CN113735926A - Synthesis process of uridine - Google Patents
Synthesis process of uridine Download PDFInfo
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- CN113735926A CN113735926A CN202111074805.7A CN202111074805A CN113735926A CN 113735926 A CN113735926 A CN 113735926A CN 202111074805 A CN202111074805 A CN 202111074805A CN 113735926 A CN113735926 A CN 113735926A
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- acid
- reaction
- uridine
- cytidine
- solution
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- DRTQHJPVMGBUCF-XVFCMESISA-N Uridine Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C=C1 DRTQHJPVMGBUCF-XVFCMESISA-N 0.000 title claims abstract description 88
- DRTQHJPVMGBUCF-PSQAKQOGSA-N beta-L-uridine Natural products O[C@H]1[C@@H](O)[C@H](CO)O[C@@H]1N1C(=O)NC(=O)C=C1 DRTQHJPVMGBUCF-PSQAKQOGSA-N 0.000 title claims abstract description 44
- DRTQHJPVMGBUCF-UHFFFAOYSA-N uracil arabinoside Natural products OC1C(O)C(CO)OC1N1C(=O)NC(=O)C=C1 DRTQHJPVMGBUCF-UHFFFAOYSA-N 0.000 title claims abstract description 44
- 229940045145 uridine Drugs 0.000 title claims abstract description 44
- 238000000034 method Methods 0.000 title claims abstract description 27
- 238000003786 synthesis reaction Methods 0.000 title abstract description 13
- 230000015572 biosynthetic process Effects 0.000 title abstract description 10
- 238000006243 chemical reaction Methods 0.000 claims abstract description 65
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 32
- UHDGCWIWMRVCDJ-UHFFFAOYSA-N 1-beta-D-Xylofuranosyl-NH-Cytosine Natural products O=C1N=C(N)C=CN1C1C(O)C(O)C(CO)O1 UHDGCWIWMRVCDJ-UHFFFAOYSA-N 0.000 claims abstract description 28
- UHDGCWIWMRVCDJ-PSQAKQOGSA-N Cytidine Natural products O=C1N=C(N)C=CN1[C@@H]1[C@@H](O)[C@@H](O)[C@H](CO)O1 UHDGCWIWMRVCDJ-PSQAKQOGSA-N 0.000 claims abstract description 28
- UHDGCWIWMRVCDJ-ZAKLUEHWSA-N cytidine Chemical compound O=C1N=C(N)C=CN1[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O1 UHDGCWIWMRVCDJ-ZAKLUEHWSA-N 0.000 claims abstract description 28
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 12
- 239000002904 solvent Substances 0.000 claims abstract description 7
- IOVCWXUNBOPUCH-UHFFFAOYSA-N Nitrous acid Chemical compound ON=O IOVCWXUNBOPUCH-UHFFFAOYSA-N 0.000 claims abstract description 6
- 239000012445 acidic reagent Substances 0.000 claims abstract description 6
- 150000007522 mineralic acids Chemical class 0.000 claims abstract description 6
- 150000007524 organic acids Chemical class 0.000 claims abstract description 5
- 238000004321 preservation Methods 0.000 claims abstract description 4
- 239000000243 solution Substances 0.000 claims description 29
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 27
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 claims description 26
- 239000002253 acid Substances 0.000 claims description 21
- 238000002425 crystallisation Methods 0.000 claims description 16
- 230000008025 crystallization Effects 0.000 claims description 16
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 15
- 238000000746 purification Methods 0.000 claims description 15
- 235000010288 sodium nitrite Nutrition 0.000 claims description 13
- OPTASPLRGRRNAP-UHFFFAOYSA-N cytosine Chemical class NC=1C=CNC(=O)N=1 OPTASPLRGRRNAP-UHFFFAOYSA-N 0.000 claims description 11
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 10
- 239000003153 chemical reaction reagent Substances 0.000 claims description 10
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 9
- 229940104302 cytosine Drugs 0.000 claims description 9
- 239000002777 nucleoside Substances 0.000 claims description 9
- 239000012266 salt solution Substances 0.000 claims description 9
- IOVCWXUNBOPUCH-UHFFFAOYSA-M Nitrite anion Chemical compound [O-]N=O IOVCWXUNBOPUCH-UHFFFAOYSA-M 0.000 claims description 8
