CN107098943A - A kind of preparation method of high-purity Vidarabine Monophosphate - Google Patents
A kind of preparation method of high-purity Vidarabine Monophosphate Download PDFInfo
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- CN107098943A CN107098943A CN201710422276.2A CN201710422276A CN107098943A CN 107098943 A CN107098943 A CN 107098943A CN 201710422276 A CN201710422276 A CN 201710422276A CN 107098943 A CN107098943 A CN 107098943A
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- 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 title claims abstract description 38
- 238000002360 preparation method Methods 0.000 title claims abstract description 16
- 238000006243 chemical reaction Methods 0.000 claims abstract description 40
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims abstract description 36
- 239000003480 eluent Substances 0.000 claims abstract description 31
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 31
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims abstract description 27
- 239000000243 solution Substances 0.000 claims abstract description 22
- 238000002425 crystallisation Methods 0.000 claims abstract description 18
- 230000008025 crystallization Effects 0.000 claims abstract description 18
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims abstract description 14
- 238000010521 absorption reaction Methods 0.000 claims abstract description 11
- 239000008213 purified water Substances 0.000 claims abstract description 11
- 239000011347 resin Substances 0.000 claims abstract description 11
- 229920005989 resin Polymers 0.000 claims abstract description 11
- 238000006366 phosphorylation reaction Methods 0.000 claims abstract description 7
- 239000011780 sodium chloride Substances 0.000 claims abstract description 7
- 239000003957 anion exchange resin Substances 0.000 claims abstract description 6
- 239000003960 organic solvent Substances 0.000 claims abstract description 6
- 230000026731 phosphorylation Effects 0.000 claims abstract description 4
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 3
- 150000002500 ions Chemical class 0.000 claims abstract description 3
- 238000000638 solvent extraction Methods 0.000 claims abstract description 3
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 claims description 32
- 229910019213 POCl3 Inorganic materials 0.000 claims description 16
- 230000007062 hydrolysis Effects 0.000 claims description 14
- 238000006460 hydrolysis reaction Methods 0.000 claims description 14
- 238000001914 filtration Methods 0.000 claims description 10
- 238000000034 method Methods 0.000 claims description 7
- 230000008859 change Effects 0.000 claims description 3
- 239000007864 aqueous solution Substances 0.000 claims 1
- 235000002639 sodium chloride Nutrition 0.000 abstract description 8
- 229960002668 sodium chloride Drugs 0.000 abstract description 2
- 238000010790 dilution Methods 0.000 abstract 1
- 239000012895 dilution Substances 0.000 abstract 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 33
- 239000000047 product Substances 0.000 description 22
- 238000003756 stirring Methods 0.000 description 16
- 239000003814 drug Substances 0.000 description 11
- 150000001450 anions Chemical class 0.000 description 10
- 238000004128 high performance liquid chromatography Methods 0.000 description 9
- 239000012535 impurity Substances 0.000 description 9
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 8
- 229910052698 phosphorus Inorganic materials 0.000 description 8
- 239000011574 phosphorus Substances 0.000 description 8
- 239000002585 base Substances 0.000 description 7
- 238000001953 recrystallisation Methods 0.000 description 7
- DQWPFSLDHJDLRL-UHFFFAOYSA-N triethyl phosphate Chemical compound CCOP(=O)(OCC)OCC DQWPFSLDHJDLRL-UHFFFAOYSA-N 0.000 description 6
- 239000012043 crude product Substances 0.000 description 5
- WVLBCYQITXONBZ-UHFFFAOYSA-N trimethyl phosphate Chemical compound COP(=O)(OC)OC WVLBCYQITXONBZ-UHFFFAOYSA-N 0.000 description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- 238000011084 recovery Methods 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- NWUYHJFMYQTDRP-UHFFFAOYSA-N 1,2-bis(ethenyl)benzene;1-ethenyl-2-ethylbenzene;styrene Chemical compound C=CC1=CC=CC=C1.CCC1=CC=CC=C1C=C.C=CC1=CC=CC=C1C=C NWUYHJFMYQTDRP-UHFFFAOYSA-N 0.000 description 2
