CN106397514B - A kind of double labelling uridine-(13C,15N2) synthetic method - Google Patents

A kind of double labelling uridine-(13C,15N2) synthetic method Download PDF

Info

Publication number
CN106397514B
CN106397514B CN201610753806.7A CN201610753806A CN106397514B CN 106397514 B CN106397514 B CN 106397514B CN 201610753806 A CN201610753806 A CN 201610753806A CN 106397514 B CN106397514 B CN 106397514B
Authority
CN
China
Prior art keywords
double labelling
uridine
uracil
solvent
added
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Active
Application number
CN201610753806.7A
Other languages
Chinese (zh)
Other versions
CN106397514A (en
Inventor
徐建飞
杜晓宁
王伟
雷雯
宋明鸣
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Shanghai Research Institute of Chemical Industry SRICI
Original Assignee
Shanghai Research Institute of Chemical Industry SRICI
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Shanghai Research Institute of Chemical Industry SRICI filed Critical Shanghai Research Institute of Chemical Industry SRICI
Priority to CN201610753806.7A priority Critical patent/CN106397514B/en
Publication of CN106397514A publication Critical patent/CN106397514A/en
Application granted granted Critical
Publication of CN106397514B publication Critical patent/CN106397514B/en
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

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
    • C07H19/06—Pyrimidine radicals
    • C07H19/067—Pyrimidine radicals with ribosyl as the saccharide radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H1/00—Processes for the preparation of sugar derivatives

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 relates to a kind of double labelling uridine-(13C,15N2) synthetic method, this method using anhydrous benzene as solvent, double labelling urea-(13C,15N2) and propiolic acid be raw material carry out cyclization, obtain double labelling uracil-(13C,15N2)；In Ar2Under atmosphere, acetonitrile as solvents, double labelling uracil-(13C,15N2) and 1- acetoxyl group -2,3,5- thribenzoyl-β-D-RIBOSE mixing, are subsequently added into hexamethyldisilazane and trifluoromethane sulfonic acid trimethyl silicone grease, the intermediate obtained after post-treated is hydrolyzed with ammonium hydroxide, can be obtained double labelling uridine-(13C,15N2).Compared with prior art, present invention process is simple, and yield is higher, and isotope abundance does not decline, be suitble to Laboratory Production double labelling uridine-(13C,15N2)。

