CN111944000A - 5-Substituted-2,4-dithio-2',3'-O-di-tert-butyldisilyl nucleoside compound and synthesis method - Google Patents

Abstract

The invention belongs to the field of synthetic chemistry, and discloses a 5-substituted-2,4-disulfide-2',3'-O-di-tert-butyldisilyl nucleoside compound and a synthesis method. Under nitrogen protection, the 5-substituted deoxynucleoside compound was reacted with tert-butyldimethylsilyl chloride (TBSCl), and after the reaction was completed, post-treatment was performed to obtain compound a; compound a was then dissolved with 1,2,4-triazole Reaction in anhydrous acetonitrile solvent to obtain light yellow solid b; finally compound b reacts with thioacetic acid in anhydrous acetonitrile to obtain yellow solid compound c; finally compound c and Lawesson's Reagent are anhydrous at 80°C Stir overnight in toluene to give final product d. Provided is a 5-substituted-2,4-disulfide-2',3'-O-di-tert-butyldisilyl nucleoside compound which is simple, efficient, mild and simple in post-processing. This synthesis method has the advantages of avoiding the use of toxic H ₂ S gas and expensive chlorosaccharide compounds with poor shelf life in the synthesis process.

Description

5-substituted-2,4-dithio-2',3'-O-di-tert-butyldisilyl nucleoside compound and synthesis method

technical field

The invention belongs to the technical field of chemical synthesis, and relates to a 5-substituted-2,4-dithio-2',3'-O-di-tert-butyldisilyl nucleoside compound and a synthesis method thereof.

Background technique

Natural nucleosides are glycosides formed from ribose or deoxyribose and a base (such as adenine, thymine, guanine, cytosine or uracil), which are important components of DNA and RNA and play a role in life activities in nature. an irreplaceable role. Since Lipsett (Lipsett M N. The Journal of biological chemistry, 1965, 240 (10).) isolated 4-thiouracil nucleotides from Escherichia coli, thiobases and nucleosides have attracted extensive research attention .

Compared with natural nucleotides, sulfhydryl-containing pyrimidine ring series nucleoside compounds have anticancer activity and immune enhancement (NIGMN SC, SAHARA GS, SHAMM HR. Indian Chem Soc, 1983, 60: 583-586.), in addition Studies have shown that nucleoside compounds containing a thiocarbonyl group have a large absorbance after the 4-position carbonyl oxygen on the pyrimidine base is replaced by sulfur, and the maximum absorption peak is red-shifted, which is extremely sensitive to light (Huo Shuhua, Li Depeng, Wang Jian, et al. Molecular Acta Scientifica, 2013, 29(5): 392-396.), making DNA molecules sensitive to long-wave ultraviolet (UVA) or near-ultraviolet light.

Studies have found that 4-thionucleoside analogs are sensitive to ultraviolet light and can be used as potential antitumor drugs, especially when combined with near ultraviolet light (UVA) for the treatment of skin cancer (Pridgeon SW, Heer R, Taylor GABr.J. Cancer 2011, 104, 1869.). Therefore, Xu Yaozhong and Karran et al. (Massey M, Xu YZ, Karran P.Curr.Biol.2011,11,1142) proposed a new photochemotherapy method, namely ultraviolet light-assisted 4-thiothymidine therapy. This therapy utilizes the similar structure of thiothymidine to natural thymidine, the rapid self-replication and growth of cancer cells in the human body, and incorporates 4-thiothymidine analogs into cancerous tissues, selectively damaging by interacting with UVA of specific wavelengths DNA of cancer cells, so as to selectively kill cancer cells and reduce the cytotoxicity of drugs.

Due to the limited tissue penetration ability of UVA, S ⁴ TdR/UVA therapy is effective for malignant tumors of some solid organs close to the skin surface, such as the skin surface, urinary tract, digestive tract, upper respiratory tract, etc. This therapy may not work well for some malignancies of solid organs that UVA cannot access, such as lung, brain, liver, kidney.

Therefore, in order to solve this problem, based on 4-thiodeoxythymidine, new structural modifications and substitutions were carried out to make the absorption wavelength of the thio compounds develop to the visible light region. The therapy can also be applied to the treatment of deep-derived tumors.

