CN107892707B - Synthetic method of vidarabine - Google Patents
Synthetic method of vidarabine Download PDFInfo
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- CN107892707B CN107892707B CN201711069775.4A CN201711069775A CN107892707B CN 107892707 B CN107892707 B CN 107892707B CN 201711069775 A CN201711069775 A CN 201711069775A CN 107892707 B CN107892707 B CN 107892707B
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- 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
- C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
- C07H19/16—Purine radicals
- C07H19/19—Purine radicals with arabinosyl as the saccharide radical
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H1/00—Processes for the preparation of sugar derivatives
Abstract
Adding 8-hydroxy-N, 3',5' -O-diacetyl-2 ' -O-p-toluenesulfonyl adenosine, adding hydrazine hydrate with the mass percentage concentration of 80% and the mass multiple of 1.1-1.4, heating to 78-85 ℃, and carrying out heat preservation reaction for 45-50 h; distilling under reduced pressure to remove hydrazine hydrate; adding 5-8 mass times of water and 0.03-0.12 mass times of potassium permanganate serving as a catalytic oxidant into the raw materials, stirring and reacting for 6-8 hours at normal temperature, and filtering the reaction solution to obtain a solid, namely an vidarabine crude product; and decoloring the crude product with activated carbon, and recrystallizing to obtain the pure vidarabine. The invention adopts a one-pot two-step series reaction, adopts hydrazine hydrate to complete the inversion and deprotection of the configuration by one-pot boiling, replaces two-step reactions of methanol-ammonia system cyclization and hydrogen sulfide system hydrogenation ring opening to achieve the purpose of configuration inversion, avoids using a flammable catalyst Raney nickel to remove sulfydryl, and improves the safety of the whole reaction. The potassium permanganate is subjected to hydrazine removal, so that the reaction activity is improved, and the content of heavy metal in the wastewater is reduced.
Description
Technical Field
The invention belongs to the technical field of chemical synthesis, and particularly relates to a synthetic method of vidarabine.
Background
The chemical name of vidarabine (vidarabine) is 9-beta-D-arabinofuranosyl adenine, and the structural formula is shown as follows:
vidarabine is an effective anti-herpes and herpes zoster virus medicament, and is a key intermediate for synthesizing vidarabine monophosphate for resisting deoxyribonucleic acid (DNA) virus and a specific medicament fludarabine for treating B-cell Chronic Lymphocytic Leukemia (CLL).
At present, the methods for preparing vidarabine at home and abroad mainly comprise a chemical synthesis method and a biological fermentation method. The production period of the biological fermentation method is long, the yield is low, and the production cost is greatly increased, so the chemical synthesis method is mainly adopted for producing the vidarabine. The traditional chemical method for synthesizing the vidarabine is to use 5' -adenine nucleotide (5' -AMP) as a raw material, selectively carry out tosylation, hydrolysis dephosphorization, bromination and acetylation on the raw material to obtain 8-hydroxy-N, 3',5' -O-diacetyl-2 ' -O-tosyladenosine, cyclize the obtained product in methanol-ammonia, carry out ring opening on the obtained product in methanol-hydrogen sulfide to obtain 8-mercaptovidarabine, and finally carry out hydrogenolysis desulfurization on the obtained product to obtain the vidarabine. The conventional synthesis of vidarabine is as follows:
a large amount of waste gas is generated during ammonia cyclization of methanol, highly toxic hydrogen sulfide gas is required for ring opening, the condition for removing sulfydryl is harsh, a flammable catalyst Raney nickel is required to be used, special equipment is required, and the production cost is increased. Therefore, the method improves the defects of the traditional synthetic method, simplifies the reaction steps, and improves the reaction economy so as to be more effectively utilized in industrial production, thereby becoming the maximum target for researching the synthesis of the vidarabine.
Disclosure of Invention
In order to solve the technical problems of the existing vidarabine synthesis method, the invention aims to provide a high-efficiency and convenient vidarabine synthesis method which effectively reduces pollution. The method can improve the regioselectivity, the activity and the safety of the reaction and reduce the cost of raw materials, so that the method can be effectively applied to industrial production.