Description

A kind of double labelling uridine-(13C,15N2) synthetic method
Technical field
The present invention relates to the preparation method of the organic compound of stable isotope labeling more particularly to a kind of double labelling urine are phonetic Pyridine nucleosides-(13C,15N2) methodology of organic synthesis.
Background technique
Uridine is white, needle-shaped crystals or powder, odorlessness, taste slightly sweet tea and micro-pungent, is slightly soluble in dilute alcohol, does not dissolve in Dehydrated alcohol is the related ingredient for constituting zooblast nucleic acid.It is indispensable raw material in biomedical research, while It is the basic element for preparing biologics.Uridine is a kind of drug, be usually used in treatment resist huge red blood cell anaemia and liver, The diseases such as the cerebrovascular, angiocarpy, and manufacture fluorouracil (S-FC), deoxyribonucleoside, iodoxuridine (IDUR), bromine glycosides (BUDR), fluorine The primary raw material of the drugs such as glycosides (FUDR).
In order to study uridine and its derivative drug to the organism mechanism of action, need to compound and its metabolism Object is tracked, but since compound is in factors such as high noisy background, complicated matrix effect, preceding processing and mass detectors Under the influence of, it is affected to analysis method measurement result.In order to avoid the inaccuracy of analysis, stable isotope mark is used Remember compound, the error that can effectively occur in bearing calibration significantly improves the stability of detection method.Double labelling uracil Nucleosides-(13C,15N2) can effective and accurate detection nucleoside medicine and its metabolin as isotopic label.
Currently, the method for preparing uridine has RNA chemical hydrolysis and fermentation method.Traditional uridine preparation Method is using RNA through chemical hydrolysis, then prepare 2 kinds of pyrimidine nucleosides (Kazarinova LA, Livshits VA, Preobrazhenskaya ES,et al.Method for producing uridine-5'-monophosphate by fermentation using mutantstrains of coryneform bacteria [P].United States Patent:6344344,2002-02-05), this method not only needs a large amount of high quality rna raw material, but also is not suitable for preparing same position Element label uridine；Fermentation method (progress [J] biotechnology communications of Wang Rui pyrimidine nucleoside, 2007,18 (3): 539~541.) be by means of microorganism have synthesize itself needed for nucleosides ability, at the mutagenesis to specified microorganisms Reason, selects auxotroph and nucleoside analog resistant mutant strain, to release the feedback inhibition in Metabolism regulation and feedback resistance Hold back, to achieve the purpose that accumulate pyrimidine nucleoside during the fermentation, addition precursor fermentation method is closed using nucleotide biology Pyrimidine bases are made to pass through benefit by adding precursor uracil in the culture medium that nucleosides produces bacterium at the remedial pathway of approach The direct synthetic nucleosides of approach are rescued, to increase the production quantity of uridine.Fermentation method is with fermentation condition is simple, the period is short and yield is high The advantages that, but it is more difficult to select useful strain, and isotope abundance is easy to be diluted.
Summary of the invention
It is simple, feasible that it is an object of the present invention to overcome the above-mentioned drawbacks of the prior art and provide a kind of methods And double labelling uridine-suitable for mass production (13C,15N2) synthetic method.
The purpose of the present invention can be achieved through the following technical solutions: a kind of double labelling uridine-(13C,15N2) Synthetic method, which is characterized in that this method using anhydrous benzene as solvent, double labelling urea-(13C,15N2) and propiolic acid be raw material Carry out cyclization, obtain double labelling uracil-(13C,15N2)；In Ar2Under atmosphere, acetonitrile as solvents, double labelling uracil- (13C,15N2) and 1- acetoxyl group -2,3,5- thribenzoyl-β-D-RIBOSE mixing is subsequently added into two silicon nitrogen of hexamethyl Alkane and trifluoromethane sulfonic acid trimethyl silicone grease, the intermediate obtained after post-treated are hydrolyzed with ammonium hydroxide, and double labelling urine can be obtained Pyrimidine nucleoside-(13C,15N2)。
The method have the following steps are included:
