CN113563400A - Synthesis method of 4-sulfur-5-fluoro-2 ',3',5' -O-triacetyl uridine - Google Patents
Synthesis method of 4-sulfur-5-fluoro-2 ',3',5' -O-triacetyl uridine Download PDFInfo
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Abstract
The invention belongs to the field of chemical synthesis, and discloses a method for synthesizing 4-sulfur-5-fluoro-2 ',3',5' -O-triacetyl uridine. The method comprises the steps of taking 5-F-2', 3,5' -O-triacetyl uridine shown in a formula (I) as a raw material, taking phosphorus pentasulfide and Lawson reagent as a vulcanizing agent in a combined manner, taking 1, 4-dioxane as a solvent, and carrying out a chemical reaction under the assistance of microwaves to finally prepare 4-s-5-F-2', 3, 5-O-triacetyl uridine shown in a formula (II); the invention relates to a method for preparing P2S5The novel synthesis method not only greatly shortens the reaction time, but also improves the yield to the maximum extent, has few byproducts, and is simpler and more convenient in post-treatment.
Description
Technical Field
The invention belongs to the field of chemical synthesis, and relates to a method for synthesizing 4-sulfur-5-fluoro-2 ',3',5' -O-triacetyl uridine.
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. Methods for treating cancer include: radiotherapy; chemotherapy; performing surgical treatment; ultraviolet light and nucleoside therapy. Photochemotherapy, in which ultraviolet radiation or visible light-sensitive drugs are combined to produce a therapeutic effect, neither the drug nor the radiation is achieved alone, is a mature non-malignant proliferative treatment of skin conditions and various cancers.
According to a great amount of recent researches, the nucleoside compounds modified by glycosyl and base show good antitumor activity, and 4-thionucleoside analogues are widely applied to clinic as antiviral and antitumor drugs.
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.
Disclosure of Invention
In order to overcome the defects of the prior art, the invention provides a method for synthesizing 4-sulfur-5-fluoro-2 ',3',5' -O-triacetyl uridine, and P is synthesized by the method2S5The novel synthesis method not only greatly shortens the reaction time, but also improves the yield to the maximum extent, has few byproducts, and is simpler and more convenient in post-treatment.
The above purpose of the invention is realized by the following technical scheme:
a method for synthesizing 4-sulfur-5-fluoro-2 ',3',5 '-O-triacetyl uridine comprises the steps of taking 5-F-2', 3,5 '-O-triacetyl uridine shown in a formula (I) as a raw material, taking phosphorus pentasulfide and Lawson reagent as a vulcanizing agent, taking 1, 4-dioxane as a solvent, and carrying out chemical reaction under the assistance of microwaves to finally prepare 4-s-5-F-2', 3, 5-O-triacetyl uridine shown in a formula (II);
the synthesis method comprises the following specific steps:
2.20mmol of 5-F-2', 3,5' -o-triacetyl uridine is dissolved in 50mL-90mL of 1, 4-dioxane;
b. placing into a microwave reactor, and radiating for 8min under the power of 700 w;
c. after the reaction is finished, filtering with diatomite, collecting filtrate, and removing the solvent under reduced pressure to obtain a crude product;
d. the crude product was separated by silica gel chromatography to give 0.76g of a yellow oily liquid compound in 94% yield.
In a preferred embodiment of the present invention, the microwave reaction in step b is followed by TLC.
As a preferred technical scheme of the invention, the reaction temperature is 85-115 ℃, and the reaction time is 20min-1.5 h.
In a preferred embodiment of the present invention, the molar ratio of the phosphorus pentasulfide to the lawson reagent is 1:1 to 15: 1.
Compared with the prior art, the invention has the beneficial effects that:
1: the invention provides a novel and rapid sulfurization method for sulfurization reaction, which not only greatly shortens the time, but also greatly improves the yield, particularly makes up for the defect that the Lawesson reagent method can not sulfurize nucleoside compounds with furan and thiophene groups at the 5-position of the basic group, and speculates that a novel structural compound can be generated through preliminary analysis and inference of the novel sulfurization agent.
