CN113735926B - Synthesis process of uridine - Google Patents
Synthesis process of uridine Download PDFInfo
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- CN113735926B CN113735926B CN202111074805.7A CN202111074805A CN113735926B CN 113735926 B CN113735926 B CN 113735926B CN 202111074805 A CN202111074805 A CN 202111074805A CN 113735926 B CN113735926 B CN 113735926B
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- acid
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- uridine
- cytidine
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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 23
- 238000003786 synthesis reaction Methods 0.000 title abstract description 11
- 230000015572 biosynthetic process Effects 0.000 title abstract description 8
- 238000006243 chemical reaction Methods 0.000 claims abstract description 68
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 35
- 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 30
- 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 30
- 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 30
- 238000002425 crystallisation Methods 0.000 claims abstract description 18
- 230000008025 crystallization Effects 0.000 claims abstract description 18
- IOVCWXUNBOPUCH-UHFFFAOYSA-N Nitrous acid Chemical compound ON=O IOVCWXUNBOPUCH-UHFFFAOYSA-N 0.000 claims abstract description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 12
- 239000012445 acidic reagent Substances 0.000 claims abstract description 11
- 239000002904 solvent Substances 0.000 claims abstract description 7
- 150000007524 organic acids Chemical class 0.000 claims abstract description 5
- 150000007522 mineralic acids Chemical class 0.000 claims abstract description 4
- 230000002194 synthesizing effect Effects 0.000 claims abstract description 4
- 239000000243 solution Substances 0.000 claims description 32
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 claims description 24
- 239000002253 acid Substances 0.000 claims description 23
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 15
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 13
- 238000000746 purification Methods 0.000 claims description 12
- 235000010288 sodium nitrite Nutrition 0.000 claims description 12
- OPTASPLRGRRNAP-UHFFFAOYSA-N cytosine Natural products NC=1C=CNC(=O)N=1 OPTASPLRGRRNAP-UHFFFAOYSA-N 0.000 claims description 11
- 229940104302 cytosine Drugs 0.000 claims description 11
- 239000002777 nucleoside Substances 0.000 claims description 11
- -1 cytosine nucleoside Chemical class 0.000 claims description 10
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 9
- 239000012266 salt solution Substances 0.000 claims description 9
- 239000003153 chemical reaction reagent Substances 0.000 claims description 5
- 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
- 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
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 2
- 235000019253 formic acid Nutrition 0.000 claims description 2
- 229910052500 inorganic mineral Inorganic materials 0.000 claims description 2
- OWFXIOWLTKNBAP-UHFFFAOYSA-N isoamyl nitrite Chemical compound CC(C)CCON=O OWFXIOWLTKNBAP-UHFFFAOYSA-N 0.000 claims description 2
- 239000011707 mineral Substances 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
- 239000002994 raw material Substances 0.000 abstract description 13
- 238000004321 preservation Methods 0.000 abstract description 4
- 230000006837 decompression Effects 0.000 abstract 1
- 230000036632 reaction speed Effects 0.000 abstract 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 24
- 230000001276 controlling effect Effects 0.000 description 9
- 230000001105 regulatory effect Effects 0.000 description 9
- 239000012065 filter cake Substances 0.000 description 8
- 238000004128 high performance liquid chromatography Methods 0.000 description 6
- 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
- 230000008034 disappearance Effects 0.000 description 4
- 238000001914 filtration 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
- 239000003814 drug Substances 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 238000002156 mixing Methods 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 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
- 239000007789 gas Substances 0.000 description 2
- GQPLMRYTRLFLPF-UHFFFAOYSA-N nitrous oxide Inorganic materials [O-][N+]#N GQPLMRYTRLFLPF-UHFFFAOYSA-N 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- VZSRBBMJRBPUNF-UHFFFAOYSA-N 2-(2,3-dihydro-1H-inden-2-ylamino)-N-[3-oxo-3-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)propyl]pyrimidine-5-carboxamide Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)C(=O)NCCC(N1CC2=C(CC1)NN=N2)=O VZSRBBMJRBPUNF-UHFFFAOYSA-N 0.000 description 1
- 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
- 208000024172 Cardiovascular disease Diseases 0.000 description 1
- GHASVSINZRGABV-UHFFFAOYSA-N Fluorouracil Chemical compound FC1=CNC(=O)NC1=O GHASVSINZRGABV-UHFFFAOYSA-N 0.000 description 1
