CN101531639B - Method for iodinating 5th position of ferric inorganic salt catalyzed 2-pyrimidone and derivatives thereof - Google Patents
Method for iodinating 5th position of ferric inorganic salt catalyzed 2-pyrimidone and derivatives thereof Download PDFInfo
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- CN101531639B CN101531639B CN2009100494443A CN200910049444A CN101531639B CN 101531639 B CN101531639 B CN 101531639B CN 2009100494443 A CN2009100494443 A CN 2009100494443A CN 200910049444 A CN200910049444 A CN 200910049444A CN 101531639 B CN101531639 B CN 101531639B
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- Prior art keywords
- pyrimidone
- inorganic salt
- derivative
- iodine
- ferric inorganic
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Links
- 238000000034 method Methods 0.000 title claims abstract description 22
- VTGOHKSTWXHQJK-UHFFFAOYSA-N pyrimidin-2-ol Chemical compound OC1=NC=CC=N1 VTGOHKSTWXHQJK-UHFFFAOYSA-N 0.000 title claims abstract description 18
- 229910017053 inorganic salt Inorganic materials 0.000 title claims abstract description 16
- 230000002083 iodinating effect Effects 0.000 title abstract 2
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims abstract description 11
- 239000011630 iodine Substances 0.000 claims abstract description 11
- 229910052740 iodine Inorganic materials 0.000 claims abstract description 11
- 239000002904 solvent Substances 0.000 claims abstract description 5
- MVFCKEFYUDZOCX-UHFFFAOYSA-N iron(2+);dinitrate Chemical compound [Fe+2].[O-][N+]([O-])=O.[O-][N+]([O-])=O MVFCKEFYUDZOCX-UHFFFAOYSA-N 0.000 claims abstract description 4
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 24
- 238000006243 chemical reaction Methods 0.000 claims description 12
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 10
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 claims description 8
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 8
- 125000002346 iodo group Chemical group I* 0.000 claims description 8
- 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 claims description 6
- 238000006555 catalytic reaction Methods 0.000 claims description 5
- 239000003586 protic polar solvent Substances 0.000 claims description 5
- 238000010992 reflux Methods 0.000 claims description 5
- 238000010438 heat treatment Methods 0.000 claims description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 claims description 3
- 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 claims description 3
- 238000001914 filtration Methods 0.000 claims description 3
- 229910052742 iron Inorganic materials 0.000 claims description 3
- DRTQHJPVMGBUCF-UHFFFAOYSA-N uracil arabinoside Natural products OC1C(O)C(CO)OC1N1C(=O)NC(=O)C=C1 DRTQHJPVMGBUCF-UHFFFAOYSA-N 0.000 claims description 3
- 229940045145 uridine Drugs 0.000 claims description 3
- 238000005406 washing Methods 0.000 claims description 3
- MXHRCPNRJAMMIM-SHYZEUOFSA-N 2'-deoxyuridine Chemical compound C1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C=C1 MXHRCPNRJAMMIM-SHYZEUOFSA-N 0.000 claims description 2
- 150000001875 compounds Chemical class 0.000 claims description 2
- MXHRCPNRJAMMIM-UHFFFAOYSA-N desoxyuridine Natural products C1C(O)C(CO)OC1N1C(=O)NC(=O)C=C1 MXHRCPNRJAMMIM-UHFFFAOYSA-N 0.000 claims description 2
- PVHCYDBPRLPQMP-UHFFFAOYSA-N 5-iodo-1h-pyrimidin-2-one Chemical compound OC1=NC=C(I)C=N1 PVHCYDBPRLPQMP-UHFFFAOYSA-N 0.000 abstract description 5
- 229910002651 NO3 Inorganic materials 0.000 abstract description 2
- 230000007613 environmental effect Effects 0.000 abstract description 2
- 230000035484 reaction time Effects 0.000 abstract description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 abstract 1
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 abstract 1
