CN112175032B - Rapid synthesis method of 5-substituted-4-sulfur-2 ',3' -O-di-tert-butyldisilyl deoxynucleoside compound - Google Patents
Rapid synthesis method of 5-substituted-4-sulfur-2 ',3' -O-di-tert-butyldisilyl deoxynucleoside compound Download PDFInfo
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Abstract
The invention belongs to the technical field of chemical synthesis, and discloses a method for quickly synthesizing a 5-substituted-4-sulfur-2 ',3' -O-di-tert-butyldimethylsilyl deoxynucleoside compound. Under the protection of nitrogen, 5-substituted deoxynucleoside is compoundedReacting the product with tert-butyldimethylsilyl chloride, and performing post-treatment after the reaction is finished to obtain a compound a; compound a in NaHCO 3 Under catalysis with P 2 S 5 And carrying out chemical reaction in diethanol dimethyl ether to finally obtain a compound b. The synthesis method has the advantages of short reaction time, single product, high reaction yield, few byproducts, simple post-treatment and the like, avoids using a pyridine solvent with high toxicity and malodor, avoids using a 1, 4-dioxane solvent with high boiling point, avoids using a Lawson reagent which is easy to deteriorate and has a large number of reaction byproducts, and simplifies the post-treatment column passing process.
Description
Technical Field
The invention belongs to the technical field of chemical synthesis, and relates to a method for quickly synthesizing a 5-substituted-4-sulfur-2 ',3' -O-di-tert-butyldisilyl deoxynucleoside compound.
Background
Thiopyrimidine nucleosides are promising photosensitizers that act synergistically with UVA to selectively kill faster proliferating cancer cells (jiang, robo, xu yan, et al. Study of near uv-light assisted 4-thiodeoxythymidine anticancer effects [ J ] chemical evolution, 2016,28 (8): 1224-1237 ]. Thiopyrimidine nucleosides are structurally different from natural nucleosides in that they are obtained by sulfurizing the oxygen atom at the 4-position of a natural pyrimidine nucleoside and are significantly different from natural nucleosides in biological properties. Compared with natural nucleotide, 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, 583-586.), and other researches show that the absorbance of nucleoside compound containing thiocarbonyl group is increased after 4-carbonyl oxygen on pyrimidine base is replaced by sulfur, the maximum absorption peak is red shifted, and the nucleoside compound is extremely sensitive to light (Hodgkin, liDepeng, wangjian, et al. Molecular science reports, 2013, 29 (5): 392-396), so that DNA molecule is sensitive to long wave ultraviolet ray (UVA) or near ultraviolet ray.
Research shows that the 4-thiodeoxynucleoside analogue is sensitive to ultraviolet rays and can be used as a potential anti-tumor medicament, in particular to be combined with near ultraviolet light (UVA) to be used for treating skin cancer (Pridgon SW, heer R, taylor GABr. J.cancer 2011,104, 1869.). Brady-dazzling 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 to natural thymidine and cancer cells rapidly replicate and grow in a human body, 4-thiothymidine analogues are incorporated into cancerous tissues, and DNA of the cancer cells is selectively damaged through the synergistic effect of UVA with a specific wavelength, so that the purpose of selectively killing the cancer cells is achieved (Jiang leather, rongfen, xudazao, and the like, near ultraviolet light assists in the research of the anti-cancer effect of 4-thiodeoxythymidine [ J ] chemical development, 2016,28 (8): 1224-1237 ].
Based on the unique biological properties of 4-thiodeoxynucleoside analogs, a large number of syntheses of 4-thiodeoxynucleosides have been reported, but most have used lawson's reagent or phosphorus pentasulfide (P) 2 S 5 ) To synthesize 4-thiodeoxynucleoside analogs using Lawson's reagent or phosphorus pentasulfide (P) 2 S 5 ) In the reaction process of the sulfurized deoxynucleoside, the reaction time is too long, the used reaction solvent has a strong taste and a high boiling point, and the sulfurized deoxynucleoside is difficult to remove by means of reduced pressure evaporation. In addition, when the thionization reaction is carried out using the lawson reagent, a large amount of black by-products are produced, and the post-treatment is difficult, and it is also difficult to obtain a pure substance by column purification.
