CN114149475B - Technological method for synthesizing alzvudine - Google Patents
Technological method for synthesizing alzvudine Download PDFInfo
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- C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
- C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
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Abstract
The invention discloses a process method for synthesizing alzvudine, and belongs to the field of synthesis of pharmaceutical intermediates nucleoside. Taking a 2 '-fluoro-4' -azido-uracil nucleoside intermediate as a raw material, firstly removing a protecting group through alkaline hydrolysis, and then performing silyl ether aminolysis to obtain the Azvudine. According to the invention, an aminolysis product is obtained in one step, so that the reaction steps are reduced, and the yield is improved; the hexamethyl-silazane and the amide are adopted to directly convert the 4-hydroxyl of pyrimidine into amino, the operation is simple, less waste water is generated in the reaction process, and the environmental protection is facilitated. The whole process is simple to operate, the yield is stable in the amplifying process, and the yield fluctuation generated in the use process of phosphorus oxychloride and the risk of influencing the product quality are avoided.
Description
Technical Field
The invention belongs to the field of organic chemistry, relates to synthesis of pyrimidine nucleoside, and in particular relates to a process method for synthesizing alzvudine.
Background
Azvudine, chemical name: molecular formula C 9 H 13 FN 6 O 4 Is an HIV reverse transcriptase inhibitor, can effectively inhibit the reverse transcription and replication of the HIV in vivo, and the Azvudine is a novel nucleoside reverse transcriptase and auxiliary protein Vif inhibitor, and is also the first double-target anti-HIV-1 drug. Can selectively enter CD4 cells or CD14 cells in HIV-1 target cell peripheral blood mononuclear cells to play a role in inhibiting viral replication. The variety is marketed to provide new treatment options for HIV-1 infected individuals. Reported in the literatureThe method comprises the following steps:
first category: markSmith et al report that 4 '-azido-uracil nucleoside was used as a raw material, 2' -epoxyuridine was synthesized by dehydration, 2 '-fluorouracil nucleoside was obtained by fluorination, and then end product Azvudine was obtained by chlorination and aminolysis of phosphorus oxychloride, the authors report that another synthetic method was used in the article, that 4' -azido-uracil nucleoside was synthesized first, 4-imidazolyl nucleoside was obtained by substitution of phosphorus oxychloride chloroimidazole by one pot method, and end product was obtained by aminolysis, and that both methods were first chloro-then aminolysis to obtain end product. The protective group needs to be removed in the aminolysis process, and reagents such as phosphorus oxychloride and the like with serious pollution are used in the reaction process.
The second category: chang Junbiao et al report that a process of obtaining 4' -azido uridine from fluoroglycoses by a multi-step reaction, then performing chlorination and aminolysis, and simultaneously removing protecting groups is simpler than the previous process, however, more wastes are generated in the aminolysis process, the refining of the final product is complicated, and reagents with serious pollution such as phosphorus oxychloride are used.
In the existing synthesis method, the commonly used reaction steps are that hydroxyl is subjected to chlorination and then aminolysis, reagents with dangerous operation, such as phosphorus oxychloride, and the like, troublesome post-treatment and serious pollution are needed, and the reaction steps are complicated and the energy consumption needed by industrial production is high.
Disclosure of Invention
In order to overcome the defects, the invention discloses a method for synthesizing the alzvudine, which can complete the reaction through two steps. The adopted raw materials are common reagents, so that the method has the advantages of convenient sources, low price, high total yield, easy industrial production and good application prospect.
The invention discloses a process method for synthesizing alzvudine, which comprises the following steps:
taking 2 '-fluoro-4' -azido-uracil nucleoside 1 as a raw material, removing a protecting group on a sugar ring through alkaline hydrolysis to obtain an intermediate 2, obtaining a crude product through silicon etherification and aminolysis, and obtaining the Azvudine through refining.
The reaction equation is as follows:
further, in the above technical solution, the method specifically includes the following steps:
firstly, mixing 2 '-fluoro-4' -azido-uracil nucleoside 1, an organic solvent and alkali, and heating to 50-60 ℃ for reaction; after the reaction is finished, glacial acetic acid is adopted to adjust the pH value to be 6-7, alcohol is slowly added, and the intermediate 2 is obtained through filtration and drying;
step two, mixing the intermediate 2, the silyl ether reagent and the amide, and heating to 100-120 ℃ for reaction; after the reaction is finished, the reaction liquid is cooled to room temperature, methanol is added, and the crude product is obtained after filtration and drying, and the Azvudine is obtained after refining.
