CN110105416B - Synthesis method of 4-S-5-Br-2 ', 3 ', 5 ' -O-triacetyluridine - Google Patents
Synthesis method of 4-S-5-Br-2 ', 3 ', 5 ' -O-triacetyluridine Download PDFInfo
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- CN110105416B CN110105416B CN201910522976.8A CN201910522976A CN110105416B CN 110105416 B CN110105416 B CN 110105416B CN 201910522976 A CN201910522976 A CN 201910522976A CN 110105416 B CN110105416 B CN 110105416B
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H1/00—Processes for the preparation of sugar derivatives
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H1/00—Processes for the preparation of sugar derivatives
- C07H1/06—Separation; Purification
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- 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
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- 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
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Abstract
The invention belongs to the field of chemical synthesis, and discloses a method for synthesizing 4-S-5-Br-2 ', 3 ', 5 ' -O-triacetyl uridine. The synthesis method comprises the steps of taking a compound 5-Br-2 ', 3', 5 '-O-triacetyluridine as a raw material, taking phosphorus pentasulfide and a Lawson reagent as a vulcanization reagent in a combined manner, taking 1, 4-dioxane as a solvent to perform a chemical reaction, and finally preparing 4-S-5-Br-2', 3 ', 5' -O-triacetyluridine; the synthesis method of 4-S-5-Br-2 ', 3 ', 5 ' -O-triacetyl uridine provided by the invention shortens the reaction time and greatly improves the vulcanization efficiency. The synthesis method provided by the invention reduces the cost, is simple and convenient for post-reaction treatment, and simultaneously improves the yield of the reactive thionucleoside compound.
Description
Technical Field
The invention belongs to the field of chemical synthesis, and relates to a method for synthesizing 4-S-5-Br-2 ', 3 ', 5 ' -O-triacetyl uridine by using sulfamide.
Background
In the course of the development of long-life research, the research on cancer is always the focus of attention. The main cause of carcinogenesis is DNA damage[1]. Methods for treating cancer include: radiotherapy; chemotherapy; performing surgical treatment; ultraviolet light and nucleoside therapy. Photochemotherapy, in which ultraviolet radiation (UVR: 280-400nm) or visible light-sensitive drugs are combined to produce a therapeutic effect[2]Neither drug nor radiation can be achieved alone, and is a mature non-malignant proliferative treatment for skin conditions and various cancers.
According to a great deal of recent research, the nucleoside compounds modified by glycosyl and base show good antitumor activity, and the 4-thio nucleoside analogues are used as antiviral agents[3]The antitumor drug is widely applied to clinic[4]。
Such as 5-iodouridine (5IU), 5-bromouridine (5BrU) and 5-fluorouridine (5FU), and can be used as sensitizer for antiviral and antitumor drugs[5,6]. Such as 4-thiothymidine, can specifically kill tumor cells under the irradiation of near Ultraviolet (UVA)[7-11]It can kill and kill the epidermis and tumor close to the epidermis[12-13]The 4-position sulfo-modification of the nucleoside base provides a new approach for treating cancers under the coordination of near ultraviolet light.
A plurality of methods for synthesizing the thionucleoside reagent exist, but the existing method is not environment-friendly and has higher cost. As is known, phosphorus pentasulfide has been widely used in various types of vulcanization reactions, but phosphorus pentasulfide is highly toxic, easily generates flammable gas of hydrogen sulfide when meeting water, and has too long reaction time for experimental reactions; the lawson reagent recently discovered by our group of subjects is also critical to storage conditions, prone to deterioration and expensive, long in time for experimental reactions and low in yield.
Reference documents
[1]T.Lindahl.Instability and decay of the primary structure of DNA[J].Nature,1993,362:709-715.
[2]REELFS O，XU Y Z，MASSEY A，et al.s[J].Mol Cancer Ther，2007，6(9):2487-2495
[3] Attention is drawn to Zbranchman, the use of metathesis reactions in nucleoside analogue synthesis [ J ]. chemical evolution, 2010,22(8): 1583-.
[4]Wigerinck,P.,Pannecouque,C.,Snoeck,R.,et al.5-(5-Bromothien-2-yl)-2'-deoxyuridine and 5-(5-chlorothien-2-yl)-2'-deoxyuridine are equipotent to(E)-5-(2-bromovinyl)-2'-deoxyuridine in the inhibition of herpes simplex virus type I replication.Journal of Medicinal Chemistry,34,2883-2389.http://dx.doi.org/10.1021/jm00112a011
[5]R.L.Erikson,W.Szybalski.5-Iodo-2’-Deoxyuridine[J].Radiat.Res,1963,20:252-622.