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 2
- 206010067484 Adverse reaction Diseases 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- -1 Vidarabine Monophosphates Chemical class 0.000 description 2
- 229960000643 adenine Drugs 0.000 description 2
- 230000006838 adverse reaction Effects 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 239000003456 ion exchange resin Substances 0.000 description 2
- 229920003303 ion-exchange polymer Polymers 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- 238000010850 salt effect Methods 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 238000010189 synthetic method Methods 0.000 description 2
- 238000012360 testing method Methods 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
- 229960003636 vidarabine Drugs 0.000 description 2
- 230000003612 virological effect Effects 0.000 description 2
- 102000040650 (ribonucleotides)n+m Human genes 0.000 description 1
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 1
- 229930024421 Adenine Natural products 0.000 description 1
- GFFGJBXGBJISGV-UHFFFAOYSA-N Adenine Chemical compound NC1=NC=NC2=C1N=CN2 GFFGJBXGBJISGV-UHFFFAOYSA-N 0.000 description 1
- 241000272814 Anser sp. Species 0.000 description 1
- 208000007514 Herpes zoster Diseases 0.000 description 1
- 241000175212 Herpesvirales Species 0.000 description 1
- 206010020751 Hypersensitivity Diseases 0.000 description 1
- 206010054949 Metaplasia Diseases 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 229930182555 Penicillin Natural products 0.000 description 1
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 1
- 241000700584 Simplexvirus Species 0.000 description 1
- 241000700618 Vaccinia virus Species 0.000 description 1
- 241000700605 Viruses Species 0.000 description 1
- 241000234314 Zingiber Species 0.000 description 1
- 235000006886 Zingiber officinale Nutrition 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 150000003838 adenosines Chemical class 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 208000026935 allergic disease Diseases 0.000 description 1
- 230000007815 allergy Effects 0.000 description 1
- 230000000840 anti-viral effect Effects 0.000 description 1
- 125000000328 arabinofuranosyl group Chemical group C1([C@@H](O)[C@H](O)[C@H](O1)CO)* 0.000 description 1
- PYMYPHUHKUWMLA-WDCZJNDASA-N arabinose Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)C=O PYMYPHUHKUWMLA-WDCZJNDASA-N 0.000 description 1
- PYMYPHUHKUWMLA-UHFFFAOYSA-N arabinose Natural products OCC(O)C(O)C(O)C=O PYMYPHUHKUWMLA-UHFFFAOYSA-N 0.000 description 1
- SRBFZHDQGSBBOR-UHFFFAOYSA-N beta-D-Pyranose-Lyxose Natural products OC1COC(O)C(O)C1O SRBFZHDQGSBBOR-UHFFFAOYSA-N 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 238000003889 chemical engineering Methods 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 230000018044 dehydration Effects 0.000 description 1
- 238000006297 dehydration reaction Methods 0.000 description 1
- XQRLCLUYWUNEEH-UHFFFAOYSA-N diphosphonic acid Chemical compound OP(=O)OP(O)=O XQRLCLUYWUNEEH-UHFFFAOYSA-N 0.000 description 1
- 238000003912 environmental pollution Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 235000008397 ginger Nutrition 0.000 description 1
- 210000004907 gland Anatomy 0.000 description 1
- 229930182470 glycoside Natural products 0.000 description 1
- 150000002338 glycosides Chemical class 0.000 description 1
- 208000006454 hepatitis Diseases 0.000 description 1
- 231100000283 hepatitis Toxicity 0.000 description 1
- 238000005342 ion exchange Methods 0.000 description 1
- 229920002521 macromolecule Polymers 0.000 description 1
- 239000002075 main ingredient Substances 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 230000015689 metaplastic ossification Effects 0.000 description 1
- 238000005065 mining Methods 0.000 description 1
- 150000002825 nitriles Chemical class 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 239000013558 reference substance Substances 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 239000010865 sewage Substances 0.000 description 1
