CN111944000A - 5-substituted-2, 4-dithio-2 ', 3' -O-di-tert-butyldisilyl nucleoside compound and synthetic method thereof - Google Patents

Abstract

The invention belongs to the field of synthetic chemistry, and discloses a 5-substituted-2, 4-dithio-2 ', 3' -O-di-tert-butyldisilyl nucleoside compound and a synthetic method thereof. Under the protection of nitrogen, reacting a 5-substituted deoxynucleoside compound with tert-butyldimethylsilyl chloride (TBSCl), and performing post-treatment after the reaction 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 compound c was stirred with Lawesson's Reagent in 80 ℃ dry toluene overnight to give final product d. Provides a synthesis method of 5-substituted-2, 4-dithio-2 ', 3' -O-di-tert-butyldisilyl nucleoside compound, which is simple, efficient, mild and simple in post-treatment. The synthesis method has the advantage of avoiding using H with high toxicity in the synthesis process₂S gas and expensive chloro-sugar compounds with poor quality guarantee period, and the like.

Description

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

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-butyldimethylsilyl nucleoside compound and a synthesis method thereof.

Background

Natural nucleosides, which are glycosides of ribose or deoxyribose and a base (e.g., adenine, thymine, guanine, cytosine, or uracil), are important components of DNA and RNA and play irreplaceable roles in natural life activities. Since the isolation of 4-thiouracil nucleotides from E.coli by Lipsett M.N.the Journal of biological chemistry,1965,240(10), sulfur-containing bases and nucleosides have attracted considerable research interest.

Compared with natural nucleotide, the pyrimidine ring series nucleoside compound containing sulfhydryl group has anticancer activity and immunity enhancement effect (NIGMN SC, SAHARA GS, SHAMM HR. Indian Chem Soc, 1983, 60: 583-.

4-thio nucleoside analogues have been found to be very sensitive to ultraviolet radiation and to be potentially useful as anti-neoplastic agents, particularly in combination with near ultraviolet light (UVA) for the treatment of skin cancer (Pridgon SW, Heer R, Taylor GABr. J. cancer 2011,104,1869.). Thus, bradyflares and Karran et al (Massey M, Xu YZ, Karran p. curr. biol.2011,11,1142) propose a new photochemotherapeutic approach, i.e. ultraviolet light assisted 4-thiothymidine therapy. The therapy utilizes the characteristics that thiothymidine has a similar structure with natural thymidine and cancer cells can rapidly and self-replicate and grow in a human body, 4-thiothymidine analogues are incorporated into cancerated tissues, and DNA of the cancer cells is selectively damaged through interaction with UVA with a specific wavelength, so that the aims of selectively killing the cancer cells and reducing drug cytotoxicity are fulfilled.

S due to limited tissue penetration of UVA⁴TdR/UVA therapy is effective against malignancies in some solid organs close to the skin surface, such as the skin surface, urinary tract, digestive tract, upper respiratory tract, etc. For some malignancies in solid organs that are inaccessible to UVA, this therapy may not work well, such as lung, brain, liver, kidney.

Therefore, in order to solve the problem, based on 4-thiodeoxythymidine, new structural modification and substitution are carried out, so that the absorption wavelength of a thio compound is developed to a visible light region, and the development of the thio compound is matched with the development of optical fibers in clinic, which means that the therapy can be applied to the treatment of the deep-source tumor in future.

Marvin polar proposes that the maximum absorption wavelength of 2, 4-dithiothymine is at 363nm (Pollum M, Jockusch S, Crespo-Hernandez CE.J Am Chem Soc.2014; 136(52):17930-3.), which provides a theoretical basis for realizing the development of the absorption wavelength of a thio compound to a visible light region. However, the synthesis method of the disulfide compound is only reported in documents, so that the disulfide compound has important significance for the development of the sulfur-containing nucleoside derivatives and the research on the synthesis method.

Disclosure of Invention

In order to overcome the defects of the prior art, the 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-treatment.

The above purpose of the invention is realized by the following technical scheme:

a 5-substituted-2, 4-dithio-2 ', 3' -O-di-tert-butyldisilyl nucleoside compound; having the general formula (d):

wherein X is CH₃、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 synthesis method thereof; taking deoxynucleoside as a raw material, taking a Lawson reagent as a vulcanizing agent, and carrying out chemical reaction in an anhydrous toluene solvent to finally obtain a compound shown as a general formula d;

wherein, X is H, CH₃、F、Cl、Br、I。

Further, the synthesis method of the 5-substituted-2, 4-dithio-2 ', 3' -O-di-tert-butyldisilyl nucleoside compound comprises the following steps: under the protection of nitrogen, reacting a 5-substituted deoxynucleoside compound with tert-butyldimethylsilyl chloride (TBSCl), and performing post-treatment after the reaction 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 compound c was stirred with Lawesson's Reagent in 80 ℃ dry toluene overnight to give final product d.