Further, in the above technical scheme, in the first step, the organic solvent is methanol, ethanol or isopropanol.
Further, in the above technical scheme, in the first step, the base is ammonia, sodium methoxide, sodium ethoxide, sodium hydroxide or potassium hydroxide.
Further, in the above technical scheme, in the first step, the molar ratio of the compound 1 to the base is 1:2-4.
Further, in the above technical scheme, in the second step, the silyl ether reagent is hexamethyldisilazane, N, O-bis (trimethylsilyl) acetamide, N, O-bis (trimethylsilyl) trifluoroacetamide, or trimethylchlorosilane.
Further, in the above technical scheme, in the second step, the amide is acetamide, formamide or propionamide.
Further, in the above technical scheme, in the second step, the quenching adopts methanol, ethanol, isopropanol or water.
Further, in the above technical scheme, in the second step, the molar ratio of the intermediate 2 to the silyl ether reagent is 1:3-6.
Further, in the above technical scheme, in the second step, one or more of methanol, ethanol, isopropanol, acetone, tetrahydrofuran or water is adopted for the refining.
The invention has the beneficial effects that:
1. the design route is novel, the process does not pass through the phosphorus oxychloride chloro-amine hydrolysis process, an amine hydrolysis product can be obtained in one step, and the reaction steps are reduced, so that the yield is improved.
2. The process adopts hexamethyl-silazane and amide to directly convert the 4-hydroxyl of pyrimidine into amino, has simple operation, generates less waste water in the reaction process, and is beneficial to environmental protection.
3. The method is simple to operate, stable in the process of amplifying the yield, and avoids the severe conditions required in the process of using phosphorus oxychloride, thereby generating yield fluctuation and the risk of influencing the product quality.
Specific examples:
example 1
Firstly, adding 2 '-fluoro-4' -azido-uracil nucleoside (20 g,0.038 mol) into a reaction kettle, adding 25% ammonia/methanol 100mL, heating to 50-60 ℃ for reaction for 5h, tracking a liquid phase until the raw materials are basically disappeared, concentrating the reaction liquid to be solid, and adding 75% ethanol 60mL for crystallization to obtain 9.8g of intermediate with the yield of 89.5%.
In the second step, intermediate 2 (9.8 g,0.034 mol), hexamethyldisilazane (15 g,0.093 mol) and acetamide (5.49 g,0.093 mol) were added to the reaction vessel, the temperature was raised to 120℃and the reaction was carried out for 24 hours, and the liquid phase HPLC was followed until the reaction time was reduced to 1% or less for starting material 2. The reaction solution was cooled to room temperature, 50mL of methanol was slowly added to precipitate a large amount of white solid, 6.9g of crude product was obtained by suction filtration and drying, and 5.72g (0.02 mol) of finished product Azvudine was obtained by refining with 70mL of 50% ethanol water, the yield was 58.8%, and the HPLC purity was 99.2%.
Example 2
Firstly, adding 2 '-fluoro-4' -azido-uracil nucleoside (20 g,0.038 mol) into a reaction kettle, adding 25% ammonia/ethanol 100mL, heating to 50-60 ℃ for reaction for 5h, tracking a liquid phase until the raw materials are basically disappeared, concentrating the reaction liquid to be solid, and adding 75% ethanol 60mL for crystallization to obtain 9.1g of intermediate with the yield of 84.2%.
In the second step, intermediate 2 (9.1 g,0.032 mol), hexamethyldisilazane (14.2 g,0.088 mol) and acetamide (5.19 g,0.088 mol) were added to the reaction vessel, the temperature was raised to 120℃and the reaction was carried out for 24 hours, and the liquid phase HPLC was followed until the reaction time was reduced to 1% or less for starting material 2. The reaction solution was cooled to room temperature, 50mL of methanol was slowly added to precipitate a large amount of white solid, 6.2g of crude product was obtained by suction filtration and drying, and 5.2g (0.018 mol) of finished product Azvudine was obtained by refining with 70mL of 50% ethanol water, the yield was 56.3%, and the HPLC purity was 99.3%.
Example 3
In the first step, 2 '-fluoro-4' -azido-uracil nucleoside (20 g,0.038 mol), methanol (100 mL) and sodium methoxide (4.86 g,0.09 mol) are added into a reaction kettle, the temperature is raised to 50-60 ℃ for reaction for 5h, the liquid phase is tracked until the raw materials basically disappear, the reaction solution is concentrated to solid, and then 60mL of 75% ethanol is added for crystallization to obtain 8.2g of intermediate with the yield of 75.2%.
