CN107286212B - Preparation method of high-purity didanosine impurity - Google Patents

Abstract

The invention discloses a preparation method of high-purity didanosine impurities, which is characterized by easy acquisition of adopted reagents, simple synthesis operation, mild reaction conditions and high product purity. Which comprises the following steps: 1) taking 2-acetoxy isobutyryl chloride and inosine as initial raw materials, and carrying out bromination reaction and acylation reaction in a solvent under the catalysis of lithium bromide; 2) concentrating the reaction solution obtained in the step 1, removing the solvent, and dissolving the reaction solution in a polar solvent to be directly used in the next step; 3) adding an alkaline reagent into the mixture at low temperature, adjusting the pH value to be in a strong alkali condition, and reacting to obtain the 2 ', 3' -anhydroinosine.

Description

A kind of preparation method of high-purity didanosine impurity

technical field

The invention relates to the field of organic synthesis, in particular to a method for preparing a high-purity didanosine impurity.

Background technique

The chemical name of didanosine (DDI) is 2,3-dideoxyinosine. The drug is an HIV-1 reverse transcriptase inhibitor developed by Bristol-Myers Squibb Company in the United States and first listed in the United States in 1991.

This product prevents the replication of the virus by interfering with reverse transcriptase and increases the number of CD4 cells in AIDS patients, thereby prolonging the survival time of patients and reducing the incidence of pathogenic bacterial infection. It has been clinically used for AIDS patients who cannot tolerate zidovudine (AZT), who are ineffective in AZT treatment or asymptomatic HIV infection.

Although didanosine has been on the market for more than two decades, there are relatively few studies on impurities in its production process. Especially the discovery of 2',3'-anhydroinosine, the applicant discovered the impurity 2',3'-anhydroinosine in the production process of didanosine, and verified the amount and reaction of this impurity through a large number of chemical experiments The degree of progress is related, and its structural formula is as follows:

From the perspective of safe drug use, the synthesis of 2', 3'-anhydroinosine standard samples (that is, the reference substance) is particularly important for synthesizing high-quality didanosine, reducing side effects, and improving the survival rate and quality of life of AIDS patients. For pharmaceutical factories, high-purity impurity control can provide data support and theoretical basis for us to monitor the production process, reduce the occurrence of side reactions, and improve product yield and purity. On the other hand, international competition is becoming more and more intense, and high-quality products can improve the competitiveness of products.

SUMMARY OF THE INVENTION

The purpose of the present invention is to provide a kind of preparation method of high-purity didanosine impurity 2', 3'-dehydroinosine, the reagent that this method adopts is easy to obtain, the synthesis operation is simple, the reaction condition is mild, and the product purity is high.

The purpose of this invention is to realize through the following technical solutions:

A kind of preparation method of didanosine impurity 2', 3'-dehydrated inosine, comprises the following steps:

1. Take 2-acetoxyisobutyryl chloride and inosine as starting materials, and react in a solvent under the catalysis of lithium bromide;

In this step, bromination reaction and acylation reaction occur to obtain 5-O-(2,4,4-trimethyl-1,3-dioxo-cyclopentanonyl)-2-bromo-3-acetoxy-carboxyl glycosides and 5-O-(2,4,4-trimethyl-1,3-dioxolanone)-3-bromo-2-acetoxy-inosine;

2. The reaction solution obtained in step 1 is concentrated to remove the solvent and then dissolved in a polar solvent to be directly used in the next step;

3. Add an alkaline reagent to the polar solvent obtained in step 2) under low temperature conditions, adjust the pH to react under strong alkaline conditions, and filter to obtain 2',3'-dehydrated inosine.

The above steps are expressed as:

Preferably, in the above technical solution, the operation steps of step 1 are: adding anhydrous lithium bromide to the solvent to heat up, and waiting for the anhydrous lithium bromide to dissolve; then adding 2-acetoxyisobutyryl chloride to react; Inosine was added for the reaction.

Preferably, in the above technical solution, in step 1, the mass ratio of anhydrous lithium bromide, 2-acetoxyisobutyryl chloride and inosine is 30-40:50-60:25-35, which can be 35-40:55- 58:28-32, eg: 37.5:55:30.

Preferably, in the above technical solution, the temperature increase in step 1 is to increase to 70-75°C, and the temperature decrease in step 1 is to decrease to below 10°C.

Preferably, in the above technical solution, 2-acetoxyisobutyryl chloride is added in step 1 and reacted for 0.5-2h, such as 1h; in step 1, inosine is added and reacted for 3-6h, such as 4h.

Preferably, in the above technical solution, the solvent in step 1 is acetonitrile.

Preferably, in the above technical solution, 5-15g of acetonitrile is used for every 1g of inosine used in step 1.

Preferably, in the above technical solution, steps 1 and 2 further include neutralizing the reaction solution obtained in step 1 to a neutral or weakly alkaline environment, such as: neutralizing to pH 6.5-7.0 with anhydrous sodium acetate.