Marvin Pollum proposed that the maximum absorption wavelength of 2,4-dithiothymine is at 363 nm (Pollum M, Jockusch S, Crespo-Hernandez CE. J Am Chem Soc. 2014; 136(52): 17930-3.), which It provides a theoretical basis for realizing the development of the absorption wavelength of thio compounds to the visible light region. However, there are few literature reports on the synthesis of disulfide compounds, so the research on the development and synthesis of such sulfur-containing nucleoside derivatives is of great significance.

SUMMARY OF THE INVENTION

In order to overcome the deficiencies of the prior art, the present invention provides a 5-substituted-2,4-dithio-2',3'-O-di-tert-butyldisilyl nucleoside compound and a synthesis method thereof. The synthesis method is simple, efficient, mild and simple in post-processing.

Above-mentioned purpose of the present invention is achieved through the following technical solutions:

A 5-substituted-2,4-dithio-2',3'-O-di-tert-butyldisilyl nucleoside compound; has the structure of general formula (d):

Wherein, X=CH ₃ , H, F, Cl, Br, I.

The specific structural formula of the 5-substituted-2,4-dithio-2',3'-O-di-tert-butyldisilyl nucleoside compound is as follows:

Wherein A is deoxythymidine, B is deoxyuridine, C is 5-fluorodeoxynucleoside, D is 5-chlorodeoxynucleoside, E is 5-bromodeoxynucleoside, and F is 5-iododeoxynucleoside. .

A 5-substituted-2,4-dithio-2',3'-O-di-tert-butyldisilyl nucleoside compound and a method for synthesizing the same; using deoxynucleoside as raw material, using Lawson's reagent as sulfur agent, chemical reaction takes place in anhydrous toluene solvent, and finally the compound shown in general formula d is obtained;

Wherein, X=H, CH ₃ , F, Cl, Br, I.

Further, the above-mentioned 5-substituted-2,4-dithio-2',3'-O-di-tert-butyldisilyl nucleoside compound synthesis method steps are: under the protection of nitrogen, 5-substituted deoxynucleoside The glycoside compound is reacted with tert-butyldimethylsilyl chloride (TBSCl), and after the reaction is completed, post-treatment is performed to obtain compound a; compound a is then reacted with 1,2,4-triazole dissolved in anhydrous acetonitrile solvent to obtain light yellow solid b; finally compound b reacted with thioacetic acid in anhydrous acetonitrile to obtain yellow solid compound c; finally compound c and Lawesson's Reagent were stirred overnight in anhydrous toluene at 80°C to obtain final product d.

Further, the specific steps of the above-mentioned 5-substituted-2,4-disulfide-2',3'-O-di-tert-butyldisilyl nucleoside compound synthesis method are:

S1. Synthesis of compound a: under nitrogen protection, dissolve 1 equivalent of 5-substituted deoxynucleoside compound and 3 equivalents of imidazole in dichloromethane, and stir under an ice-water bath (0°C) for 30 minutes; after 30 minutes, add the reaction 2.5 equivalents of tert-butyldimethylsilyl chloride (TBSCl) was added to the system, and stirred at room temperature for 1 hour; after the reaction was detected by TLC, quenched with water and extracted with dichloromethane; the organic phases were combined, washed with saturated NaCl, and anhydrous NaSO _4. Dry, filter, and evaporate the solvent under reduced pressure to obtain compound a as a white solid, and proceed directly to the next step S2 without purification;

S2. Synthesis of compound b: dissolve 14 equivalents of 1,2,4-triazole in anhydrous acetonitrile, slowly add phosphorus oxychloride and triethylamine under stirring in an ice-water bath (0°C); after 1 hour of reaction, 1 equivalent of white solid compound a prepared by the above-mentioned S1 was added, and stirred overnight at room temperature; after the reaction was detected by TLC, the reaction solution was filtered, the organic phase was diluted with dichloromethane, washed with saturated NaHCO solution, washed with saturated _NaCl solution, and washed with anhydrous Na ₂ Dry over SO ₄ , filter, and evaporate the solvent under reduced pressure to obtain compound b as a light yellow solid, and proceed directly to the next step S3 without purification;

S3. Synthesis of compound c: dissolve 1 equivalent of compound b in anhydrous acetonitrile, add 14 equivalents of thioacetic acid, and stir overnight at room temperature; after TLC detects the reaction, the reaction solution is diluted with dichloromethane, saturated NaHCO ₃ The solution was washed with saturated NaCl solution, dried over anhydrous Na ₂ SO ₄ , filtered, and the solvent was evaporated under reduced pressure to obtain a yellow solid, which was separated and purified on a silica gel column to obtain compound c;

S4. Synthesis of compound d: dissolve 1 equivalent of compound c in anhydrous toluene, add 2 equivalents of Lawesson's Reagent, and stir at 80°C overnight. Silica gel column separation and purification to obtain compound d as a yellow solid.