In order to achieve the purpose, the technical scheme adopted by the invention is as follows: a method for synthesizing vidarabine is characterized by comprising the following steps: 8-hydroxy-N, 3',5' -O-diacetyl-2 ' -O-p-methylsulfonyl adenosine is used as a raw material, and the final product vidarabine is prepared by a one-pot two-step series reaction. The specific method comprises the following steps:
(1) adding 8-hydroxy-N, 3',5' -O-diacetyl-2 '-O-p-toluenesulfonyl adenosine into a reaction kettle, adding hydrazine hydrate with the mass percentage concentration of 80% and the mass multiple of 1.1-1.4 into the reaction kettle, heating to 78-85 ℃, keeping the temperature, reacting for 45-50 h, and detecting the content of the initial raw material 8-hydroxy-N, 3',5 '-O-diacetyl-2' -O-p-toluenesulfonyl adenosine in the reaction liquid by using a high performance liquid chromatography to finish the reaction when the content is less than 1%.
(2) Distilling under reduced pressure to remove four fifths of hydrazine hydrate, adding hot water with the temperature of 55-65 ℃ which is equal to that of the initial raw material into the reaction kettle, continuing distilling under reduced pressure to carry out residual hydrazine hydrate in the kettle, wherein the residual solid is 8-hydrazinoarabinosyladenosine crude product.
(3) Adding 5-8 mass times of water of an initial raw material into the same reaction kettle, namely the reaction kettle in which the 8-hydrazino vidarabine crude product exists, adding 0.03-0.12 mass times of catalyst potassium permanganate of the initial raw material, stirring and reacting for 6-8 h at normal temperature, and finishing the reaction when the content of the 8-hydrazino vidarabine in the reaction liquid is less than 1% by high performance liquid phase detection. Filtering the reaction liquid to obtain a solid, namely the crude product of the vidarabine.
(4) And (3) decoloring the crude product by using active carbon, and then recrystallizing to obtain the pure vidarabine.
The synthetic route of the vidarabine provided by the invention is as follows:
the invention essentially adopts a one-pot two-step series reaction to replace the traditional three-step reaction comprising cyclization configuration inversion, methanol-hydrogen sulfide ring opening deacetylation and hydro-desulfhydrylation to prepare the vidarabine. Its main advantage lies in:
firstly, hydrazine hydrate is boiled in one pot to complete configuration turning and deprotection, two-step reactions of methanol-ammonia system cyclization and hydrogen sulfide system hydrogenation ring opening are replaced to achieve the purpose of configuration turning, meanwhile, the use of a flammable catalyst Raney nickel for mercapto removal can be avoided, and the safety of the whole reaction is improved.
Secondly, the high-efficiency catalytic oxidant potassium permanganate is selected for removing hydrazine, so that the activity of the reaction is improved, and meanwhile, the by-product manganese dioxide can be recycled, so that the content of heavy metals in the wastewater is reduced.
Detailed Description
The present invention will be described in more detail with reference to examples. In the invention, all parts and percentages are weight units, and all equipment, raw materials and the like can be purchased from the market or are commonly used in the industry, if not specified. The methods in the following examples are conventional in the art unless otherwise specified.
Example 1
Firstly, 10g (0.019 mol) of 8-hydroxy-N, 3',5' -O-diacetyl-2 '-O-p-toluenesulfonyl adenosine (1) and 13g of hydrazine hydrate with the mass concentration of 80% are added into a 250mL three-neck flask, the temperature is raised to 78 ℃, the reaction is kept for 50 hours, and the reaction is finished when the content of 8-hydroxy-N, 3',5 '-O-diacetyl-2' -O-p-toluenesulfonyl adenosine serving as the initial raw material in the reaction solution is 0.96% by high performance liquid chromatography detection.
Then, after four fifths of hydrazine hydrate was distilled off under reduced pressure, 10g of hot water at 55 ℃ was added to the reaction flask, and distillation under reduced pressure was continued to take out the hydrazine hydrate remaining in the reaction flask, and the remaining solid was crude 8-hydrazinoarabinoadenosine (2).