- -1 cytosine nucleoside Chemical class 0.000 claims description 7
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 4
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 4
- 239000003960 organic solvent Substances 0.000 claims description 3
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 claims description 2
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 claims description 2
- AZFNGPAYDKGCRB-XCPIVNJJSA-M [(1s,2s)-2-amino-1,2-diphenylethyl]-(4-methylphenyl)sulfonylazanide;chlororuthenium(1+);1-methyl-4-propan-2-ylbenzene Chemical compound [Ru+]Cl.CC(C)C1=CC=C(C)C=C1.C1=CC(C)=CC=C1S(=O)(=O)[N-][C@@H](C=1C=CC=CC=1)[C@@H](N)C1=CC=CC=C1 AZFNGPAYDKGCRB-XCPIVNJJSA-M 0.000 claims description 2
- 230000001476 alcoholic effect Effects 0.000 claims description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 2
- 235000019253 formic acid Nutrition 0.000 claims description 2
- OWFXIOWLTKNBAP-UHFFFAOYSA-N isoamyl nitrite Chemical compound CC(C)CCON=O OWFXIOWLTKNBAP-UHFFFAOYSA-N 0.000 claims description 2
- 229910017604 nitric acid Inorganic materials 0.000 claims description 2
- 239000004304 potassium nitrite Substances 0.000 claims description 2
- 235000010289 potassium nitrite Nutrition 0.000 claims description 2
- 230000002194 synthesizing effect Effects 0.000 claims description 2
- 239000002994 raw material Substances 0.000 abstract description 10
- 238000002360 preparation method Methods 0.000 abstract description 2
- 230000036632 reaction speed Effects 0.000 abstract 1
- 239000012065 filter cake Substances 0.000 description 8
- 238000004128 high performance liquid chromatography Methods 0.000 description 8
- 239000007864 aqueous solution Substances 0.000 description 5
- KCURWTAZOZXKSJ-IAIGYFSYSA-N 4-amino-1-[(2r,3r,4s,5r)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]pyrimidin-2-one;hydrochloride Chemical compound Cl.O=C1N=C(N)C=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](CO)O1 KCURWTAZOZXKSJ-IAIGYFSYSA-N 0.000 description 4
- 238000001914 filtration Methods 0.000 description 4
- 238000010438 heat treatment Methods 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- 208000012839 conversion disease Diseases 0.000 description 3
- 238000006193 diazotization reaction Methods 0.000 description 3
- 230000008034 disappearance Effects 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 2
- XQFRJNBWHJMXHO-RRKCRQDMSA-N IDUR Chemical compound C1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C(I)=C1 XQFRJNBWHJMXHO-RRKCRQDMSA-N 0.000 description 2
- ISAKRJDGNUQOIC-UHFFFAOYSA-N Uracil Chemical compound O=C1C=CNC(=O)N1 ISAKRJDGNUQOIC-UHFFFAOYSA-N 0.000 description 2
- 239000007853 buffer solution Substances 0.000 description 2
- 229940126600 bulk drug product Drugs 0.000 description 2
- 239000007789 gas Substances 0.000 description 2
- 229960004716 idoxuridine Drugs 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- WOVKYSAHUYNSMH-RRKCRQDMSA-N 5-bromodeoxyuridine Chemical compound C1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C(Br)=C1 WOVKYSAHUYNSMH-RRKCRQDMSA-N 0.000 description 1
- GHASVSINZRGABV-UHFFFAOYSA-N Fluorouracil Chemical compound FC1=CNC(=O)NC1=O GHASVSINZRGABV-UHFFFAOYSA-N 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 230000021736 acetylation Effects 0.000 description 1
- 238000006640 acetylation reaction Methods 0.000 description 1
- 238000006136 alcoholysis reaction Methods 0.000 description 1
- 208000007502 anemia Diseases 0.000 description 1
- 238000004061 bleaching Methods 0.000 description 1
- 230000002490 cerebral effect Effects 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 239000012954 diazonium Substances 0.000 description 1