[6]Franken,N.A.,Van Bree,C.,Veltmaat,M.A.,Rodermond,H.M.,Haveman,J.and Barendsen,G.W.J.(2001)Analysis of linear and quadratic parameters of radiation survival curves of two human tumor cell lines.Journal of Radiation Research(Tokyo),42,179-190.
[7]Massey A.；Xu Y.-Z.and Karran,P.Photoactivation of DNA thiobases as a potential novel therapeutic option，Current Biology，2001，11,1142-1146.
[8]Massey A,XuYZ,KarranP.Ambiguous coding is required for the lethal interaction between methylated DNA bases and DNA mismatch repair[J].DNA Repair(Amst),2002,1(4):275-286.
[9]ReelfsO,XuYZ,MasseyA,etal.Thiothymidine plus low-dose UVA kills hyperproliferative human skin cells independently of their human papilloma virus status[J].Mol Cancer Ther,2007,6(9):2487-2495.
[10]Harada Y,SuzukiT,IchimuraT,etal.Triplet formation of 4-thiothymidine and its photosensitization to oxygen studied by time-resolved thermal lensing technique[J].J Phys Chem B,2007,111(19):5518-5524.
[11]Pridgeon S W，Heer R，Taylor GA，et al.Thiothymidine combined with UVA as a potential novel therapy for bladder cancer[J].Br.J.Cancer，2011，104(12):1869-1876.
[12]Gemenetzidis E，Shavorskaya O，Xu Y Z，et al.Topical 4-thiothymidine is a viable photosensitiser for the photodynamic therapy of skin malignancies[J/OL].J.Dermatol.Treatment.
[13] Yinhong goose, Zheng Zhi, Caohong Yu, Zhang Xiaohui (2013) 4-thiothymidine synthesis and its interaction with human serum albumin, Luumina, 1,104-plus 110.
[14]Erikson,R.L.and Szybalski,W.(1963)5-Iodo-2’-Deoxyuridine.Radiation Research,20,252-622.
[15]Porcher,S.and Pitsch,S.(2005)Synthesis of 2’-O-[(triisopropylsilyl)oxy]methyl protected ribonucleoside phospho-ramidites containing various nucleobase analogues.Helvetica Chimica Acta,88,2683-2704.
[16]Lakshman,M.K.(2005)Azide-tetrazole equilibrium of C-6azidopurine nucleosides and their ligation reactions with alkynes.Current Organic Synthesis,2,83-112.
Disclosure of Invention
In order to overcome the defects of the prior art, the invention aims to provide a green, environment-friendly and efficient high-yield vulcanization method by using phosphorus pentasulfide (P) with different molar ratios2S5) And Lawesson 'S reagent (Lawesson) in combination as a sulfurizing agent to prepare 4-S-5-Br-2', 3 ', 5' -O-triacetyluridine. The invention provides a method for synthesizing 4-S-5-Br-2 ', 3 ', 5 ' -O-triacetyl uridineThe method shortens the reaction time and greatly improves the vulcanization efficiency. The synthesis method provided by the invention reduces the cost, is simple and convenient for post-reaction treatment, and simultaneously improves the yield of the reactive thionucleoside compound.
The above purpose of the invention is realized by the following technical scheme:
a method for synthesizing 4-S-5-Br-2 ', 3 ', 5 ' -O-triacetyluridine uses 5-Br-2 ', 3 ', 5 ' -O-triacetyluridine shown in formula (I) as a raw material, uses phosphorus pentasulfide and Lawson reagent as a vulcanizing agent, uses 1, 4-dioxane as a solvent to perform chemical reaction, and finally prepares 4-S-5-Br-2 ', 3 ', 5 ' -O-triacetyluridine shown in formula (II);
further, the molar ratio of the 5-Br-2 ', 3 ', 5 ' -O-triacetyl uridine to the vulcanizing agent is 1: 1.2.
Further, the molar ratio of the vulcanizing agent phosphorus pentasulfide to the Lawson reagent is 2: 1-15:1.
According to the synthesis method, the reaction temperature is 90-115 ℃, and preferably 95 ℃; the reaction time is 1.3 to 4 hours, preferably 1.3 hours.
