CN106749460A - A kind of preparation method of Vidarabine Monophosphate - Google Patents
A kind of preparation method of Vidarabine Monophosphate Download PDFInfo
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- CN106749460A CN106749460A CN201611259671.5A CN201611259671A CN106749460A CN 106749460 A CN106749460 A CN 106749460A CN 201611259671 A CN201611259671 A CN 201611259671A CN 106749460 A CN106749460 A CN 106749460A
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- vidarabine monophosphate
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- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H1/00—Processes for the preparation of sugar derivatives
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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
- C07H1/06—Separation; Purification
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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
- C07H19/20—Purine radicals with the saccharide radical esterified by phosphoric or polyphosphoric acids
- C07H19/207—Purine radicals with the saccharide radical esterified by phosphoric or polyphosphoric acids the phosphoric or polyphosphoric acids being esterified by a further hydroxylic compound, e.g. flavine adenine dinucleotide or nicotinamide-adenine dinucleotide
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Abstract
The invention provides a kind of preparation method of Vidarabine Monophosphate, the method, with strong-acid ion exchange resin as catalyst, Vidarabine Monophosphate is generated by a step esterification with arabinosy ladenosine and phosphoric acid as raw material.The process route is short, and yield is higher, and catalyst resin is reusable after regeneration.Avoid using strong smoke, the POCl3 of strong and stimulating in reaction, improve production operation security, it is more environmentally-friendly.The method is simple to operate, it is easy to accomplish industrialized production, improves production efficiency.
Description
Technical field
The present invention relates to a kind of synthetic method of antiviral drugs, and in particular to a kind of preparation side of Vidarabine Monophosphate
Method.
Background technology
(chemical name is Vidarabine Monophosphate:9- (β-D- arabinofuranoses) adenine 5 '-phosplate, Ara-
AMP), belong to nucleotide antiviral agent, be the second generation preparation of arabinosy ladenosine (Ara-A).Its pharmacological action is de- with virus
Oxygen ribonucleic acid polymerase is combined, and is reduced its activity and is synthesized so as to suppress DNA.After Vidarabine Monophosphate enters cell, warp
Peroxophosphoric acid metaplasia is into arabinosy ladenosine diphosphonic acid and arabinosy ladenosine triphosphoric acid.Antiviral activity is mainly drawn by arabinosy ladenosine triphosphoric acid
Rise, it is attached on viral DNA with what deoxyadenosine triphosphate was competed, so that Selective depression varial polymerases and nucleotides are also
Original enzyme activity, it is suppressed that the continuation synthesis of viral DNA.
Vidarabine Monophosphate is the soluble derivative of arabinosy ladenosine, has obvious inhibitory activity to various DNA virus,
It is widely used in the diseases such as treatment virus hepatitis, herpes zoster.
The preparation method of document report Vidarabine Monophosphate includes Enzyme catalyzed synthesis method and chemical synthesis, wherein chemistry
Synthetic method mainly includes following several.
（1）With AMP as initiation material in patent CN200410015563.4, through bromination, ammonification, sulfhydrylation, hydrogen
The reaction such as change, obtains Vidarabine Monophosphate；
The method reactions steps are more, and product yield is low, are unfavorable for industrialized production.
（2）With arabinosy ladenosine as initiation material in patent CN200910246573.1, with triethyl phosphate as solvent, with three
There is phosphorylation reaction in chlorethoxyfos, prepare Vidarabine Monophosphate；
The method reactions steps are short, but trichlorine oxygen that is strong using corrosivity in course of reaction, having strong smoke, have intense irritation
Phosphorus, is unfavorable for production operation.
The content of the invention
It is an object of the invention to provide one kind with arabinosy ladenosine as initiation material, process route is short, high income, operation letter
A kind of preparation method of Vidarabine Monophosphate that is single, being capable of achieving industrialized production.
