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CAS No. : | 7791-71-1 | MDL No. : | MFCD00038462 |
Formula : | C29H28N2O5 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | - |
M.W : | 484.54 | Pubchem ID : | - |
Synonyms : |
|
Num. heavy atoms : | 36 |
Num. arom. heavy atoms : | 24 |
Fraction Csp3 : | 0.24 |
Num. rotatable bonds : | 7 |
Num. H-bond acceptors : | 5.0 |
Num. H-bond donors : | 2.0 |
Molar Refractivity : | 136.15 |
TPSA : | 93.55 Ų |
GI absorption : | High |
BBB permeant : | No |
P-gp substrate : | Yes |
CYP1A2 inhibitor : | No |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | Yes |
CYP2D6 inhibitor : | Yes |
CYP3A4 inhibitor : | Yes |
Log Kp (skin permeation) : | -6.78 cm/s |
Log Po/w (iLOGP) : | 3.92 |
Log Po/w (XLOGP3) : | 3.49 |
Log Po/w (WLOGP) : | 3.07 |
Log Po/w (MLOGP) : | 2.2 |
Log Po/w (SILICOS-IT) : | 4.43 |
Consensus Log Po/w : | 3.42 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 0.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -5.07 |
Solubility : | 0.00408 mg/ml ; 0.00000843 mol/l |
Class : | Moderately soluble |
Log S (Ali) : | -5.14 |
Solubility : | 0.00353 mg/ml ; 0.00000729 mol/l |
Class : | Moderately soluble |
Log S (SILICOS-IT) : | -8.2 |
Solubility : | 0.00000309 mg/ml ; 0.0000000064 mol/l |
Class : | Poorly soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 4.9 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P280-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H302+H312+H332-H315-H319-H335 | Packing Group: | N/A |
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 |
---|---|---|
97.1% | at 20℃; for 21.5 h; | Synthesized in the following manner according to literature [Nucleosides Nucleotides, 8, 1529-1535 (1989)]: In a stream of nitrogen, triphenylmethyl chloride (15 g, 53.7 mmols) was added to a pyridine (40 ml) solution of thymidine (10 g, 41.3 mmols) at room temperature, and the mixture was stirred for 21.5 hours at room temperature. A saturated aqueous solution of sodium bicarbonate was added to the reaction mixture, and the system was extracted with a methylene chloride solution. The organic layer was washed with a saturated aqueous solution of sodium chloride, and then dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (ethyl acetate:n-hexane = 1:1)* to obtain Compound 41 (19.4 g, 97.1percent) as a colorless acicular substance. |
48% | at 65℃; for 16 h; Inert atmosphere | In a 25ml round bottom flask 100mg (0.39mmol) of4was evaporated 3 times with 3mL of dry pyridine and dissolved in 3mL of dry pyridine. Trityl chloride (120.0mg, 0.43mmol) was added and the reaction mixture was heated at 65°C for 16h under argon atmosphere. After 16h, the mixture was cooled to room temperature, quenched with 3mL of MeOH and stirred for 30min. The mixture was evaporated to dryness. The obtained crude compound was purified by column chromatography to obtain 92mg (48percent) of17. TLC (CH2Cl2/MeOH, 9:1):Rf=0.70.1H NMR (500MHz, CDCl3):δ8.61 (bs, 1H), 7.56 (s, 1H), 7.42–7.26 (m, 15H), 6.42–6.40 (m, 1H, H-1′), 4.58 (s, 1H), 4.20–4.10 (m, 1H), 3.49–3.46 (m, 1H), 3.40–3.37 (m, 1H), 2.44–2.40 (m, 1H, H-2′/H-2″), 2.34–2.30 (m, 1H, H-2′/H-2″), 1.48 (s, 3H, 5-CH3).13C NMR (125MHz, CDCl3):δ163.6, 150.3, 143.3, 135.5, 128.6, 128.2, 128.0, 127.5, 111.3, 87.5, 86.0, 84.6, 72.4, 70.7, 63.7, 40.9, 11.9; HRMS (EI+): m/z for [C42H48N4O10Na]+, calcd. 507.1890; found 507.1907. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
44% | Stage #1: With 15-crown-5; sodium bis(2-methoxyethoxy)aluminium dihydride In tetrahydrofuran; toluene at 0 - 5℃; for 1 h; Stage #2: at 5℃; for 0.25 h; |