In the second step, intermediate 2 (8.2 g,0.028 mol), hexamethyldisilazane (12.4 g,0.077 mol) and acetamide (4.55 g,0.077 mol) were added to the reaction vessel, the temperature was raised to 120℃and the reaction was carried out for 24 hours, and the liquid phase HPLC was followed until the reaction time was reduced to 1% or less for starting material 2. The reaction solution was cooled to room temperature, 50mL of methanol was slowly added to precipitate a large amount of white solid, 5.8g of crude product was obtained by suction filtration and drying, and 4.8g (0.016 mol) of finished product Azvudine was obtained by refining with 70mL of 50% ethanol water, the yield was 57.1%, and the HPLC purity was 99.1%.
Example 4
Firstly, adding 2 '-fluoro-4' -azido-uracil nucleoside (20 g,0.038 mol) into a reaction kettle, adding 25% ammonia/methanol 100mL, heating to 50-60 ℃ for reaction for 5h, tracking a liquid phase until the raw materials are basically disappeared, concentrating the reaction liquid to be solid, and adding 75% ethanol 60mL for crystallization to obtain 9.8g of intermediate with the yield of 89.5%.
In the second step, intermediate 2 (9.8 g,0.034 mol), N, O-bis (trimethylsilyl) trifluoroacetamide (23.9 g,0.093 mol) and acetamide (5.49 g,0.093 mol) were added to the reaction vessel, the temperature was raised to 120℃for 24 hours, and the liquid phase HPLC trace reaction was carried out until the starting material 2 was reduced to below 1%. The reaction solution was cooled to room temperature, 50mL of methanol was slowly added to precipitate a large amount of white solid, 7.0g of crude product was obtained by suction filtration and drying, and 5.8g (0.02 mol) of finished product Azvudine was obtained by refining with 70mL of 50% ethanol water, the yield was 59.6%, and the HPLC purity was 99.3%.
Example 5
Firstly, adding 2 '-fluoro-4' -azido-uracil nucleoside (20 g,0.038 mol) into a reaction kettle, adding 25% ammonia/methanol 100mL, heating to 50-60 ℃ for reaction for 5h, tracking a liquid phase until the raw materials are basically disappeared, concentrating the reaction liquid to be solid, and adding 75% ethanol 60mL for crystallization to obtain 9.8g of intermediate with the yield of 89.5%.
In the second step, intermediate 2 (9.8 g,0.034 mol), hexamethyldisilazane (15 g,0.093 mol) and formamide (4.19 g,0.093 mol) were added to the reaction vessel, the temperature was raised to 120℃and the reaction was carried out for 24 hours, and the liquid phase HPLC was followed until the reaction was carried out until the starting material 2 was reduced to 1% or less. The reaction solution was cooled to room temperature, 50mL of methanol was slowly added to precipitate a large amount of white solid, 5.7g of crude product was obtained by suction filtration and drying, and 4.8g (0.017 mol) of finished product Azvudine was obtained by refining with 70mL of 50% ethanol water, the yield was 50%, and the HPLC purity was 98.7%.
Example 6
Firstly, adding 2 '-fluoro-4' -azido-uracil nucleoside (20 g,0.038 mol) into a reaction kettle, adding 25% ammonia/methanol 100mL, heating to 50-60 ℃ for reaction for 5h, tracking a liquid phase until the raw materials are basically disappeared, concentrating the reaction liquid to be solid, and adding 75% ethanol 60mL for crystallization to obtain 9.8g of intermediate with the yield of 89.5%.
In the second step, intermediate 2 (9.8 g,0.034 mol), hexamethyldisilazane (19.4 g,0.12 mol) and acetamide (5.49 g,0.093 mol) were added to the reaction vessel, the temperature was raised to 120℃and the reaction was carried out for 24 hours, and the liquid phase HPLC was followed until the reaction time was reduced to 1% or less for starting material 2. The reaction mixture was cooled to room temperature, 50mL of methanol was slowly added to precipitate a large amount of white solid, 7.1g of crude product was obtained by suction filtration and drying, and 5.9g (0.021 mol) of finished product Azvudine was obtained by refining with 70mL of 50% ethanol water, the yield was 61.8%, and the HPLC purity was 99.3%.
Example 7
Firstly, adding 2 '-fluoro-4' -azido-uracil nucleoside (20 g,0.038 mol) into a reaction kettle, adding 25% ammonia/methanol 100mL, heating to 50-60 ℃ for reaction for 5h, tracking a liquid phase until the raw materials are basically disappeared, concentrating the reaction liquid to be solid, and adding 75% ethanol 60mL for crystallization to obtain 9.8g of intermediate with the yield of 89.5%.