- 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 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- 230000021736 acetylation Effects 0.000 description 1
- 238000006640 acetylation reaction Methods 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 230000001476 alcoholic effect Effects 0.000 description 1
- 238000006136 alcoholysis reaction Methods 0.000 description 1
- 208000007502 anemia Diseases 0.000 description 1
- 230000009286 beneficial effect Effects 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
- 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
- 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
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 150000008160 idosides Chemical class 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
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 229940035893 uracil Drugs 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
- C07H19/06—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
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 invention discloses a process for synthesizing uridine, and belongs to the technical field of organic synthesis. The invention takes cytidine as main raw material, and the cytidine is evenly mixed with water, the temperature is controlled to be 10-60 ℃, nitrous acid reagent, inorganic acid or organic acid are respectively added, the reaction is carried out for 1-10 hours after the heat preservation, the reaction is finished after the raw material is used for hours, the pH value is controlled to be 1-4 after the reaction is finished, the uridine concentrated solution is obtained by decompression concentration, then alcohol solvent is dripped into the uridine concentrated solution, and the uridine is obtained by crystallization. The process is easy to operate, thorough 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 as high as more than 80%, and the purity is more than 99.5%.
Description
Technical Field
The invention particularly relates to a process for synthesizing uridine, and belongs to the technical field of organic synthesis.
Background
Uridine is a drug, such as anti-giant erythrocyte anemia, for treating liver, cerebral vessels, cardiovascular diseases, etc., and is also a main raw material for preparing fluorouracil (S-FC), deoxynucleoside, idoside (IDUR), bromoglycoside (BUDR), fluoroglycoside (FUDR), etc.
The main production method of uridine at present is a biological fermentation method, the process of the method is more complex, and the output is less; the chemical synthesis method mainly uses uracil as a raw material to prepare uridine through the steps of acetylation, condensation, hydrolysis, alcoholysis and crystallization.
Disclosure of Invention
Aiming at the defects existing in the prior art, the invention designs a uridine synthesis process which has the advantages of simple synthesis process, high synthesis conversion rate, convenient post-treatment and low production cost.
The invention takes cytidine (cytidine) as a raw material, and is matched with specific reaction conditions to directly convert cytidine into uridine in aqueous solution through one-step diazotization reaction; then, the uridine raw material medicine with the purity of more than 99.5 percent is obtained by applying a specific post-treatment purification process. At present, cytidine has been produced in large quantities in China, and has sufficient supply and low price, so that 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 nitrous acid reagent in water to prepare nitrous acid reagent solution; then, firstly adding water into a reaction container, controlling the temperature to be 10-60 ℃, respectively dripping the prepared cytidine acid salt solution and nitrous acid reagent solution into the reaction container, and carrying out heat preservation reaction on the mixed system after dripping is finished; after the reaction is finished, crystallizing and purifying to obtain uridine.
In one embodiment of the invention, the molar ratio of cytosine nucleoside to acid in the acid salt solution of cytidine is 1: (2-5); specifically, the ratio of the two components can be 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 comprises acetic acid and formic acid. Mineral acids are preferred.
In one embodiment of the invention, the molar ratio of cytosine nucleoside to nitrous reagent is 1: (1.5-6); preferably 1: (2.2-6).
In one embodiment of the invention, the mass concentration of the acid salt solution of cytidine is 20wt% to 50wt%; in particular, 40wt% may be preferable.
In one embodiment of the invention, the nitrous acid reagent solution has a mass concentration of 20wt% to 30wt%; specifically, 25wt% may be used.
In one embodiment of the invention, the nitrous reagent is selected from any one or more of the following: sodium nitrite, potassium nitrite, isoamyl nitrite.
In one embodiment of the invention, the concentration of cytosine nucleosides in the mixed system is from 10wt% to 20wt%; specifically, 16.7wt% may be used.
In one embodiment of the present invention, the pH in the reaction vessel is controlled to 3.5 to 4.5 during the dropwise addition.