2: the invention relates to a novel rapid vulcanization method and P2S5Compared with the vulcanization of Lawesson reagent method and the reaction time and yield under microwave-assisted reaction, the novel rapid vulcanization method is found to have outstanding advantages in reaction time, greatly improved yield and reaction time after the P is singly used2S5Several hours and even overnight with Lawesson's reagent and microwave reactor to several tens of minutes from the novel rapid vulcanization process, the yield increased from the previous 50% to 90% and most importantly, the novel rapid vulcanization process compensated for 4-thio-5- (2 "-thienyl) -2',3',5' -O-triacetyluridine, 4-thio-5-iodo-2 ',3',5' when previously vulcanized with Lawesson's reagent alone 'The shortage that O-triacetyluridine cannot undergo thionation reaction.
Drawings
FIG. 1 is a nuclear magnetic spectrum of the product of example 1 of the present invention.
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 adopted by the invention are all conventional methods, and experimental equipment, materials, reagents and the like used in the experimental method can be obtained from commercial sources.
Instrument for measuring the position of a moving object
Reagent
Example 1
A synthesis method of 4-sulfur-5-fluoro-2 ',3',5 '-O-triacetyl uridine comprises the steps of taking 5-F-2', 3,5 '-O-triacetyl uridine shown in a formula (I) as a raw material, taking phosphorus pentasulfide and Lawson reagent as a vulcanizing agent, taking 1, 4-dioxane as a solvent, carrying out chemical reaction under the assistance of microwaves, and finally preparing 4-s-5-F-2', 3, 5-O-triacetyl uridine shown in a formula (II),
further, the method comprises the following specific steps:
2.20mmol of 5-F-2', 3,5' -o-triacetyl uridine is dissolved in 50mL-90mL of 1, 4-dioxane;
b. placing into a microwave reactor, and radiating for 8min under the power of 700 w;
c. after the reaction is finished, filtering with diatomite, collecting filtrate, and removing the solvent under reduced pressure to obtain a crude product;
d. the crude product was separated by silica gel chromatography to give 0.76g of a yellow oily liquid compound in 94% yield.
When the microwave reaction is carried out in the step b, the detection is carried out by TLC tracking.
The reaction temperature is 85-115 ℃, and the reaction time is 20min-1.5 h.
The molar ratio of the phosphorus pentasulfide to the Lawson reagent is 1:1-15: 1.
Specifically, under the protection of Ar gas, 5-fluoro-2 ',3',5' -O-triacetyl uridine (1g,2.58mmol) is put into a round-bottom flask filled with anhydrous 1, 4-dioxane (50mL) and stirred until being dissolved, the round-bottom flask is put into a microwave reactor, the round-bottom flask is irradiated for 8min under 700w of power, tracking detection is carried out by TLC, and then a new sulfuration reagent PL-11[ P ] is added2S5(0.34g,1.55mmol), Lawesson's reagent (0.63g,1.55mmol)]The reaction was stirred continuously at a temperature of 95 ℃ with a reflux apparatus installed, and purified by TLC [ V (petroleum ether): v (ethyl acetate) ═ 1:1]The reaction was monitored and after 1.6h the starting material point had disappeared completely, i.e. the reaction was complete, the solvent was removed by distillation under reduced pressure and the crude product was separated by chromatography on silica gel with eluent V (petroleum ether): v (ethyl acetate) ═ 5:1, and dried to give 4-thio-5-fluoro-2 ',3',5' -O-triacetyluridine (0.52g, 1.29mmol) as a yellow solid in 94% yield. As shown in fig. 1, the product nuclear magnetic data is as follows:1H-NMR(400Hz,CH3Cl-d6)(ppm):9.73(s,1H,NH),7.55(d,1H,J＝4Hz,6-H),6.03(d,1H,J＝8Hz,1’-H),5.32(brs,2H,2’-H,3’-H),4.41(m,3H,4’-H,5’-H,5”-H),2.12-2.10(t,3-H,-OC＝OCH3。
comparative example 1
Under the protection of Ar gas, 5-fluoro-2 ',3',5' -O-triacetyl uridine (1.00g,2.58mmol) is put into a round bottom flask with anhydrous 1, 4-dioxane (50mL) and stirred until being dissolved, the round bottom flask is put into a microwave reactor, the reaction solution is radiated for 8min under 700w of power, the detection is carried out by TLC, and then P is added2S5(0.69g,3.10mmol), reflux apparatus was set up and the reaction was stirred continuously at a temperature of 95 deg.CBy TLC [ V (petroleum ether): v (ethyl acetate) ═ 1:1]The reaction was monitored and after 7.5h the starting material point had completely disappeared i.e. the reaction was complete. The solvent was removed by distillation under reduced pressure and the crude product was chromatographed on silica gel using eluent V (petroleum ether): v (ethyl acetate) ═ 5:1, and dried to give 4-thio-5-bromo-2 ',3',5' -O-triacetyluridine (0.70g, 1.73mmol) as a yellow solid in 67% yield.