Preferably, in the above technical scheme, after removing the solvent in step 2 and before dissolving in the polar solvent, the following steps are further included: adding the intermediate product to the mixture of dichloromethane and water, stirring, and statically layering, and taking the dichloromethane layer The dichloromethane was evaporated to dryness, and the obtained product was used. The ratio of dichloromethane to water can be 1:10～10:1, or 1:3～3:1, the impurities are partially dissolved in water, and the intermediate product is dissolved in dichloromethane; Add 6-10ml, can be 6-8ml of a mixture of dichloromethane and water per 1g of the intermediate product.

Preferably, in the above technical solution, the polar solvent in step 2 is methanol, ethanol, isopropanol or tert-butanol.

Preferably, in the above technical solution, the low temperature condition in step 3 is -20-10°C, such as: 5-10°C.

Preferably, in the above technical solution, the alkaline reagents in step 3 are sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, methylamine and their corresponding aqueous solutions.

Preferably, in the above technical solution, the strong alkali condition in step 3 is that the pH value is greater than or equal to 10, which may be pH value 12-14.

Preferably, in the above technical solution, the time required for the reaction in step 3 is 8-16h, such as 12h. The heat preservation reaction at low temperature enables deprotection, formation of epoxy bonds, and crystallization to proceed simultaneously.

Compared with the prior art, the invention has the following beneficial effects: the reagents used in the method are easy to obtain, the synthesis operation is simple, the reaction conditions are mild, and the product purity is high, which can reach more than 99.5%, and the weight yield can also reach 84%. Above, the molar yield can reach more than 90%. And through the synthesis of 2', 3'-anhydroinosine, a standard sample is provided for the qualitative and quantitative detection of didanosine impurities.

Description of drawings

Fig. 1 is the hydrogen nuclear magnetic resonance spectrum of didanosine impurity 2', 3'-anhydroinosine of the present invention, ¹ H NMR (400MHz, DMSO): δ=8.30(s, 1H, 1-H), 8.10(s ,1H,2-H),6.17(s,1H,3-H),4.46(d,J=4.0Hz,1H,4-H),4.21-4.18(m,J=8.0Hz,2H,5- H), 3.53 (d, J=4.0 Hz, 2H, 6-H). The peak at 2.50 is the DMSO solvent peak.

Fig. 2 is the mass spectrum of didanosine impurity 2', 3'-anhydroinosine of the present invention.

Detailed ways

The specific embodiments of the present invention will be described in detail below with reference to the accompanying drawings, but it should be understood that the protection scope of the present invention is not limited by the specific embodiments.

Example 1

1) 250g of acetonitrile was dropped into a dry reaction flask, 37.5g of anhydrous lithium bromide was added under stirring and the temperature was raised to 70-75°C, until the anhydrous lithium bromide was dissolved; then 55g of 2-acetoxyisobutyryl chloride was added to react for 1 hour; After the obtained reaction solution was cooled to below 10 °C, 30 g of inosine was added to carry out the reaction for 4 h;

2) Add anhydrous sodium acetate to neutralize the pH to 6.5-7.0, and concentrate in vacuo to remove acetonitrile to obtain a milky white solid thick substance; add 8 ml of a mixture of dichloromethane and water, a mixture of dichloromethane and water per 1 g of the milky white solid thick substance The volume ratio was 1:1, stirring for 15 minutes, static layering, taking the dichloromethane layer, evaporating the dichloromethane layer to dryness, and dissolving the obtained product in 150 ml of ethanol;

3) Add 120ml of alkaline reagent 5% sodium hydroxide aqueous solution to it at 5-10°C, adjust the pH to pH 13, react for 12h, filter, and dry to obtain 25.8g of 2',3'-anhydroinosine , the purity is above 99.0%, and the weight yield is 86% (molar yield 92.2%).

Example 2

1) 250g of acetonitrile was dropped into a dry reaction flask, 37.5g of anhydrous lithium bromide was added under stirring and the temperature was raised to 70-75°C, until the anhydrous lithium bromide was dissolved; then 55g of 2-acetoxyisobutyryl chloride was added to react for 1 hour; After the obtained reaction solution was cooled to below 10 °C, 30 g of inosine was added to carry out the reaction for 4 h;

2) Add anhydrous sodium acetate to neutralize the pH to 6.5-7.0, and concentrate in vacuo to remove acetonitrile to obtain a milky white solid thick substance; add 8 ml of a mixture of dichloromethane and water, a mixture of dichloromethane and water per 1 g of the milky white solid thick substance The volume ratio was 1:1, stirred for 15 minutes, separated into layers, and the dichloromethane layer was evaporated to dryness, and the obtained product was dissolved in 150 ml of methanol;

3) Add 120ml of alkaline reagent methylamine aqueous solution to it at 5-10°C, adjust the pH to a strong base pH value of 12, react for 12h, filter, and dry to obtain 25.2g of 2',3'-anhydroinosine, The purity is 99.5% or more, and the weight yield is 84% or more (molar yield 90.1%).