(1) using anhydrous benzene as solvent, double labelling urea-(13C,15N2) and propiolic acid be added in solvent, 20~150 DEG C are anti- It answers 10~40 hours, is separated water into during the reaction with water segregator, obtained dark red solution is added in ice water, immediately There is the crystal of uracil to be precipitated, stands overnight, gained crystallization double labelling uracil-(13C,15N2) filtering, vacuum drying；
(2) in Ar2Under atmosphere, by double labelling uracil-(13C,15N2) and 1- acetoxyl group -2,3,5- tri-benzoyl oxygen Base-β-D-RIBOSE is added in solvent, is stirred at room temperature, and is then placed in cooling in ice bath, is successively added with glass syringe Hexamethyldisilazane and trifluoromethane sulfonic acid trimethyl silicone grease, solution is clarified after stirring, after 0~5 DEG C is stirred 10~50 minutes It is stirred overnight at room temperature；
(3) reaction solution is spin-dried for solvent, residue after purification, with saturation Na2CO3It washes, organic phase anhydrous Na2SO4It is dry Dry overnight, filtering obtains intermediate after being spin-dried for solvent；
(4) intermediate is dissolved in methanol, ammonium hydroxide is added, solution is stirred 12~48 hours and is hydrolyzed at room temperature, is spin-dried for Crude product CH afterwards3OH-CH2Cl2Silica gel column purification is crossed as eluent, obtaining colorless solid is target product double labelling uridine diphosphate Glycosides-(13C,15N2)。
Reaction route is as follows:
Double labelling urea-described in step (1) (13C,15N2) and propiolic acid reaction molar ratio be 1:1~2.
Double labelling urea-described in step (1) (13C,15N2) and propiolic acid reaction molar ratio be 1:1.2~1.5, reaction Temperature is 80 DEG C and reacts 20 hours.
The temperature stood overnight described in step (1) is 0~5 DEG C, preferably 4 DEG C.
Double labelling uracil-described in step (2) (13C,15N2) and 1- acetoxyl group -2,3,5- thribenzoyl-β - The molar ratio of D-RIBOSE reaction is 1:1~2；The solvent is one of acetonitrile, methylene chloride, chloroform or more Kind；Be added hexamethyldisilazane mole be uracil-(13C,15N2) 2~6 times；Trifluoromethane sulfonic acid trimethyl is added The mole of silicone grease is uracil -- (13C,15N2) 0.5~3 times；
Double labelling uracil-described in step (2) (13C,15N2) and 1- acetoxyl group -2,3,5- thribenzoyl-β - The molar ratio of D-RIBOSE reaction is 1:1.2~1.5；The solvent is acetonitrile；Mole of hexamethyldisilazane is added Amount be uracil-(13C,15N2) 3 times；The mole that trifluoromethane sulfonic acid trimethyl silicone grease is added is uracil -- (13C,15N2) 2 times.
Purifying described in step (3) is that residue is dissolved in solvent, and the solvent used is ethyl acetate, chloroform, second One of ether is a variety of.
Ammonium hydroxide solubility described in step (4) is 5%~20%, and ammonium hydroxide hydrolysis time is 20 hours.
Compared with prior art, in order to effectively and accurately detect the metabolic pathway of pyridimine nucleosides drug, this Invention is used using anhydrous benzene as solvent, double labelling urea-(13C,15N2) and propiolic acid be that raw material carries out cyclization, crude product is through de- Color and recrystallization after obtain double labelling uracil-(13C,15N2).In Ar2Under atmosphere, acetonitrile as solvents, double labelling uracil- (13C,15N2) and 1- acetoxyl group -2,3,5- thribenzoyl-β-D-RIBOSE be stirred, then use glass syringe Hexamethyldisilazane and trifluoromethane sulfonic acid trimethyl silicone grease is added.The intermediate obtained after post-treated is hydrolyzed with ammonium hydroxide, Can be obtained double labelling uridine-(13C,15N2).Yield >=72% (with double labelling urea-(13C,15N2) meter),13C and15N Abundance is both greater than 98% (being measured with the liquid chromatograph-mass spectrometer and MAT271 isotope mass spectrometer of Thermo), and chemistry is pure Degree is greater than 99% (the Mahna-IR550 determination of infrared spectroscopy of Waters liquid chromatogram and Nicole company).The method label13C,15N2Isotope simple process, yield is higher, and isotope abundance does not decline, and is suitble to Laboratory Production double labelling uridine diphosphate Glycosides-(13C,15N2)。
Specific embodiment
It elaborates below to the embodiment of the present invention, the present embodiment carries out under the premise of the technical scheme of the present invention Implement, the detailed implementation method and specific operation process are given, but protection scope of the present invention is not limited to following implementation Example.