- 150000001989 diazonium salts Chemical class 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 230000002526 effect on cardiovascular system Effects 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 210000003743 erythrocyte Anatomy 0.000 description 1
- 238000000855 fermentation Methods 0.000 description 1
- 230000004151 fermentation Effects 0.000 description 1
- ODKNJVUHOIMIIZ-RRKCRQDMSA-N floxuridine Chemical compound C1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C(F)=C1 ODKNJVUHOIMIIZ-RRKCRQDMSA-N 0.000 description 1
- 229960002949 fluorouracil Drugs 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 229910000403 monosodium phosphate Inorganic materials 0.000 description 1
- 235000019799 monosodium phosphate Nutrition 0.000 description 1
- ZQBVUULQVWCGDQ-UHFFFAOYSA-N propan-1-ol;propan-2-ol Chemical compound CCCO.CC(C)O ZQBVUULQVWCGDQ-UHFFFAOYSA-N 0.000 description 1
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 229940035893 uracil Drugs 0.000 description 1
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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
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
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- 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 invention discloses a uridine synthesis process, and belongs to the technical field of organic synthesis. The preparation method comprises the steps of taking cytidine as a main raw material, uniformly mixing the cytidine with water, controlling the temperature to be 10-60 ℃, respectively adding a nitrous acid reagent and an inorganic acid or an organic acid, reacting for 1-10 hours under heat preservation, finishing the reaction after the raw material is hours, controlling the pH to be 1-4 after the reaction is finished, concentrating under reduced pressure to obtain a uridine concentrated solution, dripping an alcohol solvent into the uridine concentrated solution, and crystallizing to obtain the uridine product. The process is easy to operate, complete in reaction and high in reaction speed, and the synthesis period is greatly shortened. In addition, the conversion rate of the process is as high as more than 90%, the yield is more than 80%, and the purity is more than 99.5%.
Description
Technical Field
The invention particularly relates to a uridine synthesis process, and belongs to the technical field of organic synthesis.
Background
Uridine is a medicine, such as giant erythrocyte anemia resistant medicine, for treating diseases of liver, cerebral vessels, cardiovascular and the like, and is also a main raw material for preparing medicines such as fluorouracil (S-FC), deoxynucleoside, Idoxuridine (IDUR), Bromoglycoside (BUDR), Fluoroglycoside (FUDR) and the like.
At present, the main production method of uridine is a biological fermentation method, and the method has more complex process and less output; the chemical synthesis method mainly comprises the steps of acetylation, condensation, hydrolysis, alcoholysis and crystallization of uracil which is used as a raw material to finally prepare uridine.
Disclosure of Invention
Aiming at the defects in the prior art, the invention designs the uridine synthesis process which is simple in synthesis process, high in synthesis conversion rate, convenient in post-treatment and low in production cost.
The invention takes cytidine as raw material, matches with specific reaction conditions, and directly converts cytidine into uridine in aqueous solution through one-step diazotization reaction; then applying a specific post-treatment purification process to obtain the uridine bulk drug product with the purity of more than 99.5 percent. At present, the cytidine is produced in large batch in China, the supply is sufficient, and the price is low, so the process has the condition of industrial production.
