CN1266161C - Synthesis process of adenosine aose monophosphate - Google Patents
Synthesis process of adenosine aose monophosphate Download PDFInfo
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- CN1266161C CN1266161C CN 200410015563 CN200410015563A CN1266161C CN 1266161 C CN1266161 C CN 1266161C CN 200410015563 CN200410015563 CN 200410015563 CN 200410015563 A CN200410015563 A CN 200410015563A CN 1266161 C CN1266161 C CN 1266161C
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- phosphate
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- vidarabine
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- vidarabine phosphate
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- 230000015572 biosynthetic process Effects 0.000 title claims abstract description 9
- 238000000034 method Methods 0.000 title claims description 12
- 230000008569 process Effects 0.000 title description 5
- OIRDTQYFTABQOQ-KQYNXXCUSA-N adenosine Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O OIRDTQYFTABQOQ-KQYNXXCUSA-N 0.000 title description 4
- 239000002126 C01EB10 - Adenosine Substances 0.000 title description 2
- 229960005305 adenosine Drugs 0.000 title description 2
- 150000004712 monophosphates Chemical class 0.000 title 1
- UDMBCSSLTHHNCD-UHTZMRCNSA-N [(2r,3s,4s,5r)-5-(6-aminopurin-9-yl)-3,4-dihydroxyoxolan-2-yl]methyl dihydrogen phosphate Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](COP(O)(O)=O)[C@@H](O)[C@@H]1O UDMBCSSLTHHNCD-UHTZMRCNSA-N 0.000 claims abstract description 25
- 238000006243 chemical reaction Methods 0.000 claims abstract description 17
- UDMBCSSLTHHNCD-KQYNXXCUSA-N adenosine 5'-monophosphate Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](COP(O)(O)=O)[C@@H](O)[C@H]1O UDMBCSSLTHHNCD-KQYNXXCUSA-N 0.000 claims abstract description 9
- UDMBCSSLTHHNCD-UHFFFAOYSA-N Coenzym Q(11) Natural products C1=NC=2C(N)=NC=NC=2N1C1OC(COP(O)(O)=O)C(O)C1O UDMBCSSLTHHNCD-UHFFFAOYSA-N 0.000 claims abstract description 8
- RWSOTUBLDIXVET-UHFFFAOYSA-N Dihydrogen sulfide Chemical compound S RWSOTUBLDIXVET-UHFFFAOYSA-N 0.000 claims abstract description 6
- 238000005893 bromination reaction Methods 0.000 claims abstract description 6
- 229910000037 hydrogen sulfide Inorganic materials 0.000 claims abstract description 6
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- 230000031709 bromination Effects 0.000 claims abstract description 5
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- 239000002253 acid Substances 0.000 claims abstract description 4
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- 239000003456 ion exchange resin Substances 0.000 claims abstract description 4
- 229920003303 ion-exchange polymer Polymers 0.000 claims abstract description 4
- 239000000376 reactant Substances 0.000 claims abstract description 4
- 238000006735 epoxidation reaction Methods 0.000 claims abstract description 3
- 229950006790 adenosine phosphate Drugs 0.000 claims description 11
- 230000000694 effects Effects 0.000 claims description 7
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- 229960003636 vidarabine Drugs 0.000 abstract description 6
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- BHVOFCPOXNYVCE-UHFFFAOYSA-N 6-amino-7,9-dihydropurine-8-thione Chemical compound NC1=NC=NC2=C1NC(=S)N2 BHVOFCPOXNYVCE-UHFFFAOYSA-N 0.000 abstract 2
- 238000006640 acetylation reaction Methods 0.000 abstract 1
- LNQVTSROQXJCDD-UHFFFAOYSA-N adenosine monophosphate Natural products C1=NC=2C(N)=NC=NC=2N1C1OC(CO)C(OP(O)(O)=O)C1O LNQVTSROQXJCDD-UHFFFAOYSA-N 0.000 abstract 1
- 150000001875 compounds Chemical class 0.000 abstract 1
- 238000009776 industrial production Methods 0.000 abstract 1
- OIRDTQYFTABQOQ-UHTZMRCNSA-N Vidarabine Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@@H]1O OIRDTQYFTABQOQ-UHTZMRCNSA-N 0.000 description 8
- 238000002360 preparation method Methods 0.000 description 7
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- 108020005202 Viral DNA Proteins 0.000 description 5
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- 230000026731 phosphorylation Effects 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
- 238000001042 affinity chromatography Methods 0.000 description 3
- 230000000840 anti-viral effect Effects 0.000 description 3
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 3
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 2
- KDCGOANMDULRCW-UHFFFAOYSA-N 7H-purine Chemical compound N1=CNC2=NC=NC2=C1 KDCGOANMDULRCW-UHFFFAOYSA-N 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- -1 Hydrogen sodium oxide Chemical class 0.000 description 2
- 229910000831 Steel Inorganic materials 0.000 description 2
- SUYVUBYJARFZHO-RRKCRQDMSA-N dATP Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@H]1C[C@H](O)[C@@H](COP(O)(=O)OP(O)(=O)OP(O)(O)=O)O1 SUYVUBYJARFZHO-RRKCRQDMSA-N 0.000 description 2
- 230000030609 dephosphorylation Effects 0.000 description 2