In one embodiment of the invention, the time of dripping is controlled to be 1-5h; the reaction time of heat preservation 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 decompressed and concentrated at 20-80 ℃, the pH is adjusted to be 5-7 after the acid gas is removed, and the reaction system is continuously concentrated and then crystallized and purified.
In one embodiment of the invention, concentration is carried out to a uridine concentration of 10wt% to 80wt%; specifically, 30wt% is selected.
In one embodiment of the present invention, the vacuum degree of the reduced pressure concentration ranges from-0.1 MPa to-0.08 MPa.
In one embodiment of the present invention, the solvent used for crystallization and purification is an alcoholic organic solvent, including any one or more of the following: methanol, ethanol, isopropanol. Methanol and ethanol are preferable.
In one embodiment of the invention, the solvent used for crystallization purification is used in an amount of 100 to 1500mL/100g of cytosine nucleoside relative to the cytosine nucleoside starting material. Preferably 600-1000mL/100g cytosine nucleoside.
In one embodiment of the present invention, the crystallization and purification temperature is 0 to 25℃and the time is 1 to 12 hours.
In one embodiment of the invention, the synthetic route of the method is:
in one embodiment of the present invention, the method specifically includes:
(1) The cytidine is mixed with acid to be dissolved, so as to prepare an acid salt solution of cytidine, and a nitrous acid reagent solution is prepared; 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 cytidine with a diazotization reagent after dripping to generate corresponding diazonium salt, and continuously reacting in the aqueous solution to generate uridine, thus finally obtaining the aqueous solution of uridine;
(2) The pH value of the obtained aqueous solution is controlled to be 1-5, the pressure is reduced, the concentration is carried out, the temperature is controlled to be 20-80 ℃, the pH value is adjusted to be 5-7 after the acid gas is removed, the concentration is continued to be carried out until the concentration of uridine is 10-80%, and then alcohol organic solvent is dripped for crystallization, thus obtaining pure uridine.
The beneficial effects are that:
the invention takes cytidine as a raw material, and is matched with specific reaction conditions to directly convert cytidine into uridine in aqueous solution through one-step diazotization reaction; then, the uridine raw material medicine with the purity of more than 99.5 percent is obtained by applying a specific post-treatment purification process. The invention has simple synthesis process, high synthesis conversion rate which is up to more than 90%, high yield which is up to more than 80%, convenient post-treatment and low production cost.
Drawings
FIG. 1 is an HPLC chart of uridine obtained in example 1.
FIG. 2 is a nuclear magnetic resonance spectrum of uridine obtained in example 1.
Detailed Description
In order to make the above objects, features and advantages of the present invention more comprehensible, the present invention is further described by way of specific examples, but the scope of the present invention is not limited thereto:
the detection conditions of HPLC related to the invention are as follows: liquid chromatograph shimadzu 10A; chromatographic column: INERTESIL ODS-SP 5um 4.6.250 mm; mobile phase: buffer solution: acetonitrile=97:3; wherein, buffer solution is prepared: 1.884g of disodium hydrogen phosphate and 0.726g of sodium dihydrogen phosphate are dissolved in 1000ml of water; wavelength: 260nm; flow rate: 1.0ml/min.
Example 1:
firstly, adding 100g of water into a reaction bottle, controlling the temperature to be 15 ℃, and then mixing 100g (0.411 mol) of cytidine with 150g (1.233 mol) of 30wt% hydrochloric acid to dissolve, so as to prepare 250g of cytidine hydrochloride solution; and preparing 250g (0.906 mol) of 25wt% sodium nitrite solution, simultaneously dripping 250g of cytidine hydrochloride solution and 250g of 25% sodium nitrite solution into a reaction bottle, stirring for reaction, controlling the pH value of the reaction to be 3.5-4.0, dripping for 3 hours, dripping at 15 ℃ for 3 hours, after dripping is completed, preserving heat for 5 hours, detecting the disappearance of residual raw materials by HPLC, and finishing the reaction, wherein the reaction conversion rate reaches 98.5%.