The invention aims to provide a method for synthesizing uridine, which comprises the following steps:
dissolving cytidine in an acid solution to prepare an acid salt solution of cytidine; dispersing a nitrite reagent in water to prepare a nitrite reagent solution; then, firstly adding water into a reaction container, controlling the temperature to be 10-60 ℃, respectively dropwise adding the prepared acid salt solution of cytidine and the prepared nitrous acid reagent solution into the reaction container, and after dropwise adding, carrying out heat preservation reaction on a mixed system; after the reaction is finished, the uridine is obtained by crystallization and purification.
In one embodiment of the present invention, the acid salt solution of cytidine has a molar ratio of cytosine nucleotides to acid of 1: (2-5); specifically, the ratio of the total amount of the components is 1: 3.
In one embodiment of the invention, the acid in the acid solution comprises an inorganic acid and/or an organic acid; wherein the inorganic acid comprises hydrochloric acid, phosphoric acid, nitric acid, and sulfuric acid; the organic acid includes acetic acid and formic acid. Inorganic acids are preferred.
In one embodiment of the invention, the molar ratio of cytosine nucleoside to nitrite reagent is 1: (1.5-6); preferably 1: (2.2-6).
In one embodiment of the present invention, the mass concentration of the acid salt solution of cytidine is 20 wt% to 50 wt%; specifically, 40 wt% may be preferred.
In one embodiment of the invention, the nitrous acid reagent solution has a mass concentration of 20 wt% to 30 wt%; specifically, it may be 25 wt%.
In one embodiment of the invention, the nitrite reagent is selected from any one or more of: sodium nitrite, potassium nitrite, isoamyl nitrite.
In one embodiment of the present invention, the concentration of cytosine nucleosides in the mixed system is 10 wt% to 20 wt%; specifically, it may be 16.7 wt%.
In one embodiment of the present invention, the pH in the reaction vessel is controlled to 3.5 to 4.5 at the time of dropwise addition.
In one embodiment of the invention, the dripping time is controlled to be 1-5 h; the time of the heat preservation reaction is 1-10 h.
In one embodiment of the invention, after the reaction is finished, the pH of the reaction system is controlled to be 1-5, then the reaction system is subjected to reduced pressure concentration at the temperature of 20-80 ℃, the pH is adjusted to be 5-7 after acid gas is removed, the concentration is continued, and then the crystallization and purification are carried out.
In one embodiment of the invention, the concentration is to a uridine concentration of 10 wt% to 80 wt%; specifically, 30 wt% may be selected.
In one embodiment of the present invention, the vacuum degree of the vacuum concentration is in the range of-0.1 MPa to-0.08 MPa.
In one embodiment of the present invention, the solvent used for crystallization purification is an alcoholic organic solvent, including any one or more of the following: methanol, ethanol, isopropanol. Methanol and ethanol are preferred.
In one embodiment of the present invention, the amount of the solvent used for purification by crystallization is 1500mL/100g of cytosine nucleoside relative to the amount of the starting cytosine nucleoside. Preferably 600-1000mL/100g cytosine nucleosides.
In one embodiment of the invention, the temperature for crystallization and purification is 0-25 ℃ and the time is 1-12 h.
In one embodiment of the present invention, the synthetic route of the method is:
in an embodiment of the present invention, the method specifically includes:
(1) dissolving cytidine in acid to prepare acid salt solution of cytidine and nitrous acid reagent solution; adding water into a reactor, controlling the temperature to be 10-60 ℃, then dripping an acid salt solution of cytidine and a nitrous acid reagent solution into the reactor according to a certain proportion, controlling the pH of the reaction to react, reacting the cytidine with a diazotization reagent after the dripping to generate a corresponding diazonium salt, and continuously reacting in an aqueous solution to generate uridine, thereby finally obtaining an aqueous solution of uridine;
(2) and controlling the pH value of the obtained aqueous solution to be 1-5, carrying out reduced pressure concentration, controlling the temperature to be 20-80 ℃, removing acid gas, adjusting the pH value to be 5-7, continuously concentrating until the concentration of uridine is 10-80%, and then dropwise adding an alcohol organic solvent for crystallization to obtain a pure uridine product.