- 238000009776 industrial production Methods 0.000 abstract 1
- FBAFATDZDUQKNH-UHFFFAOYSA-M iron chloride Chemical compound [Cl-].[Fe] FBAFATDZDUQKNH-UHFFFAOYSA-M 0.000 abstract 1
- 239000007800 oxidant agent Substances 0.000 abstract 1
- 239000002994 raw material Substances 0.000 abstract 1
- LQZMLBORDGWNPD-UHFFFAOYSA-N N-iodosuccinimide Chemical compound IN1C(=O)CCC1=O LQZMLBORDGWNPD-UHFFFAOYSA-N 0.000 description 6
- 238000002360 preparation method Methods 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- OSYLPIYJUCCMTQ-UHFFFAOYSA-O azanium;cerium(3+);nitrate Chemical compound [NH4+].[Ce+3].[O-][N+]([O-])=O OSYLPIYJUCCMTQ-UHFFFAOYSA-O 0.000 description 5
- 239000003153 chemical reaction reagent Substances 0.000 description 5
- 239000000543 intermediate Substances 0.000 description 5
- 230000026045 iodination Effects 0.000 description 4
- 238000006192 iodination reaction Methods 0.000 description 4
- 239000003814 drug Substances 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- 239000012065 filter cake Substances 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- 238000000967 suction filtration Methods 0.000 description 3
- 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
- 229960000935 dehydrated alcohol Drugs 0.000 description 2
- 229960004756 ethanol Drugs 0.000 description 2
- 229930182470 glycoside Natural products 0.000 description 2
- 150000002338 glycosides Chemical class 0.000 description 2
- ICIWUVCWSCSTAQ-UHFFFAOYSA-M iodate Chemical compound [O-]I(=O)=O ICIWUVCWSCSTAQ-UHFFFAOYSA-M 0.000 description 2
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 150000005703 5-iodopyrimidines Chemical class 0.000 description 1
- KSNXJLQDQOIRIP-UHFFFAOYSA-N 5-iodouracil Chemical compound IC1=CNC(=O)NC1=O KSNXJLQDQOIRIP-UHFFFAOYSA-N 0.000 description 1
- MYMOFIZGZYHOMD-UHFFFAOYSA-N Dioxygen Chemical compound O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 description 1
- 208000000903 Herpes simplex encephalitis Diseases 0.000 description 1
- 208000005100 Herpetic Keratitis Diseases 0.000 description 1
- 206010073938 Ophthalmic herpes simplex Diseases 0.000 description 1
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 229910001882 dioxygen Inorganic materials 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000003912 environmental pollution Methods 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 229960004716 idoxuridine Drugs 0.000 description 1
- 238000011031 large-scale manufacturing process Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 150000003230 pyrimidines Chemical class 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
The invention provides a method for iodinating the 5th position of ferric inorganic salt catalyzed 2-pyrimidone and derivatives thereof, using 2-pyrimidone, derivatives thereof and iodine as raw materials. In solvent, under a refluence condition, 5-iodo-2-pyrimidone and the derivatives thereof are synthesized by adopting ferric inorganic salt as an oxidizing agent, such as iron nitrate or iron chloride, with yield about 70 percent and purity over 98 percent. The method adopts the ferric inorganic salt to replace the prior ammonium ceric nitrate which pollutes environment severely, has the characteristic of environmental protection and high efficiency, and uses iodine with low price. The method has the advantages of simple operation, short reaction time and high reproduction quality, and is applicable to industrial production in large scale.
Description
Technical field
The present invention relates to 5 iodate methods of a kind of pyrimidine and derivative thereof, be specifically related to 5 iodo methods of the ferric inorganic salt catalysis of a kind of usefulness 2-pyrimidone and derivative thereof.