A kind of preparation method of Vidarabine Monophosphate that the present invention is provided is comprised the following steps：
Arabinosy ladenosine is that compound 1 is added in the reaction vessel with water knockout drum by a, prime minister, be subsequently adding acetonitrile, 85% phosphoric acid,
Resin, is warming up to 76 ~ 78 DEG C of 3 ~ 5h of reaction, and the acetonitrile water mixed liquid for steaming is removed in course of reaction；After reaction terminates, cross and filter
Remove resin；Gained filtrate is added slowly in cold ethanol, 20 ~ 30min is lasted；The follow-up continuous 1 ~ 2h of insulated and stirred of completion of dropping, mistake
Filter, obtains Vidarabine Monophosphate crude product；
Described compound 1 is 1 with the mol ratio of phosphoric acid:1.1~1.3；Described compound 1 is 1g with the ratio of acetonitrile：3~
5mL；Described compound 1 is 1 with the mass ratio of resin：0.3~0.5；The temperature of described cold ethanol is 0 ~ 5 DEG C, its volume
It is 5 ~ 8 times of solvent acetonitrile；
B, the Vidarabine Monophosphate crude product obtained by step a is recrystallized using water, obtain Vidarabine Monophosphate and refine
Product.
According to the preparation method of above-mentioned Vidarabine Monophosphate, the resin described in step a is strongly acidic styrene system
Cationic ion-exchange resin, concrete model is any in 001 × 7,001 × 8 and NKC-9.
According to the preparation method of above-mentioned Vidarabine Monophosphate, the resin described in step a need to be by activation process, its
The concrete operations of activation are：
A certain amount of resin is taken, is rinsed to draining with distilled water clarifying, distilled water immersion 24h makes it fully expand；With tree
The 2mol/L hydrochloric acid solutions immersion of 4 times of amounts of fat volume, stirring 2h, distillation are washed to neutrality；Again with 4 times of amounts of resin volume
The immersion of 2mol/L sodium hydroxide solutions, stirring 2h, distillation are washed to neutrality；Finally with 4 times of 2mol/L hydrochloric acid of amount of resin volume
Solution immersion, stirring 2h, distillation are washed to neutrality.
According to the preparation method of above-mentioned Vidarabine Monophosphate, the concrete operations of the recrystallization described in step b are：
Vidarabine Monophosphate crude product is added in reactor, purified water is subsequently adding and is heated to 80 ~ 90 DEG C, stirring is to complete
Dissolving；Activated carbon is added, continues insulated and stirred decolouring 30min, heat filtering is carried out after reaction, gained filtrate is cooled to 0 ~ 5 DEG C, stirs
Crystallization 2h is mixed, crystallization 5h is stood；Filtered after crystallization, gained filter cake obtains Vidarabine Monophosphate in 12 ~ 18h is dried at 60 ~ 70 DEG C
Finished product；
The addition ratio of the Vidarabine Monophosphate crude product and purified water is 1g：15mL；The Vidarabine Monophosphate is thick
Product and activated carbon addition ratio are 1：0.1.
Positive beneficial effect of the invention：
1st, with arabinosy ladenosine as initiation material, Vidarabine Monophosphate is obtained through single step reaction, reactions steps are short, reaction condition temperature
With high income；
2nd, POCl3 is substituted with phosphoric acid in reacting, corrosivity is small, without smoke, have no irritating odor, operate it is safer, to environment
Pollution is small, is more beneficial for industrialization；
3rd, with highly acidic resin as catalyst, catalyst can be separated with reaction solution by simple filtration, treatment is convenient, together
When, the resin after use is reusable by regeneration treatment, cost-effective.
Brief description of the drawings
The Vidarabine Monophosphate preparation process chemical equation of the present invention of accompanying drawing 1
The relevant material pattern of the Vidarabine Monophosphate of the gained of 2 embodiment of the present invention of accompanying drawing 1.
Specific embodiment
Below in conjunction with specific embodiment, the present invention is described in detail, but is not intended to limit present disclosure.