- 238000001179 sorption measurement Methods 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 230000008719 thickening Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 239000008215 water for injection Substances 0.000 description 1
Classifications
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H1/00—Processes for the preparation of sugar derivatives
- C07H1/02—Phosphorylation
-
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Engineering & Computer Science (AREA)
- Biochemistry (AREA)
- Biotechnology (AREA)
- General Health & Medical Sciences (AREA)
- Genetics & Genomics (AREA)
- Molecular Biology (AREA)
- Saccharide Compounds (AREA)
Abstract
The present invention provides a kind of preparation method of Vidarabine Monophosphate, it is characterised in that the preparation method comprises the following steps：（1）Arabinosy ladenosine is mixed in tricresyl phosphate alkyl ester, adds phosphorylation agent, temperature control reaction；（2）Reaction, which is finished, is slowly added to reaction solution in purified water, hydrolyzes；（3）Organic solvent extraction is added, water layer adjusts PH to 6.0~8.0, obtains upper prop stoste with sodium hydroxide；（4）Absorption is swapped by the cloudy daughter ion exchanger resin of strong base with certain flow velocity after the dilution of upper prop stoste；（5）Eluted with the eluent of debita spissitudo, collect the eluent of OD value >=100；（6）Eluent is concentrated, crystallization, filter to obtain Vidarabine Monophosphate：The step（4）Strong basic type anion-exchange resin is selected from 201 × 7,201 × Final 8 alkalescence anion-exchange resin；The step（5）Eluent select 0.01~0.05mol/L aqueous hydrochloric acid solutions, 0.3%~0.8% sodium-chloride water solution.It is Vidarabine Monophosphate preparation method purity height of the present invention, high income, simple to operate.
Description
Technical field
The invention belongs to technical field of medicine synthesis, and in particular to a kind of preparation side of high-purity Vidarabine Monophosphate
Method.
Background technology
Vidarabine Monophosphate（Vidarabine MonopHospHate, structural formula one）,
Entitled 9- (β-D- the arabinofuranoses)-adenine 5'- phosplates of chemistry.
Vidarabine Monophosphate is the mono-phosphorylated compound of arabinosy ladenosine, is that a kind of artificial synthesized adenosine class resists
Viral medicine.Vidarabine Monophosphate enters after cell, and arabinosy ladenosine diphosphonic acid and arabinosy ladenosine triphosphoric acid are generated by phosphorylation,
Antiviral activity is derived mainly from arabinosy ladenosine triphosphoric acid.Current Vidarabine Monophosphate is mainly used in chronic viral in China
Hepatitis, herpes simplex virus, herpes zoster virus, vaccinia virus and many animals herpesviral and a small number of oncornavirus RNAs
Deng.Vidarabine Monophosphate clinical efficacy is definite, but its drug safety and adverse reaction it is similarly subjected to extensive concern.In medicine
During thing Clinical practice, the adverse reaction of generation is relevant except the pharmacological property with medication people's constitution and medicine in itself
Outside, also there is very big relation with medicine impurity present in, for example, causing the main of allergy using antibiotic such as penicillin
Reason is containing macromolecule impurities such as polymers among medicine.Because Vidarabine Monophosphate is big in the quantity of China, it is
The security of clinical application is further ensured that, by improving the process exploitation of Vidarabine Monophosphate purity to reduce in medicine
Impurity just seems particularly necessary.
At present majority producers prepare synthetic route that Vidarabine Monophosphate generally uses for：Arabinosy ladenosine and POCl3
Phosphorylation reaction is carried out in organic solvent, and Vidarabine Monophosphate is obtained after hydrolysis.
According to reaction mechanism, during phosphorylation reaction, while required 5'- phosplates are obtained, 3' can be also produced,
5'- bisphosphates（Structural formula two）, 5', 5'- monophosphate diester（Structural formula three）, 3', 5'- monophosphate diester（Structural formula four）Deng
Major impurity.