The synthesis method comprises the following specific steps: dissolving 2.20mmol of 5-Br-2 ', 3 ', 5 ' -O-triacetyluridine in 50-90 mL of 1, 4-dioxane, heating to 90-115 ℃, stirring to fully dissolve, then adding phosphorus pentasulfide and Lawson reagent in a molar ratio of 2:1-15:1 as vulcanizing agents, and monitoring the reaction condition by TLC; the reaction is completed within 1.3h to 4 h; the solvent was evaporated under reduced pressure at 55 ℃. And (3) carrying out column separation on the crude product (PE: EA is 6: 1; 4:1), recrystallizing with absolute ethyl alcohol, and carrying out suction filtration and drying to obtain white solid 4-S-5-Br-2 ', 3 ', 5 ' -O-triacetyluridine.
Compared with the prior art, the invention has the beneficial effects that:
1. in the prior art, P is singly used when synthesizing 4-S-5-Br-2 ', 3 ', 5 ' -O-triacetyl uridine2S5Or the vulcanization of the C-4 position of the base by Lawesson alone as a vulcanizing agent. Both of these synthetic methods have some disadvantages such as excessively long reaction time, overnight reaction sometimes required, low yield of the product, and the like. The synthesis method provided by the invention adopts P with different molar ratios2S5The compound is combined with Lawesson to be used as a vulcanizing agent to provide an optimized reaction system for synthesizing 4-S-5-Br-2 ', 3 ', 5 ' -O-triacetyl uridine; avoids the disadvantages of overlong reaction time, low yield, high cost and the like. The synthesis method provided by the invention adopts P with different molar ratios2S5Lawesson is used as a solid powdery vulcanizing agent, so that the reaction time is shortened, the vulcanizing efficiency is greatly improved, the cost is reduced, and the reaction efficiency is improved; the post-reaction treatment is simple and convenient, and the product yield is improved; the synthesis method is safe, cheap, green, wide in application range, simple in operation, cheap and safe, high in yield, environment-friendly, suitable for industrial production and has important significance on the research of synthetic thio compounds.
2. The synthesis method provided by the invention is simple and convenient to operate, the post-reaction treatment is simple and convenient, and the product can be collected by directly using an ethyl acetate petroleum ether system (EA: PE: 6: 1; 4:1) for column separation. The product yield reaches 97 percent; compared with the prior method of adopting P alone2S5Or the Lawson reagent is used as a vulcanizing agent, so that the vulcanizing agent is more green and efficient.
3. Using different molar ratios of P2S5After the reaction with Lawesson reagent, when silica gel column separation is carried out, part of impurities in the Lawesson reagent can be filtered out by pure petroleum ether, so that the separation process is simpler, more convenient and quicker, and the obtained product is purer.
4. Phosphorus pentasulfide is the most commonly used vulcanizing agent, also known as tetrasulfide disulfide. It is preferably used in pure form and in at least stoichiometric amounts, usually in excess of stoichiometric amounts in actual practice. The purpose of the sulfide is to provide at least one sulfur atom, preferably at least about two sulfur atoms, per carbonyl group, based on considerations of post-reaction treatment and considerations of completeness of reaction. The molar ratio of the 5-Br-2 ', 3 ', 5 ' -O-triacetyluridine to the vulcanizing agent in the invention is 1: 1.2. Since the molar ratio of 5-Br-2 ', 3', 5 '-O-triacetyluridine to the sulfurizing agent is 1:1 according to the chemical formula, the molar ratio of 5-Br-2', 3 ', 5' -O-triacetyluridine to the sulfurizing agent used in the present invention is 1:1.2 since 1mol of phosphorus pentasulfide provides less S than 1 mol.
Detailed Description
The invention is described in more detail below with reference to specific examples, without limiting the scope of the invention. Unless otherwise specified, the experimental methods used in the present invention are conventional methods, and the experimental devices, materials, reagents, etc. used therein are commercially available.
Instrument
Medicine and food additive
Example 1
Dissolving 5-Br-2 ', 3 ', 5 ' -O-triacetyluridine (1.00g,2.20mmol) in 50mL of 1, 4-dioxane, stirring at room temperature to dissolve it sufficiently, and adding P at different molar ratios2S5(0.391g, 1.76mmol) and Lawesson (0.356g, 0.88mmol) as sulfurizing agent, the reaction temperature is 95 ℃, the reaction condition is monitored by TLC, the raw material point disappears after 1.3h, the reaction is proved to be complete, the solvent is evaporated under the condition of reduced pressure of 55 ℃, the crude product is subjected to column separation (PE: EA is 6: 1; 4:1), mixed with absolute ethyl alcohol and petroleum ether for recrystallization after separation, and after suction filtration and drying, 0.90g of solid 4-S-5-Br-2 ', 3 ', 5 ' -O-triacetyluridine is obtained, and the yield is 88%.