Embodiment 1
A, the strongly acidic styrene type cation exchange resin for taking 20g models 001 × 7, are rinsed to draining with distilled water and clarified
Untill, distilled water immersion 24h makes it fully expand；Soaked with the 2mol/L hydrochloric acid solutions of resin volume 80mL, stir 2h, steamed
Distilled water is washed till neutrality；Soaked with the 2mol/L sodium hydroxide solutions of resin volume 80mL again, stir 2h, distillation is washed to neutrality；
Finally soaked with the 2mol/L hydrochloric acid solutions of resin volume 80mL, stir 2h, distillation is washed to neutrality, stand-by；
B, it is that compound 1 is added to the reaction vessel with water knockout drum by the resin and 40g arabinosy ladenosines after step a activation process
In, 160mL acetonitriles, 11mL85% phosphoric acid are subsequently adding, it is warming up to 76 ~ 78 DEG C of reaction 4h, the acetonitrile water that will be steamed in course of reaction
Mixed liquor is removed；After reaction terminates, resin is filtered to remove；Gained filtrate is added slowly in 0 ~ 5 DEG C of cold ethanol of 960mL, is lasted
30min；The follow-up continuous insulated and stirred 2h of completion of dropping, filtering, obtains Vidarabine Monophosphate crude product 73.6g；
C, Vidarabine Monophosphate crude product is added in reactor, is subsequently adding 1.1L purified waters, be heated to 85 DEG C, stirring is extremely
It is completely dissolved；7.4g activated carbons are added, continues insulated and stirred decolouring 30min, heat filtering is carried out after reaction, gained filtrate is cooled to
0 ~ 5 DEG C, stirring and crystallizing 2h stands crystallization 5h；Filtering, gained filter cake obtains Vidarabine Monophosphate finished product in 16h is dried at 70 DEG C
48.3g, yield 88.2%.
Embodiment 2
A, the strongly acidic styrene type cation exchange resin for taking 12g models 001 × 8, are rinsed to draining with distilled water and clarified
Untill, distilled water immersion 24h makes it fully expand；Soaked with the 2mol/L hydrochloric acid solutions of resin volume 48mL, stir 2h, steamed
Distilled water is washed till neutrality；Soaked with the 2mol/L sodium hydroxide solutions of resin volume 48mL again, stir 2h, distillation is washed to neutrality；
Finally soaked with the 2mol/L hydrochloric acid solutions of resin volume 48mL, stir 2h, distillation is washed to neutrality, stand-by；
B, by step a activate after resin and 40g arabinosy ladenosines be that compound 1 is added in the reaction vessel with water knockout drum, so
200mL acetonitriles, 12mL85% phosphoric acid are added afterwards, are warming up to 76 ~ 78 DEG C of reaction 5h, the acetonitrile water mixing that will be steamed in course of reaction
Liquid is removed；After reaction terminates, resin is filtered to remove；Gained filtrate is added slowly in 0 ~ 5 DEG C of cold ethanol of 1L, 30min is lasted；
The follow-up continuous insulated and stirred 1h of completion of dropping, filtering, obtains Vidarabine Monophosphate crude product 71.5g；
C, Vidarabine Monophosphate crude product is added in reactor, is subsequently adding 1.07L purified waters, be heated to 90 DEG C, stirring
To being completely dissolved；7.2g activated carbons are added, continues insulated and stirred decolouring 30min, heat filtering, the cooling of gained filtrate are carried out after reaction
To 0 ~ 5 DEG C, stirring and crystallizing 2h stands crystallization 5h；Filtering, gained filter cake in 18h is dried at 60 DEG C, obtain Vidarabine Monophosphate into
Product 44.9g, yield 81.96%.
Embodiment 3：
A, the strongly acidic styrene type cation exchange resin for taking 20g models NKC-9, with distilled water rinse to draining clarify be
Only, distilled water immersion 24h, makes it fully expand；Soaked with the 2mol/L hydrochloric acid solutions of resin volume 80mL, stir 2h, distillation
It is washed to neutrality；Soaked with the 2mol/L sodium hydroxide solutions of resin volume 80mL again, stir 2h, distillation is washed to neutrality；Most
Soaked with the 2mol/L hydrochloric acid solutions of resin volume 80mL afterwards, stir 2h, distillation is washed to neutrality, stand-by；
B, by step a activate after resin and 40g arabinosy ladenosines be that compound 1 is added in the reaction vessel with water knockout drum, so
120mL acetonitriles, 12mL85% phosphoric acid are added afterwards, are warming up to 76 ~ 78 DEG C of reaction 5h, the acetonitrile water mixing that will be steamed in course of reaction
Liquid is removed；After reaction terminates, resin is filtered to remove；Gained filtrate is added slowly in 0 ~ 5 DEG C of cold ethanol of 960mL, is lasted
30min；The follow-up continuous insulated and stirred 1h of completion of dropping, filtering, obtains Vidarabine Monophosphate crude product 73.1g；
C, Vidarabine Monophosphate crude product is added in reactor, is subsequently adding 1.1L purified waters, be heated to 90 DEG C, stirring is extremely
It is completely dissolved；7.3g activated carbons are added, continues insulated and stirred decolouring 30min, heat filtering is carried out after reaction, gained filtrate is cooled to
0 ~ 5 DEG C, stirring and crystallizing 2h stands crystallization 5h；Filtering, gained filter cake obtains Vidarabine Monophosphate finished product in 18h is dried at 60 DEG C
46.3g, yield 84.5%.