Background technology
5-iodo-2-pyrimidone and derivative thereof are very important medicine intermediates, are used to herpes simplex keratitis and herpesencephalitis such as the medicine Idoxuridine in usefulness.In addition, 5-iodo-pyrimidine class intermediate also can carry out structural modification usefulness, prepares its prolongation carbochain and obtains directly at the essential intermediate of the carbochain derivative of pyrimidine 5-position.
5-iodo-2-pyrimidone and derivative thereof generally are to carry out iodo by 2-pyrimidone and derivative thereof 5 of base and obtain, and make 2-pyrimidone and derivative thereof become the critical materials of this type of medicine intermediate.
Method about 2-pyrimidone and 5 iodos of derivative thereof has many bibliographical informations, comprising iodine/cerous ammonium nitrate method (Canadian Journal of Chemistry, 84 (4), 580-586; 2006), iodine/dioxygen water law (Molecules, 10 (10), 1307-1317; 2005), the N-iodosuccinimide method (U.S.Pat.Appl.Publ., 2005038041,17Feb 2005) etc.Wherein industry oxygenant commonly used is a cerous ammonium nitrate, and cerous ammonium nitrate is comparatively serious to the pollution of environment.The cost of N-iodosuccinimide is high again, the large-scale production of restriction 5-iodo-2-pyrimidone and derivative thereof.
Summary of the invention
The present invention is exactly in order to address the above problem, and the method that overcomes 2-pyrimidone and 5 iodos of derivative thereof adopts reagent environmental pollution and the high problem of cost, and 5 iodo methods of a kind of ferric inorganic salt catalysis 2-pyrimidone and derivative thereof are provided.The objective of the invention is to use ferric inorganic salt as oxygenant 5 in miazines intermediate to be carried out iodate, this method substitutes conventional oxidation agent cerous ammonium nitrate with iron nitrate or iron(ic) chloride, reacts in protic solvent.This invention is applicable to the preparation of 5-iodo-2-pyrimidone and derivative thereof, the plant-scale preparation of particularly suitable.
The technical problem that will solve required for the present invention can be achieved through the following technical solutions:
5 iodo methods of a kind of ferric inorganic salt catalysis 2-pyrimidone and derivative thereof,
(1) in reaction flask, adds protic solvent, add iodination reagent and 2-pyrimidone and derivative thereof, add ferric inorganic salt again, carry out reacting by heating as oxygenant;
(2) through heat filtering, solvent is washed, washing, and oven dry obtains target compound.
2-pyrimidone and derivative thereof described in the step (1) for structural formula be:
R1 is H, 5 yuan or 6 yuan of sugar rings,
R2 is H or hydroxyl.
2-pyrimidone and derivative thereof, it is 1: 0.45～0.7: 0.1～0.5 that the molar ratio of iodination reagent and ferric inorganic salt closes.
The described reacting by heating of step (1) is under refluxad carried out, and keeps refluxing 20 minutes-5 hours.
The described protic solvent of step (1) is methyl alcohol, ethanol, Virahol, perhaps its arbitrary combination.
The described ferric inorganic salt of step (1) are iron nitrate or iron(ic) chloride.
The described iodination reagent of step (1) is an iodine, and consumption is the 0.4-1 equivalent.
Step (2) solvent is methyl alcohol, ethanol, Virahol, perhaps its arbitrary combination.
Beneficial effect of the present invention:
1, the present invention is without the serious cerous ammonium nitrate of contaminative, makes production process environmental protection more, safety.
2, the present invention uses cheap iodine, has avoided using expensive iodination reagent N-iodosuccinimide, and cost is cheaper.
3, the present invention is simple to operate, and the reaction times is short, the circulation ratio height.
In sum, the present invention is applicable to the big production of industry.
Embodiment
In order to make technique means of the present invention, creation characteristic, to reach purpose and effect is easy to understand,, further set forth the present invention below in conjunction with specific embodiment.