Further, in step S4, the reaction temperature of compound c in anhydrous toluene is 80°C.

The beneficial effects of the present invention compared with the prior art are:

The invention provides a synthetic method for preparing such 5-substituted-2,4-dithio-2',3'-O-di-tert-butyldisilyl nucleoside compounds. In the synthesis of compounds (b)-(d), firstly, the purpose of sulfur at the 4-position of the deoxynucleoside compound is achieved by using triazole to sulfide the deoxynucleoside compound, and then the 4-thiodeoxynucleoside compound 2 is obtained by using Lawesson's reagent. On the S atom, the synthesis of 5-substituted-2,4-disulfide-2' was achieved by changing the order of sulfur addition to deoxynucleoside compounds and using two sulfurizing reagents, thioacetic acid and Lawson's reagent, respectively. , The purpose of 3'-O-di-tert-butyldisilyl nucleoside compounds. This synthesis method has the advantages of mild conditions, low environmental pollution, high yield, easy separation and purification, etc. In the synthesis process, the use of flammable, explosive and highly toxic H ₂ S gas is avoided, and the first synthesis of H ₂ S gas is avoided. 2-thiodeoxynucleoside is a cumbersome method for resynthesizing 2,4-dithiodeoxynucleoside with low yield and configuration change, avoiding the use of expensive chlorosugar compounds with poor shelf life.

Description of drawings

Fig. 1 is the nuclear magnetic characterization spectrum of compound a1 of Example 1 of the present invention.

FIG. 2 is the NMR characterization spectrum of compound b1 of Example 1 of the present invention.

Fig. 3 is the nuclear magnetic characterization spectrum of compound c1 of Example 1 of the present invention.

FIG. 4 is the nuclear magnetic characterization spectrum of compound d1 of Example 1 of the present invention.

Detailed ways

The present invention is described in detail below through specific embodiments, but the protection scope of the present invention is not limited. Unless otherwise specified, the experimental methods used in the present invention are all conventional methods, and the experimental equipment, materials, reagents, etc. used can be obtained from commercial sources.

Example 1

2,4-Dithio-2',3'-O-di-tert-butyldimethylsilyldeoxythymidine, whose structural formula is shown in general formula d ₁ ,

S1. Synthesis _of compound a1: Under nitrogen protection, deoxythymidine (3 g) and imidazole (2.52 g) were dissolved in dichloromethane (20 ml), and stirred for 30 minutes in an ice-water bath. After 30 minutes, tert-butyldimethylsilyl chloride (TBSCl) (4.65 g) was added to the reaction system, and the mixture was stirred at room temperature for 1 hour. After TLC detection, the reaction was quenched with water and extracted with dichloromethane. The organic phases were combined, washed with saturated NaCl, dried over anhydrous NaSO ₄ , filtered, and the solvent was evaporated under reduced pressure to obtain compound a ₁ as a white solid, 5.8 g, yield 99%, directly proceed to the next step S2 without purification. ¹ H NMR (CDCl ₃ , 500MHz) δ: 8.11 (s, 1H), 7.48 (s, 1H), 6.34 (t, J=6.7 Hz, 1H), 4.42-4.36 (m, 1H), 3.95-3.72 ( m, 3H), 2.27–2.19 (m, 1H), 2.05–1.96 (m, 1H), 1.92 (s, 3H), 0.91 (d, J=17.9Hz, 18H), 0.14–0.04 (m, 12H) .