Example 2
Dissolving 5-Br-2 ', 3 ', 5 ' -O-triacetyluridine (1.00g,2.20mmol) in 50mL of 1, 4-dioxane, stirring at room temperature to dissolve completely, and adding P at different molar ratios2S5(0.439g, 1.98mmol) and Lawesson (0.267g, 0.66mmol) as vulcanizing agents, the reaction temperature is 95 ℃, the reaction condition is monitored by TLC, the raw material point disappears after 1.3h, the reaction is proved to be complete, the solvent is evaporated under the condition of reduced pressure of 55 ℃, the crude product is subjected to column separation (PE: EA is 6: 1; 4:1), the separated crude product is mixed with absolute ethyl alcohol and petroleum ether for recrystallization, and solid 4-S-5-Br-2 ', 3 ', 5 ' -O-triacetyluridine is obtained after suction filtration and drying, wherein the yield is 90 percent.
Example 3
Dissolving 5-Br-2 ', 3 ', 5 ' -O-triacetyluridine (1.00g,2.20mmol) in 50mL of 1, 4-dioxane, stirring at room temperature to dissolve completely, and adding P at different molar ratios2S5(0.488g, 2.2mmol) and Lawesson (0.178g, 0.44mmol) as a vulcanizing agent, the reaction temperature is 95 ℃, the reaction condition is monitored by TLC, the raw material point disappears after 1.3h, the reaction is proved to be complete, the solvent is evaporated under the condition of reduced pressure of 55 ℃, the crude product is subjected to column separation (PE: EA is 6: 1; 4:1), mixed by absolute ethyl alcohol and petroleum ether for recrystallization after separation, and 0.93g of solid 4-S-5-Br-2 ', 3 ', 5 ' -O-triacetyluridine is obtained after suction filtration and drying, and the yield is 91%.
Example 4
Dissolving 5-Br-2 ', 3 ', 5 ' -O-triacetyluridine (1.00g,2.20mmol) in 50mL of 1, 4-dioxane, stirring at room temperature to dissolve it sufficiently, and adding P at different molar ratios2S5(0.527g, 2.37mmol) and Lawesson (0.106g, 0.264mmol) as vulcanizing agents, the reaction temperature is 95 ℃, the reaction condition is monitored by TLC, the raw material point disappears after 1.3h, the reaction is proved to be complete, the solvent is evaporated under the condition of reduced pressure of 55 ℃, the crude product is subjected to column separation (PE: EA is 6: 1; 4:1), the separated crude product is mixed with absolute ethyl alcohol and petroleum ether for recrystallization, and solid 4-S-5-Br-2 ', 3 ', 5 ' -O-triacetyl uridine is obtained after suction filtration and drying, wherein the yield is 94%.
Example 5
Dissolving 5-Br-2 ', 3 ', 5 ' -O-triacetyluridine (1.00g,2.20mmol)Dissolving in 50mL 1, 4-dioxane under stirring at room temperature, and adding P at different molar ratios2S5(0.549g, 2.48mmol) and Lawesson (0.066g, 0.16mmol) as vulcanizing agents, the reaction temperature is 95 ℃, the reaction condition is monitored by TLC, the raw material point disappears after 1.3h, the reaction is proved to be complete, the solvent is distilled out under the condition of reduced pressure of 55 ℃, the crude product is subjected to column separation (PE: EA is 6: 1; 4:1), the separated crude product is mixed with absolute ethyl alcohol and petroleum ether for recrystallization, and solid 4-S-5-Br-2 ', 3 ', 5 ' -O-triacetyl uridine is obtained after suction filtration and drying, wherein the yield is 89%.
The reaction conditions for examples 1-5 are shown in Table 1 below:
| serial number | P2S5：Lawesson(mol) | Yield of product | Reaction time (h) |
| 1 | 2:1 | 88％ | 4h |
| 2 | 3:1 | 90％ | 3.5h |
| 3 | 5:1 | 91％ | 3h |
| 4 | 9:1 | 94％ | 1.3h |
| 5 | 15:1 | 89％ | 2.5h |
Comparative example 1
5-Br-2 ', 3 ', 5 ' -O-triacetyluridine (1.00g,2.20mmol) was dissolved in 50mL of 1, 4-dioxane, and the solution was stirred at room temperature to dissolve it sufficiently, followed by addition of P2S5As a vulcanizing agent (0.59g,2.64mmol), the oil bath kettle is heated to 95 ℃ and the reaction condition is monitored by TLC, the raw material point disappears after 6.5h, the reaction is proved to be complete, the solvent is distilled off under the condition of reduced pressure of 55 ℃, the crude product is subjected to column separation (PE: EA is 6: 1; 4:1), after separation, anhydrous ethanol and petroleum ether are mixed for recrystallization, and after suction filtration and drying, 0.86g of solid 4-S-5-Br-2 ', 3 ', 5 ' -O-triacetyluridine is obtained, and the yield is 85%.
