High-efficiency anti-hepatitis B virus compound and its preparation method and application
A hepatitis B virus and compound technology, which is applied in the directions of antiviral agents, compounds of Group 5/15 elements of the periodic table, chemical instruments and methods, etc. , to achieve good antiviral effect and good fat solubility
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[0031] The present invention also discloses a preparation method of an anti-hepatitis B virus compound, comprising the following steps:
[0032] Step 1: Preparation of 9-(4-hydroxy-3-hydroxymethyl-2-methylenecyclopent-1-yl)guanine.
[0033]In the present invention, 9-(4-hydroxy-3-hydroxymethyl-2-methylenecyclopent-1-yl)guanine D can be prepared according to the prior art, and will not be described in detail here. The chemical structural formula of 9-(4-hydroxyl-3-hydroxymethyl-2-methylenecyclopent-1-yl) guanine is: .
[0034] Step 2: preparing phosphoric acid ester compounds or phosphoric acid amide compounds, wherein the phosphoric acid ester compounds include phosphoric acid triester compounds and phosphoric diester compounds.
[0035] In this embodiment, a preparation method of phosphate triester compound is provided, that is, R 1 The structure is: ; 4 The structure is: ; 7 and R 8 for H; R 9 for -CH 3 ; of course, in other embodiments, R 1 , R 4 , R 7 , R ...
Embodiment 1
[0045] Prepare the compound Y403 of K1 type anti-hepatitis B virus, the reaction route is:
[0046] .
[0047] In this example, compound C is the compound C prepared in the aforementioned step 2, and compound D can be prepared by existing techniques.
[0048] The specific synthesis method is:
[0049] Compound D (1 g, 3.61 mmol) and compound C (2.16 g, 6.49 mmol) were dissolved in tetrahydrofuran (THF, 50 mL), and the reaction solution was replaced with argon to remove air, and the reaction solution was under argon protection , using ice water to cool down the reaction solution to 0°C, then add 3-nitro-1H-1,2,4-triazole (823 mg, 7.2 mmol), diisopropylethylamine (DIPEA, 1.86 g, 14.43 mmol) and bis (2-oxo-3-oxazolidinyl) phosphorous oxychloride (BOP-Cl, 1.84 g, 7.21 mmol), then the reaction solution was naturally warmed to room temperature and stirred for 30 min, and samples were taken for LC-MS Detect to confirm that the reaction of raw materials is complete. Then add eth...
Embodiment 2
[0053] The compound Y402 of K2 anti-hepatitis B virus is prepared, and the reaction route is:
[0054] .
[0055] In combination with the aforementioned chemical structure general formula K, in this embodiment, R 1 The structure is: ; 5 is phenyl, R 6 is an amino acid ester structure; R 10 for H or -CH 3 ; 11 for -CH 3 or H; R 12 for-C 3 -C 10 branched chain hydrocarbon group; of course, in other embodiments, R 5 , R 6 , R 10 , R 11 and R 12 The structure of can be other aforementioned structural formulas, which is not limited here.
[0056] The specific synthesis method is:
[0057] Compound D (1 g, 3.6 mmol) was added to N-methylpyrrolidone (23 mL), cooled to 0°C with ice water, and stirred for 15 min, then slowly added tert-butylmagnesium chloride (t-BuMgCl, 7.2 mL , 7.2 mmol), after the dropwise addition, continue to keep stirring at 0°C for 40 min, then slowly add dropwise the mixed solution of compound F (1.78 g, 3.97 mmol) and tetrahydrofuran (30 mL)...
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