S2. Synthesis of compound b ₁ : Dissolve 1,2,4-triazole (10.22g) in anhydrous acetonitrile (120ml), slowly add phosphorus oxychloride (3.192ml), triethylamine ( 24ml). After the reaction for 1 hour, the white solid (5 g) of compound a1 prepared in the above S1 was added, and the mixture was stirred at room temperature overnight. After the reaction was detected by TLC, the reaction solution was filtered, the organic phase was diluted with dichloromethane, washed with saturated NaHCO ₃ solution, washed with saturated NaCl solution, dried over anhydrous Na ₂ SO ₄ , filtered, and the solvent was evaporated under reduced pressure to obtain compound b ₁ , was a light yellow solid, 5.16 g, the yield was 99%, directly proceeded to the next step S3 without purification. ¹ H NMR (CDCl ₃ , 500MHz) δ: 9.28(s, 1H), 8.25(s, 1H), 8.11(s, 1H), 6.29(t, J=6.2Hz, 1H), 4.39(s, 1H) ,4.06(s,1H),3.88(dd,J＝83.3,11.5Hz,3H),2.67–2.54(m,1H),2.44(s,3H),2.08(dd,J＝13.3,6.5Hz,1H ), 0.90 (d, J=7.9Hz, 18H), 0.09 (dd, J=17.8, 6.5Hz, 12H).

S3. Synthesis of compound c ₁ : Compound b ₁ (5 g) was dissolved in anhydrous acetonitrile (191 ml), thioacetic acid (9.6 ml) was added, and the mixture was stirred at room temperature overnight. After the reaction was detected by TLC, the reaction solution was diluted with dichloromethane, washed with saturated NaHCO ₃ solution, washed with saturated NaCl solution, dried over anhydrous Na ₂ SO ₄ , filtered, and the solvent was evaporated under reduced pressure to obtain a yellow solid, which was separated and purified on a silica gel column. Compound c ₁ was obtained, 3.74 g in 80% yield. ¹ H NMR (CDCl ₃ , 500MHz) δ: 9.39(s, 1H), 7.51(s, 1H), 6.21(t, J=6.7Hz, 1H), 4.34(s, 1H), 3.91(s, 1H) ,3.86–3.65(m,2H),2.29–2.20(m,1H),2.04(s,3H),1.95(dt,J=13.2,6.8Hz,1H),0.85(d,J=15.1Hz,18H ), 0.04 (d, J=15.7Hz, 12H).

S4. Synthesis of compound 4: Compound c ₁ (2 g) was dissolved in anhydrous toluene (17 ml), Lawesson's Reagent (3.32 g) was added, and the mixture was stirred at 80° C. overnight. Silica gel column separation and purification to obtain compound d ₁ as a yellow solid, 1.13 g, yield 55%. ¹ H NMR (CDCl ₃ , 500MHz) δ: 10.62(s, 1H), 7.73(s, 1H), 6.74(t, J=6.3Hz, 1H), 4.38(s, 1H), 4.05-3.73(m, 3H), 2.56(dt, J＝13.2, 4.3Hz, 1H), 2.12(s, 3H), 1.97(dt, J＝13.2, 6.7Hz, 1H), 0.91(d, J＝10.3Hz, 18H), 0.12(d,J＝4.1Hz,6H),0.09(d,J＝8.4Hz,6H).

Example 2

2,4-Dithio-2',3'-O-di-tert-butyldisilyldeoxyuridine; its structural formula is shown in general formula d ₂ ,

S1. Synthesis of compound a ₂ : Under nitrogen protection, deoxyuridine (5 g) and imidazole (4.49 g) were dissolved in dichloromethane (34 ml), and stirred for 30 minutes in an ice-water bath. After 30 minutes, tert-butyldimethylsilyl chloride (TBSCl) (8.3 g) was added to the reaction system, followed by stirring at room temperature for 1 hour. After TLC detection, the reaction was quenched with water and extracted with dichloromethane. The organic phases were combined, washed with saturated NaCl, dried over anhydrous NaSO ₄ , filtered, and the solvent was evaporated under reduced pressure to obtain compound a ₂ as a white solid, 9.9 g, yield 99%, directly proceed to the next step S2 without purification. ¹ H NMR (CDCl ₃ , 500MHz) δ: 8.72 (s, 1H), 7.95-7.87 (m, 1H), 6.30 (t, J=6.1 Hz, 1H), 5.69 (d, J=8.1 Hz, 1H) ,4.41(dd,J＝6.0,3.6Hz,1H),3.83(dd,J＝73.6,11.5Hz,3H),2.32(dt,J＝10.8,5.0Hz,1H),2.07(dt,J＝12.7 , 5.8Hz, 1H), 0.91 (d, J=15.0Hz, 18H), 0.09 (d, J=15.3Hz, 12H).