Comparative example 2
5-fluoro-2 ',3',5 '-O-triacetyluridine (1.00g,2.58mmol) was taken into a round-bottomed flask containing anhydrous 1, 4-dioxane (50mL) under Ar gas and stirred until dissolved, placed into a microwave reactor, irradiated at 700W power for 8min, followed by TLC detection, Lawesson's reagent (1.25g,3.10mmol) was added, reflux apparatus was set up, the reaction was stirred continuously at a temperature of 95 deg.C, and TLC [ V (petroleum ether): the reaction was monitored with 1: 1V (ethyl acetate), and after 8h the starting material point had completely disappeared, i.e. the reaction was complete. The solvent was removed by distillation under reduced pressure and the crude product was chromatographed on silica gel using eluent V (petroleum ether): v (ethyl acetate) ═ 5:1, and dried to give 4-thio-5-fluoro-2 ',3',5' -O-triacetyluridine (0.76g, 1.88mmol) as a yellow solid in 73% yield.
Will P2S5And Lawesson's reagent at different molar ratios, the results are shown in Table 1 below:
TABLE 1 different molar ratios P2S5And the Effect of Lawesson on yield and reaction time
From Table 1, P is known2S5Molar ratio to Lawesson reagent 9:1, the product yield is highest and the reaction time is relatively short;
vulcanization condition screening (temperature and solvent)
By analyzing the above table in addition to considering that Lawesson's reagent is expensive and easily degenerates, the option of using P with the aid of microwaves is to choose2S5Combined with Lawesson reagent as vulcanizing agent to screen novel speedThe optimal reaction conditions of the rapid vulcanization method are that the reaction temperature is 85 ℃, 95 ℃ and 115 ℃; the reaction solvent is 1, 4-dioxane and pyridine;
TABLE 2P2S5Influence of Lawesson sulfiding agent on reaction time and yield
PL-91 in the table is P in a 9:1 molar ratio2S5Lawesson reagent; is a novel sulfuration reagent.
As can be seen from Table 2, when the temperature of the reaction solvent reaches 95 ℃, the maximum yield is obtained, the reaction time is prolonged due to too low temperature, and the raw materials cannot be reacted completely; the color of the solvent deepens when the temperature is too high, and the TLC tracks and detects that the by-products of the reaction increase.
TABLE 3 Effect of 95 ℃ solvent on the efficiency of different vulcanization processes
Table 3 shows that the novel sulfurizing reagent PL-91, i.e., P, is present when the temperature of the reaction solution reaches 95 ℃ under the assistance of microwaves2S5Lawesson's reagent mole ratio of 9:1 has better yield in different reaction solvents;
TABLE 4 influence of microwave radiation power on reaction yield
| power/ |
500 | 600 | 700 | 800 |
| Yield/% | 84 | 88 | 94 | 90 |
As can be seen from Table 4, the yield gradually increased with increasing the radiation power at a reaction temperature of 95 ℃ and the yield began to decrease with a radiation power of 700W or more. The microwave power is too high, so that the reaction liquid is boiled violently, the reaction is influenced, the color gradually becomes dark, and the byproducts of the TLC tracking detection reaction increase, so 700W is the optimal radiation power.
