect spillage. Hazardous to the aquatic environment |
P301 + P310 | IF SWALLOWED: Immediately call a POISON CENTER or doctor/physician. |
P301 + P312 | IF SWALLOWED: call a POISON CENTER or doctor/physician IF you feel unwell. |
P301 + P330 + P331 | IF SWALLOWED: Rinse mouth. Do NOT induce vomiting. |
P302 + P334 | IF ON SKIN: Immerse in cool water/wrap in wet bandages. |
P302 + P350 | IF ON SKIN: Gently wash with plenty of soap and water. |
P303 + P361 + P353 | IF ON SKIN (or hair): Remove/Take off Immediately all contaminated clothing. Rinse SKIN with water/shower. |
P304 + P312 | IF INHALED: Call a POISON CENTER or doctor/physician if you feel unwell. |
P304 + P340 | IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing. |
P304 + P341 | IF INHALED: If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P305 + P351 + P338 | IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing. |
P306 + P360 | IF ON CLOTHING: Rinse Immediately contaminated CLOTHING and SKIN with plenty of water before removing clothes. |
P307 + P311 | IF exposed: call a POISON CENTER or doctor/physician. |
P308 + P313 | IF exposed or concerned: Get medical advice/attention. |
P309 + P311 | IF exposed or if you feel unwell: call a POISON CENTER or doctor/physician. |
P332 + P313 | IF SKIN irritation occurs: Get medical advice/attention. |
P333 + P313 | IF SKIN irritation or rash occurs: Get medical advice/attention. |
P335 + P334 | Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages. |
P337 + P313 | IF eye irritation persists: Get medical advice/attention. |
P342 + P311 | IF experiencing respiratory symptoms: call a POISON CENTER or doctor/physician. |
P370 + P376 | In case of fire: Stop leak if safe to Do so. |
P370 + P378 | In case of fire: |
P370 + P380 | In case of fire: Evacuate area. |
P370 + P380 + P375 | In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion. |
P371 + P380 + P375 | In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion. |
Storage | |
Code | Phrase |
P401 | |
P402 | Store in a dry place. |
P403 | Store in a well-ventilated place. |
P404 | Store in a closed container. |
P405 | Store locked up. |
P406 | Store in corrosive resistant/ container with a resistant inner liner. |
P407 | Maintain air gap between stacks/pallets. |
P410 | Protect from sunlight. |
P411 | |
P412 | Do not expose to temperatures exceeding 50 oC/ 122 oF. |
P413 | |
P420 | Store away from other materials. |
P422 | |
P402 + P404 | Store in a dry place. Store in a closed container. |
P403 + P233 | Store in a well-ventilated place. Keep container tightly closed. |
P403 + P235 | Store in a well-ventilated place. Keep cool. |
P410 + P403 | Protect from sunlight. Store in a well-ventilated place. |
P410 + P412 | Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF. |
P411 + P235 | Keep cool. |
Disposal | |
Code | Phrase |
P501 | Dispose of contents/container to ... |
P502 | Refer to manufacturer/supplier for information on recovery/recycling |
Physical hazards | |
Code | Phrase |
H200 | Unstable explosive |
H201 | Explosive; mass explosion hazard |
H202 | Explosive; severe projection hazard |
H203 | Explosive; fire, blast or projection hazard |
H204 | Fire or projection hazard |
H205 | May mass explode in fire |
H220 | Extremely flammable gas |
H221 | Flammable gas |
H222 | Extremely flammable aerosol |
H223 | Flammable aerosol |
H224 | Extremely flammable liquid and vapour |
H225 | Highly flammable liquid and vapour |
H226 | Flammable liquid and vapour |
H227 | Combustible liquid |
H228 | Flammable solid |
H229 | Pressurized container: may burst if heated |
H230 | May react explosively even in the absence of air |
H231 | May react explosively even in the absence of air at elevated pressure and/or temperature |
H240 | Heating may cause an explosion |
H241 | Heating may cause a fire or explosion |
H242 | Heating may cause a fire |
H250 | Catches fire spontaneously if exposed to air |
H251 | Self-heating; may catch fire |
H252 | Self-heating in large quantities; may catch fire |
H260 | In contact with water releases flammable gases which may ignite spontaneously |
H261 | In contact with water releases flammable gas |
H270 | May cause or intensify fire; oxidizer |
H271 | May cause fire or explosion; strong oxidizer |
H272 | May intensify fire; oxidizer |
H280 | Contains gas under pressure; may explode if heated |
H281 | Contains refrigerated gas; may cause cryogenic burns or injury |
H290 | May be corrosive to metals |
Health hazards | |
Code | Phrase |
H300 | Fatal if swallowed |
H301 | Toxic if swallowed |
H302 | Harmful if swallowed |
H303 | May be harmful if swallowed |
H304 | May be fatal if swallowed and enters airways |
H305 | May be harmful if swallowed and enters airways |
H310 | Fatal in contact with skin |
H311 | Toxic in contact with skin |
H312 | Harmful in contact with skin |
H313 | May be harmful in contact with skin |
H314 | Causes severe skin burns and eye damage |
H315 | Causes skin irritation |
H316 | Causes mild skin irritation |
H317 | May cause an allergic skin reaction |
H318 | Causes serious eye damage |
H319 | Causes serious eye irritation |
H320 | Causes eye irritation |
H330 | Fatal if inhaled |
H331 | Toxic if inhaled |
H332 | Harmful if inhaled |
H333 | May be harmful if inhaled |
H334 | May cause allergy or asthma symptoms or breathing difficulties if inhaled |
H335 | May cause respiratory irritation |
H336 | May cause drowsiness or dizziness |
H340 | May cause genetic defects |
H341 | Suspected of causing genetic defects |
H350 | May cause cancer |
H351 | Suspected of causing cancer |
H360 | May damage fertility or the unborn child |
H361 | Suspected of damaging fertility or the unborn child |
H361d | Suspected of damaging the unborn child |
H362 | May cause harm to breast-fed children |
H370 | Causes damage to organs |
H371 | May cause damage to organs |
H372 | Causes damage to organs through prolonged or repeated exposure |
H373 | May cause damage to organs through prolonged or repeated exposure |
Environmental hazards | |
Code | Phrase |
H400 | Very toxic to aquatic life |
H401 | Toxic to aquatic life |
H402 | Harmful to aquatic life |
H410 | Very toxic to aquatic life with long-lasting effects |
H411 | Toxic to aquatic life with long-lasting effects |
H412 | Harmful to aquatic life with long-lasting effects |
H413 | May cause long-lasting harmful effects to aquatic life |
H420 | Harms public health and the environment by destroying ozone in the upper atmosphere |
Sorry,this product has been discontinued.
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