Disclosure of Invention
In order to overcome the defects of the prior art, the invention provides a 5-substituted-4-sulfur-2 ',3' -O-di-tert-butyldisilyl deoxynucleoside compound and a rapid synthesis method thereof. The synthesis method has the advantages of short reaction time (generally, the reaction is completed within 1 hour), high yield, no difficultly separated by-product and few by-products, only water washing is needed for post-treatment, dichloromethane is used for extraction, and reduced pressure evaporation is carried out to obtain the relatively pure 5-substituted-4-sulfur-2 ',3' -O-di-tert-butyldisilyl deoxynucleoside compound, and the relatively pure 5-substituted-4-sulfur-2 ',3' -O-di-tert-butyldisilyl deoxynucleoside compound can be rapidly separated by column chromatography.
The above purpose of the invention is realized by the following technical scheme:
a 5-substituted-4-thio-2 ',3' -O-di-tert-butyldisilyl deoxynucleoside compound; having a structure of formula (b):
wherein X = CH 3 、H、F、Cl、Br、I。
The specific structural formula of the 5-substituted-4-sulfur-2 ',3' -O-di-tert-butyldisilyl deoxynucleoside compound is as follows:
wherein A is 4-thio-2 ',3' -O-di-tert-butyldisilyl deoxythymidine, B is 4-thio-2 ',3' -O-di-tert-butyldisilyl deoxyuridine, C is 4-thio-5-fluoro-2 ',3' -O-di-tert-butyldisilyl deoxyuridine, D is 4-thio-5-chloro-2 ',3' -O-di-tert-butyldisilyl deoxyuridine, E is 4-thio-5-bromo-2 ',3' -O-di-tert-butyldisilyl deoxyuridine, and F is 4-thio-5-iodo-2 ',3' -O-di-tert-butyldisilyl deoxyuridine.
The rapid synthesis method of the 5-substituted-4-sulfur-2 ',3' -O-di-tert-butyldisilyl nucleoside compound; taking deoxynucleoside as raw material and P 2 S 5 As a sulfurizing agent, naHCO 3 Is used as a catalyst and undergoes chemical reaction in diethanol dimethyl ether to finally obtain a compound b shown as a general formula (b);
wherein, X = CH 3 、H、F、Cl、Br、I。
Further, the rapid synthesis method of the 5-substituted-4-thio-2 ',3' -O-di-tert-butyldisilyl deoxynucleoside 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 shown in a general formula (a); the compound a is then reacted with P dissolved in diethanol dimethyl ether solvent 2 S 5 And NaHCO 3 And reacting to obtain a yellow solid b.
Further, the method for rapidly synthesizing the 5-substituted-4-thio-2 ',3' -O-di-tert-butyldisilyl deoxynucleoside compound comprises the following specific 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, 2.5 equivalents of tert-butyldimethylsilyl chloride (TBSCl) were added to the reaction system and stirred 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, anhydrous NaSO 4 Drying, filtering, and evaporating the solvent under reduced pressure to obtain a compound a which is a white solid and is directly subjected to the next step S2 without purification;
s2, synthesis of a compound b: adding 1 equivalent of compound a into a solution of 2 equivalents of P 2 S 5 After being stirred uniformly, 4 equivalents of NaHCO are added into the diethanol dimethyl ether solution 3 The solid is added into the reaction system, and the reaction speed depends on CO 2 And (4) precipitating. The reaction was stirred further to 110 ℃ until the end of the TLC detection reaction. After the reaction is finished, the reaction solution is poured into cold water, yellow solid is separated out, the mixture is filtered and separated, and is washed by cold water, and the product is collected.