And then, in the same reaction bottle, continuously adding 50g of water and 0.3g of potassium permanganate into the obtained 8-hydrazino-arabino-adenosine crude product, stirring and reacting for 8 hours at normal temperature, and finishing the reaction when the content of the 8-hydrazino-arabino-adenosine in the reaction solution is 0.94% by high performance liquid detection.
And finally, filtering the reaction solution to obtain a crude product of the vidarabine (3), decoloring the crude product by using activated carbon, and recrystallizing to obtain a pure vidarabine product of 2.96 g.
Example 2
First, 100g (0.192 mol) of 8-hydroxy-N, 3',5' -O-diacetyl-2 '-O-p-toluenesulfonyladenosine (1) and 120g of hydrazine hydrate with the mass concentration of 80% are added into a 2L three-necked flask, the temperature is raised to 80 ℃, the reaction is kept for 48 hours, and the reaction is ended when the content of 8-hydroxy-N, 3',5 '-O-diacetyl-2' -O-p-toluenesulfonyladenosine in the reaction solution is 0.96% by high performance liquid chromatography detection.
Then, after four fifths of hydrazine hydrate was distilled off under reduced pressure, 100g of hot water at 60 ℃ was added to the reaction flask, and distillation under reduced pressure was continued to take out the hydrazine hydrate remaining in the reaction flask, leaving a solid, i.e., crude 8-hydrazinoarabinoadenosine (2).
And then, in the same reaction bottle, continuously adding 600g of water and 6g of potassium permanganate into the obtained 8-hydrazino-arabino adenosine crude product, stirring and reacting for 7 hours at normal temperature, and finishing the reaction when the content of the 8-hydrazino-arabino adenosine in the reaction liquid is 0.89% by high performance liquid detection.
And finally, filtering the reaction solution to obtain a crude product of the vidarabine (3), decoloring the crude product by using activated carbon, and recrystallizing to obtain a pure vidarabine product of 30.46 g.
Example 3
Firstly, 1kg (1.92 mol) of 8-hydroxy-N, 3',5' -O-diacetyl-2 '-O-p-toluenesulfonyl adenosine (1) and 1.3kg of hydrazine hydrate with the mass concentration of 80% are added into a 20L reaction kettle, the temperature is raised to 85 ℃, the reaction is kept for 45 hours, and the reaction is finished when the content of the 8-hydroxy-N, 3',5 '-O-diacetyl-2' -O-p-toluenesulfonyl adenosine in the reaction solution is 0.95% by high performance liquid phase detection.
Then, after four fifths of hydrazine hydrate is distilled off under reduced pressure, 1kg of hot water at 65 ℃ is added into the reaction kettle, the reduced pressure distillation is continued, the hydrazine hydrate remained in the kettle is carried out, and the residual solid, namely the crude product of the 8-hydrazinoarabinoadenosine (2), is obtained.
And then, continuously adding 7kg of water and 90g of potassium permanganate into the obtained 8-hydrazino-arabinoside crude product in the same reaction kettle, stirring and reacting for 6 hours at normal temperature, and finishing the reaction when the content of the 8-hydrazino-arabinoside in the reaction liquid is 0.9% by high performance liquid detection.
And finally, filtering the reaction solution to obtain a crude product of the vidarabine (3), decoloring the crude product by using activated carbon, and recrystallizing to obtain 289.38g of a pure vidarabine product.
Example 4
Firstly, 10kg (19.2 mol) of 8-hydroxy-N, 3',5' -O-diacetyl-2 '-O-p-toluenesulfonyladenosine (1) and 14kg of hydrazine hydrate with the mass concentration of 80% are added into a 200L reaction kettle, the temperature is raised to 83 ℃, the reaction is kept for 47 hours, and when the content of the 8-hydroxy-N, 3',5 '-O-diacetyl-2' -O-p-toluenesulfonyladenosine in the reaction solution is 0.92% by high performance liquid chromatography detection, the reaction is ended.
Then, after four fifths of hydrazine hydrate is distilled off under reduced pressure, 10kg of hot water at 65 ℃ is added into the reaction kettle, the reduced pressure distillation is continued, the hydrazine hydrate remained in the kettle is carried out, and the residual solid, namely the crude product of the 8-hydrazinoarabinoadenosine (2), is obtained.