Further, the synthesis method of the 5-substituted-2, 4-dithio-2 ', 3' -O-di-tert-butyldisilyl nucleoside compound comprises the following steps:

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 (0 ℃); after 30 minutes, adding 2.5 equivalents of tert-butyldimethylsilyl chloride (TBSCl) into the reaction system, and stirring at room temperature for 1 hour; 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 stirring in an ice-water bath (0 ℃); 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 reaction, the reaction solution is filtered, and the organic phase is diluted with dichloromethane and saturatedAnd 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 Lawesson's Reagent were added and stirred at 80 ℃ overnight. And (5) separating and purifying by a silica gel column to obtain a compound d as a yellow solid.

Further, the temperature of the compound c in the anhydrous toluene reaction in the step S4 was 80 ℃.

Compared with the prior art, the invention has the beneficial effects that:

the invention provides a synthesis method for preparing the 5-substituted-2, 4-dithio-2 ', 3' -O-di-tert-butyldisilyl nucleoside compound. In the synthesis from the compounds (b) to (d), the purpose of sulfurizing at the 4-position of a deoxynucleoside compound is achieved first by sulfurizing a deoxynucleoside with a triazole, followed by sulfurizing at the 2-position of a 4-thiodeoxynucleoside compound with a Lawson reagent, by changing the order of the sulfurization on the deoxynucleoside compound, and by using two sulfurizing reagents, thioacetic acid and Lawson reagent, respectively, the purpose of synthesizing a 5-substituted-2, 4-dithio-2 ', 3' -O-di-t-butyldimethylsilyl nucleoside compound is achieved. The synthesis method has the advantages of mild conditions, little environmental pollution, high yield, easy separation and purification and the like, and avoids the use of H which is flammable and explosive and has high toxicity in the synthesis process₂S gas, avoiding passing through H₂S gas is synthesized into 2-thiodeoxynucleoside and then synthesized into 2, 4-dithiodeoxynucleoside, and the complex means of low yield and configuration change avoids the use of expensive chloro-sugar compounds with poor quality guarantee period and the like.

Drawings

FIG. 1 is a nuclear magnetic characterization map of compound a1 of example 1 of the present invention.

FIG. 2 is a nuclear magnetic characterization map of compound b1 of example 1 of the present invention.

FIG. 3 is a nuclear magnetic characterization map of compound c1 of example 1 of the present invention.

FIG. 4 is a nuclear magnetic characterization map of compound d1 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.

Example 1

2, 4-dithio-2 ', 3' -O-di-tert-butyldisilyl deoxythymidine with the structural formula of d₁As shown in the drawings, the above-described,

s1. Compound a₁The synthesis of (2): deoxythymidine (3g) and imidazole (2.52g) were dissolved in dichloromethane (20ml) under nitrogen and stirred for 30 minutes in an ice-water bath. After 30 minutes, t-butyldimethylsilyl chloride (TBSCl) (4.65g) was added to the reaction system, and the mixture was stirred at room temperature for 1 hour. After the TLC detection reaction, the reaction mixture was quenched with water and extracted with dichloromethane. The organic phases were combined, washed with saturated NaCl and anhydrous NaSO₄Drying, filtering, and vacuum evaporating to remove solvent to obtain compound a₁As a white solid, 5.8g, yield 99%, the next step S2 was carried out without purification.¹H NMR(CDCl₃,500MHz):8.11(s,1H),7.48(s,1H),6.34(t,J＝6.7Hz,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. Compound b₁The synthesis of (2): 1,2, 4-triazole (10.22g) was dissolved in anhydrous acetonitrile (1)20ml), phosphorus oxychloride (3.192ml) and triethylamine (24ml) were added slowly with stirring in an ice-water bath. After 1 hour of reaction, compound a1 white solid (5g) prepared in S1 above was charged 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 vacuum evaporating to remove solvent to obtain compound b₁As a pale yellow solid, 5.16g, yield 99%, and was directly subjected to the next step S3 without purification.¹H NMR(CDCl₃,500MHz):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. Compound c₁The synthesis of (2): compound b₁(5g) Was dissolved in anhydrous acetonitrile (191ml), and thioacetic acid (9.6ml) was added thereto, followed by 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, distilling under reduced pressure to remove solvent to obtain yellow solid, separating and purifying with silica gel column to obtain compound c₁3.74g, yield 80%.¹H NMR(CDCl₃,500MHz):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 a compound 4: compound c₁(2g) Dissolved in anhydrous toluene (17ml), and Lawesson's Reagent (3.32g) was added thereto, followed by stirring at 80 ℃ overnight. Separating and purifying by silica gel column to obtain compound d₁As a yellow solid, 1.13g, 55% yield.¹H NMR(CDCl₃,500MHz):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-butyldisilyldioxouridine; the structural formula is shown as the general formula d₂As shown in the drawings, the above-described,