Embodiment 1
Take double labelling urea-(13C,15N2) 10mmol and propiolic acid 15mmol be added in the solution that anhydrous benzene is solvent, 80 DEG C are reacted 40 hours, are separated water into during the reaction with water segregator, obtained dark red solution is added in ice water, are stood There is the crystal of uracil to be precipitated, 4 DEG C stand overnight.Crystallization double labelling uracil-(13C,15N2) filtering, it is dried in vacuo, obtains 1.01g product (1).
In Ar2Under atmosphere, using acetonitrile as solvent, by 10mmol uracil-(13C,15N2) and 20mmol 1- acetoxyl group- 2,3,5- thribenzoyl-β-D-RIBOSE is added in solution, is stirred at room temperature, and is then placed in cooling in ice bath, uses glass 60mmol hexamethyldisilazane and 5mmol trifluoromethane sulfonic acid trimethyl silicone grease, solution after stirring is successively added in glass syringe Clarification, 0 DEG C stirring 30 minutes after be stirred overnight at room temperature.
Reaction solution is spin-dried for solvent, residue is dissolved in ethyl acetate, with saturation Na2CO3It is washed till pH neutrality, is saturated NaCl Organic phase 3 times are washed, organic phase anhydrous Na2SO4It is dried overnight.Filtering obtains intermediate (2) after being spin-dried for solvent.
Intermediate (2) is dissolved in methanol, 10% ammonium hydroxide is added, solution ammonia hydrolyzes 20 hours at room temperature, thick after being spin-dried for Product CH3OH-CH2Cl2Silica gel column purification is crossed as eluent, product is obtained and is washed with n-hexane, colorless solid is obtained after vacuum drying is For target product double labelling uridine-(13C,15N2), total recovery be 72.5% (with double labelling urea-(13C,15N2) meter) ,13C >=98%,15N >=98%, chemical purity >=99%.
Embodiment 2
Take double labelling urea-(13C,15N2) 10mmol and propiolic acid 10mmol be added in the solution that anhydrous benzene is solvent, 20 DEG C are reacted 20 hours, are separated water into during the reaction with water segregator, obtained dark red solution is added in ice water, are stood There is the crystal of uracil to be precipitated, 4 DEG C stand overnight.Crystallization double labelling uracil-(13C,15N2) filtering, it is dried in vacuo, obtains 0.86g product (1).
In Ar2Under atmosphere, using acetonitrile as solvent, by 10mmol uracil-(13C,15N2) and 13mmol 1- acetoxyl group- 2,3,5- thribenzoyl-β-D-RIBOSE is added in solution, is stirred at room temperature, and is then placed in cooling in ice bath, uses glass 30mmol hexamethyldisilazane and 10mmol trifluoromethane sulfonic acid trimethyl silicone grease, solution after stirring is successively added in glass syringe Clarification, 0 DEG C stirring 30 minutes after be stirred overnight at room temperature.
Reaction solution is spin-dried for solvent, residue is dissolved in ethyl acetate, with saturation Na2CO3It is washed till pH neutrality, is saturated NaCl Organic phase 3 times are washed, organic phase anhydrous Na2SO4It is dried overnight.Filtering obtains intermediate (2) after being spin-dried for solvent.
Intermediate (2) is dissolved in methanol, 20% ammonium hydroxide is added, solution ammonia hydrolyzes 12 hours at room temperature, thick after being spin-dried for Product CH3OH-CH2Cl2Silica gel column purification is crossed as eluent, product is obtained and is washed with n-hexane, colorless solid is obtained after vacuum drying is For target product double labelling uridine-(13C,15N2), total recovery be 73.0% (with double labelling urea-(13C,15N2) meter) ,13C >=98%,15N >=98%, chemical purity >=99%.
Embodiment 3
Take double labelling urea-(13C,15N2) 10mmol and propiolic acid 20mmol be added in the solution that anhydrous benzene is solvent, 150 DEG C are reacted 10 hours, are separated water into during the reaction with water segregator, obtained dark red solution is added in ice water, There is the crystal of uracil to be precipitated immediately, 4 DEG C stand overnight.Crystallization double labelling uracil-(13C,15N2) filtering, it is dried in vacuo, obtains To 1.00g product (1).
In Ar2Under atmosphere, using acetonitrile as solvent, by 10mmol uracil-(13C,15N2) and 10mmol 1- acetoxyl group- 2,3,5- thribenzoyl-β-D-RIBOSE is added in solution, is stirred at room temperature, and is then placed in cooling in ice bath, uses glass 20mmol hexamethyldisilazane and 30mmol trifluoromethane sulfonic acid trimethyl silicone grease, solution after stirring is successively added in glass syringe Clarification, 0 DEG C stirring 30 minutes after be stirred overnight at room temperature.