S2. Synthesis of compound b ₂ : 1,2,4-triazole (6.7g) was dissolved in anhydrous acetonitrile, and phosphorus oxychloride (2.1ml) and triethylamine (15.8ml) were slowly added under stirring in an ice-water bath. . After 1 hour of reaction, the compound a2 prepared in the above S1 was put into white solid ( ₃ g), and the mixture was stirred at room temperature overnight. After the reaction was detected by TLC, the reaction solution was filtered, the organic phase was diluted with dichloromethane, washed with saturated NaHCO ₃ solution, washed with saturated NaCl solution, dried over anhydrous Na ₂ SO ₄ , filtered, and the solvent was evaporated under reduced pressure to obtain compound b ₂ , was a light yellow solid, 3.3 g, the yield was 99%, directly proceeded to the next step S3 without purification.

S3. Synthesis of compound c ₂ : Compound b ₂ (3 g) was dissolved in anhydrous acetonitrile, thioacetic acid (5.9 ml) was added, and stirred overnight at room temperature. After TLC detected the reaction, the reaction solution was diluted with dichloromethane, saturated with Washed with NaHCO ₃ solution, washed with saturated NaCl solution, dried over anhydrous Na ₂ SO ₄ , filtered, and evaporated the solvent under reduced pressure to obtain a yellow solid, which was separated and purified by silica gel column to obtain compound c ₂ , 2.17 g, yield 78%. ¹ H NMR (CDCl ₃ , 500MHz) δ: 9.58 (s, 1H), 7.81 (s, 1H), 6.42-6.32 (m, 1H), 6.23 (q, J=6.0, 4.3Hz, 1H), 3.96-3.71 ( m, 3H), 2.52 (d, J=4.7Hz, 1H), 2.35 (h, J=4.8Hz, 1H), 2.12–2.03 (m, 1H), 0.90 (d, J=15.6Hz, 18H), 0.09 (d, J=13.9 Hz, 12H).

S4. Synthesis of compound d ₂ : Compound c ₂ (2 g) was dissolved in anhydrous toluene (17 ml), Lawesson's Reagent (3.4 g) was added, and the mixture was stirred at 80° C. overnight. Silica gel column separation and purification to obtain compound d ₂ as a yellow solid, 1.027 g, yield 50%.

Example 3

5-F-2,4-dithio-2',3'-O-di-tert-butyldimethylsilyldeoxyuridine; its structural formula is shown in general formula d ₃ ,

S1. Synthesis of compound a ₃ : Under nitrogen protection, deoxythymidine (5 g) and imidazole (4.15 g) were dissolved in dichloromethane (34 ml), and stirred for 30 minutes in an ice-water bath. After 30 minutes, tert-butyldimethylsilyl chloride (TBSCl) (7.65 g) was added to the reaction system, followed by stirring at room temperature for 1 hour. After TLC detection, the reaction was quenched with water and extracted with dichloromethane. The organic phases were combined, washed with saturated NaCl, dried over anhydrous NaSO ₄ , filtered, and the solvent was evaporated under reduced pressure to obtain compound a ₃ as a white solid, 9.54 g, yield 99%, directly proceed to the next step S2 without purification. ¹ H NMR (CDCl ₃ , 500 MHz) δ: 8.62 (s, 1H), 8.07 (d, J=6.2 Hz, 1H), 6.30 (t, J=6.0 Hz, 1H), 4.41 (dt, J=6.2, 3.1Hz, 1H), 3.94 (d, J=12.5Hz, 2H), 3.77 (d, J=11.1Hz, 1H), 2.32 (ddd, J=13.2, 6.1, 3.5Hz, 1H), 2.06 (p, J=6.3Hz, 1H), 0.91 (d, J=19.1Hz, 18H), 0.11 (dd, J=24.6, 2.9Hz, 12H).