The invention proves that P is synthesized through a large number of experiments2S5The novel synthesis method not only greatly shortens the reaction time, but also improves the yield to the maximum extent, has few byproducts, and is simpler and more convenient in post-treatment.
Finally, it should be noted that: although the present invention has been described in detail with reference to the foregoing embodiments, it will be apparent to those skilled in the art that changes may be made in the embodiments and/or equivalents thereof without departing from the spirit and scope of the invention. Any modification, equivalent replacement, or improvement made within the spirit and principle of the present invention should be included in the protection scope of the present invention.
Claims (5)
1. A synthesis method of 4-sulfur-5-fluoro-2 ',3',5 '-O-triacetyl uridine is characterized in that 5-F-2', 3,5 '-O-triacetyl uridine shown in formula (I) is used as a raw material, phosphorus pentasulfide and Lawson reagent are used as a vulcanizing agent in combination, 1, 4-dioxane is used as a solvent to carry out chemical reaction under the assistance of microwaves, and finally 4-s-5-F-2', 3, 5-O-triacetyl uridine shown in formula (II) is prepared,
2. the method for synthesizing 4-thio-5-fluoro-2 ',3',5' -O-triacetyluridine according to claim 1, wherein the specific steps are as follows:
2.20mmol of 5-F-2', 3,5' -o-triacetyl uridine is dissolved in 50mL-90mL of 1, 4-dioxane;
b. placing into a microwave reactor, and radiating for 8min under the power of 700 w;
c. after the reaction is finished, filtering with diatomite, collecting filtrate, and removing the solvent under reduced pressure to obtain a crude product;
d. the crude product was separated by silica gel chromatography to give 0.76g of a yellow oily liquid compound in 94% yield.
3. The process for the synthesis of 4-thio-5-fluoro-2 ',3',5' -O-triacetyluridine according to claim 1, wherein the microwave reaction in step b is followed by TLC.
4. The method for synthesizing 4-thio-5-fluoro-2 ',3',5' -O-triacetyluridine according to claim 1, wherein the reaction temperature is 85 ℃ to 115 ℃ and the reaction time is 20min to 1.5 h.
5. The process of claim 1, wherein the molar ratio of phosphorus pentasulfide to lawson's reagent is from 1:1 to 15: 1.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102718822A (en) * | 2012-05-18 | 2012-10-10 | 大连大学 | Synthetic method of 4-sulfur thymidine and analogues of 4-sulfur thymidine under microwave irradiation |
| CN110105416A (en) * | 2019-06-17 | 2019-08-09 | 大连大学 | A kind of 4-S-5-Br-2 ', 3 ', 5 '-O- triacetyl uridine synthetic methods |
| CN110204584A (en) * | 2019-06-17 | 2019-09-06 | 大连大学 | A kind of 4-S-2 ', 3 ', 5 '-O- triacetyl uridine synthetic methods |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102718822A (en) * | 2012-05-18 | 2012-10-10 | 大连大学 | Synthetic method of 4-sulfur thymidine and analogues of 4-sulfur thymidine under microwave irradiation |
| CN110105416A (en) * | 2019-06-17 | 2019-08-09 | 大连大学 | A kind of 4-S-5-Br-2 ', 3 ', 5 '-O- triacetyl uridine synthetic methods |
| CN110204584A (en) * | 2019-06-17 | 2019-09-06 | 大连大学 | A kind of 4-S-2 ', 3 ', 5 '-O- triacetyl uridine synthetic methods |
Non-Patent Citations (1)
| Title |
|---|
| GRAZYNA WENSKA ET AL.: "Photochemical transformations of 5-halogeno-4-thiouridines", 《J. CHEM. SOC., PERKIN TRANS.1》, no. 1, pages 53 - 57 * |
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