Has the advantages that:
the invention takes cytidine as raw material, matches with specific reaction conditions, and directly converts the cytidine into uridine in aqueous solution through one-step diazotization reaction; then applying a specific post-treatment purification process to obtain the uridine bulk drug product with the purity of more than 99.5 percent. The invention has simple synthesis process, high synthesis conversion rate which is more than 90 percent, higher yield which is more than 80 percent, convenient post-treatment and low production cost.
Drawings
FIG. 1 is an HPLC chromatogram of uridine obtained in example 1.
FIG. 2 is a nuclear magnetic hydrogen spectrum of uridine obtained in example 1.
Detailed Description
In order to make the aforementioned objects, features and advantages of the present invention comprehensible, the present invention is further described in detail by the following examples, but the scope of the present invention is not limited thereto:
the HPLC detection conditions of the present invention are as follows: liquid chromatograph Shimadzu 10A; a chromatographic column: INERTSIL ODS-SP 5um 4.6 × 250 mm; mobile phase: buffer solution: acetonitrile 97: 3; wherein, buffer solution preparation: 1.884g of disodium hydrogen phosphate and 0.726g of sodium dihydrogen phosphate are dissolved in 1000ml of water; wavelength: 260 nm; flow rate: 1.0 ml/min.
Example 1:
firstly, 100g of water is added into a reaction bottle, the temperature is controlled to be 15 ℃, and then 100g (0.411mol) of cytidine and 150g (1.233mol) of 30 wt% hydrochloric acid are mixed and dissolved to prepare 250g of cytidine hydrochloride solution; and preparing 250g (0.906mol) of 25 wt% sodium nitrite solution, dropwise adding 250g of cytidine hydrochloride solution and 250g of 25% sodium nitrite solution into a reaction bottle at the same time, stirring for reaction, controlling the pH of the reaction to be 3.5-4.0, wherein the dropwise adding time is 3 hours, the dropwise adding temperature is 15 ℃, after 3 hours, keeping the temperature for reaction for 5 hours after the dropwise adding is finished, and detecting the disappearance of raw material residues by HPLC (high performance liquid chromatography), wherein the reaction conversion rate reaches 98.5 percent after the reaction is finished.
After the reaction is finished, adjusting the pH of the reaction solution to 2.0, heating to 60 ℃, concentrating under reduced pressure for 30 minutes, adjusting the pH to 7.0, continuously concentrating to 30 percent (300mL) of uridine concentration, beginning to drop 1000mL of ethanol for 5 hours, dropping at 5 ℃, keeping the temperature and crystallizing for 12 hours at 5 ℃, filtering, rinsing a filter cake with 95 percent ethanol, drying the filter cake to constant weight at 80 ℃, and finally obtaining 90.5g (0.37mol) of uridine with the purity of 99.7 percent and the yield of 90.14 percent.
Nuclear magnetic characterization of the structure: h1-NMR(D2O):(A,B):3.684～3.816(2H),(C):4.004～4.024(1H)，(D):4.028～4.113(1H)，(E):4.124～4.242(1H)，(F,G):5.766～5.796(2H),(J):7.756～7.773(1H).
Example 2:
firstly, 100g of water is added into a reaction bottle, the temperature is controlled to be 15 ℃, and then 100g (0.411mol) of cytidine and 150g (1.233mol) of 30 wt% hydrochloric acid are mixed and dissolved to prepare 250g of cytidine hydrochloride solution; and additionally preparing 250g (0.906mol) of 25 wt% sodium nitrite solution, dropwise adding 250g of cytidine hydrochloride solution and 250g of 25% sodium nitrite solution into the reaction bottle at the same time, stirring for reaction, controlling the pH of the reaction to be 3.5-4.0, wherein the dropwise adding time is 3 hours, the dropwise adding temperature is 15 ℃, after 3 hours, keeping the temperature for reaction for 5 hours after the dropwise adding is finished, and detecting the disappearance of raw material residues by HPLC (high performance liquid chromatography), wherein the reaction conversion rate is 98.7 percent after the reaction is finished.