S2. Synthesis of compound b ₃ : 1,2,4-triazole (6.44g) was dissolved in anhydrous acetonitrile (41.05ml), phosphorus oxychloride (153.33ml) was slowly added under stirring in an ice-water bath, triethylamine (101.19ml). After 1 hour of reaction, the compound a3 prepared in the above S1 was put into white solid ( ₃ g), and the mixture was stirred at room temperature overnight. After the reaction was detected by TLC, the reaction solution was filtered, the organic phase was diluted with dichloromethane, washed with saturated NaHCO ₃ solution, washed with saturated NaCl solution, dried over anhydrous Na ₂ SO ₄ , filtered, and the solvent was evaporated under reduced pressure to obtain compound b ₃ , was a light yellow solid, 3.28 g, the yield was 99%, directly proceeded to the next step S3 without purification. ¹ H NMR (CDCl3, 500MHz)δ: 9.26(s, 1H), 8.86(d, J=6.0Hz, 1H), 8.22(s, 1H), 6.23(d, J=5.3Hz, 1H), 4.41( d, J=4.8Hz, 1H), 4.15–3.97 (m, 3H), 3.83 (d, J=11.5Hz, 1H), 2.61 (dq, J=13.2, 6.3, 5.2Hz, 1H), 2.23 (dt , J＝13.5, 5.0Hz, 1H), 2.05(s, 0H), 0.94(s, 9H), 0.89(s, 9H), 0.15(d, J＝9.9Hz, 6H), 0.08(s, 6H) .

S3. Synthesis of compound c ₃ : Compound b ₃ (3 g) was dissolved in anhydrous acetonitrile (115 ml), thioacetic acid (5.7 ml) was added, and the mixture was stirred at room temperature overnight. After the reaction was detected by TLC, the reaction solution was diluted with dichloromethane, washed with saturated NaHCO ₃ solution, washed with saturated NaCl solution, dried over anhydrous Na ₂ SO ₄ , filtered, and the solvent was evaporated under reduced pressure to obtain a yellow solid, which was separated and purified on a silica gel column. Compound c ₃ was obtained, 2.26 g in 81% yield. ¹ H NMR (CDCl ₃ , 500MHz) δ: 9.50 (s, 1H), 8.05 (d, J=3.9 Hz, 1H), 6.23 (d, J=5.4 Hz, 1H), 4.42 (s, 1H), 3.99 –3.66(m,3H),2.39–2.24(m,1H),2.09(dt,J=12.9,5.7Hz,1H),0.91(d,J=18.8Hz,18H),0.17–-0.00(m, 12H).

S4. Synthesis of compound d ₃ : Compound c ₃ (2 g) was dissolved in anhydrous toluene (16 ml), Lawesson's Reagent (3.23 g) was added, and the mixture was stirred at 80° C. overnight. Silica gel column separation and purification to obtain compound d ₃ as a yellow solid, 1.054 g, yield 52%. ¹ H NMR (CDCl ₃ , 500MHz) δ: 10.52 (s, 1H), 8.23 (d, J=3.7Hz, 1H), 6.61 (t, J=5.3Hz, 1H), 4.40 (t, J=5.3Hz) ,1H),4.06–3.78(m,3H),2.54(dt,J=13.1,6.1Hz,1H),2.15(dq,J=13.7,5.7,4.5Hz,1H),0.93(s,9H), 0.89 (s, 9H), 0.11 (dd, J=23.3, 5.7Hz, 12H).

The above-mentioned embodiments are only preferred embodiments of the present invention, rather than all possible embodiments of the present invention. For those skilled in the art, any obvious changes made to it without departing from the principle and spirit of the present invention should be considered to be included in the protection scope of the claims of the present invention.

Claims (4)

1. A5-substituted-2, 4-dithio-2 ', 3' -O-di-tert-butyldisilyl nucleoside compound characterized by having a structure of the general formula (d):

wherein X is CH₃、H、F、Cl、Br、I。

2. The method for synthesizing a 5-substituted-2, 4-dithio-2 ', 3' -O-di-t-butyldimethylsilyl nucleoside compound according to claim 1, wherein the synthesizing step is: under the protection of nitrogen, reacting the 5-substituted deoxynucleoside compound with tert-butyldimethylsilyl chloride, and performing post-treatment after the reaction is finished to obtain a compound a; dissolving the compound a and 1,2, 4-triazole in an anhydrous acetonitrile solvent for reaction to obtain a light yellow solid b; finally, reacting the compound b with thioacetic acid in anhydrous acetonitrile to obtain a yellow solid compound c; finally, the compound c was stirred with lawson's reagent in anhydrous toluene at 80 ℃ overnight to give the final product d.