Because above-mentioned major impurity is similar with the physicochemical property of Vidarabine Monophosphate, conventional recrystallization method can not be thorough
Bottom is removed, and the finished product purity of gained is relatively low.
Old crooked chisel, Chen Shucheng, leaf wild goose ripple Vidarabine Monophosphates synthetic method improves [J] massages and medical science of recovery therapy,
2013,4(2):98-99 is reported, and arabinosy ladenosine carries out low-temp reaction with POCl3 through high temperature dehydration in triethyl phosphate,
Hydrolysis, after dichloromethane extraction, water layer adjusts pH crystallizations to obtain Vidarabine Monophosphate product, and yield is not referred to pure up to more than 98%
Degree.
Wang Zhengxiong, Improved synthesis [J] Chemical Engineerings and the equipment, 2008 (12) of ginger Liu Wei Vidarabine Monophosphates:75-
76, the synthetic method of report is similar, and difference is, water layer is adjusted after pH, is slowly added to ethanol crystallization and obtains crude product, crude product
Vidarabine Monophosphate finished product is recrystallized to obtain in ethanol, purifying aqueous systems, total recovery 66.6%, content 99.1% there are no purity
Report（Explanation：Content is used to reflect the amount of Main Ingredients and Appearance in test sample, is relative relative to one of standard items or reference substance
Value, and purity is absolute value, the content for reflecting impurity in test sample.Even if the purity of a medicine is relatively low, its content
May also ＞ 100%）.
Zhou Lihong（Synthesis, Structural Identification and the quality research [master thesis] of Vidarabine Monophosphate, Central China science and technology
University 2006）Use, arabinosy ladenosine reacts with POCl3 in pyridine, acetonitrile mixed system, hydrolyze to obtain crude product, crude product warp
Water for injection recrystallizes to obtain Vidarabine Monophosphate finished product, total recovery about 73%.The route needs to use substantial amounts of pyridine and second
Nitrile, both expensive, toxicity are larger, and miscible with water, reclaim difficult, and production cost is high, environmental pollution is big, business metaplasia
The feasibility of production is relatively low.
Patent CN103204890B is used, and arabinosy ladenosine, in dichloromethane system, adds acid binding agent with POCl3
DIPEA, the reaction of catalyst DMAP, reaction filters to obtain solids after terminating, de- by activated carbon
Color etc. post-processes to obtain crude product, most afterwards through recrystallizing to obtain Vidarabine Monophosphate finished product, total recovery 78.1%.The route reaction is separated out
Solid directly filter, because reaction terminates rear system and still remains a certain amount of POCl3, unprocessed direct filtering meeting
Cause certain potential safety hazard.The patent has no that purity is reported.
The Vidarabine Monophosphate preparation method that current existing patented technology and document are reported is substantially similar, arabinose gland
Glycosides and POCl3 carry out phosphorylation reaction in organic solvent, through hydrolysis, crystallization, be recrystallized to give Vidarabine Monophosphate into
Product, because the major impurity of Vidarabine Monophosphate is very difficult to remove by conventional recrystallization, therefore existing patent document is almost
The not no report on purity data.Scope of the purity of current most products on the market 98.0%~98.5%, by multiple
Although recrystallization can improve the purity of product to a certain extent, because Vidarabine Monophosphate has certain dissolving in water
Degree, with recrystallization number of times increase, total yield of products is reduced on the contrary.It is badly in need of researching and developing a kind of high-purity, in high yield for this
Method prepared by Vidarabine Monophosphate.
The content of the invention
It is an object of the invention to provide a kind of high-purity, the method for the preparation of Vidarabine Monophosphate in high yield.