- 238000006209 dephosphorylation reaction Methods 0.000 description 2
- 238000010511 deprotection reaction Methods 0.000 description 2
- 230000008030 elimination Effects 0.000 description 2
- 238000003379 elimination reaction Methods 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- 238000007789 sealing Methods 0.000 description 2
- 229910001948 sodium oxide Inorganic materials 0.000 description 2
- 239000010959 steel Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- UNXRWKVEANCORM-UHFFFAOYSA-N triphosphoric acid Chemical compound OP(O)(=O)OP(O)(=O)OP(O)(O)=O UNXRWKVEANCORM-UHFFFAOYSA-N 0.000 description 2
- 229940048102 triphosphoric acid Drugs 0.000 description 2
- 238000001291 vacuum drying Methods 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- AEOBEOJCBAYXBA-UHFFFAOYSA-N A2P5P Natural products C1=NC=2C(N)=NC=NC=2N1C1OC(COP(O)(O)=O)C(O)C1OP(O)(O)=O AEOBEOJCBAYXBA-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
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- 239000004593 Epoxy Substances 0.000 description 1
- 206010019799 Hepatitis viral Diseases 0.000 description 1
- 241000701085 Human alphaherpesvirus 3 Species 0.000 description 1
- 102000004316 Oxidoreductases Human genes 0.000 description 1
- 108090000854 Oxidoreductases Proteins 0.000 description 1
- 241000700584 Simplexvirus Species 0.000 description 1
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical class [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
- DWAQJAXMDSEUJJ-UHFFFAOYSA-M Sodium bisulfite Chemical class [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 0.000 description 1
- 102000004357 Transferases Human genes 0.000 description 1
- 108090000992 Transferases Proteins 0.000 description 1
- 241000700618 Vaccinia virus Species 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 125000001246 bromo group Chemical class Br* 0.000 description 1
- 244000309464 bull Species 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- OEERIBPGRSLGEK-UHFFFAOYSA-N carbon dioxide;methanol Chemical compound OC.O=C=O OEERIBPGRSLGEK-UHFFFAOYSA-N 0.000 description 1
- 230000008859 change Effects 0.000 description 1
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- 125000003729 nucleotide group Chemical group 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-N phosphoric acid Substances OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 1
- 229920001467 poly(styrenesulfonates) Polymers 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 150000003222 pyridines Chemical class 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 235000011091 sodium acetates Nutrition 0.000 description 1
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
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Abstract
The present invention provides a synthesis technology of adenine arabinoside monophosphate, which uses adenosine monophosphate as a raw material to obtain the adenine arabinoside monophosphate by the reactions such as protection, bromination, ammonification, sulfhydrylation, hydrogenization, etc.; after the bromination reaction, reactants are decompressed and evaporated to dryness, and acetylation reaction is directly applied to the reactants without separation; hydrogen sulfide is directly used for the open cycle of epoxidation products without protection under the action of strong-acid ion exchange resin to obtain 8-mercapto-adenine arabinoside monophosphate(8); the 8-mercapto-adenine arabinoside monophosphate(8) is hydrogenated to obtain the target compound. The present invention has the advantages of short technological line, high yield and easy realization of industrial production.
Description
Technical field
The invention relates to the synthesis technique of preparation antiviral vidarabine phosphate.
Technical background
[the chemical name chemical name is vidarabine phosphate: 9-(β-D-arbinofuranose) gland fat purine 5 '-phosplate, I] be the ucleotides antiviral, its pharmacological action is to combine with the deoxyribonucleic acid polymerase of virus, makes its activity reduction and suppress DNA synthetic.After vidarabine phosphate enters cell, generate vidarabine bisphosphate (Ara-ADP) and vidarabine triphosphoric acid (Ara-ATP) through phosphorylation.Antiviral activity is mainly caused by vidarabine triphosphoric acid (Ara-ATP), be attached on the viral DNA P to Ara-ATP and deoxyadenosine triphosphate (dATP) competition, thereby the activity of enzyme and synthesizing of viral DNA have been suppressed, suppress the activity of viral nucleotide reductase enzyme simultaneously and suppress the synthetic of viral DNA, the activity that can also suppress the viral DNA terminal deoxyribotide transferase, make Ara-A penetrate among the DNA of virus and be connected DNA chain 3 '-end of OH position, the continuation that has suppressed viral DNA is synthetic.
