Synthetic process of tenofovir

A synthesis process and reaction bottle technology, which is applied in the field of synthesis process for the preparation of anti-AIDS and anti-hepatitis B drug Tenofovir, can solve the problems of unreachable and high production costs, achieve mild reaction conditions, avoid reaction conditions, Significant economic and social benefits

Inactive Publication Date: 2011-12-28
CHANGZHOU UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0013] This route is shorter and the yield is higher, but the optical purity of the final product is only 90-94%, which cannot meet the clinical requirements and needs to be purified by other means , will inevitably lead to an increase in production costs

Method used

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  • Synthetic process of tenofovir
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  • Synthetic process of tenofovir

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0033] Example 1 (1) Preparation of R-1,2-propanediol (I)

[0034] Take a 250 mL three-neck flask, add sodium borohydride (5.7 g, 0.15 mol), methyl lactate (10.4 g, 0.10 mol) and toluene (60 mL), stir at room temperature for 2 hours, then add 5 mL of methanol (note: the reaction violently emits Add 5 mL of methanol 10 minutes later, carefully add 5 mL of methanol for the third time after 10 minutes to stop the reaction, cool to room temperature and adjust the pH value to neutral with 5 mol / L hydrochloric acid (Note: the gas is also released violently, it needs to be added carefully), the system produces a large amount of insoluble matter, the insoluble matter is filtered out, and the diol product is obtained after distilling off the solvent. It was directly used in the next reaction without purification.

[0035] (2) Preparation of R-propylene carbonate (II)

[0036] Take a 50 mL three-neck flask with a spherical condenser, add a stirring magnet, and then measure 2 mL of...

Embodiment 2

[0043] Example 2 (1) Preparation of R-1,2-propanediol (I)

[0044] Take a 250 mL three-neck flask, add lithium aluminum hydride (5.7 g, 0.15 mol) and THF (100 mL), add methyl lactate (10.4 g, 0.10 mol) in batches, stir at room temperature for 2 hours, then slowly add 50 mL THF dropwise The mixture with water was cooled to room temperature and then filtered, the filter cake was washed several times with THF, the filtrates were combined, and the diol product was obtained after distilling off the solvent. It was directly used in the next reaction without purification.

[0045] (2) Preparation of R-propylene carbonate (II)

[0046] Take a 50 mL three-neck flask with a spherical condenser, add a stirring magnet, and then measure 2 mL of absolute ethanol into the bottle. Weigh sodium methoxide (0.50 g, 0.009 mol), add diol (6.61 g, 89.7 mmol), heat to reflux for 30 minutes, slowly drop diethyl carbonate (12.98 g, 0.11 mol), control the rate of addition, the system releases ho...

Embodiment 3

[0053] Example 3 (1) Preparation of R-1,2-propanediol (I)

[0054] Take a 250 mL three-neck flask, add sodium borohydride (7.6 g, 0.20 mol), tert-butyl lactate (14.6 g, 0.10 mol) and cyclohexane (100 mL), stir at room temperature for 2 hours, then add 15 mL of methanol to stop the reaction , after cooling to room temperature, adjust the pH value to neutral with 5 mol / L hydrochloric acid, the system produces a large amount of insoluble matter, filter out the insoluble matter, and diol product is obtained after distilling off the solvent. It was directly used in the next reaction without purification.

[0055] (2) Preparation of R-propylene carbonate (II)

[0056] Take a 50 mL three-neck flask with a spherical condenser, add a stirring magnet, and then measure 2 mL of absolute ethanol into the bottle. Weigh sodium methoxide (0.50 g, 0.009 mol), add diol (6.61 g, 89.7 mmol), heat to reflux for 30 minutes, slowly drop diethyl carbonate (12.98 g, 0.11 mol), control the rate o...

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Abstract

The invention relates to a synthesis technique of tenofovir, and relates to the field of medicinal chemistry. Using natural (R)-lactate as the starting material, chiral R-1,2-propanediol is obtained through reduction, and then reacted with diethyl carbonate under the action of alkali to obtain the key reaction intermediate R-propylene carbonate ester. Use adenine and R-propylene carbonate to prepare R-9-(2-hydroxypropyl)adenine; Gained R-9-(2-hydroxypropyl)adenine and diethyl p-toluenesulfonyloxyphosphate Under the catalysis of magnesium tert-butoxide, the condensation reaction is carried out to obtain R-9[(diethylphosphorylmethoxy)propyl]purine; the obtained R-9[2-(diethylphosphorylmethoxy) Propyl]purine is hydrolyzed to obtain Tenofovir. The process has short reaction steps, short required reaction time, high quality yield and good product quality, and is suitable for industrialized production.

Description

technical field [0001] The invention relates to the field of medicinal chemistry, and relates to a synthesis process for preparing tenofovir, an anti-AIDS and anti-hepatitis B drug. Background technique [0002] Tenofovir disoproxil fumarate (tenofovir disoproxil fumarate), chemical name (R)-[[2-(6-amino-9H-purine-9- Base)-1-methylethoxy]methyl]phosphonic acid bis(isopropionyloxymethyl) fumarate, whose structure is shown in Figure 1, is a first-line treatment against hepatitis B The drug is quickly transformed into tenofovir (PMPA) after being absorbed by the human body to produce antiviral effects. PMPA has been confirmed to have broad-spectrum antiviral activity against human immunodeficiency virus HIV and HBV, and has been approved by the US FDA in 2001 as a drug for clinical treatment of AIDS. [0003] [0004] Structural formula 1 tenofovir disoproxil [0005] Tenofovir is the key intermediate of tenofovir dipivoxil, and there are mainly two kinds of synthetic met...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07F9/6561
Inventor 李剑陆国元刘莉
Owner CHANGZHOU UNIV
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