Compared with the prior art, the invention has the beneficial effects that:
the invention provides a rapid synthesis method for preparing the 5-substituted-4-sulfur-2 ',3' -O-di-tert-butyldimethylsilyl deoxynucleoside compound. From the synthesis of the compounds a-b, using P 2 S 5 As sulfurizing agent, in NaHCO 3 Under catalysis with P 2 S 5 Formation of NaSPS 2 Characteristic of salts, naSPS 2 Formation of SPS in reaction solution 2 -，SPS 2 -attack 4-carbonyl oxygen on pyrimidine ring of 5-substituted-4-sulfur-2 ',3' -O-di-tert-butyldisilyloxynucleoside compound as nucleophilic reagent, and then synthesize target compound 5-substituted-4-sulfur-2 ',3' -O-di-tert-butyldisilyloxynucleoside compound. The invention realizes the rapid vulcanization of the 4-oxygen atom of the 5-substituted-4-sulfur-2 ',3' -O-di-tert-butyldisilyl deoxynucleoside compound, which is different from the common vulcanization method, namely a direct vulcanization method, and the prior art commonly uses a Lawson reagent and phosphorus pentasulfideOr thioacetic acid, etc. directly sulfurize the oxygen atom at position 4 of pyrimidine ring of pyrimidine nucleoside compound, and the present invention utilizes SPS 2 The method has the advantages that ions are used as a nucleophilic reagent to quickly sulfide 4-oxygen atoms on a pyrimidine ring of a pyrimidine nucleoside compound, the reaction has short reaction time (generally completed within 1 hour), the product is single, the reaction yield is high, and the byproducts are few, the post-treatment process of the high-boiling point diethanol dimethyl ether solvent is simplified by utilizing the characteristic that diethanol dimethyl ether and inorganic salt are easily soluble in water, and a 5-substituted-4-sulfur-2 ',3' -O-di-tert-butyldimethylsilyl deoxynucleoside compound is difficultly soluble in water and easily soluble in dichloromethane, so that a high-boiling point diethanol dimethyl ether solvent post-treatment process is avoided.
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FIG. 1 shows Compound a of example 1 of the present invention 1 The nuclear magnetism characterization map of (1).
FIG. 2 shows Compound b of example 1 of the present invention 1 The nuclear magnetism characterization map of (1).
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
4-sulfur-2 ',3' -O-di-tert-butyldisilyl deoxythymidine with the structural formula of (b) 1 ) As shown in the drawings, the above-described,
s1. Compound a 1 The synthesis of (2): deoxythymidine (3 g) and imidazole (2.52 g) were dissolved in dichloromethane (20 ml) under nitrogen, and stirred for 30 minutes in an ice-water bath (0 ℃). After 30 minutes, t-butyldimethylsilyl chloride (TBSCl) (4.6) was added to the reaction system5g) Stirred at room temperature for 1 hour (25 ℃ -30 ℃). 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, anhydrous NaSO 4 Drying, filtering, and vacuum evaporating to remove solvent to obtain compound a 1 It was a white solid, 5.8g, 99% yield, and was carried on 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＝6.7Hz,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 b 1 The synthesis of (2): 5.47g of P 2 S 5 After sufficiently dissolving the compound in 24.64ml of diethanol dimethyl ether, the compound a prepared as described above was added 1 (5.8 g) was put into the reaction solution and sufficiently dissolved, and solid NaHCO was added 3 (4.14 g), naHCO was added 3 Then, the gas is rapidly generated, and the reaction speed is determined by CO 2 The reaction solution was further stirred to 110 ℃ until the starting material a was not detected by TLC 1 Until now. After the reaction is finished, adding cold water into the reaction liquid to separate out a large amount of yellow solid, and filtering to obtain a compound b 1 5.52g, yield 92%, the more pure compound was isolated rapidly by column chromatography (TLC: petroleum ether: ethyl acetate (V: V) = 5. 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)。
Example 2
