CN107892707A - A kind of synthetic method of arabinosy ladenosine - Google Patents
A kind of synthetic method of arabinosy ladenosine Download PDFInfo
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- CN107892707A CN107892707A CN201711069775.4A CN201711069775A CN107892707A CN 107892707 A CN107892707 A CN 107892707A CN 201711069775 A CN201711069775 A CN 201711069775A CN 107892707 A CN107892707 A CN 107892707A
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- arabinosy ladenosine
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- 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
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Abstract
A kind of arabinosy ladenosine synthetic method, 8 hydroxyl N, 3', 5'O triethyl group 2'O p-toluenesulfonyl adenosines are added, and add its quality multiple 1.1~1.4, the hydrazine hydrate that mass percentage concentration is 80%, be warming up to 78~85 DEG C of 45~50h of insulation reaction；Hydrazine hydrate is distilled off under decompression；Water, the catalytic oxidant potassium permanganate of 0.03~0.12 mass multiple of the mass multiple of initial feed 5~8 are added, 6~8h of stirring reaction under normal temperature, the solid obtained after reacting liquid filtering is arabinosy ladenosine crude product；To being recrystallized again after crude product activated carbon decolorizing, arabinosy ladenosine sterling is obtained.This invention takes one pot of two-step method cascade reaction; treated different things alike using hydrazine hydrate and complete upset and the Deprotection of configuration; the purpose that hydrogen system hydrogenation open loop two-step reaction reaches configuration reversal is cyclized and vulcanized instead of methanol ammono-system; avoid taking off sulfydryl using inflammable catalyst Raney's nickel simultaneously, improve the security of W-response.Potassium permanganate takes off hydrazine, improves the activity of reaction, reduces the content of heavy metal in waste water.
Description
Technical field
The invention belongs to technical field of chemical synthesis, and in particular to a kind of synthetic method of arabinosy ladenosine.
Background technology
Arabinosy ladenosine（vidarabine）Chemical name be 9- β-D- arabinofuranosyladenines, structural formula is as follows
It is shown：
Arabinosy ladenosine is a kind of effective anti-bleb and herpes zoster virus medicine, and synthesizes anti-DNA (DNA)
Viral prescription vidarabine phosphate and the key for treating B- Cell Chronic Lymphocytic Leukemias (CLL) specific drug fludarabine
Intermediate.
At present, state, the inside and outside method for preparing arabinosy ladenosine mainly have chemical synthesis and biological fermentation process.Biofermentation
The method production cycle is grown, and yield causes production cost to be substantially increased than relatively low, therefore the production of arabinosy ladenosine is mainly closed using chemistry
Cheng Fa.The conventional chemical methods for synthesizing arabinosy ladenosine are for raw material with 5'- adenylic acids (5'-AMP), and chosen property is to toluene
Sulfonylation, dephosphorization, bromination being hydrolyzed, acetylation obtains 8- hydroxy-ns, 3', 5'-O- triethyl group -2'-O- p-toluenesulfonyl adenosines,
It is cyclized in methanol-ammonia, then 8- sulfydryl arabinosy ladenosines is obtained in methanol-hydrogen sulfide open loop, arabinosy ladenosine is obtained through hydrogenolysis desulfurization is final.Pass
The arabinosy ladenosine synthetic method of system is as follows：
Substantial amounts of waste gas is produced when being cyclized using methanol ammonia, and needs to use the hydrogen sulfide gas open loop of severe toxicity, takes off sulfydryl
Condition harshness is, it is necessary to using inflammable catalyst Raney's nickel, it is necessary to which special installation, adds production cost.Therefore improve tradition to close
Into the deficiency of method, simplify reactions steps, improve the economy of reaction to more effectively use in industrial production just into
Study the maximum target of arabinosy ladenosine synthesis.
The content of the invention
To solve above-mentioned technical problem existing for existing arabinosy ladenosine synthetic method, the purpose of the present invention aims to provide one kind
Effectively reduce pollution, efficient easily arabinosy ladenosine synthetic method.This method can improve the regioselectivity of reaction, activity,
Security and reduction cost of material, make it effectively be applied in the industrial production.
To achieve these goals, the technical scheme that the present invention takes is as follows：A kind of arabinosy ladenosine synthetic method, its feature
It is：With 8- hydroxy-ns, 3', 5'-O- triacetyl -2'-O-, as raw material, connect anti-to methylsulfonyl adenosine through one pot of two-step method
End-product arabinosy ladenosine should be made.Specific method is as follows：
（1）In reactor, 8- hydroxy-ns, 3', 5'-O- triethyl group -2'-O- p-toluenesulfonyl adenosines are added, and add its matter
Measure multiple 1.1~1.4, the hydrazine hydrate that mass percentage concentration is 80%, be warming up to 78~85 DEG C of 45~50h of insulation reaction, efficient liquid
Mutually initial feed 8- hydroxy-ns in detection reaction solution, 3', 5'-O- triethyl group -2'-O- p-toluenesulfonyls adenosine content are less than 1%
When terminate to react.