A kind of preparation method of high-purity Vidarabine Monophosphate, it comprises the following steps：
（1）Arabinosy ladenosine is mixed in tricresyl phosphate alkyl ester, adds phosphorylation agent, temperature control reaction；
（2）Reaction, which is finished, is slowly added to reaction solution in purified water, temperature control hydrolysis；
（3）Organic solvent extraction is added, water layer adjusts pH to 6.0~8.0, obtains upper prop stoste with sodium hydroxide solution；
（4）Upper prop stoste is diluted to OD values 60~100, is handed over certain flow velocity by the cloudy daughter ion exchanger resin of strong base
Change absorption；
（5）Eluted with the eluent of debita spissitudo, collect the eluent of OD value >=100；
（6）Eluent is concentrated, aqueous hydrochloric acid solution adjusts pH crystallizations, filter high-purity Vidarabine Monophosphate finished product.
The step（1）Tricresyl phosphate alkyl ester be selected from triethyl phosphate, trimethyl phosphate.
The step（1）The rate of charge of arabinosy ladenosine and POCl3 is 1:1（w/w）.
The step（1）Arabinosy ladenosine and the rate of charge of tricresyl phosphate alkyl ester are 1:10（w/v）.
The step（1）The temperature of temperature control reaction is -10~0 DEG C, is preferably -5~0 DEG C.
The step（2）Hydrolysis temperature is 0~20 DEG C, preferably 0~10 DEG C.
The step（3）Organic solvent be selected from dichloromethane, adjust PH sodium hydroxide solution molar concentration be 10mol/L.
The step（4）Strong-base anion-exchange resin be selected from 201 × 7,201 × Final 8 alkali anion and exchange tree
Fat.
The step（4）Adsorption temp is 10~30 DEG C.
The step（5）Eluent selected from molar concentration be that 0.01~0.05mol/L aqueous hydrochloric acid solutions, mass fraction are
0.3%~0.8% sodium-chloride water solution.
The step（5）Eluting temperature is 10~30 DEG C.
The step（6）Thickening temperature is 40~70 DEG C, preferably 50~60 DEG C.
The step（6）The aqueous hydrochloric acid solution molar concentration for adjusting pH crystallizations is 6mol/L.
The step（6）Recrystallization temperature is 0~10 DEG C, preferably 0~5 DEG C.
Vidarabine Monophosphate preparation method of the present invention in view of following reason and with high-purity, in high yield, behaviour
Make advantage convenient, that production serialization degree is high：When the 1st, being adsorbed through strong basic type anion-exchange resin, it is impossible to form anion
Impurity such as arabinosy ladenosine, adenine etc. can not carry out ion exchange and be removed first；Above-mentioned major impurity（Structure two, structure three,
Structure four）Because the polarity with product has certain difference, it can just be divided with principal component using suitable eluant, eluent
From removing, finally without recrystallization, HPLC purity >=99.80% of product after the concentrated crystallization of eluent.2nd, react and hydrolyzed
Cheng Zhong, can generate more hydrochloric acid and sulfuric acid, and more inorganic salts are generated during by adjusting pH crystallizations, and salt effect can increase product and exist
Solubility in water and reduce yield.After strong base ion exchange resin, most of inorganic salts can not only be removed to disappear
The product of high-purity just can be obtained except salt effect, and without recrystallization, so as to greatly improve yield.3rd, due to ion exchange resin
Itself possess that equipment is simple and convenient to operate, producing the advantages such as serialization degree height, to be widely used in Pure water preparation, sewage net
The every field such as change, chemical synthesis, medicament research and development, food processing, mining, technical conditions are highly developed.
Embodiment：
Embodiment 1
（1）By arabinosy ladenosine（30g）It is mixed in triethyl phosphate（300ml）In, stirring is cooled to -10 DEG C, adds POCl3
（30g）Temperature control -5~0 DEG C stirring reaction；
（2）Reaction is finished, and reaction solution is slowly added in purified water, 0~10 DEG C of hydrolysis of temperature control.Add dichloromethane（300ml/
It is secondary）Twice, water layer obtains upper prop stoste to extracting and demixing with 10mol/L NaOH regulations pH=6.5；
（3）Upper prop stoste is diluted into OD values to 70, passed through with 10ml/min speed equipped with 201 × 7 strong base anion resins
Pillar.Absorption is finished, and is eluted with 0.02mol/L HCl with 10ml/min speed, collects the eluent of OD value >=100；
（4）Collection is finished, and eluent is in 50 DEG C of vacuum concentrations, the 6mol/L HCl regulation crystallizations of pH=2.0, filtering, dry single phosphorus
Sour arabinosy ladenosine finished product 35.3g, molar yield 86.1%, HPLC purity 99.86%.
