Preparation method for (R)-9-[2-(phosphonomethoxy)propyl]adenine

Abstract

The invention provides a multiphase compound discontinuous preparation method for (R)-9-[2-(phosphonomethoxy)propyl]adenine (II). The method comprises the following steps: a) reacting adenine (III) with R-propylene carbonate (IV); b) after completion of the reaction in the step a), adding p-benzenesulfonyloxy phosphoric acid diethyl ester and (RO)2Mg, wherein R is an aliphatic alkyl group with a carbon atom number of 1 to 6; and c) after completion of the reaction in the step b), adding protonic acid and carrying out hydrolysis reaction. The preparation method is characterized in that after-treatment is not needed after completion of the reaction or subsequent reaction can be carried out without separation of target intermediates during the reactions. The multiphase compound discontinuous preparation method has low energy consumption, is friendly to the environment and employs cheap and easily available reagents, which enables cost to be obviously reduced.

Description

technical field

[0001] The invention relates to drug synthesis, in particular to a synthesis method of (R)-9-(2-phosphomethoxypropyl)adenine. Background technique

[0002] Tenofovir dipivoxil (also known as tenofovir bisisopropionyloxymethyl ester), the chemical name is (R)-[[2-(6-amino-9H-purin-9-yl)-1- Methylethoxy] methyl] phosphonic acid bis (isopropionyloxymethyl) ester, its structure is as shown in formula (I), is a kind of anti-hepatitis B first-line therapeutic drug, changes rapidly after the human body absorbs into (R)-9-(2-phosphomethoxypropyl)adenine (PMPA), whose structural formula is as formula (II). PMPA has been confirmed to have broad-spectrum antiviral activity against human immunodeficiency virus HIV and HBV. It was approved by the US FDA in 2001 as a drug for clinical treatment of AIDS.

[0003]

[0004] Chinese patent application CN 102295660 and CN 101418017 react R-9-(2-hydroxypropyl) adenine with adenine and R-propylene carbonate; Gained R-9-(2-hy...

Examples

specific Embodiment approach

[0037] In order to enable those skilled in the art to better understand the technical solutions of the present invention, some non-limiting examples are further disclosed below to further describe the present invention in detail.

[0038] The reagents used in the present invention can be purchased from the market or can be prepared by the methods described in the present invention.

[0039] In the present invention, g means gram, and ml means milliliter.

Embodiment 1

[0040] The preparation of embodiment 1R-9-(2-hydroxypropyl) adenine

[0041] Add 10g of adenine, 9.83g of R-propylene carbonate, 50ml of DMF and 0.44g of NaOH into a 250ml reaction flask, and stir at room temperature for 10 minutes. After the system is uniform, it begins to heat up to about 130°C. HPLC detects that the product in the reaction solution is The purity is 90.5%. After the reaction is completed, the temperature of the reaction solution is lowered to 70°C.

Embodiment 2

[0042] The preparation of embodiment 2R-9-[(diethylphosphorylmethoxy) propyl] adenine

[0043] Add 13.9g of magnesium tert-butoxide to the reaction solution at 70°C prepared in Example 1, heat and stir for 0.5 hours, then start to add 47.7g of p-toluenesulfonyloxy diethyl phosphate dropwise; after the dropwise addition and stirring for 6 hours, HPLC detects that the purity of the product in the reaction solution is 92.3%, and the purity of the raw material is less than or equal to 1.0%. After the reaction is completed, anhydrous acetic acid (2ml) is added dropwise; after the dropwise addition, the room temperature is stirred for 30 minutes; DMF is evaporated under reduced pressure, After distillation, there was no need to isolate the target intermediate, and R-9-[2-(diethylphosphorylmethoxy)propyl]adenine oil was obtained.

technical field

[0001] The invention relates to drug synthesis, in particular to a synthesis method of (R)-9-(2-phosphomethoxypropyl)adenine. Background technique

[0002] Tenofovir dipivoxil (also known as tenofovir bisisopropionyloxymethyl ester), the chemical name is (R)-[[2-(6-amino-9H-purin-9-yl)-1- Methylethoxy] methyl] phosphonic acid bis (isopropionyloxymethyl) ester, its structure is as shown in formula (I), is a kind of anti-hepatitis B first-line therapeutic drug, changes rapidly after the human body absorbs into (R)-9-(2-phosphomethoxypropyl)adenine (PMPA), whose structural formula is as formula (II). PMPA has been confirmed to have broad-spectrum antiviral activity against human immunodeficiency virus HIV and HBV. It was approved by the US FDA in 2001 as a drug for clinical treatment of AIDS.

[0003]

[0004] Chinese patent application CN 102295660 and CN 101418017 react R-9-(2-hydroxypropyl) adenine with adenine and R-propylene carbonate; Gained R-9-(2-hy...

Examples

specific Embodiment approach

[0037] In order to enable those skilled in the art to better understand the technical solutions of the present invention, some non-limiting examples are further disclosed below to further describe the present invention in detail.

[0038] The reagents used in the present invention can be purchased from the market or can be prepared by the methods described in the present invention.

[0039] In the present invention, g means gram, and ml means milliliter.

Embodiment 1

[0040] The preparation of embodiment 1R-9-(2-hydroxypropyl) adenine

[0041] Add 10g of adenine, 9.83g of R-propylene carbonate, 50ml of DMF and 0.44g of NaOH into a 250ml reaction flask, and stir at room temperature for 10 minutes. After the system is uniform, it begins to heat up to about 130°C. HPLC detects that the product in the reaction solution is The purity is 90.5%. After the reaction is completed, the temperature of the reaction solution is lowered to 70°C.

Embodiment 2

[0042] The preparation of embodiment 2R-9-[(diethylphosphorylmethoxy) propyl] adenine

[0043] Add 13.9g of magnesium tert-butoxide to the reaction solution at 70°C prepared in Example 1, heat and stir for 0.5 hours, then start to add 47.7g of p-toluenesulfonyloxy diethyl phosphate dropwise; after the dropwise addition and stirring for 6 hours, HPLC detects that the purity of the product in the reaction solution is 92.3%, and the purity of the raw material is less than or equal to 1.0%. After the reaction is completed, anhydrous acetic acid (2ml) is added dropwise; after the dropwise addition, the room temperature is stirred for 30 minutes; DMF is evaporated under reduced pressure, After distillation, there was no need to isolate the target intermediate, and R-9-[2-(diethylphosphorylmethoxy)propyl]adenine oil was obtained.

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