Reaction solution is spin-dried for solvent, residue is dissolved in ethyl acetate, with saturation Na2CO3It is washed till pH neutrality, is saturated NaCl Organic phase 3 times are washed, organic phase anhydrous Na2SO4It is dried overnight.Filtering obtains intermediate (2) after being spin-dried for solvent.
Intermediate (2) is dissolved in methanol, 5% ammonium hydroxide is added, solution ammonia hydrolyzes 48 hours at room temperature, is spin-dried for rear crude product Use CH3OH-CH2Cl2Silica gel column purification is crossed as eluent, product is obtained and is washed with n-hexane, colorless solid is obtained after vacuum drying is Target product double labelling uridine-(13C,15N2), total recovery be 73.5% (with double labelling urea-(13C,15N2) meter),13C >=98%,15N >=98%, chemical purity >=99%.
Embodiment 4
Take double labelling urea-(13C,15N2) 10mmol and propiolic acid 12mmol be added in the solution that anhydrous benzene is solvent, 100 DEG C are reacted 20 hours, are separated water into during the reaction with water segregator, obtained dark red solution is added in ice water, There is the crystal of uracil to be precipitated immediately, 0 DEG C stands overnight.Crystallization double labelling uracil-(13C,15N2) filtering, it is dried in vacuo, obtains To 1.00g product (1).
In Ar2Under atmosphere, using methylene chloride as solvent, by 10mmol uracil-(13C,15N2) and 12mmol 1- acetyl Oxygroup -2,3,5- thribenzoyl-β-D-RIBOSE are added in solution, are stirred at room temperature, and are then placed in cooling in ice bath, 30mmol hexamethyldisilazane and 20mmol trifluoromethane sulfonic acid trimethyl silicone grease are successively added with glass syringe, after stirring Solution clarification, 5 DEG C of stirrings are stirred overnight at room temperature after ten minutes.
Reaction solution is spin-dried for solvent, residue is dissolved in chloroform, with saturation Na2CO3It is washed till pH neutrality, saturation NaCl has been washed Machine phase 3 times, organic phase anhydrous Na2SO4It is dried overnight.Filtering obtains intermediate (2) after being spin-dried for solvent.
Intermediate (2) is dissolved in methanol, 10% ammonium hydroxide is added, solution ammonia hydrolyzes 24 hours at room temperature, thick after being spin-dried for Product CH3OH-CH2Cl2Silica gel column purification is crossed as eluent, product is obtained and is washed with n-hexane, colorless solid is obtained after vacuum drying is For target product double labelling uridine-(13C,15N2), total recovery be 73.8% (with double labelling urea-(13C,15N2) meter) ,13C >=98%,15N >=98%, chemical purity >=99%.
Embodiment 5
Take double labelling urea-(13C,15N2) 10mmol and propiolic acid 16mmol be added in the solution that anhydrous benzene is solvent, 110 DEG C are reacted 30 hours, are separated water into during the reaction with water segregator, obtained dark red solution is added in ice water, There is the crystal of uracil to be precipitated immediately, 10 DEG C stand overnight.Crystallization double labelling uracil-(13C,15N2) filtering, vacuum drying, Obtain 1.00g product (1).
In Ar2Under atmosphere, using chloroform as solvent, by 10mmol uracil-(13C,15N2) and 15mmol 1- acetoxyl group- 2,3,5- thribenzoyl-β-D-RIBOSE is added in solution, is stirred at room temperature, and is then placed in cooling in ice bath, uses glass 30mmol hexamethyldisilazane and 20mmol trifluoromethane sulfonic acid trimethyl silicone grease, solution after stirring is successively added in glass syringe Clarification, 0 DEG C stirring 30 minutes after be stirred overnight at room temperature.
Reaction solution is spin-dried for solvent, residue is dissolved in chloroform, with saturation Na2CO3It is washed till pH neutrality, saturation NaCl has been washed Machine phase 3 times, organic phase anhydrous Na2SO4It is dried overnight.Filtering obtains intermediate (2) after being spin-dried for solvent.
Intermediate (2) is dissolved in methanol, 15% ammonium hydroxide is added, solution ammonia hydrolyzes 36 hours at room temperature, thick after being spin-dried for Product CH3OH-CH2Cl2Silica gel column purification is crossed as eluent, product is obtained and is washed with n-hexane, colorless solid is obtained after vacuum drying is For target product double labelling uridine-(13C,15N2), total recovery be 74% (with double labelling urea-(13C,15N2) meter),13C >=98%,15N >=98%, chemical purity >=99%.