Embodiment 2
（1）By arabinosy ladenosine（30g）It is mixed in triethyl phosphate（300ml）In, stirring is cooled to -10 DEG C, adds POCl3
（30g）Temperature control -5~0 DEG C stirring reaction；
（2）Reaction is finished, and reaction solution is slowly added in purified water, 0~10 DEG C of hydrolysis of temperature control.Add dichloromethane（300ml/
It is secondary）Twice, water layer obtains upper prop stoste to extracting and demixing with 10mol/L NaOH regulations pH=7.5；
（3）Upper prop stoste is diluted into OD values to 90, passed through with 10ml/min speed equipped with 201 × 7 strong base anion resins
Pillar.Absorption is finished, and is eluted with 0.6% NaCl with 10ml/min speed, collects the eluent of OD value >=100；
（4）Collection is finished, and eluent is in 55 DEG C of vacuum concentrations, the 6mol/L HCl regulation crystallizations of pH=2.0, filtering, dry single phosphorus
Sour arabinosy ladenosine finished product 35.7g, molar yield 87.0%, HPLC purity 99.91%.
Embodiment 3
（1）By arabinosy ladenosine（30g）It is mixed in triethyl phosphate（300ml）In, stirring is cooled to -10 DEG C, adds POCl3
（30g）Temperature control -5~0 DEG C stirring reaction；
（2）Reaction is finished, and reaction solution is slowly added in purified water, 0~10 DEG C of hydrolysis of temperature control.Add dichloromethane（300ml/
It is secondary）Twice, water layer obtains upper prop stoste to extracting and demixing with 10mol/L NaOH regulations pH=6.0；
（3）Upper prop stoste is diluted into OD values to 80, passed through with 10ml/min speed equipped with 201 × Final 8 alkaline resin anion (R.A.)
Pillar.Absorption is finished, and is eluted with 0.04mol/L HCl with 10ml/min speed, collects the eluent of OD value >=100；
（4）Collection is finished, and eluent is in 50 DEG C of vacuum concentrations, the 6mol/L HCl regulation crystallizations of PH=2.0, filtering, dry single phosphorus
Sour arabinosy ladenosine finished product 34.9g, molar yield 85.1%, HPLC purity 99.80%.
Embodiment 4
（1）By arabinosy ladenosine（30g）It is mixed in triethyl phosphate（300ml）In, stirring is cooled to -10 DEG C, adds POCl3
（30g）Temperature control -5~0 DEG C stirring reaction；
（2）Reaction is finished, and reaction solution is slowly added in purified water, 0~10 DEG C of hydrolysis of temperature control.Add dichloromethane（300ml/
It is secondary）Twice, water layer obtains upper prop stoste to extracting and demixing with 10mol/L NaOH regulations pH=7.0；
（3）Upper prop stoste is diluted into OD values to 90, passed through with 10ml/min speed equipped with 201 × Final 8 alkaline resin anion (R.A.)
Pillar.Absorption is finished, and is eluted with 0.4% NaCl with 10ml/min speed, is collected the eluent of OD value >=100；
（4）Collection is finished, and eluent is in 50 DEG C of vacuum concentrations, the 6mol/L HCl regulation crystallizations of pH=2.0, filtering, dry single phosphorus
Sour arabinosy ladenosine finished product 35.3g, molar yield 86.1%, HPLC purity 99.88%.