Claims (4)
1. a kind of preparation method of Vidarabine Monophosphate, it is characterised in that the preparation method is comprised the following steps：
Arabinosy ladenosine is that compound 1 is added in the reaction vessel with water knockout drum by a, prime minister, be subsequently adding acetonitrile, 85% phosphoric acid,
Resin, is warming up to 76 ~ 78 DEG C of 3 ~ 5h of reaction, and the acetonitrile water mixed liquid for steaming is removed in course of reaction；After reaction terminates, cross and filter
Remove resin；Gained filtrate is added slowly in cold ethanol, 20 ~ 30min is lasted；The follow-up continuous 1 ~ 2h of insulated and stirred of completion of dropping, mistake
Filter, obtains Vidarabine Monophosphate crude product；
Described compound 1 is 1 with the mol ratio of phosphoric acid:1.1~1.3；Described compound 1 is 1g with the ratio of acetonitrile：3~
5mL；Described compound 1 is 1 with the mass ratio of resin：0.3~0.5；The temperature of described cold ethanol is 0 ~ 5 DEG C, its volume
It is 5 ~ 8 times of solvent acetonitrile；
B, the Vidarabine Monophosphate crude product obtained by step a is recrystallized using water, obtain Vidarabine Monophosphate and refine
Product.
2. the preparation method of Vidarabine Monophosphate according to claim 1, it is characterised in that：Tree described in step a
Fat is strongly acidic styrene type cation exchange resin, and concrete model is any in 001 × 7,001 × 8 and NKC-9.
3. the preparation method of Vidarabine Monophosphate according to claim 1, it is characterised in that：Tree described in step a
Fat need to be by activation process, and the concrete operations of its activation are：
A certain amount of resin is taken, is rinsed to draining with distilled water clarifying, distilled water immersion 24h makes it fully expand；With tree
The 2mol/L hydrochloric acid solutions immersion of 4 times of amounts of fat volume, stirring 2h, distillation are washed to neutrality；Again with 4 times of amounts of resin volume
The immersion of 2mol/L sodium hydroxide solutions, stirring 2h, distillation are washed to neutrality；Finally with 4 times of 2mol/L hydrochloric acid of amount of resin volume
Solution immersion, stirring 2h, distillation are washed to neutrality.
4. the preparation method of Vidarabine Monophosphate according to claim 1, it is characterised in that：Weight described in step b
The concrete operations of crystallization are：
Vidarabine Monophosphate crude product is added in reactor, purified water is subsequently adding and is heated to 80 ~ 90 DEG C, stirring is to complete
Dissolving；Activated carbon is added, continues insulated and stirred decolouring 30min, heat filtering is carried out after reaction, gained filtrate is cooled to 0 ~ 5 DEG C, stirs
Crystallization 2h is mixed, crystallization 5h is stood；Filtered after crystallization, gained filter cake obtains Vidarabine Monophosphate in 12 ~ 18h is dried at 60 ~ 70 DEG C
Finished product；
The addition ratio of the Vidarabine Monophosphate crude product and purified water is 1g：15mL；The Vidarabine Monophosphate is thick
Product and activated carbon addition ratio are 1：0.1.
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| Application Number | Priority Date | Filing Date | Title |
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| CN201611259671.5A CN106749460A (en) | 2016-12-30 | 2016-12-30 | A kind of preparation method of Vidarabine Monophosphate |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110407892A (en) * | 2019-08-21 | 2019-11-05 | 甘肃泰升化工科技有限公司 | A kind of preparation method of Vidarabine Monophosphate |
| CN113398993A (en) * | 2021-07-20 | 2021-09-17 | 厦门大学 | Catalyst and preparation method and application thereof |
-
2016
- 2016-12-30 CN CN201611259671.5A patent/CN106749460A/en active Pending
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110407892A (en) * | 2019-08-21 | 2019-11-05 | 甘肃泰升化工科技有限公司 | A kind of preparation method of Vidarabine Monophosphate |
| CN113398993A (en) * | 2021-07-20 | 2021-09-17 | 厦门大学 | Catalyst and preparation method and application thereof |
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Application publication date: 20170531 |