Claims (8)

1. a kind of double labelling uridine-(13C,15N2) synthetic method, which is characterized in that this method with anhydrous benzene be it is molten Agent, double labelling urea-(13C,15N2) and propiolic acid be raw material carry out cyclization, obtain double labelling uracil-(13C,15N2)； In Ar2Under atmosphere, acetonitrile as solvents, double labelling uracil-(13C,15N2) and 1- acetoxyl group -2,3,5- thribenzoyl - β-D-RIBOSE mixing is subsequently added into hexamethyldisilazane and trifluoromethane sulfonic acid trimethyl silicone grease, obtains after post-treated To intermediate hydrolyzed with ammonium hydroxide, can be obtained double labelling uridine-(13C,15N2)；
The method have the following steps are included:
(1) using anhydrous benzene as solvent, double labelling urea-(13C,15N2) and propiolic acid be added in solvent, 20~150 DEG C reaction 10 It~40 hours, is separated water into during the reaction with water segregator, obtained dark red solution is added in ice water, there is urine immediately The crystal of pyrimidine is precipitated, and stands overnight, gained crystallization double labelling uracil-(13C,15N2) filtering, vacuum drying；
(2) in Ar2Under atmosphere, by double labelling uracil-(13C,15N2) and 1- acetoxyl group -2,3,5- thribenzoyl-β - D-RIBOSE is added in solvent, is stirred at room temperature, and is then placed in cooling in ice bath, hexamethyl is successively added with glass syringe Disilazane and trifluoromethane sulfonic acid trimethyl silicone grease, after stirring solution clarify, 0~5 DEG C stirring 10~50 minutes after room temperature stir It mixes overnight；
(3) reaction solution is spin-dried for solvent, after residue is dissolved in solvent purification, with saturation Na2CO3It washes, organic phase is with anhydrous Na2SO4It is dried overnight, filters, obtain intermediate after being spin-dried for solvent；
(4) intermediate is dissolved in methanol, ammonium hydroxide is added, solution is stirred 12~48 hours and is hydrolyzed at room temperature, thick after being spin-dried for Product CH3OH-CH2Cl2Silica gel column purification is crossed as eluent, obtaining colorless solid is target product double labelling uridine- (13C,15N2)。
2. double labelling uridine-according to claim 1 (13C,15N2) synthetic method, which is characterized in that step (1) described in double labelling urea-(13C,15N2) and propiolic acid reaction molar ratio be 1:1~2.
3. double labelling uridine-according to claim 1 or 2 (13C,15N2) synthetic method, which is characterized in that step Suddenly double labelling urea-described in (1) (13C,15N2) and propiolic acid reaction molar ratio be 1:1.2~1.5, reaction temperature be 80 DEG C Reaction 20 hours.
4. double labelling uridine-according to claim 1 (13C,15N2) synthetic method, which is characterized in that step (1) temperature stood overnight described in is 0~10 DEG C.
5. double labelling uridine-according to claim 1 (13C,15N2) synthetic method, which is characterized in that step (2) described in double labelling uracil-(13C,15N2) and 1- acetoxyl group -2,3,5- thribenzoyl-β-D-RIBOSE it is anti- The molar ratio answered is 1:1~2；The solvent is one or more of acetonitrile, methylene chloride, chloroform；Hexamethyl is added The mole of disilazane be uracil-(13C,15N2) 2~6 times；The mole of trifluoromethane sulfonic acid trimethyl silicone grease is added For uracil-(13C,15N2) 0.5~3 times.
6. according to claim 1 or 5 double labelling uridine-(13C,15N2) synthetic method, which is characterized in that step Suddenly double labelling uracil-described in (2) (13C,15N2) and 1- acetoxyl group -2,3,5- thribenzoyl-β-D-RIBOSE The molar ratio of reaction is 1:1.2~1.5；The solvent is acetonitrile；The mole that hexamethyldisilazane is added is uracil- (13C,15N2) 3 times；Be added trifluoromethane sulfonic acid trimethyl silicone grease mole be uracil-(13C,15N2) 2 times.
7. double labelling uridine-according to claim 1 (13C,15N2) synthetic method, which is characterized in that step (3) purifying described in is that residue is dissolved in solvent, the solvent used for one of ethyl acetate, chloroform, ether or It is a variety of.
8. double labelling uridine-according to claim 1 (13C,15N2) synthetic method, which is characterized in that step (4) the ammonium hydroxide solubility described in is 5%~20%, and ammonium hydroxide hydrolysis time is 20 hours.
CN201610753806.7A 2016-08-29 2016-08-29 A kind of double labelling uridine-(13C,15N2) synthetic method Active CN106397514B (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN201610753806.7A CN106397514B (en) 2016-08-29 2016-08-29 A kind of double labelling uridine-(13C,15N2) synthetic method