3. The method for synthesizing a 5-substituted-2, 4-dithio-2 ', 3' -O-di-t-butyldimethylsilyl nucleoside compound according to claim 2, wherein the synthesizing step is:

s1, synthesis of a compound a: under the protection of nitrogen, dissolving 5-substituted deoxynucleoside compound and imidazole in dichloromethane, stirring in ice-water bath, and adding tert-butyl dimethyl silicon chlorideAlkane, stirring for 1 hour at room temperature; after TLC detection reaction is finished, quenching with water and extracting with dichloromethane; the organic phases were combined, washed with saturated NaCl and anhydrous NaSO₄Drying, filtering, and evaporating the solvent under reduced pressure to obtain compound a as white solid, which is directly subjected to the next step S2 without purification;

s2, synthesis of a compound b: dissolving 1,2, 4-triazole in anhydrous acetonitrile, and slowly adding phosphorus oxychloride and triethylamine under the stirring of ice-water bath; after the reaction, 1 equivalent of the white solid compound a prepared in S1 was added and stirred at room temperature overnight; after TLC detection, the reaction solution was filtered, the organic phase was diluted with dichloromethane and saturated NaHCO₃Solution washing, saturated NaCl solution washing, anhydrous Na₂SO₄Drying, filtering, and evaporating the solvent under reduced pressure to obtain a compound b which is a light yellow solid and is directly subjected to the next step S3 without purification;

s3, synthesis of a compound c: dissolving the compound b in anhydrous acetonitrile, adding 14 equivalents of thioacetic acid, and stirring at room temperature overnight; after TLC detection reaction is finished, the reaction solution is diluted by dichloromethane and saturated NaHCO₃Solution washing, saturated NaCl solution washing, anhydrous Na₂SO₄Drying, filtering, decompressing and distilling off the solvent to obtain yellow solid, and separating and purifying by a silica gel column to obtain a compound c;

s4, synthesis of a compound d: 1 equivalent of compound c was dissolved in anhydrous toluene, added with Lawson's reagent and stirred at 80 ℃ overnight. And (5) separating and purifying by a silica gel column to obtain a compound d as a yellow solid.

4. The method for synthesizing a 5-substituted-2, 4-dithio-2 ', 3' -O-di-tert-butyldimethylsilyl nucleoside compound according to claim 3, wherein the synthesizing step is specifically:

s1, synthesis of a compound a: under the protection of nitrogen, 1 equivalent of 5-substituted deoxynucleoside compound and 3 equivalents of imidazole are dissolved in dichloromethane and stirred for 30 minutes in ice-water bath; after 30 minutes, adding 2.5 equivalents of tert-butyldimethylsilyl chloride into the reaction system, and stirring for 1 hour at room temperature; after TLC detection reaction is finished, quenching with water and extracting with dichloromethane;the organic phases were combined, washed with saturated NaCl and anhydrous NaSO₄Drying, filtering, and evaporating the solvent under reduced pressure to obtain compound a as white solid, which is directly subjected to the next step S2 without purification;

s2, synthesis of a compound b: dissolving 14 equivalents of 1,2, 4-triazole in anhydrous acetonitrile, and slowly adding phosphorus oxychloride and triethylamine under the stirring of ice-water bath; after 1 hour of reaction, 1 equivalent of the white solid compound a prepared in S1 was added and stirred at room temperature overnight; after TLC detection, the reaction solution was filtered, the organic phase was diluted with dichloromethane and saturated NaHCO₃Solution washing, saturated NaCl solution washing, anhydrous Na₂SO₄Drying, filtering, and evaporating the solvent under reduced pressure to obtain a compound b which is a light yellow solid and is directly subjected to the next step S3 without purification;

s3, synthesis of a compound c: dissolving 1 equivalent of the compound b in anhydrous acetonitrile, adding 14 equivalents of thioacetic acid, and stirring at room temperature overnight; after TLC detection reaction is finished, the reaction solution is diluted by dichloromethane and saturated NaHCO₃Solution washing, saturated NaCl solution washing, anhydrous Na₂SO₄Drying, filtering, decompressing and distilling off the solvent to obtain yellow solid, and separating and purifying by a silica gel column to obtain a compound c;

s4, synthesis of a compound d: 1 equivalent of compound c was dissolved in anhydrous toluene, 2 equivalents of lawson's reagent was added, and stirring was carried out overnight at 80 ℃. And (5) separating and purifying by a silica gel column to obtain a compound d as a yellow solid.

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