And then, in the same reaction kettle, continuously adding 80kg of water and 1.2kg of potassium permanganate into the obtained 8-hydrazino-arabino-adenosine crude product, stirring and reacting for 5 hours at normal temperature, and finishing the reaction when the content of the 8-hydrazino-arabino-adenosine in the reaction liquid is 0.76% by high performance liquid detection.
And finally, filtering the reaction solution to obtain a crude product of the vidarabine (3), decoloring the crude product by using activated carbon, and recrystallizing to obtain 2.98kg of a pure vidarabine product.
Example 5
Firstly, 50kg (96 mol) of 8-hydroxy-N, 3',5' -O-diacetyl-2 '-O-p-toluenesulfonyladenosine (1) and 60kg of hydrazine hydrate with the mass concentration of 80% are added into a 500L reaction kettle, the temperature is raised to 80 ℃, the reaction is kept for 48 hours, and when the content of the 8-hydroxy-N, 3',5 '-O-diacetyl-2' -O-p-toluenesulfonyladenosine in the reaction solution is 0.98% by high performance liquid phase detection, the reaction is ended.
Then, after four fifths of hydrazine hydrate is distilled off under reduced pressure, 50kg of hot water at 60 ℃ is added into the reaction kettle, the reduced pressure distillation is continued, the hydrazine hydrate remained in the kettle is carried out, and the residual solid, namely the crude product of the 8-hydrazinoarabinoadenosine (2), is obtained.
And then, in the same reaction kettle, continuously adding 300kg of water and 3kg of potassium permanganate into the obtained 8-hydrazino vidarabine crude product, stirring and reacting for 6 hours at normal temperature, and finishing the reaction when the content of the 8-hydrazino vidarabine in the reaction liquid is 0.90% by high performance liquid detection.
And finally, filtering the reaction solution to obtain a crude product of the vidarabine (3), decoloring the crude product by using activated carbon, and recrystallizing to obtain 15.6kg of a pure vidarabine product.
Example 6
Firstly, 10kg of 8-hydroxy-N, 3',5' -O-diacetyl-2 '-O-p-toluenesulfonyladenosine and 12kg of hydrazine hydrate with the mass concentration of 80% are added into a 200L reaction kettle, the temperature is raised to 80 ℃, the reaction is kept for 48 hours, and when the content of the 8-hydroxy-N, 3',5 '-O-diacetyl-2' -O-p-toluenesulfonyladenosine in the reaction solution is detected to be 0.96% by high performance liquid chromatography, the reaction is ended.
Then, after four fifths of hydrazine hydrate is removed by distillation under reduced pressure, 10kg of hot water at 60 ℃ is added into the reaction kettle, the distillation under reduced pressure is continued, the hydrazine hydrate remained in the kettle is carried out, and the residual solid, namely the 8-hydrazinoarabinosyladenosine crude product is remained.
And then, in the same reaction kettle, continuously adding 60kg of water and 0.6kg of potassium permanganate into the obtained 8-hydrazino-arabino-adenosine crude product, stirring and reacting for 6 hours at normal temperature, and finishing the reaction when the content of the 8-hydrazino-arabino-adenosine in the reaction liquid is 0.88% by high performance liquid detection.
And finally, filtering the reaction solution to obtain a crude product of the vidarabine (3), decoloring the crude product by using activated carbon, and recrystallizing to obtain 3.1kg of a pure vidarabine product.