Embodiment 5
（1）By arabinosy ladenosine（30g）It is mixed in trimethyl phosphate（300ml）In, stirring is cooled to -10 DEG C, adds POCl3
（30g）Temperature control -5~0 DEG C stirring reaction；
（2）Reaction is finished, and reaction solution is slowly added in purified water, 0~10 DEG C of hydrolysis of temperature control.Add dichloromethane（300ml/
It is secondary）Twice, water layer obtains upper prop stoste to extracting and demixing with 10mol/L NaOH regulations pH=7.8；
（3）Upper prop stoste is diluted into OD values to 100, passed through with 10ml/min speed equipped with 201 × 7 strong base anion resins
Pillar.Absorption is finished, and is eluted with 0.05mol/L HCl with 10ml/min speed, collects the eluent of OD value >=100；
（4）Collection is finished, and eluent is in 50 DEG C of vacuum concentrations, the 6mol/L HCl regulation crystallizations of pH=2.0, filtering, dry single phosphorus
Sour arabinosy ladenosine finished product 34.7g, molar yield 84.6%, HPLC purity 99.82%.
Embodiment 6
（1）By arabinosy ladenosine（30g）It is mixed in trimethyl phosphate（300ml）In, stirring is cooled to -10 DEG C, adds POCl3
（30g）Temperature control -5~0 DEG C stirring reaction；
（2）Reaction is finished, and reaction solution is slowly added in purified water, 0~10 DEG C of hydrolysis of temperature control.Add dichloromethane（300ml/
It is secondary）Twice, water layer obtains upper prop stoste to extracting and demixing with 10mol/L NaOH regulations pH=6.8；
（3）Upper prop stoste is diluted into OD values to 75, passed through with 10ml/min speed equipped with 201 × 7 strong base anion resins
Pillar.Absorption is finished, and is eluted with 0.5% NaCl with 10ml/min speed, collects the eluent of OD value >=100；
（4）Collection is finished, and eluent is in 55 DEG C of vacuum concentrations, the 6mol/L HCl regulation crystallizations of pH=2.0, filtering, dry single phosphorus
Sour arabinosy ladenosine finished product 35.5g, molar yield 86.6%, HPLC purity 99.89%.
Embodiment 7
（1）By arabinosy ladenosine（30g）It is mixed in trimethyl phosphate（300ml）In, stirring is cooled to -10 DEG C, adds POCl3
（30g）Temperature control -5~0 DEG C stirring reaction；
（2）Reaction is finished, and reaction solution is slowly added in purified water, 0~10 DEG C of hydrolysis of temperature control.Add dichloromethane（300ml/
It is secondary）Twice, water layer obtains upper prop stoste to extracting and demixing with 10mol/L NaOH regulations pH=6.8；
（3）Upper prop stoste is diluted into OD values to 60, passed through with 10ml/min speed equipped with 201 × Final 8 alkaline resin anion (R.A.)
Pillar.Absorption is finished, and is eluted with 0.02mol/L HCl with 10ml/min speed, collects the eluent of OD value >=100；
（4）Collection is finished, and eluent is in 55 DEG C of vacuum concentrations, the 6mol/L HCl regulation crystallizations of PH=2.0, filtering, dry single phosphorus
Sour arabinosy ladenosine finished product 34.6g, molar yield 84.4%, HPLC purity 99.80%.
Embodiment 8
（1）By arabinosy ladenosine（30g）It is mixed in trimethyl phosphate（300ml）In, stirring is cooled to -10 DEG C, adds POCl3
（30g）Temperature control -5~0 DEG C stirring reaction；
（2）Reaction is finished, and reaction solution is slowly added in purified water, 0~10 DEG C of hydrolysis of temperature control.Add dichloromethane（300ml/
It is secondary）Twice, water layer obtains upper prop stoste to extracting and demixing with 10mol/L NaOH regulations pH=7.5；
（3）Upper prop stoste is diluted into OD values to 85, passed through with 10ml/min speed equipped with 201 × Final 8 alkaline resin anion (R.A.)
Pillar.Absorption is finished, and is eluted with 0.5% NaCl with 10ml/min speed, collects the eluent of OD value >=100；
（4）Collection is finished, and eluent is in 55 DEG C of vacuum concentrations, the 6mol/L HCl regulation crystallizations of pH=2.0, filtering, dry single phosphorus
Sour arabinosy ladenosine finished product 35.1g, molar yield 85.6%, HPLC purity 99.85%.