After the reaction is finished, adjusting the pH of the reaction solution to 2.0, heating to 60 ℃, concentrating under reduced pressure for 30 minutes, adjusting the pH to 7.0, continuously concentrating to 30 percent (300mL) of uridine concentration, beginning to drop 600mL of methanol for 3 hours, dropping at 5 ℃, keeping the temperature and crystallizing for 12 hours at 5 ℃, filtering, rinsing a filter cake with methanol, drying the filter cake to constant weight at 80 ℃, and finally obtaining 82.2g of uridine with the purity of 99.82% and the total yield of 81.87%.
Example 3:
firstly, 100g of water is added into a reaction bottle, the temperature is controlled to be 15 ℃, then 100g (0.411mol) of cytidine and 74g (1.233mol) of acetic acid are mixed and dissolved to prepare 174g of cytidine acetate solution; preparing 250g (0.906mol) of 25 wt% sodium nitrite solution, stirring 174g of cytidine acetate solution and 250g of 25% sodium nitrite solution for reaction, controlling the pH value of the reaction to be 4.0-4.5, wherein the dripping time is 3 hours, the dripping temperature is 15 ℃, after 3 hours, finishing the dripping, preserving the temperature for 7 hours, detecting the disappearance of the raw material residue by HPLC, finishing the reaction, and ensuring the reaction conversion rate to be 96.1%.
After the reaction is finished, adjusting the pH of the reaction solution to 2.0, heating to 60 ℃, concentrating under reduced pressure for 30 minutes, adjusting the pH to 7.0, continuously concentrating to 30 percent (300mL) of uridine concentration, beginning to drop 1000mL of ethanol for 5 hours, dropping at 5 ℃, keeping the temperature and crystallizing for 12 hours at 5 ℃, filtering, rinsing a filter cake with 95 percent ethanol, drying the filter cake to constant weight at 80 ℃, and finally obtaining 84.2g (0.345mol) of uridine with the purity of 99.36 percent and the total yield of 83.94 percent.
Example 4:
referring to example 1, uridine was prepared by changing only the amount of 25% sodium nitrite, and the others were unchanged. The results are shown in table 1:
TABLE 1
| 25% of sodium nitrite | n (cytidine): n (sodium nitrite) | Conversion rate of reaction | Yield of uridine | Purity of |
| 200 | 1:1.8 | 70％ | - | - |
| 225 | 1:2 | 91.5％ | 76.3％- | 95.2％- |
| 250g (example 1) | 1:2.2 | 98.5％ | 90.14％ | 99.7％ |
| 300 | 1:2.6 | 98.6％ | 86.5％ | 99.11％ |
Wherein "-" means that the purification by crystallization is not continued in the case where the conversion is low.
Referring to example 1, uridine was prepared by changing only the amount of 30% hydrochloric acid and the others were unchanged. The results are shown in table 2:
TABLE 2
| 30% hydrochloric acid dosage | n (cytidine): n (HCl) | Conversion rate of reaction | Yield of uridine | Purity of |
| 100 | 1:2 | 61.5％ | - | - |
| 125 | 1:2.5 | 82.8％ | 65.3％ | 93.5％ |
| 150 (example 1) | 1:3 | 98.5％ | 90.14％ | 99.7％ |
| 175 | 1:3.5 | 97.9％ | 87.8％ | 98.85％ |
Wherein "-" means that the purification by crystallization is not continued in the case where the conversion is low.