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN201610753806.7A CN106397514B (en) 2016-08-29 2016-08-29 A kind of double labelling uridine-(13C,15N2) synthetic method

Publications (2)

Publication Number Publication Date
CN106397514A CN106397514A (en) 2017-02-15
CN106397514B true CN106397514B (en) 2019-04-02

Family

ID=58002595

Family Applications (1)

Application Number Title Priority Date Filing Date
CN201610753806.7A Active CN106397514B (en) 2016-08-29 2016-08-29 A kind of double labelling uridine-(13C,15N2) synthetic method

Country Status (1)

Country Link
CN (1) CN106397514B (en)

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
《Preparation of Uracil》;Ralph J. De Pasquale;《J.Org.Chem》;19771231;第42卷(第12期);2185-2187
《SYNTHESIS OF ISOTOPICALLY LABELLED DNA DEGRADATION PRODUCTS FOR USE IN MASS SPECTROMETRIC STUDIES OF CELLULAR DNA DAMAGE》;SAIC Frederick;《Journal of labelled compounds and radiopharmaceuticals》;19960831;第XXXVIII卷(第8期);713-723
《The economical synthesis of 【2-13C，1，3-15N2】uridine；preliminary conformational studies by solid state NMR》;Simon G.Patching;《Org. Biomol.Chem.》;20031231(第1期);2058,2061-2062
《同位素标记胞嘧啶的合成研究》;徐建飞;《化学试剂》;20160630;572

Also Published As

Publication number Publication date
CN106397514A (en) 2017-02-15

Similar Documents

Publication Publication Date Title
CN102199183B (en) C-di-GMP, analogues thereof and preparation method thereof
Schweizer et al. Aminoacyl nucleosides. VII. N-(Purin-6-ylcarbamoyl) threonine. A new component of transfer ribonucleic acid
CN112724180B (en) Preparation method of beta-nicotinamide mononucleotide
CN101570559B (en) Method for preparing 5-aza-2'-deoxycytidine and its intermediates
CN104910229A (en) Poly phosphoric acid end fluorescent labeled nucleotide and application thereof
CN103360391A (en) Novel apixaban crystal form and preparation method thereof
Pan et al. Janus-type AT nucleosides: synthesis, solid and solution state structures
US3658788A (en) Aminooxazolines and products thereof and processes for synthesizing same
CN106397514B (en) A kind of double labelling uridine-(13C,15N2) synthetic method
CN113307804B (en) Synthetic method and application of fluorine-containing indole quinoline compound
CN105199101A (en) Dipeptide polyethyleneimine polymer as well as preparation method and application thereof
Endo et al. Photoisomerization of 2′-deoxyribofuranosyl and ribofuranosyl 2-phenylazoimidazole
KR101963570B1 (en) Method for the Preparation of Amorphous Dinucleoside Polyphosphate Compound
WO2021092919A1 (en) Nicotinamide mononucleotide intermediate and method for synthesizing nicotinamide mononucleotide
Timmons et al. On the synthesis of the 2, 6-dideoxysugar l-digitoxose
CN115490736A (en) Method for synthesizing deoxynucleoside triphosphate and derivative thereof
Doerr et al. Nucleosides. L. Synthesis of 2, 3'-imino-1-(2-deoxy-. beta.-D-threo-pentofuranosyl) thymine and related derivatives
Rajappan et al. A flexible synthesis of carbanucleosides and 5′-nor-1′-homo carbanucleosides from a common precursor
Gogritchiani et al. Photochromic nucleic base units suitable for nucleic acid labelling
Chaudhuri et al. Development of a Novel Synthetic Process for 2-Deoxy-3, 5-di-O-p-toluoyl-α-l-ribofuranosyl Chloride: A Versatile Intermediate in the Synthesis of 2 ‘-Deoxy-l-ribonucleosides
Gade et al. Dideoxy nucleoside triphosphate (ddNTP) analogues: Synthesis and polymerase substrate activities of pyrrolidinyl nucleoside triphosphates (prNTPs)
CN111875531B (en) Method for preparing 3-nitropyrrole based on sodium peroxodisulfate
CN111533700B (en) 5-substituted uracil derivative and preparation method and application thereof
WO2022227117A1 (en) Method for synthesizing vidarabine monophosphate and use thereof
JP3499896B2 (en) Method for producing 2'-deoxynucleosides

Legal Events

Date Code Title Description
C06 Publication
PB01 Publication
C10 Entry into substantive examination
SE01 Entry into force of request for substantive examination
CB02 Change of applicant information

Address after: 200062 Shanghai city Putuo District Yunling Road No. 345

Applicant after: Shanghai Chemical Research Institute Co., Ltd.

Address before: 200062 Shanghai city Putuo District Yunling Road No. 345

Applicant before: Shanghai Research Institute of Chemical Industry

CB02 Change of applicant information
GR01 Patent grant
GR01 Patent grant