（2）After 4/5ths hydrazine hydrate is distilled off under decompression, into reactor add with initial feed equivalent, 55~
65 DEG C of hot water, continue to be evaporated under reduced pressure, take the hydrazine hydrate remained in kettle out of, remaining solid is 8- diazanyl arabinosy ladenosine crude products.
（3）In same reactor, i.e., add initial feed 5 in reactor of existing 8- diazanyl arabinosy ladenosine crude products in it
The water of~8 mass multiples, and the catalyst potassium permanganate of the mass multiple of initial feed 0.03~0.12 is added, stirred under normal temperature anti-
6~8h is answered, efficient liquid phase detects to be terminated to react when 8- diazanyl arabinosy ladenosines content is less than 1% in reaction solution.After reacting liquid filtering
To solid be arabinosy ladenosine crude product.
（4）Recrystallized again after carrying out activated carbon decolorizing to the crude product, obtain arabinosy ladenosine sterling.
Arabinosy ladenosine synthetic route provided by the invention is as follows：
The present invention substantially takes one pot of two-step method cascade reaction and instead of traditional three-step reaction including being cyclized configuration reversal, first
The method that alcohol-hydrogen sulfide open loop deacetylation and the de- sulfydryl of hydrogenation prepare arabinosy ladenosine.Its major advantage is：
One, treated different things alike using hydrazine hydrate and complete upset and the Deprotection of configuration, instead of the cyclisation of methanol ammono-system and hydrogen sulfide
System hydrogenation open loop two-step reaction reaches the purpose of configuration reversal, while can also avoid taking off mercapto using inflammable catalyst Raney's nickel
Base, improve the security of W-response.
Secondly, the efficient catalytic oxidant potassium permanganate of selection take off hydrazine, improve the activity of reaction, while accessory substance dioxy
Changing manganese can recycle, and reduce the content of heavy metal in waste water.
Embodiment
With reference to embodiment, more specific description present disclosure.In the present invention, if not refering in particular to, all parts,
Percentage is unit of weight, and all equipment and raw material etc. are commercially available or the industry is conventional.Following implementations
Method in example, is the conventional method of this area unless otherwise instructed.
Embodiment 1
First, in 250mL three-neck flasks, 10g is added（0.019mol）8- hydroxy-ns, 3', 5'-O- triethyl group -2'-O- are to toluene
Sulfonyl adenosine（1）And 13g mass concentrations are 80% hydrazine hydrate, 78 DEG C of insulation reaction 50h are warming up to, efficient liquid phase detection is anti-
Initial feed i.e. 8- hydroxy-ns in liquid are answered, 3', when 5'-O- triethyl group -2'-O- p-toluenesulfonyls adenosine content is 0.96%, are tied
Shu Fanying.
Then, after 4/5ths hydrazine hydrate being distilled off under decompression, 10g, 55 DEG C of hot water are added into reaction bulb, after
It is continuous to be evaporated under reduced pressure, take the hydrazine hydrate remained in reaction bulb out of, remaining solid is 8- diazanyl arabinosy ladenosines（2）Crude product.
Then, in same reaction bulb, continue to add 50g water into obtained 8- diazanyl arabinosy ladenosine crude products and 0.3g is high
Potassium manganate, stirring reaction 8h under normal temperature, when 8- diazanyl arabinosy ladenosines content is 0.94% in efficient liquid phase detection reaction solution, terminate
Reaction.
Finally, filtering reacting liquid obtains arabinosy ladenosine（3）Crude product, recrystallized again after carrying out activated carbon decolorizing to the crude product,
Obtain arabinosy ladenosine sterling 2.96g.
Embodiment 2
First, in 2L three-neck flasks, 100g is added（0.192mol）8- hydroxy-ns, 3', 5'-O- triethyl group -2'-O- are to toluene sulphur
Acyl group adenosine（1）And 120g mass concentrations are 80% hydrazine hydrate, 80 DEG C of insulation reaction 48h, efficient liquid phase detection reaction are warming up to
8- hydroxy-ns in liquid, 3', when the content of 5'-O- triethyl group -2'-O- p-toluenesulfonyl adenosines is 0.96%, terminate reaction.
Then, after 4/5ths hydrazine hydrate being distilled off under decompression, 100g, 60 DEG C of hot water are added into reaction bulb,
Continue to be evaporated under reduced pressure, take the hydrazine hydrate remained in reaction bulb out of, remaining solid is 8- diazanyl arabinosy ladenosines（2）Crude product.