Vidarabine phosphate is the soluble derivative of vidarabine, and various dna virus such as I type and II type herpes simplex virus, varicella zoster virus, varicella virus, vaccinia virus are all had obvious inhibiting activity; In China, vidarabine phosphate also is widely used in the treatment Type B viral hepatitis.
But the vidarabine phosphate clinical medicine dose is bigger, must possess the synthesis technique that is fit to industrial vidarabine phosphate for satisfying the clinical application needs.
The chemical synthesis process of bibliographical information mainly contains two kinds.
Article one, synthetic route (M.Ikebara, et al.Tetrahedron Let 1972; 28:3695.) be raw material with single adenosine phosphate, preparation vidarabine earlier, the latter obtains vidarabine phosphate through phosphorylation:
Reaction process comprises dephosphorylation and two processes of phosphorylation, and step is longer, and productive rate is lower, and overall yield has only 8%; Particularly the phosphorylation reaction by product is more, brings difficulty to separation and purification.
Second synthetic route (Masakatsu Kaneko, et al.Chem Pharm Bull 1977; 25:1892.) be raw material with single adenosine phosphate, bromination after protecting through reactions such as ammonification, sulfhydrylation, hydrogenations, obtains vidarabine phosphate again:
The whole process of this technology need not dephosphorylation and phosphorylation; overall yield can reach 12%. but most of intermediate and the finished product need analyse with resinbed with the activated carbon affinity chromatography and separate; and react to relate to and repeatedly protect and deprotection, be unfavorable for suitability for industrialized production.
Summary of the invention
The object of the present invention is to provide a kind of is raw material with single adenosine phosphate, and operational path is short, yield is higher, can realize the synthesis technique of a kind of vidarabine phosphate of suitability for industrialized production.
The object of the present invention is achieved like this: a kind of synthesis technique of vidarabine phosphate; be to be raw material with single adenosine phosphate; bromination after protecting; acetylize; again through ammonification; sulfhydrylation; hydrogenation; obtain vidarabine phosphate; after bromo-reaction is finished; with the reactant evaporated under reduced pressure; directly carry out acetylization reaction without separating; with the epoxidation product of aminating reaction gained under the strong-acid ion exchange resin effect; directly using the hydrogen sulfide open loop without protection, obtaining 8-sulfydryl vidarabine phosphate (VIII), the latter obtains vidarabine phosphate through hydrogenation.
The concrete synthetic route of vidarabine phosphate is as follows among the present invention:
Get rid of the activated carbon affinity chromatography in the technology of the present invention, simplified operation; Save protection and deprotection two-step reaction, improved productive rate; Got rid of the activated carbon affinity chromatography simultaneously; Simplified operation.Synthesis technique reactions steps after the improvement was reduced to for 5 steps; Overall yield is calculated and can be reached about 20% with single adenosine phosphate, and operation is greatly simplified.
Description of drawings
Fig. 1 is a process flow diagram of the present invention.
Embodiment
Below in conjunction with drawings and Examples the present invention is done to describe further, but do not constitute any limitation of the invention.
As shown in Figure 1, technical process of the present invention is: evaporated under reduced pressure after the protection of single adenosine phosphate, the bromination, acetylize, change, under the strong-acid ion exchange resin effect with the hydrogen sulfide open loop then hydrogenation obtain vidarabine phosphate.
Embodiment:
The preparation of (one) 2 '-oxygen-right-tolylsulfonyl ester-5 '-adenosine phosphate (II)
In the mixing solutions of 150 milliliters of dioxane and 350 milliliter of 1 Equivalent Hydrogen sodium oxide, add 34.7 grams, 5 '-AMP; After waiting to dissolve, in this solution, add the p-toluenesulfonyl chloride of 22.8 gram porphyrizes, after 15 hours, add 35 milliliters of 6 equivalent hydrochloric acid, regulate pH to 4.0 in 0 ℃ of stirring reaction.The crystallization that the filter collection is separated out gets 46.4 gram crystalline powder II.
(2) preparation of 8-bromo-2 '-oxygen-right-tolylsulfonyl ester-5 '-adenosine phosphate (III)
In 240 milliliters of 2M sodium-acetates (pH 4) solution, add 46 gram II, be cooled to 0-5 ℃.In this solution, drip 19 milliliters of bromines then, keep 0-5 ℃.Under this temperature, stirred 18 hours.At 0-5 ℃, in reaction solution, add 28 gram sodium bisulfites.Stir after 15 minutes, regulate pH to 4.0 (about 90-100 milliliter) with 5 Equivalent Hydrogen sodium oxides.Evaporated under reduced pressure, the gained solid is directly used in the next step.