4-thio-2 ',3' -O-di-tert-butyldisilyl deoxyuridine, the structural formula of which is shown as the general formula (b) 2 ) As shown in the drawings, the above-described,
s1. Compound a 2 The synthesis of (2): deoxyuridine (5 g) and imidazole (4.49 g) were dissolved in dichloromethane (34 ml) under nitrogen protection, and stirred for 30 minutes in an ice-water bath (0 ℃ C.)A clock. After 30 minutes, t-butyldimethylsilyl chloride (TBSCl) (8.3 g) was added to the reaction system, and stirred at room temperature for 1 hour (25 ℃ C. -30 ℃ C.). 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 NaSO 4 Drying, filtering, and evaporating the solvent under reduced pressure to obtain the compound a 2 It was a white solid, 9.9g, 99% yield, and was directly subjected 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＝6.1Hz,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 b 2 The synthesis of (2): 4.87g of P 2 S 5 After sufficiently dissolving in 21.89ml of diethanol dimethyl ether, compound a prepared as described above was added 2 (5g) Adding into the reaction solution, dissolving completely, adding solid NaHCO 3 (3.68 g), naHCO was added 3 Then, the gas is rapidly generated, and the reaction speed is determined by CO 2 The reaction solution was further stirred to 110 ℃ until the starting material a was not detected by TLC 2 Until now. After the reaction is finished, adding cold water into the reaction liquid to separate out a large amount of yellow solid, and filtering to obtain a compound b 2 4.65g, yield 90%, the more pure compound was isolated rapidly by column chromatography (TLC: petroleum ether: ethyl acetate (V: V) = 5. 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＝13.9Hz,12H)。
The embodiments described above are merely preferred embodiments of the invention, rather than all possible embodiments of the invention. Any obvious modifications thereof, which would occur to one skilled in the art without departing from the principles and spirit of the invention, are to be considered as included within the scope of the following claims.
Claims (2)
1. A synthetic method of a 5-substituted-4-sulfur-2 ',3' -O-di-tert-butyldisilyl deoxynucleoside compound is characterized in that deoxynucleoside is used as a raw material, and P is used as 2 S 5 As a sulfurizing agent, naHCO 3 As a catalyst, carrying out chemical reaction in diethanol dimethyl ether to finally obtain a compound b shown as a general formula (b);
wherein X = CH 3 、H、F、Cl、Br、I；
The synthesis steps are as follows: under the protection of nitrogen, reacting a 5-substituted deoxynucleoside compound with tert-butyldimethylsilyl chloride, and after the reaction is finished, carrying out post-treatment to obtain a compound a shown in a general formula (a); compound a in NaHCO 3 Under catalysis with P 2 S 5 And carrying out chemical reaction in diethanol dimethyl ether to finally obtain a compound b.
2. The method for synthesizing a 5-substituted-4-thio-2 ',3' -O-di-tert-butyldimethylsilyl deoxynucleoside compound according to claim 1, wherein the synthesizing step comprises:
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 at 0 ℃ 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 NaSO 4 Drying, filtering, and distilling under reduced pressure to remove the solvent to obtain a compound a as a white solid, wherein the compound a is directly subjected to the next step S2 without purification;
s2, synthesis of a compound b: adding 1 equivalent of compound a into a solution of 2 equivalents of P 2 S 5 After being uniformly stirred, 4 equivalents of NaHCO are added into the solution of the diethanol dimethyl ether 3 The solid is added into the reaction system, and the reaction speed depends on CO 2 Precipitation of (2); will be provided withThe reaction solution is continuously stirred to 110 ℃ until the TLC detection reaction is finished; after the reaction is finished, the reaction solution is poured into cold water, yellow solid is separated out, the mixture is filtered and separated, and is washed by cold water, and the product is collected.
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