Claims (5)
1. a kind of preparation method of high-purity Vidarabine Monophosphate, this method comprises the following steps：
（1）Arabinosy ladenosine is mixed in tricresyl phosphate alkyl ester, adds phosphorylation agent, temperature control reaction；
（2）Reaction, which is finished, is slowly added to reaction solution in purified water, temperature control hydrolysis；
（3）Organic solvent extraction is added, water layer adjusts pH to 6.0~8.0, obtains upper prop stoste with sodium hydroxide solution；
（4）Upper prop stoste is diluted to OD values 60~100, is handed over certain flow velocity by the cloudy daughter ion exchanger resin of strong base
Change absorption；
（5）Eluted with the eluent of debita spissitudo, collect the eluent of OD value >=100；
（6）Eluent is concentrated, aqueous hydrochloric acid solution adjusts pH crystallizations, filter high-purity Vidarabine Monophosphate finished product.
2. a kind of preparation method of high-purity Vidarabine Monophosphate as claimed in claim 1, it is characterised in that：The step
（1）The rate of charge of arabinosy ladenosine and POCl3 is 1:1（w/w）.
3. a kind of preparation method of high-purity Vidarabine Monophosphate as claimed in claim 1, it is characterised in that：The step
（4）Strong-base anion-exchange resin be selected from 201 × 7,201 × Final 8 alkalescence anion-exchange resin.
4. a kind of preparation method of high-purity Vidarabine Monophosphate as claimed in claim 1, it is characterised in that：The step
（5）Eluent selected from molar concentration be that 0.01~0.05mol/L aqueous hydrochloric acid solutions, mass fraction are 0.3%~0.8% sodium chloride
The aqueous solution.
5. a kind of preparation method of high-purity Vidarabine Monophosphate as claimed in claim 1, it is characterised in that：The step
（6）Specially by eluent in 50~60 DEG C of vacuum concentrations, the crystallization of pH=2.0 is adjusted with 6mol/L HCl, it is filtering, singly dry
Vidarabine phosphate finished product.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107793458A (en) * | 2017-09-22 | 2018-03-13 | 海南葫芦娃药业集团股份有限公司 | A kind of preparation method of Vidarabine Monophosphate |
| 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 |
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| CN101023968A (en) * | 2007-02-09 | 2007-08-29 | 上海大学 | Coenzyme composition preparing method |
| CN102079766A (en) * | 2009-11-29 | 2011-06-01 | 海南中化联合制药工业股份有限公司 | Preparation method of vidarabine monophosphate |
| CN103122017A (en) * | 2013-02-06 | 2013-05-29 | 广东先强药业股份有限公司 | Refining method of vidarabine monophosphate |
| CN103204890A (en) * | 2013-02-22 | 2013-07-17 | 广东先强药业股份有限公司 | Phosphorylation method for preparing vidarabine monophosphate |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| US3703507A (en) * | 1969-09-26 | 1972-11-21 | Parke Davis & Co | Process for the production of 9-(beta-d-arabinofuranosyl) adenine,5'-phosphate and salts thereof |
| CN101023968A (en) * | 2007-02-09 | 2007-08-29 | 上海大学 | Coenzyme composition preparing method |
| CN102079766A (en) * | 2009-11-29 | 2011-06-01 | 海南中化联合制药工业股份有限公司 | Preparation method of vidarabine monophosphate |
| CN103122017A (en) * | 2013-02-06 | 2013-05-29 | 广东先强药业股份有限公司 | Refining method of vidarabine monophosphate |
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| CN107793458A (en) * | 2017-09-22 | 2018-03-13 | 海南葫芦娃药业集团股份有限公司 | A kind of preparation method of Vidarabine Monophosphate |
| CN107793458B (en) * | 2017-09-22 | 2020-04-21 | 海南葫芦娃药业集团股份有限公司 | Preparation method of vidarabine monophosphate |
| 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 |
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