(3) 8-hydroxyl-nitrogen ', the preparation of 3 '-diacetyl-2 '-oxygen-right-tolylsulfonyl ester-5 '-adenosine phosphate (IV)
In last step reaction product, add 80 milliliters of acetate and 80 ml acetic anhydride, stirring and refluxing reaction 2 hours.After being chilled to room temperature, add 60 ml methanol.Evaporate to dryness.Add ethanol, evaporate to dryness; Add ethanol again, again evaporate to dryness.Residue with a small amount of as far as possible water heating for dissolving, is cooled to 5 ℃ under stirring, and placement is spent the night.Filter, with a small amount of washing, vacuum-drying gets 60.2 gram solids.
(4) 5 '-phosphoric acid 8, the preparation of 2 '-epoxy adenosine (V)
In reactor, 60 gram IV are suspended in 300 milliliters of ethanol, to saturated, the sealing back was in 65-70 ℃ of stirring reaction 20 hours at 0-5 ℃ of logical ammonia.After being chilled to room temperature, the steel still was placed dry ice-methanol bath (or cryosel bath) 2 hours.The solid that the filter collection is separated out is washed with cold methanol, gets 35 gram V, can be used for the next step.
(5) preparation of vidarabine phosphate (I)
35 gram V are dissolved with 240 milliliters of pyridines, be loaded in the steel still, add 5 gram Dowex 50x4; Logical exsiccant hydrogen sulfide is to saturated.The sealing back was in 95-100 ℃ of heating 15 hours.The hydrogen sulfide that it is excessive that logical nitrogen is rushed is evaporated to reaction solution dried.Residue is dissolved the elimination insolubles with 600 ml waters.In filtrate, add 20 gram Raney nickels, back flow reaction 2.5 hours; Add 6 gram Raney nickels again, back flow reaction 0.5 hour is added 4 gram Raney nickels, back flow reaction 0.5 hour again.The elimination insolubles is concentrated into 200 milliliters with filtrate decompression, and the hydrochloric acid with 37% is regulated pH2.5, adds crystal seed, is cooled to 5 ℃ under stirring, and placement is spent the night.Filter, with a small amount of washing, vacuum-drying gets 7.2 gram vidarabine phosphate (I) white solids.
Claims (1)
1. the synthesis technique of a vidarabine phosphate, be by synthetic route as follows, with the single adenosine phosphate that abbreviates AMP as is raw material, bromination, acetylize after overprotection, again through ammonification, sulfhydrylation, hydrogenation, obtain the vidarabine phosphate of formula I, it is characterized in that: after bromo-reaction is finished, the reactant evaporated under reduced pressure; The epoxidation product of aminating reaction gained under the strong-acid ion exchange resin effect, is directly used the hydrogen sulfide open loop without protection, obtain 8-sulfydryl vidarabine phosphate, obtain vidarabine phosphate through hydrogenation.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 200410015563 CN1266161C (en) | 2004-03-05 | 2004-03-05 | Synthesis process of adenosine aose monophosphate |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 200410015563 CN1266161C (en) | 2004-03-05 | 2004-03-05 | Synthesis process of adenosine aose monophosphate |
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| Publication Number | Publication Date |
|---|---|
| CN1560065A CN1560065A (en) | 2005-01-05 |
| CN1266161C true CN1266161C (en) | 2006-07-26 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN 200410015563 Expired - Lifetime CN1266161C (en) | 2004-03-05 | 2004-03-05 | Synthesis process of adenosine aose monophosphate |
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| Country | Link |
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| CN (1) | CN1266161C (en) |
Families Citing this family (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103204890B (en) * | 2013-02-22 | 2016-03-09 | 广东先强药业有限公司 | A kind of phosphorylation prepares the method for vidarabine phosphate |
| CN103159815B (en) * | 2013-03-22 | 2014-11-19 | 海南中化联合制药工业股份有限公司 | Monophosphate vidarabine crystalline compound, medical composition and preparation method thereof |
| CN107056862B (en) * | 2017-03-24 | 2020-12-29 | 甘肃成纪生物药业有限公司 | Synthesis method of vidarabine monophosphate |
| CN107141328A (en) * | 2017-06-14 | 2017-09-08 | 上海华理生物医药有限公司 | A kind of Vidarabine Monophosphate novel crystal forms and preparation method thereof |
| CN113173957B (en) * | 2021-04-28 | 2023-10-27 | 海南锦瑞制药有限公司 | Synthesis method and application of vidarabine monophosphate |
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- 2004-03-05 CN CN 200410015563 patent/CN1266161C/en not_active Expired - Lifetime
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