Referring to example 1, uridine was prepared by changing only the amount of water to control the reaction concentration of cytidine substrate, and keeping the others unchanged. The results are shown in Table 3:
TABLE 3
Referring to example 1, uridine was prepared by keeping the reaction process unchanged, changing the solvent environment used for crystallization purification during purification, and otherwise unchanged. The results are shown in Table 4:
TABLE 4
| Crystallization solvent | Yield of uridine | Purity of |
| Methanol | 81.87％ | 99.82％ |
| Ethanol | 90.14％ | 99.7％ |
| Isopropanol (I-propanol) | 94.25％ | 94.5％ |
| Methanol + isopropanol (volume ratio 1:1) | 88.9％ | 98.5％ |
As can be seen from table 4, the purity of 99.5% or more can be achieved by using methanol or ethanol as the crystallization reagent; and the selected isopropanol or the mixed solvent of the isopropanol and the methanol has a weak purity effect and cannot meet the product requirement of more than 99.5 percent.
Comparative example 1:
first, 100g of water was added to a reaction flask, and then 100g of cytosine nucleoside was added to the reaction flask0.411mol) Adding into a reaction bottle, controlling the temperature at 15 ℃, and adding 250g of 25 percent sodium nitrite solution (sodium nitrite solution)0.906mol) Adding the mixture into a reaction bottle, stirring the mixture until the mixture is completely dissolved, dropwise adding 150g (1.233mol) of 30% hydrochloric acid for 3 hours at the dropwise adding temperature of 15 ℃, keeping the temperature for reaction for 20 hours after the dropwise adding is finished, detecting by HPLC that the raw material residue disappears, and finishing the reaction until the conversion rate of uridine is 88.6%. After the reaction is finished, adjusting the pH of the reaction solution to 2.0, heating to 60 ℃, concentrating under reduced pressure for 30 minutes, adjusting the pH to 7.0, continuously concentrating until the concentration of uridine reaches 30% (300ml), beginning to drop 1000ml of ethanol for 5 hours, dropping at 5 ℃, keeping the temperature and crystallizing for 12 hours at 5 ℃, filtering, and bleaching a filter cake by using 95% ethanolWashed clean and the filter cake is dried to constant weight at 80 ℃ to finally obtain 75.5g (0.309mol) of uridine with purity of 96.68% and yield of 75.18%.
Claims (10)
1. A method for synthesizing uridine, comprising the steps of: dissolving cytidine in an acid solution to prepare an acid salt solution of cytidine; dispersing a nitrite reagent in water to prepare a nitrite reagent solution; then, firstly adding water into a reaction container, controlling the temperature to be 10-60 ℃, respectively dropwise adding the prepared acid salt solution of cytidine and the prepared nitrous acid reagent solution into the reaction container, and after dropwise adding, carrying out heat preservation reaction on a mixed system; after the reaction is finished, the uridine is obtained by crystallization and purification.
2. The method according to claim 1, wherein the molar ratio of cytosine nucleotides to acid in the acid salt solution of cytidine is 1: (2-5).
3. The method of claim 1, wherein the molar ratio of cytosine nucleoside to nitrite reagent is 1: (1.5-6).
4. The method according to claim 1, wherein the concentration of the cytosine nucleoside in the mixed system is 10 wt% to 20 wt%.
5. The method according to claim 1, wherein the pH in the reaction vessel is controlled to 3.5 to 4.5 at the time of dropwise addition.
6. The method according to claim 1, wherein the solvent used for crystallization purification is an alcoholic organic solvent comprising any one or more of: methanol, ethanol, isopropanol.
7. The method as claimed in claim 1, wherein the solvent used for the purification by crystallization is 1500mL/100g of cytosine nucleoside in an amount of 100-.
8. The method as claimed in claim 1, wherein after the reaction is finished, the pH of the reaction system is controlled to be 1-5, then the reaction system is subjected to reduced pressure concentration at 20-80 ℃, acid gas is removed, then the pH is adjusted to be 5-7, the concentration is continued, and then the crystallization and purification are carried out.
