Non-hydrolyzable nucleoside di- or tri-phosphate derivatives and uses thereof
A compound and hydrocarbon-based technology, applied in the field of polyphosphate nucleoside derivatives and pharmaceutical compositions containing them, can solve problems such as unqualified and unstable alkaline phosphatase
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Embodiment 1
[0122] Example 1. β,γ-CH 2 -2MeS-adenosine-5'-triphosphate (2) synthesis
[0123] β,γ-CH was prepared by two methods as shown in Scheme 1 and described below 2 -2MeS-adenosine-5'-triphosphate (2):
[0124] Method A. Bis(tributylammonium)methylene diphosphonate was prepared as described above. In a flame-dried two-necked flask, 1,8-bis(dimethylamino)naphthalene (117mg, 0.57mmol, 1.5eq) was added to 2 ',3'-O-methoxymethylene-2-MeS-adenosine (5a) (130 mg, 0.37 mmol), and the reaction was stirred for 20 minutes until a clear solution was obtained. Add POCl at 0°C 3 (67 μl, 1.09 mmol, 3 eq). The solution was stirred at 0 °C for 3 hours. A 0.5M solution of bis(tributylammonium)methylene diphosphonate (386mg, 2.19mmol, 6eq) in anhydrous DMF (4.3ml) and tributylamine (360μl, 1.46mmol, 4eq) were added at 0°C , and the reaction mixture was stirred for 1.6 minutes. A 0.25M solution of ammonium acetate (10 ml) was added at room temperature and the reaction mixture was stirred for ...
Embodiment 2
[0126] Example 2. Adenosine-β,γ-CH 2 Synthesis, Isolation and Characterization of -5'-O-(1-Borane Triphosphate)(3)
[0127] Adenosine-β,γ-CH 2 -5'-O-(1-borane triphosphate) (3) synthesis
[0128] Bis(tributylammonium)methylene diphosphonate was prepared by mixing Bu 3 N (2 eq) was added to the free acid of methylene diphosphonic acid in EtOH and stirred for 2 hours, then the solvent was removed under reduced pressure to give a white solid. As described in Scheme 2, 2′,3′-O-methoxymethyleneadenosine 9 (100 mg, 0.32 mmol) was dissolved in trimethylphosphate in a flame-dried two-necked flask under nitrogen ester (2.5ml). At 0°C, 1,8-bis(dimethylamino)naphthalene (138mg, 0.65mmol, 2eq) was added and the reaction was stirred for 20 minutes until a clear solution was obtained. Add PCl at 0°C 3 (56 μl, 0.65 mmol, 2 eq), a white solid precipitated. The suspension was stirred at 0°C for 30 minutes. Then, a 1M solution of bis(tributylammonium)methylene diphosphonate (642 mg, 1.9...
Embodiment 32
[0135] Example 3.2MeS-adenosine-β,γ-CH 2 Synthesis, Isolation and Characterization of -5'-O-(1-Borane Triphosphate)(4)
[0136] 2MeS-adenosine-β,γ-CH 2 -5'-O-(1-borane triphosphate) (4) synthesis
[0137] In the same manner as described for product 3 in Example 2, product 4 was obtained from 5a in 28% overall yield after LC separation as shown in Scheme 2 below.
[0138] 2MeS-adenosine-β,γ-CH 2 -Isolation of 5'-O-(1-borane triphosphate) (4)
[0139] Separation of the 4 diastereomers was achieved using a semi-preparative reversed-phase Gemini 5u column (C-18110A, 250 x 10.00 mm, 5 microns) and isocratic elution: a solvent system I of 75:25 A:B was applied ( See Example 1), the flow rate is 5ml / min. Final separation of the two diastereomers was achieved using an analytical Gemini 5u column (C-18110A, 150 x 4.6 mm) and solvent system I (see Example 1): Gradient 82:18 to 74:26 A:B , lasted 20 minutes, the flow rate was 1ml / min. Fractions containing the same isomer [Rt = 9.7...
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