After the reaction is completed, the pH of the reaction solution is regulated to 2.0, the temperature is raised to 60 ℃, the reaction solution is concentrated for 30 minutes under reduced pressure, the pH is regulated to 7.0, the concentration of uridine is continuously concentrated to 30 percent (300 mL), 1000mL of ethanol is started to be dripped, the dripping time is 5 hours, the dripping temperature is 5 ℃, the crystallization is carried out for 12 hours under the condition of 5 ℃, the filtration is carried out, the filter cake is rinsed with 95 percent ethanol, the filter cake is dried to constant weight under the condition of 80 ℃, and 90.5g (0.37 mol) of uridine is finally obtained, the purity is 99.7 percent, and the yield is 90.14 percent.
Uridine (uridine)
Nuclear magnetic characterization of the structure: h 1 -NMR(D 2 O):(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, adding 100g of water into a reaction bottle, controlling the temperature to be 15 ℃, and then mixing 100g (0.411 mol) of cytidine with 150g (1.233 mol) of 30wt% hydrochloric acid to dissolve, so as to prepare 250g of cytidine hydrochloride solution; and preparing 250g (0.906 mol) of 25wt% sodium nitrite solution, simultaneously dripping 250g of cytidine hydrochloride solution and 250g of 25% sodium nitrite solution into a reaction bottle, stirring for reaction, controlling the pH value of the reaction to be 3.5-4.0, dripping for 3 hours, dripping at 15 ℃ for 3 hours, after dripping is completed, preserving heat for 5 hours, detecting the disappearance of residual raw materials by HPLC, and finishing the reaction, wherein the reaction conversion rate is 98.7%.
After the reaction is completed, the pH of the reaction solution is regulated to 2.0, the temperature is raised to 60 ℃, the reaction solution is concentrated under reduced pressure for 30 minutes, the pH is regulated to 7.0, the concentration is continued to 30 percent (300 mL) of uridine, 600mL of methanol is dripped, the dripping time is 3 hours, the dripping temperature is 5 ℃, the crystallization is carried out for 12 hours at the temperature of 5 ℃, the filtration is carried out, the filter cake is rinsed with methanol, the filter cake is dried to constant weight at the temperature of 80 ℃, 82.2g of uridine is finally obtained, the purity is 99.82 percent, and the total yield is 81.87 percent.
Example 3:
firstly, adding 100g of water into a reaction bottle, controlling the temperature to be 15 ℃, and then mixing and dissolving 100g (0.411 mol) of cytidine with 74g (1.233 mol) of acetic acid to prepare 174g of cytidine acetate solution; in addition, 250g (0.906 mol) of 25wt% sodium nitrite solution is prepared, 174g of cytidine acetate solution and 250g of 25% sodium nitrite solution are stirred for reaction, the pH value of the reaction is controlled to be 4.0-4.5, the dripping time is 3 hours, the dripping temperature is 15 ℃, after 3 hours, the temperature is kept for 7 hours after the dripping is finished, the HPLC detects the disappearance of the residual raw materials, the reaction is finished, and the reaction conversion rate is 96.1%.
After the reaction is completed, the pH of the reaction solution is regulated to 2.0, the temperature is raised to 60 ℃, the reaction solution is concentrated under reduced pressure for 30 minutes, the pH is regulated to 7.0, the concentration is continued to 30 percent (300 mL) of uridine, 1000mL of ethanol is started to be dripped, the dripping time is 5 hours, the dripping temperature is 5 ℃, the crystallization is carried out for 12 hours under the condition of 5 ℃, the filtration is carried out, the filter cake is rinsed with 95 percent ethanol, the filter cake is dried to constant weight under the condition of 80 ℃, and finally 84.2g (0.345 mol) of uridine is obtained, the purity is 99.36 percent, and the total yield is 83.94 percent.
Example 4:
referring to example 1, uridine was prepared with only 25% sodium nitrite being used, and the others being unchanged. The results are shown in Table 1:
TABLE 1
| 25% sodium nitrite dosage | n (cytidine): n (sodium nitrite) | Conversion of reaction | Uridine yield | 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％ |
In this case, "-" means that the crystallization purification is not continued in the case where the conversion rate is low.