9. The method of claim 1, wherein the acid in the acid solution comprises an inorganic acid and/or an organic acid; wherein the inorganic acid is selected from any one or more of the following: hydrochloric acid, phosphoric acid, nitric acid, sulfuric acid; the organic acid is selected from acetic acid and/or formic acid.
10. The method according to any one of claims 1-9, wherein the nitrite reagent is selected from any one or more of the group consisting of: sodium nitrite, potassium nitrite, isoamyl nitrite.
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Citations (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0757056A1 (en) * | 1995-08-03 | 1997-02-05 | PRO.BIO.SINT. S.r.l. | Method for preparing 1-beta-D-arabinofuranosylcytosine |
| JPH0959292A (en) * | 1995-08-25 | 1997-03-04 | Yamasa Shoyu Co Ltd | Production of 4-aminopyrimidine nucleoside |
| CN101717420A (en) * | 2009-11-12 | 2010-06-02 | 浙江先锋化工科技有限公司 | Novel method for synthesizing uridine |
| CN102250177A (en) * | 2011-05-06 | 2011-11-23 | 宋道淮 | New method for synthesizing uridylic acid disodium |
| CN104447922A (en) * | 2013-09-25 | 2015-03-25 | 杭州美亚药业有限公司 | Preparation method of uridine-5'-monophosphate disodium |
| CN108409818A (en) * | 2018-05-16 | 2018-08-17 | 新乡拓新药业股份有限公司 | A kind of method of synthesizing cytimidine nucleosides |
| CN110776535A (en) * | 2019-12-09 | 2020-02-11 | 美亚药业海安有限公司 | Preparation method of disodium xanthate |
| CN110981928A (en) * | 2019-12-18 | 2020-04-10 | 美亚药业海安有限公司 | Method for producing uridylic acid disodium by continuous flow reaction device |
-
2021
- 2021-09-14 CN CN202111074805.7A patent/CN113735926B/en active Active
Patent Citations (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0757056A1 (en) * | 1995-08-03 | 1997-02-05 | PRO.BIO.SINT. S.r.l. | Method for preparing 1-beta-D-arabinofuranosylcytosine |
| JPH0959292A (en) * | 1995-08-25 | 1997-03-04 | Yamasa Shoyu Co Ltd | Production of 4-aminopyrimidine nucleoside |
| CN101717420A (en) * | 2009-11-12 | 2010-06-02 | 浙江先锋化工科技有限公司 | Novel method for synthesizing uridine |
| CN102250177A (en) * | 2011-05-06 | 2011-11-23 | 宋道淮 | New method for synthesizing uridylic acid disodium |
| CN104447922A (en) * | 2013-09-25 | 2015-03-25 | 杭州美亚药业有限公司 | Preparation method of uridine-5'-monophosphate disodium |
| CN108409818A (en) * | 2018-05-16 | 2018-08-17 | 新乡拓新药业股份有限公司 | A kind of method of synthesizing cytimidine nucleosides |
| CN110776535A (en) * | 2019-12-09 | 2020-02-11 | 美亚药业海安有限公司 | Preparation method of disodium xanthate |
| CN110981928A (en) * | 2019-12-18 | 2020-04-10 | 美亚药业海安有限公司 | Method for producing uridylic acid disodium by continuous flow reaction device |
Non-Patent Citations (2)
| Title |
|---|
| NAGANO, TETSUO等: "Reactions of nitric oxide with amines in the presence of dioxygen", 《TETRAHEDRON LETTERS》, vol. 36, no. 45, pages 8239 - 8242 * |
| 张亮仁,等: "《核酸药物化学》", 30 April 1997, pages: 97 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114990176A (en) * | 2022-05-26 | 2022-09-02 | 宁夏华吉生物有限公司 | Method for producing uridine |
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Denomination of invention: A synthesis process of uridine Granted publication date: 20230725 Pledgee: Rudong sub branch of Bank of China Ltd. Pledgor: JIANGSU XIANGDI CHEMICAL CO.,LTD. Registration number: Y2024980006182 |