CN107286212B - Preparation method of high-purity didanosine impurity - Google Patents
Preparation method of high-purity didanosine impurity Download PDFInfo
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- CN107286212B CN107286212B CN201610220005.4A CN201610220005A CN107286212B CN 107286212 B CN107286212 B CN 107286212B CN 201610220005 A CN201610220005 A CN 201610220005A CN 107286212 B CN107286212 B CN 107286212B
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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
Technical Field
The invention relates to the field of organic synthesis, and particularly relates to a preparation method of a high-purity didanosine impurity.
Background
Didanosine (DDI) is chemically known as 2, 3-dideoxyinosine. The drug was developed by Bristol-Myers Squibb, USA, and was first marketed in 1991 in the United states as an HIV-1 reverse transcriptase inhibitor.
The product can inhibit virus replication by interfering reverse transcriptase to increase CD4 cell number of AIDS patients, thereby prolonging survival time of patients and reducing incidence of pathogenic bacteria infection. Has been clinically used in AIDS patients who cannot tolerate zidovudine (AZT), A ZT treatment ineffective or asymptomatic HIV infection.
Although didanosine is marketed for more than twenty years, there is relatively little research on impurities in its production process. In particular to the discovery of 2 ', 3' -anhydroinosine, the applicant discovers the impurity 2 ', 3' -anhydroinosine in the production process of didanosine and verifies that the amount of the impurity is related to the reaction progress degree through a large number of chemical experiments, and the structural formula is as follows:
standing in the aspect of safe medication, the synthesis of the 2 ', 3' -anhydroinosine standard sample (namely a reference substance) is particularly important for synthesizing high-quality didanosine, reducing side effects and improving the survival rate and the life quality of AIDS patients. For pharmaceutical factories, high purity impurity controls can provide data support and theoretical basis for monitoring the production process, reducing the occurrence of side reactions, and improving product yield and purity. On the other hand, international competition is more and more intense, and high-quality products can improve the competitiveness of the products.
Disclosure of Invention
The invention aims to provide a preparation method of high-purity didanosine impurity 2 ', 3' -anhydroinosine, which adopts easily obtained reagents, has simple synthesis operation, mild reaction conditions and high product purity.
The purpose of the invention is realized by the following technical scheme:
a method for preparing didanosine impurity 2 ', 3' -anhydroinosine comprises the following steps:
1. 2-acetoxyisobutyryl chloride and inosine are used as initial raw materials to react in a solvent under the catalysis of lithium bromide;
the bromination reaction and the acylation reaction are carried out in the step to obtain 5-O- (2,4, 4-trimethyl-1, 3-dioxo-cyclopentyloxy) -2-bromo-3-acetoxyl-inosine and 5-O- (2,4, 4-trimethyl-1, 3-dioxolanyloxy) -3-bromo-2-acetoxyl-inosine;
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 polar solvent obtained in the step 2) at a low temperature, adjusting the pH value to a strong alkali condition for reaction, and filtering to obtain 2 ', 3' -anhydroinosine.
The above steps are expressed by the following reaction formula:
preferably, in the above technical solution, the operation steps of step 1 are: adding anhydrous lithium bromide into the solvent, and heating until the anhydrous lithium bromide is dissolved; then adding 2-acetoxy isobutyryl chloride for reaction; and cooling the obtained reaction liquid, and adding inosine for reaction.
Preferably, in the above technical scheme, the mass ratio of the anhydrous lithium bromide, the 2-acetoxyisobutyryl chloride and the inosine in the step 1 is 30-40:50-60:25-35, and may be 35-40:55-58:28-32, such as: 37.5:55:30.
Preferably, in the above technical scheme, the temperature in step 1 is raised to 70-75 ℃, and the temperature in step 1 is lowered to below 10 ℃.
Preferably, in the above technical scheme, the 2-acetoxyisobutyryl chloride is added in the step 1 and then reacts for 0.5 to 2 hours, such as: 1 h; adding inosine in the step 1, and reacting for 3-6h, wherein the reaction time is as follows: and 4 h.
Preferably, in the above technical scheme, the solvent in step 1 is acetonitrile.
Preferably, in the above technical scheme, 5-15g of acetonitrile is used for every 1g of inosine used in step 1.
Preferably, in the above technical scheme, the step 1 and the step 2 further comprise neutralizing the reaction solution obtained in the step 1 to a neutral or slightly alkaline environment, such as: neutralized to pH6.5-7.0 with anhydrous sodium acetate.
Preferably, in the above technical solution, after the solvent is removed in step 2 and before the solvent is dissolved in the polar solvent, the method further comprises the following steps: and adding the intermediate product into a mixture of dichloromethane and water, stirring, standing, layering, taking a dichloromethane layer, and evaporating dichloromethane to dryness to obtain a product for later use. The ratio of the dichloromethane to the water can be 1: 10-10: 1, and can also be 1: 3-3: 1, the impurities are partially dissolved in the water, and the intermediate product is dissolved in the dichloromethane; step 2 the solvent is removed and 6-10ml, optionally 6-8ml, of a mixture of dichloromethane and water is added per 1g of 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 scheme, the low temperature in step 3 is-20 to 10 ℃, for example: 5-10 ℃.
Preferably, in the above technical scheme, the alkaline reagent in step 3 is sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, methylamine and corresponding aqueous solution thereof.
Preferably, in the above technical scheme, the alkali condition in step 3 is that the pH value is greater than or equal to 10, and may be 12-14.
Preferably, in the above technical scheme, the time required for the reaction in step 3 is 8-16h, such as: and (4) 12 h. The reaction is carried out at low temperature to simultaneously carry out deprotection, formation of epoxy bond and crystallization.