Example 3

1) 300g of acetonitrile was dropped into a dry reaction flask, 40g of anhydrous lithium bromide was added under stirring and the temperature was raised to 70-75°C, until the anhydrous lithium bromide was dissolved; then 60g of 2-acetoxyisobutyryl chloride was added to react for 1 hour; the obtained After the reaction solution was cooled to below 10°C, 30g of inosine was added to react for 4h;

2) Add anhydrous sodium acetate to neutralize the pH to 6.5-7.0, and concentrate in vacuo to remove acetonitrile to obtain a milky white solid thick substance; add 6 ml of a mixture of dichloromethane and water, a mixture of dichloromethane and water per 1 g of the milky white solid thick substance The volume ratio was 1:3, stirring for 15 minutes, static layering, taking the dichloromethane layer, evaporating the dichloromethane layer to dryness, and dissolving the obtained product in 150 ml of tert-butanol;

3) Add 130ml of alkaline reagent 5% sodium hydroxide aqueous solution to it at 5-10°C, adjust the pH to a strong base pH value of 14, react for 12h, filter, and dry to obtain 2',3'-anhydroinosine 22.5 g, purity 99.0% or more, weight yield 75% (molar yield 80.4%).

The foregoing descriptions of specific exemplary embodiments of the present invention have been presented for purposes of illustration and description. These descriptions are not intended to limit the invention to the precise forms disclosed, but the exemplary embodiments were chosen and described for the purpose of explaining certain principles of the invention and their practical application, to enable those skilled in the art to make and utilize the invention Various exemplary embodiments of the invention, as well as various choices and modifications. The scope of the invention is intended to be defined by the claims and their equivalents.

Claims (9)

1. A method for preparing didanosine impurity 2 ', 3' -anhydroinosine is characterized by comprising the following steps:

1) taking 2-acetoxy isobutyryl chloride and inosine as initial raw materials, and carrying out bromination reaction and acylation reaction in a solvent under the catalysis of lithium bromide;

wherein, the operation steps of the step 1) are as follows: adding anhydrous lithium bromide into the solvent, and heating until the anhydrous lithium bromide is dissolved; then adding 2-acetoxy isobutyryl chloride for reaction; cooling the obtained reaction liquid, and then adding inosine for reaction; the temperature is raised to 70-75 ℃, and the temperature is lowered to below 10 ℃;

in the step 1), the mass ratio of the anhydrous lithium bromide to the 2-acetoxyisobutyryl chloride to the inosine is 30-40:50-60: 25-35;

2) concentrating the reaction solution obtained in the step 1), removing the solvent, and dissolving the reaction solution in a polar solvent to be directly used in the next step;

3) adding an alkaline reagent into the mixture at low temperature, adjusting the pH value to be in a strong alkali condition for reaction, and filtering to obtain 2 ', 3' -anhydroinosine;

wherein, before the reaction solution is concentrated to remove the solvent in the step 2), the method also comprises the step of neutralizing the reaction solution obtained in the step 1) to a neutral environment;

after the solvent is removed in the step 2) and before the solvent is dissolved in the polar solvent, the method also comprises the step of removing impurities, wherein the step of removing the impurities comprises the following steps: adding the intermediate product into a mixture of dichloromethane and water, stirring, standing for layering, taking a dichloromethane layer, and evaporating dichloromethane to dryness;

in the step 3), the low-temperature condition is 0-10 ℃, and the strong alkali condition is that the pH is 10-14.

2. The method for preparing didanosine impurity, 2 ', 3' -anhydroinosine, according to claim 1, wherein the mass ratio of the anhydrous lithium bromide, the 2-acetoxyisobutyryl chloride, and the inosine in the step 1) is 37.5:55: 30.

3. The method for preparing didanosine impurity 2 ', 3' -anhydroinosine according to claim 1, wherein the step 1) is performed for 0.5 to 2 hours after 2-acetoxyisobutyryl chloride is added; adding inosine in the step 1) and reacting for 3-6 h.

4. The method for preparing didanosine impurity, 2 ', 3' -anhydroinosine, according to claim 3, wherein the reaction time after adding 2-acetoxyisobutyryl chloride in the step 1) is 1 hour; inosine was added in step 1) and the reaction was carried out for 4 h.

5. The method for preparing didanosine impurity, 2 ', 3' -anhydroinosine, according to claim 1, wherein the solvent used in step 1) is acetonitrile, and 5-15g of acetonitrile is used for every 1g of inosine used in step 1).

6. The method for preparing didanosine impurity 2 ', 3' -anhydroinosine according to claim 1, wherein the polar solvent in the step 2) is methanol or ethanol.

7. The method for preparing didanosine impurity, 2 ', 3' -anhydroinosine, according to claim 1, wherein the low temperature condition in the step 3) is 5 to 10 ℃; the time required for the reaction in the step 3) is 8-16 h.

8. The method for preparing didanosine impurity, 2 ', 3' -anhydroinosine, according to claim 7, wherein the time required for the reaction in the step 3) is 12 hours.

9. The method for preparing didanosine impurity 2 ', 3' -anhydroinosine according to claim 1, wherein the alkaline reagent in the step 3) is sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, methylamine and corresponding aqueous solutions thereof.

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