s1. Compound a₂The synthesis of (2): deoxyuridine (5g) and imidazole (4.49g) were dissolved in dichloromethane (34ml) under nitrogen protection and stirred for 30 minutes in an ice-water bath. After 30 minutes, tert-butyldimethylsilyl chloride (TBSCl) (8.3g) was added to the reaction system, and the mixture was stirred at room temperature for 1 hour. After the TLC detection reaction, the reaction mixture was quenched with water and extracted with dichloromethane. The organic phases were combined, washed with saturated NaCl and anhydrous NaSO₄Drying, filtering, and vacuum evaporating to remove solvent to obtain compound a₂As a white solid, 9.9g, yield 99%, the next step S2 was carried out without purification.¹H NMR(CDCl₃,500MHz):8.72(s,1H),7.95–7.87(m,1H),6.30(t,J＝6.1Hz,1H),5.69(d,J＝8.1Hz,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. Compound b₂The synthesis of (2): 1,2, 4-triazole (6.7g) was dissolved in anhydrous acetonitrile, and phosphorus oxychloride (2.1ml) and triethylamine (15.8ml) were slowly added with stirring in an ice-water bath. After 1 hour of reaction, the compound a prepared in S1 described above was charged₂White solid (3g), stirred at rt 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 vacuum evaporating to remove solvent to obtain compound b₂As a pale yellow solid, 3.3g, yield 99%, and was directly subjected to the next step S3 without purification.

S3. Compound c₂The synthesis of (2): compound b₂(3g) Dissolving in anhydrous acetonitrile, adding thioacetic acid (5.9ml, stirring overnight at room temperature, detecting by TLC, diluting the reaction solution with dichloromethane, and saturatingNaHCO₃Solution washing, saturated NaCl solution washing, anhydrous Na₂SO₄Drying, filtering, distilling under reduced pressure to remove solvent to obtain yellow solid, separating and purifying with silica gel column to obtain compound c₂2.17g, yield 78%.¹H NMR(CDCl₃,500MHz):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＝13.9Hz,12H)。

S4. Compound d₂The synthesis of (2): compound c₂(2g) Dissolved in anhydrous toluene (17ml), and Lawesson's Reagent (3.4g) was added thereto, followed by stirring at 80 ℃ overnight. Separating and purifying by silica gel column to obtain compound d₂As a yellow solid, 1.027g, 50% yield.

Example 3

5-F-2, 4-dithio-2 ', 3' -O-di-tert-butyldisilyldisiloxyuridine; the structural formula is shown as the general formula d₃As shown in the drawings, the above-described,

s1. Compound a₃The synthesis of (2): deoxythymidine (5g) and imidazole (4.15g) were dissolved in dichloromethane (34ml) under nitrogen and stirred for 30 minutes in an ice-water bath. After 30 minutes, t-butyldimethylsilyl chloride (TBSCl) (7.65g) was added to the reaction system, and the mixture was stirred at room temperature for 1 hour. After the TLC detection reaction, the reaction mixture was quenched with water and extracted with dichloromethane. The organic phases were combined, washed with saturated NaCl and anhydrous NaSO₄Drying, filtering, and vacuum evaporating to remove solvent to obtain compound a₃As a white solid, 9.54g, yield 99%, the next step S2 was carried out without purification.¹H NMR(CDCl₃,500MHz):8.62(s,1H),8.07(d,J＝6.2Hz,1H),6.30(t,J＝6.0Hz,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. Compound b₃The synthesis of (2): 1,2, 4-triazole (6.44g) was dissolved in anhydrous acetonitrile (41.05ml), and phosphorus oxychloride (153.33ml) and triethylamine (101.19ml) were added slowly with stirring in an ice-water bath. After 1 hour of reaction, the compound a prepared in S1 described above was charged₃White solid (3g), stirred at rt 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 vacuum evaporating to remove solvent to obtain compound b₃As a pale yellow solid, 3.28g, yield 99%, and was directly subjected to the next step S3 without purification.¹H NMR(CDCl3,500MHz):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. Compound c₃The synthesis of (2): compound b₃(3g) Was dissolved in anhydrous acetonitrile (115ml), and thioacetic acid (5.7ml) was added thereto, followed by 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, distilling under reduced pressure to remove solvent to obtain yellow solid, separating and purifying with silica gel column to obtain compound c₃2.26g, yield 81%.¹H NMR(CDCl₃,500MHz):9.50(s,1H),8.05(d,J＝3.9Hz,1H),6.23(d,J＝5.4Hz,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. Compound d₃The synthesis of (2): compound c₃(2g) Dissolved in anhydrous toluene (16ml), and Lawesson's Reagent (3.23g) was added thereto, followed by stirring at 80 ℃ overnight. Separating and purifying by silica gel column to obtain compound d₃As a yellow solid, 1.054g, 52% yield.¹H NMR(CDCl₃,500MHz):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 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 (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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