Comparative example 2
Dissolving 5-Br-2 ', 3 ', 5 ' -O-triacetyluridine (1.00g,2.20mmol) in 50mL of 1, 4-dioxane, stirring at normal temperature to fully dissolve the 5-Br-2 ', 3 ', 5 ' -O-triacetyluridine, adding Lawesson as a vulcanizing agent (1.06g, 2.64mmol), heating to 95 ℃, monitoring the reaction condition by TLC, allowing the raw material point to disappear after 8h, proving that the reaction is complete, evaporating the solvent under the reduced pressure of 55 ℃, performing column separation on a crude product (PE: EA: 6: 1; 4:1), mixing absolute ethyl alcohol and petroleum ether for recrystallization after separation, and performing suction filtration and drying to obtain 0.83g of solid 4-S-5-Br-2 ', 3 ', 5 ' -O-triacetyluridine, wherein the yield is 82%.
Example (4) with P alone2S5Comparative example 1 with reaction as curative, comparative example 2 with Lawesson alone as curative, three different curativesThe reaction rates and yields in the synthesis methods were compared and the results are shown in table 2 below:
the synthesis method provided by the invention uses P with different molar ratios2S5And Lawesson's reagent as a sulfurizing agent instead of the conventional Lawson's reagent method or P2S5Process, in carrying out the vulcanization reaction, the Lawesson process and P2S5The method needs to react for more than 6 hours, sometimes even overnight, but the synthesis method provided by the invention can completely react within dozens of minutes, so that the reaction time is greatly reduced; with Yin hong Yan and so on[13]Compared with the report, the yield is improved from 51% to 97%, and the raw materials are difficult to recover and difficult to reuse, so that the synthetic method reduces the waste of expensive resources such as thymidine and the like. Otherwise than by P alone2S5The synthesis method of the invention, which is used as a vulcanizing agent or singly uses Lawesson reagent as a vulcanizing agent, uses less Lawsson reagent, reduces environmental pollution, reduces reaction cost and greatly improves reaction rate.
Referring to the biological experimental influence of S4TdR/UVA synergistic treatment on the activity of A375 cells, the 5-position substituent shows that the capacity of killing A375 cells by fluorine, chlorine, bromine and iodine is gradually enhanced, i.e. 4-sulfur-5-bromouridine/-2' -deoxyuridine has great application prospect as a potential anti-cancer drug[14-16]The invention provides a simpler and more reasonable synthesis method of the 4-sulfur-nucleoside compound, which has great significance for the research of potential anticancer drugs.
The embodiments described above are merely preferred embodiments of the invention, rather than all possible embodiments of the invention. Any obvious modifications to the above would be obvious to those of ordinary skill in the art, but would not bring the invention so modified beyond the spirit and scope of the present invention.
Claims (1)
1. A method for synthesizing 4-S-5-Br-2 ', 3 ', 5 ' -O-triacetyluridine is characterized in that 5-Br-2 ', 3 ', 5 ' -O-triacetyluridine shown in a formula (I) is used as a raw material, phosphorus pentasulfide and Lawson reagent are combined to be used as a vulcanizing agent, 1, 4-dioxane is used as a solvent to perform chemical reaction, and finally 4-S-5-Br-2 ', 3 ', 5 ' -O-triacetyluridine shown in a formula (II) is prepared;
the reaction formula is shown as above;
the molar ratio of the 5-Br-2 ', 3 ', 5 ' -O-triacetyluridine to the vulcanizing agent is 1: 1.2;
the molar ratio of the vulcanizing agent phosphorus pentasulfide to the Lawson reagent is 2-15: 1;
the synthesis method comprises the following specific steps: dissolving 2.20mmol of 5-Br-2 ', 3 ', 5 ' -O-triacetyluridine in 50-90 mL of 1, 4-dioxane, heating to 90-115 ℃, stirring to fully dissolve, then adding phosphorus pentasulfide and Lawson reagent in a molar ratio of 2-15:1 as vulcanizing agents, and monitoring the reaction condition by TLC; the reaction is completed within 1.3-4 h; decompressing and evaporating the solvent at 55 ℃, carrying out column separation on the crude product, carrying out recrystallization on the crude product with PE: EA = 6:1 or 4:1 by absolute ethyl alcohol, and carrying out suction filtration and drying to obtain white solid 4-S-5-Br-2 ', 3 ', 5 ' -O-triacetyluridine.
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