Then, in same reaction bulb, continue to add 600g water into obtained 8- diazanyl arabinosy ladenosine crude products and 6g is high
Potassium manganate, stirring reaction 7h under normal temperature, when 8- diazanyl arabinosy ladenosines content is 0.89% in efficient liquid phase detection reaction solution, terminate
Reaction.
Finally, filtering reacting liquid obtains arabinosy ladenosine（3）Crude product, recrystallized again after carrying out activated carbon decolorizing to the crude product,
Obtain arabinosy ladenosine sterling 30.46g.
Embodiment 3
First, in 20L reactors, 1kg is added（1.92mol）8- hydroxy-ns, 3', 5'-O- triethyl group -2'-O- tolysulfonyl
Base adenosine（1）And 1.3kg mass concentrations are 80% hydrazine hydrate, 85 DEG C of insulation reaction 45h, efficient liquid phase detection reaction are warming up to
8- hydroxy-ns in liquid, 3', when 5'-O- triethyl group -2'-O- p-toluenesulfonyls adenosine content is 0.95%, terminate reaction.
Then, after 4/5ths hydrazine hydrate being distilled off under decompression, 1kg, 65 DEG C of hot water are added into reactor, after
It is continuous to be evaporated under reduced pressure, take the hydrazine hydrate remained in kettle out of, remaining solid is 8- diazanyl arabinosy ladenosines（2）Crude product.
Then, in same reactor, continue to add 7kg water into obtained 8- diazanyl arabinosy ladenosine crude products and 90g is high
Potassium manganate, stirring reaction 6h under normal temperature, when 8- diazanyl arabinosy ladenosines content is 0.9% in efficient liquid phase detection reaction solution, terminate anti-
Should.
Finally, filtering reacting liquid obtains arabinosy ladenosine（3）Crude product, recrystallized again after carrying out activated carbon decolorizing to the crude product,
Obtain arabinosy ladenosine sterling 289.38g.
Embodiment 4
First, in 200L reactors, 10kg is added（19.2mol）8- hydroxy-ns, 3', 5'-O- triethyl group -2'-O- are to toluene sulphur
Acyl group adenosine（1）And 14kg mass concentrations are 80% hydrazine hydrate, 83 DEG C of insulation reaction 47h, efficient liquid phase detection reaction are warming up to
8- hydroxy-ns in liquid, 3', when 5'-O- triethyl group -2'-O- p-toluenesulfonyls adenosine content is 0.92%, terminate reaction.
Then, after 4/5ths hydrazine hydrate being distilled off under decompression, 10kg, 65 DEG C of hot water are added into reactor,
Continue to be evaporated under reduced pressure, take the hydrazine hydrate remained in kettle out of, remaining solid is 8- diazanyl arabinosy ladenosines（2）Crude product.
Then, in same reactor, continue to add 80kg water and 1.2kg into obtained 8- diazanyl arabinosy ladenosine crude products
Potassium permanganate, stirring reaction 5h under normal temperature, when 8- diazanyl arabinosy ladenosines content is 0.76% in efficient liquid phase detection reaction solution, knot
Shu Fanying.
Finally, filtering reacting liquid obtains arabinosy ladenosine（3）Crude product, recrystallized again after carrying out activated carbon decolorizing to the crude product,
Obtain arabinosy ladenosine sterling 2.98kg.
Embodiment 5
First, in 500L reactors, 50kg is added（96mol）8- hydroxy-ns, 3', 5'-O- triethyl group -2'-O- tolysulfonyl
Base adenosine（1）And 60kg mass concentrations are 80% hydrazine hydrate, 80 DEG C of insulation reaction 48h, efficient liquid phase detection reaction solution are warming up to
Middle 8- hydroxy-ns, 3', when 5'-O- triethyl group -2'-O- p-toluenesulfonyls adenosine content is 0.98%, terminate reaction.
Then, after 4/5ths hydrazine hydrate being distilled off under decompression, 50kg, 60 DEG C of hot water are added into reactor,
Continue to be evaporated under reduced pressure, take the hydrazine hydrate remained in kettle out of, remaining solid is 8- diazanyl arabinosy ladenosines（2）Crude product.
Then, in same reactor, continue to add 300kg water and 3kg into obtained 8- diazanyl arabinosy ladenosine crude products
Potassium permanganate, stirring reaction 6h under normal temperature, when 8- diazanyl arabinosy ladenosines content is 0.90% in efficient liquid phase detection reaction solution, knot
Shu Fanying.
Finally, filtering reacting liquid obtains arabinosy ladenosine（3）Crude product, recrystallized again after carrying out activated carbon decolorizing to the crude product,
Obtain arabinosy ladenosine sterling 15.6kg.