In the second step, intermediate 2 (9.8 g,0.034 mol), hexamethyldisilazane (24.2 g,0.15 mol) and acetamide (5.49 g,0.093 mol) were added to the reaction vessel, and the reaction was carried out at 120℃for 24 hours, followed by liquid phase HPLC until the reaction time was reduced to 1% or less for starting material 2. The reaction solution was cooled to room temperature, 50mL of methanol was slowly added to precipitate a large amount of white solid, 7.0g of crude product was obtained by suction filtration and drying, and 5.8g (0.020 mol) of finished product Azvudine was obtained by refining with 70mL of 50% ethanol water, the yield was 58.8%, and the HPLC purity was 99.1%.
Example 8
Firstly, adding 2 '-fluoro-4' -azido-uracil nucleoside (2 Kg,3.8 mol) into a reaction kettle, adding 25% ammonia/methanol 10L, heating to 50-60 ℃ for reaction for 5h, tracking a liquid phase until the raw materials are basically disappeared, concentrating the reaction liquid to solid, and adding 75% ethanol 6L for crystallization to obtain 975g of intermediate with the yield of 89%.
In the second step, intermediate 2 (0.975 Kg,3.4 mol), hexamethyldisilazane (1.94 Kg,12 mol) and acetamide (0.549 Kg,9.3 mol) were added to the reaction vessel and stirred well. The temperature is raised to 120 ℃ for reaction for 36 hours, and the liquid phase HPLC tracks the reaction until the content of the raw material 2 is reduced to below 1 percent. The reaction solution was cooled to room temperature, 5L of methanol was slowly added to precipitate a large amount of white solid, 710g of crude product was obtained by suction filtration and drying, and 0.595Kg (2.08 mol) of finished product Azvudine was obtained by refining with 7L of 50% ethanol water, yield 61.1% and HPLC purity 99.4%.
The foregoing has shown and described the basic principles and main features of the present invention and the advantages of the present invention. It will be understood by those skilled in the art that the present invention is not limited to the embodiments described above, and that the above embodiments and descriptions are merely illustrative of the principles of the present invention, and various changes and modifications may be made without departing from the spirit and scope of the invention, which is defined in the appended claims. The scope of the invention is defined by the appended claims and equivalents thereof.
Claims (7)
1. A process for synthesizing alzvudine, comprising the steps of:
taking 2 '-fluoro-4' -azido-uracil nucleoside 1 as a raw material, removing a protecting group on a sugar ring through alkaline hydrolysis to obtain an intermediate 2, performing silicon etherification and amidoamine hydrolysis by a silyl ether reagent to obtain a crude product, and refining to obtain the Azvudine; the silyl ether reagent is hexamethyldisilazane, N, O-bis (trimethylsilyl) acetamide, N, O-bis (trimethylsilyl) trifluoroacetamide or trimethylchlorosilane; the amide is acetamide, formamide or propionamide.
2. The process for synthesizing alzvudine according to claim 1, comprising the following steps: firstly, mixing 2 '-fluoro-4' -azido-uracil core 1, an organic solvent and alkali, and heating to 50-60 ℃ for reaction; after the reaction is finished, decompressing and recovering the solvent, slowly adding alcohol, filtering and drying to obtain an intermediate 2; step two, mixing the intermediate 2, the silyl ether reagent and the amide, and heating to 100-120 ℃ for reaction; after the reaction is finished, the reaction liquid is cooled to room temperature, methanol is added, and the crude product is obtained after filtration and drying, and the Azvudine is obtained after refining.
3. A process for the synthesis of alzvudine according to claim 2, wherein: in the first step, the organic solvent is methanol, ethanol or isopropanol.
4. A process for the synthesis of alzvudine according to claim 2, wherein: in the first step, the alkali is ammonia, sodium methoxide, sodium ethoxide, sodium hydroxide or potassium hydroxide.
5. A process for the synthesis of alzvudine according to claim 2, wherein: in the first step, the molar ratio of the compound 1 to the alkali is 1:2-4.
6. A process for the synthesis of alzvudine according to claim 2, wherein: in the second step, the molar ratio of the intermediate 2 to the silyl ether reagent is 1:3-6.
7. A process for the synthesis of alzvudine according to claim 2, wherein: in the second step, one or more of methanol, ethanol, isopropanol, acetone, tetrahydrofuran or water is adopted for refining.
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