To a previously cooled (0-5° C.) mixture of 2,2'-anhydro-1-(5-O-trityl--D-arabinofuranosyl)thymine 4 (241 mg, 0.5 mmol) and 15-crown-5 (0.15 mL, 0.75 mmol) in anhydrous THF (10 mL) was added Red-Al (65percent wt. in toluene, 0.23 mL, 0.75 mmol) dropwise over a period of 5 minutes. The mixture was maintained at 0-5° C. under argon. The reaction was monitored by t.l.c. (silica, 5:95 methanol in dichloromethane) and HPLC analysis. After stirring at 0-5° C. for 1 hour, an aliquot from reaction mixture was taken into HPLC grade THF (ca. 1 mL), quenched with drops of distilled water and injected on an HPLC instrument. The result indicated only 8percent AUC (area under curve) of starting material remained and 70.8percent of product was present. The reaction was quenched by adding saturated aqueous NH4Cl solution (5 mL) at 5° C. and stirred for 15 minutes. After this time, the layers were separated and the aqueous layer was further extracted with isopropyl acetate (10 mL). The organic layers were combined, washed with brine (5 mL) and dried with anhydrous sodium sulfate. After concentration in vacuo at 40° C., the crude residue (287 mg, white foamy solid) was purified by column chromatography (silica gel, 5percent methanol in dichloromethane) to yield 2'-deoxy-5'-O-trityl--D-thymidine 5 (106 mg, 44percent yield) as a white solid. |
41% | Stage #1: With sodium bis(2-methoxyethoxy)aluminium dihydride In tetrahydrofuran; toluene at 0 - 5℃; for 6 h; |
2,2'-Anhydro-1-(5-O-trityl--D-arabinofuranosyl) thymine (Q (4.30 g, 8.91 mmol) was suspended in anhydrous tetrahydrofuran (43 mL) and cooled to about 0-5° C. using an ice-bath. In a separate flask immersed in an ice-bath at about 0-5° C., a 65percent wt solution of Red-Al in toluene (3.26 mL, 10.69 mmol) was diluted by addition to anhydrous tetrahydrofuran (21.5 mL). This diluted Red-Al solution was cooled to about 0-5° C. and added dropwise via syringe to the suspension of 2,2'-anhydro-1-(5-O-trityl--D-arabinofuranosyl) thymine (2) in tetrahydrofuran. The rate of dropwise addition of the Red-Al solution is critical to the reaction and was completed in about 1 hour. The resulting clear solution was maintained at about 0-5° C. for 1 hour after which time, t.l.c. analysis (10percent methanol in dichloromethane) indicated the presence of starting material (Rf 0.34), required product (Rf 0.47) and impurities (Rf 0.42 and 0.26). HPLC analysis indicated presence of starting material (11.35 mins, 36.5percent AUC), product (12.60 mins, 24percent) and little of the major impurity (11.7 mins, 2.9percent). After a total of about 2 hours at about 0-5° C., an additional portion of an "undiluted" 65percent wt solution of Red-Al in toluene (1.63 mL, 5.35 mmol) was added dropwise via syringe over a period of about 20 minutes to the reaction mixture, which was maintained at about 0-5° C. After about a further 1 hour, t.l.c. and HPLC analysis indicated presence of starting material (11.35 mins, 3.2percent). A further portion of a 65percent wt solution of Red-Al in toluene (0.26 mL, 0.85 mmol) was added dropwise and the reaction mixture maintained at about 0-5° C. for a further 45 minute period. After this time, t.l.c. analysis indicated only a trace amount of remaining starting material. The reaction was quenched by addition of saturated NH4Cl solution (40 mL) and the tetrahydrofuran layer was decanted. The aqueous layer was extracted with isopropylacetate (50 mL) and the resulting emulsion was broken by slow addition of 5N HCl solution (15 mL). The organic layer was separated, combined with the tetrahydrofuran layer and washed with saturated NH4Cl solution (30 mL) and then brine (30 mL). The pH of the brine layer was 6.5 to 7 at this point, and the organic layer was dried with Na2SO4, filtered and concentrated in vacuo to yield a foamy solid (4.4 g). The crude residue was co-evaporated with toluene (30 mL), concentrated in vacuo and the resulting residue was taken into toluene (25 mL) by heating to about 45° C. The mixture was cooled to room temp. and stirred at this temperature until a white solid began to precipitate. Water (8.5 mL) was added dropwise and the resulting mixture stirred at room temperature for about 3 hours. The solid was isolated by filtration and the filter cake washed with water (5 mL) and toluene (3 mL). The solid was dried at about 45° C. under high vacuum for approximately 1 hour and then at room temperature under vacuum overnight to yield 2'-deoxy-5'-O-trityl--D-thymidine (3) (1.77 g, 41percent) as a white solid. |