The preparation of embodiment 1:5-iodouracil
The 1000ml reaction flask adds the 700mL dehydrated alcohol, is preheated to backflow, adds iodine 112g (0.44mol) successively, uridylic 100g (0.89mol), and 62.5g Fe (NO3) 39H2O (0.16mol) is heated to backflow, keeps backflow 20min.Heat filtering, the 500ml dehydrated alcohol is washed, the 500mL washing, oven dry gets faint yellow solid 115.5g.Yield 68.7%.Purity is 99.67%.
The preparation of embodiment 2:5-iodo-2 '-deoxyuridine
In the 500ml reaction flask, add 36g 2 '-deoxyuridine (0.158mol), 24.1g iodine (0.095mol), 16.4g Fe (NO
3)
39H
2O (0.068mol) adds in the 240ml methyl alcohol that stirs successively, keeps refluxing 1 hour.After reaction was finished, reaction solution cooled off under ice bath and continues to stir one hour, and suction filtration obtains white filter cake, the 50ml methanol wash, and drying obtains off-white color pressed powder 43.3g, yield 77.5%, purity is 99.6%.
The preparation of embodiment 3:5-ioduria glycosides
In the 50mL reaction flask, with 4.0g uridine (16.4mmol), 2.5g iodine (9.8mmol), 1.6gFe (NO
3)
39H
2O (4.0mmol) adds in the 27mL methyl alcohol that stirs successively, keeps refluxing 5 hours.
After reaction was finished, reaction solution cooled off under ice bath and continues to stir 0.5～1 hour, and suction filtration obtains the off-white color filter cake, the 5ml methanol wash, and drying obtains off-white color pressed powder 3.2g, yield 53.0%, purity 99.5%.
The preparation of embodiment 4:5-ioduria glycosides
In the 50mL reaction flask, with 4.0g uridine (16.4mmol), 2.5g iodine (9.8mmol), 1.6gFe (NO
3)
39H
2O (4.0mmol) adds in the 27mL Virahol that stirs successively, keeps refluxing 4 hours.
After reaction was finished, reaction solution cooled off under ice bath and continues to stir 0.5～1 hour, and suction filtration obtains the off-white color filter cake, the 5ml washed with isopropyl alcohol, and drying obtains off-white color pressed powder 3.4g, and yield is 56%, purity 98.5%.
More than show and described ultimate principle of the present invention, principal character and advantage of the present invention.The technician of the industry should understand; the present invention is not restricted to the described embodiments; that describes in the foregoing description and the specification sheets just illustrates principle of the present invention; the present invention also has various changes and modifications without departing from the spirit and scope of the present invention, and these changes and improvements all fall in the claimed scope of the invention.The claimed scope of the present invention is defined by appending claims and equivalent thereof.
Claims (7)
1. 5 iodo methods of ferric inorganic salt catalysis 2-pyrimidone and derivative thereof,
(1) in reaction flask, adds protic solvent, add iodine and 2-pyrimidone and derivative thereof, add ferric inorganic salt, carry out reacting by heating as oxygenant; Described 2-pyrimidone and derivative thereof are uridylic, 2 '-deoxyuridine or uridine;
(2) through heat filtering, solvent is washed, washing, and oven dry obtains target compound.
2. method according to claim 1 is characterized in that: 2-pyrimidone and derivative thereof in the step (1), it is 1: 0.45～0.7: 0.1～0.5 that the molar ratio of iodine and ferric inorganic salt closes.
3. method according to claim 1 is characterized in that: the described reacting by heating of step (1) is under refluxad carried out, and keeps refluxing 20 minutes-5 hours.
4. method according to claim 1 is characterized in that: the described protic solvent of step (1) is a kind of or its arbitrary combination in methyl alcohol, ethanol, the Virahol.
5. method according to claim 1 is characterized in that: the described ferric inorganic salt of step (1) are iron nitrate or iron(ic) chloride.
6. method according to claim 1 is characterized in that: the described iodine consumption of step (1) is the 0.4-1 equivalent.