Compared with the prior art, the invention has the following beneficial effects: the method has the advantages of easily obtained reagents, simple synthesis operation, mild reaction conditions, high product purity of over 99.5 percent, weight yield of over 84 percent and molar yield of over 90 percent. And a standard sample is provided for the qualitative and quantitative detection of the didanosine impurity through the synthesis of 2 ', 3' -anhydroinosine.
Drawings
FIG. 1 is a nuclear magnetic resonance hydrogen spectrum of 2 ', 3' -anhydroinosine as an impurity in didanosine of the invention,1h 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 ═ 4.0Hz,2H, 6-H). The peak at 2.50 is the DMSO solvent peak.
FIG. 2 is a mass spectrum of 2 ', 3' -anhydroinosine as an impurity in didanosine according to the invention.
Detailed Description
The following detailed description of the present invention is provided in conjunction with the accompanying drawings, but it should be understood that the scope of the present invention is not limited to the specific embodiments.
Example 1
1) Putting 250g of acetonitrile into a dry reaction bottle, adding 37.5g of anhydrous lithium bromide under stirring, heating to 70-75 ℃, and waiting for the anhydrous lithium bromide to be dissolved; then adding 55g of 2-acetoxy isobutyryl chloride to react for 1 hour; cooling the obtained reaction liquid to below 10 ℃, and then adding 30g of inosine for reaction for 4 hours;
2) adding anhydrous sodium acetate to neutralize the pH value to 6.5-7.0, and performing vacuum concentration to remove acetonitrile to obtain a milky solid thick substance; adding 8ml of a mixture of dichloromethane and water into every 1g of milky white solid thick matter, wherein the volume ratio of dichloromethane to water is 1:1, stirring for 15 minutes, standing for layering, taking a dichloromethane layer, evaporating the dichloromethane layer to dryness, and dissolving the obtained product in 150ml of ethanol;
3) adding 120ml of 5% sodium hydroxide aqueous solution of alkaline reagent at 5-10 deg.C, adjusting pH to 13, reacting for 12h, filtering, and oven drying to obtain 25.8g of 2 ', 3' -anhydroinosine with purity of 99.0% or more and weight yield of 86% (molar yield of 92.2%).
Example 2
1) Putting 250g of acetonitrile into a dry reaction bottle, adding 37.5g of anhydrous lithium bromide under stirring, heating to 70-75 ℃, and waiting for the anhydrous lithium bromide to be dissolved; then adding 55g of 2-acetoxy isobutyryl chloride to react for 1 hour; cooling the obtained reaction liquid to below 10 ℃, and then adding 30g of inosine for reaction for 4 hours;
2) adding anhydrous sodium acetate to neutralize the pH value to 6.5-7.0, and performing vacuum concentration to remove acetonitrile to obtain a milky solid thick substance; adding 8ml of a mixture of dichloromethane and water into every 1g of milky solid thick matter, wherein the volume ratio of dichloromethane to water is 1:1, stirring for 15 minutes, standing for layering, evaporating a dichloromethane layer to dryness, and dissolving the obtained product in 150ml of methanol;
3) adding 120ml of alkaline reagent methylamine water solution into the mixture at the temperature of 5-10 ℃, adjusting the pH value to be 12 of strong alkali, reacting for 12h, filtering and drying to obtain 25.2g of 2 ', 3' -anhydroinosine with the purity of more than 99.5 percent and the weight yield of more than 84 percent (the molar yield is 90.1 percent).
Example 3
1) Putting 300g of acetonitrile into a dry reaction bottle, adding 40g of anhydrous lithium bromide under stirring, heating to 70-75 ℃, and waiting for the anhydrous lithium bromide to be dissolved; then adding 60g of 2-acetoxy isobutyryl chloride to react for 1 hour; cooling the obtained reaction liquid to below 10 ℃, and then adding 30g of inosine for reaction for 4 hours;
2) adding anhydrous sodium acetate to neutralize the pH value to 6.5-7.0, and performing vacuum concentration to remove acetonitrile to obtain a milky solid thick substance; adding 6ml of a mixture of dichloromethane and water into every 1g of milky solid thick matter, wherein the volume ratio of dichloromethane to water is 1:3, stirring for 15 minutes, standing for layering, taking a dichloromethane layer, evaporating the dichloromethane layer to dryness, and dissolving the obtained product in 150ml of tert-butyl alcohol;
3) adding 130ml of alkaline reagent 5% sodium hydroxide aqueous solution at 5-10 deg.C, adjusting pH to strong alkali pH value of 14, reacting for 12h, filtering, and oven drying to obtain 22.5g of 2 ', 3' -anhydroinosine with purity of above 99.0% and weight yield of 75% (molar yield of 80.4%).
The foregoing descriptions of specific exemplary embodiments of the present invention have been presented for purposes of illustration and description. The description is not intended to limit the invention to the precise form disclosed, and the exemplary embodiments are chosen and described in order to explain certain principles of the invention and its practical application to thereby enable others skilled in the art to make and use various exemplary embodiments of the invention and various alternatives and modifications. It is intended that the scope of the invention 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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| Nucleic Acid-Related Compounds.88.Efficient Conversions of Ribonucleosides into Their 2,3-Anhydro, 2(and 3)-Deoxy, 2,3-Didehydro-2,3-dideoxy,and 2,3-Dideoxynucleoside Analogs;Morris J. Robins et al.;《Journal of Organic Chemistry》;19951231;第60卷(第24期);第7902-7908页 * |
| Nucleosides,XXIII1.A Simple Access to 3-Amino-xylo- and 3,4-Unsaturated Purine Nucleosides;F.W. Lichtenthaler et al.;《Communications》;19741231;第860-862页 * |
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