Claims (5)
1. A method for synthesizing vidarabine is characterized by comprising the following steps: the final product vidarabine is prepared by taking 8-hydroxy-N, 3',5' -O-diacetyl-2 ' -O-p-methylsulfonyl adenosine as a raw material through a one-pot two-step series reaction, and the specific method is as follows:
(1) adding 8-hydroxy-N, 3',5' -O-diacetyl-2 '-O-p-toluenesulfonyl adenosine into a reaction kettle, adding hydrazine hydrate with the mass percentage concentration of 80% and the mass multiple of 1.1-1.4 into the reaction kettle, heating to 78-85 ℃, keeping the temperature, reacting for 45-50 h, and detecting the content of the initial raw material 8-hydroxy-N, 3',5 '-O-diacetyl-2' -O-p-toluenesulfonyl adenosine in the reaction liquid by using a high performance liquid chromatography to finish the reaction when the content is less than 1%;
(2) distilling under reduced pressure to remove four fifths of hydrazine hydrate, adding hot water with the same amount as the initial raw material and at the temperature of 55-65 ℃ into the reaction kettle, continuing distilling under reduced pressure to carry out residual hydrazine hydrate in the kettle, wherein the residual solid is a crude product of 8-hydrazino-arabino-adenosine;
(3) adding 5-8 mass times of water of an initial raw material into the same reaction kettle, namely adding 0.03-0.12 mass times of potassium permanganate serving as a catalytic oxidant into the reaction kettle in which the 8-hydrazino arabinoside crude product exists, stirring and reacting for 6-8 hours at normal temperature, and finishing the reaction when the content of the 8-hydrazino arabinoside in a reaction solution is detected to be less than 1% by using a high performance liquid phase; filtering the reaction solution to obtain a solid, namely a crude product of the vidarabine;
(4) and (3) decoloring the crude product by using active carbon, and then recrystallizing to obtain the pure vidarabine.
2. The method for preparing vidarabine according to claim 1, wherein: in the step (1), the mass ratio of the 8-hydroxy-N, 3',5' -O-diacetyl-2 ' -O-p-toluenesulfonyl adenosine to the hydrazine hydrate is 1: 1.2.
3. The method for preparing vidarabine according to claim 2, wherein: in the step (1), the temperature is raised to 80 ℃ and the reaction is carried out for 48 hours.
4. The method for producing vidarabine according to any one of claims 1 to 3, wherein: in the step (2), hot water is added at a temperature of 60 ℃.
5. The method for preparing vidarabine according to claim 4, wherein: in the step (3), a catalyst potassium permanganate with the mass multiple of 0.06 of that of the initial raw material is added.
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| CN201711069775.4A CN107892707B (en) | 2017-11-03 | 2017-11-03 | Synthetic method of vidarabine |
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| CN201711069775.4A CN107892707B (en) | 2017-11-03 | 2017-11-03 | Synthetic method of vidarabine |
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1128270A (en) * | 1995-02-28 | 1996-08-07 | 广东省药物研究所 | Synthetic method of arabinosyladenosine |
| CN103467468A (en) * | 2013-09-22 | 2013-12-25 | 河南师范大学 | Vidarabine and Vidarabine analogues synthesized by air oxidation hydrazine removal method |
| CN103880682A (en) * | 2014-03-27 | 2014-06-25 | 河南师范大学 | Green method for removing hydrazine in oxidizing manner |
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2017
- 2017-11-03 CN CN201711069775.4A patent/CN107892707B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1128270A (en) * | 1995-02-28 | 1996-08-07 | 广东省药物研究所 | Synthetic method of arabinosyladenosine |
| CN103467468A (en) * | 2013-09-22 | 2013-12-25 | 河南师范大学 | Vidarabine and Vidarabine analogues synthesized by air oxidation hydrazine removal method |
| CN103880682A (en) * | 2014-03-27 | 2014-06-25 | 河南师范大学 | Green method for removing hydrazine in oxidizing manner |
Non-Patent Citations (2)
| Title |
|---|
| Efficient and green synthesis of purine arabinosides via CuO catalyzed dehydrazination in tap water;Ran Xia et al.;《ARKIVOC》;20151231;第284-292页 * |
| Efficient synthesis of nebularine and vidarabine via dehydrazination of (hetero)aromatics catalyzed by CuSO4 in water;Ran Xia et al.;《Green Chemistry》;20141231;第16卷(第3期);第1077-1081页 * |
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Address after: 730000 No.1 guchengping, Chengguan District, Lanzhou City, Gansu Province Patentee after: Lanzhou Xinli Medical Science and Technology Co.,Ltd. Patentee after: GANSU CHEMICAL INDUSTRY RESEARCH INSTITUTE Co.,Ltd. Address before: 730020, 1, Gucheng Ping, Chengguan District, Gansu, Lanzhou Patentee before: LANZHOU AOKAI CHEMICAL Co.,Ltd. Patentee before: Gansu Research Institution of Chemical Industry |