Referring to example 1, uridine was prepared with only 30% hydrochloric acid, the other being unchanged. The results are shown in Table 2:
TABLE 2
| 30% hydrochloric acid dosage | n (cytidine): n (HCl) | Conversion of reaction | Uridine yield | 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％ |
In this case, "-" means that the crystallization purification is not continued in the case where the conversion rate is low.
Referring to example 1, uridine was prepared by changing only the reaction concentration of the water amount-regulated cytidine substrate, and the other was not changed. The results are shown in Table 3:
TABLE 3 Table 3
Referring to example 1, uridine was prepared while keeping the reaction process unchanged and changing the solvent environment used for crystallization and purification in the purification process, and the others were unchanged. The results are shown in Table 4:
TABLE 4 Table 4
| Crystallization solvent | Uridine yield | Purity of |
| Methanol | 81.87％ | 99.82％ |
| Ethanol | 90.14％ | 99.7％ |
| Isopropyl alcohol | 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 selecting methanol or ethanol as the crystallization reagent; the isopropanol or the mixed solvent of the isopropanol and the methanol is selected, so that the purity effect is weak, and the product requirement of more than 99.5% cannot be met.
Comparative example 1:
firstly, adding 100g of water into a reaction bottle, and then adding 100g of cytosine nucleoside into the reaction bottle0.411mol) Adding into a reaction bottle, controlling the temperature to 15 ℃, and adding 250g of 25 percent sodium nitrite solution0.906mol) Adding into a reaction bottle, stirring until the raw materials are completely dissolved, dripping 150g (1.233 mol) of 30% hydrochloric acid for 3 hours at 15 ℃, carrying out heat preservation reaction for 20 hours after dripping, detecting the disappearance of the raw material residue by HPLC, and ending the reaction, wherein the conversion rate of uridine is 88.6%. After the reaction is completed, the PH of the reaction solution is regulated to 2.0, the temperature is raised to 60 ℃, the reaction solution is concentrated for 30 minutes under reduced pressure, the pH is regulated to 7.0, the concentration is continued to 30 percent (300 ml) of uridine, 1000ml of ethanol is started to be added dropwise, the adding time is 5 hours, the adding temperature is 5 ℃, the crystallization is carried out for 12 hours under the condition of 5 ℃, the filtration is carried out, the filter cake is rinsed with 95 percent ethanol, the filter cake is dried to constant weight under the condition of 80 ℃, 75.5g (0.309 mol) of uridine is finally obtained, the purity is 96.68 percent, and the yield is 75.18 percent.
Claims (5)
1. A method of synthesizing uridine, said method comprising the steps of: dissolving cytidine in an acid solution to prepare an acid salt solution of cytidine; dispersing nitrous acid reagent in water to prepare nitrous acid reagent solution; then, firstly adding water into a reaction container, controlling the temperature to be 10-60 ℃, respectively dripping the prepared cytidine acid salt solution and nitrous acid reagent solution into the reaction container, controlling the pH value in the reaction container to be 3.5-4.5 during dripping, and after dripping, preserving the heat of the mixed system for reaction for 5-7 hours; after the reaction is finished, crystallizing and purifying to obtain uridine;
in the acid salt solution of cytidine, the molar ratio of cytidine to acid is 1:3, a step of;
the molar ratio of cytosine nucleoside to nitrous acid reagent is 1:2.2;
the concentration of cytosine nucleoside in the mixed system is 16.7wt%;
the solvent used for crystallization and purification is any one or more of the following: ethanol and isopropanol.
2. The method according to claim 1, wherein the solvent used for crystallization purification is used in an amount of 100 to 1500mL/100g of cytosine nucleoside relative to cytosine nucleoside.
3. The method according to claim 1, wherein after the reaction, the pH of the reaction system is controlled to be 1-5, then the reaction system is concentrated under reduced pressure at 20-80 ℃, the pH is adjusted to be 5-7 after the acid gas is removed, the concentration is continued, and then crystallization and purification are performed.
4. The method according to claim 1, wherein the acid in the acid solution comprises an inorganic acid and/or an organic acid; wherein the mineral 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.
5. The method of any one of claims 1-4, wherein the nitrous acid based reagent is selected from any one or more of the following: sodium nitrite, potassium nitrite, isoamyl nitrite.
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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 |