Embodiment 6
First, in 200L reactors, 10kg 8- hydroxy-ns, 3', 5'-O- triethyl group -2'-O- p-toluenesulfonyl adenosines are added
And 12kg mass concentrations are 80% hydrazine hydrate, 80 DEG C of insulation reaction 48h are warming up to, 8- hydroxyls in efficient liquid phase detection reaction solution-
When N, 3', 5'-O- triethyl group -2'-O- p-toluenesulfonyls adenosine content are 0.96%, terminate reaction.
Then, after 4/5ths hydrazine hydrate being distilled off under decompression, 10kg, 60 DEG C of hot water are added into reactor,
Continue to be evaporated under reduced pressure, take the hydrazine hydrate remained in kettle out of, remaining solid is 8- diazanyl arabinosy ladenosine crude products.
Then, in same reactor, continue to add 60kg water and 0.6kg into obtained 8- diazanyl arabinosy ladenosine crude products
Potassium permanganate, stirring reaction 6h under normal temperature, when 8- diazanyl arabinosy ladenosines content is 0.88% in efficient liquid phase detection reaction solution, knot
Shu Fanying.
Finally, filtering reacting liquid obtains arabinosy ladenosine（3）Crude product, recrystallized again after carrying out activated carbon decolorizing to the crude product,
Obtain arabinosy ladenosine sterling 3.1kg.
Claims (5)
- A kind of 1. arabinosy ladenosine synthetic method, it is characterised in that：With 8- hydroxy-ns, 3', 5'-O- triacetyl -2'-O- are to first sulphur End-product arabinosy ladenosine is made through one pot of two-step method cascade reaction as raw material in acyl adenosine；Specific method is as follows：（1）In reactor, 8- hydroxy-ns, 3', 5'-O- triethyl group -2'-O- p-toluenesulfonyl adenosines are added, and add its matter Measure multiple 1.1~1.4, the hydrazine hydrate that mass percentage concentration is 80%, be warming up to 78~85 DEG C of 45~50h of insulation reaction, efficient liquid Mutually initial feed 8- hydroxy-ns in detection reaction solution, 3', 5'-O- triethyl group -2'-O- p-toluenesulfonyls adenosine content are less than 1% When terminate to react；（2）After 4/5ths hydrazine hydrate is distilled off under decompression, into reactor add with initial feed equivalent, 55~65 DEG C Hot water, continue to be evaporated under reduced pressure, take the hydrazine hydrate remained in kettle out of, remaining solid is 8- diazanyl arabinosy ladenosine crude products；（3）In same reactor, i.e., add initial feed 5~8 in reactor of existing 8- diazanyl arabinosy ladenosine crude products in it The water of quality multiple, and the catalytic oxidant potassium permanganate of the mass multiple of initial feed 0.03~0.12 is added, stirred under normal temperature 6~8h is reacted, efficient liquid phase detects to be terminated to react when 8- diazanyl arabinosy ladenosines content is less than 1% in reaction solution；The solid obtained after reacting liquid filtering is arabinosy ladenosine crude product；（4）Recrystallized again after carrying out activated carbon decolorizing to the crude product, obtain arabinosy ladenosine sterling.
- A kind of 2. preparation method of arabinosy ladenosine according to claim 1, it is characterised in that：Step（1）In, 2,3- diethyls The quality proportioning of acyl group -4- p-toluenesulfonyl -8- hydroxyadenosines and hydrazine hydrate is 1:1.2.
- A kind of 3. preparation method of arabinosy ladenosine according to claim 2, it is characterised in that：Step（1）In, it is warming up to 80 DEG C insulation reaction 48h.
- 4. according to a kind of preparation method of any described arabinosy ladenosine of claims 1 to 3, it is characterised in that：Step（2）In, It is 60 DEG C to add hot water temperature.
- A kind of 5. preparation method of arabinosy ladenosine according to claim 4, it is characterised in that：Step（3）In, add initial The catalyst potassium permanganate of the mass multiple of raw material 0.06.
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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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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112079883A (en) * | 2020-10-13 | 2020-12-15 | 兰州欣立医药科技有限责任公司 | Production process of vidarabine |
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 |
-
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 |
|---|
| RAN XIA ET AL.: "Efficient and green synthesis of purine arabinosides via CuO catalyzed dehydrazination in tap water", 《ARKIVOC》 * |
| RAN XIA ET AL.: "Efficient synthesis of nebularine and vidarabine via dehydrazination of (hetero)aromatics catalyzed by CuSO4 in water", 《GREEN CHEMISTRY》 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112079883A (en) * | 2020-10-13 | 2020-12-15 | 兰州欣立医药科技有限责任公司 | Production process of vidarabine |
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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 |