7. method according to claim 1 is characterized in that: step (2) solvent is a kind of or its arbitrary combination in methyl alcohol, ethanol, the Virahol.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2009100494443A CN101531639B (en) | 2009-04-16 | 2009-04-16 | Method for iodinating 5th position of ferric inorganic salt catalyzed 2-pyrimidone and derivatives thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2009100494443A CN101531639B (en) | 2009-04-16 | 2009-04-16 | Method for iodinating 5th position of ferric inorganic salt catalyzed 2-pyrimidone and derivatives thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN101531639A CN101531639A (en) | 2009-09-16 |
| CN101531639B true CN101531639B (en) | 2011-10-26 |
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN2009100494443A Expired - Fee Related CN101531639B (en) | 2009-04-16 | 2009-04-16 | Method for iodinating 5th position of ferric inorganic salt catalyzed 2-pyrimidone and derivatives thereof |
Country Status (1)
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| CN (1) | CN101531639B (en) |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2005003374A2 (en) * | 2003-06-30 | 2005-01-13 | Idenix (Cayman) Limited | SYNTHESIS OF β-L-2-DEOXY NUCLEOSIDES |
| EP1674104A1 (en) * | 2004-12-24 | 2006-06-28 | Institut National De La Sante Et De La Recherche Medicale (Inserm) | Uridine derivatives as antiviral drugs against a flaviviridae, especially HCV |
| CN101054398A (en) * | 2006-04-11 | 2007-10-17 | 上海迪赛诺医药发展有限公司 | Method of synthesizing 2-deoxy-5-iodo-beta-uridine |
-
2009
- 2009-04-16 CN CN2009100494443A patent/CN101531639B/en not_active Expired - Fee Related
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2005003374A2 (en) * | 2003-06-30 | 2005-01-13 | Idenix (Cayman) Limited | SYNTHESIS OF β-L-2-DEOXY NUCLEOSIDES |
| EP1674104A1 (en) * | 2004-12-24 | 2006-06-28 | Institut National De La Sante Et De La Recherche Medicale (Inserm) | Uridine derivatives as antiviral drugs against a flaviviridae, especially HCV |
| CN101054398A (en) * | 2006-04-11 | 2007-10-17 | 上海迪赛诺医药发展有限公司 | Method of synthesizing 2-deoxy-5-iodo-beta-uridine |
Non-Patent Citations (6)
| Title |
|---|
| Mark J. Bamford, et al.Synthesis and Antiviral Activity of 3’-Deoxy-3’-C-hydroxymethyl Nucleosides.《Journal of Medicinal Chemistry》.1990,第33卷(第9期),2494-2501. * |
| Medicinal Chemistry》.2005,6015-6024. * |
| Vanessa Escuret et al.Synthesis of 5-haloethynyl- and 5-(1,2-dihalo)vinyluracil nucleosides: Antiviral activity and cellular toxicity.《Bioorganic & * |
| VanessaEscuretetal.Synthesisof5-haloethynyl-and5-(1 2-dihalo)vinyluracil nucleosides: Antiviral activity and cellular toxicity.《Bioorganic & Medicinal Chemistry》.2005 |
| 夏然 等.水溶液中微波辅助下5－碘嘧啶类化合物的合成.《化学研究与应用》.2008,第20卷(第1期),93-95. * |
| 李庶心 等.(E)-5-(2-溴乙烯基)-1-β-D-阿拉伯呋喃糖尿嘧啶的合成.《中国药物化学杂志》.2007,第17卷(第1期),37-40. * |
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Assignee: Shandong Keyuan Pharmaceutical Co., Ltd. Assignor: 2Y-Chem,Ltd. Contract record no.: 2011370000485 Denomination of invention: Method for iodinating 5th position of ferric inorganic salt catalyzed 2-pyrimidone and derivatives thereof Granted publication date: 20111026 License type: Exclusive License Open date: 20090916 Record date: 20111116 |
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