CN112239484A - Synthesis method of 5-halo-4-thio-2 ', 3' -O-di-tert-butyldimethylsilyl nucleoside compound - Google Patents
Synthesis method of 5-halo-4-thio-2 ', 3' -O-di-tert-butyldimethylsilyl nucleoside compound Download PDFInfo
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Abstract
The invention belongs to the technical field of chemical synthesis, and relates to a method for synthesizing a 5-halogenated-4-sulfur-2 ', 3' -O-di-tert-butyldimethylsilyl nucleoside compound. The invention provides a method for preparing 5-halogenated deoxyuridine by using NaHS as a vulcanizing agent and adding sodium hydroxide in an amount of acetone: carrying out chemical reaction in a solution of water (V: V-3: 1) to finally obtain a compound c; the reaction process has the advantages of extremely little taste, rapid reaction (usually completed within 30 minutes), high yield and simple post-treatment, and is a high-efficiency synthesis method of a novel compound 5-halo-4-thio-2 ', 3' -O-di-tert-butyldisilyl nucleoside compound.
Description
Technical Field
The invention belongs to the technical field of chemical synthesis, and relates to a high-efficiency synthesis method of a 5-halo-4-thio-2 ', 3' -O-di-tert-butyldimethylsilyl nucleoside compound.
Background
In 1988, Elion and Hitchings discovered "important principles of drug therapy" to gain Nobel's Physiology or medical reward, which prompted The development of a series of novel nucleic acid derivatives (The Nobel Prize in Physiology or Medicine 1988-Press Release. Nobel Media AB [ EB/OL ]. http:// www.nobelprize.org/Nobel _ prizes/Medicine/laureaates/1988/Press. html.), wherein The 6-thioguanine (6-thioguanine,6-tGua), 6-mercaptopurine (6-mercaptopropyine, 6-MP) and azathiopurine (azathiopurine) nucleic acid derivatives developed by them exhibited excellent chemotherapeutic effects in The treatment of leukemia and The inhibition of transplant organ rejection (ion G. put disease to Medicine [ J9, 4947, 19841.: 244). Compared with natural nucleoside, the sulfurized natural nucleoside compound has unique property in the aspect of biological activity, and researches show that the absorbance of the nucleoside compound containing thiocarbonyl 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 (Huosheng, Lidebpeng, Wangjian, and the like, the molecular science reports 2013, 29(5): 392-396.), so that DNA molecules are sensitive to long-wave ultraviolet rays (UVA) or near-ultraviolet rays. Among them, 4-thio-deoxynucleoside analogs are very sensitive to ultraviolet rays and can be used as potential antitumor drugs, especially for treating skin cancer after being combined with near ultraviolet light (UVA) (Pridgon SW, Heer R, Taylor GABr. J. cancer 2011,104,1869.).
Based on these unique biological properties of thio nucleosides, scientists' interest in the synthesis of novel thio nucleoside compounds has been stimulated.
No report is made on the synthesis of a novel compound, 5-halo-4-thio-2 ', 3' -O-di-tert-butyldimethylsilyl nucleoside. In the synthesis of a novel compound, 5-halo-4-thio-2 ', 3 ' -O-di-tert-butyldimethylsilyl nucleoside, conventionally used sulfurization methods such as thionation using Lawson's reagent, thioacetic acid sulfurization, and phosphosulfide sulfurization have been attempted. Although three commonly used sulfuration means are all the generation of a new compound, namely 5-halogeno-4-thio-2 ', 3' -O-di-tert-butyldisilyl nucleoside compound, the reaction process has certain defects. Wherein, 1) the Lawson reagent sulfurization method has the disadvantages of over-high reaction temperature (about 90 ℃), difficult post-treatment and difficult column chromatography to obtain a pure product; 2) thioacetic acid vulcanization has the disadvantages of excessively long reaction time (usually overnight), extremely bad smell of thioacetic acid, complicated post-treatment, and separation of unpleasant by-products, especially in column chromatography. In addition, when thioacetic acid is used as a vulcanizing agent to synthesize a novel compound, namely 5-halo-4-thio-2 ', 3' -O-di-tert-butyldimethylsilyl nucleoside compound, the yield is found to be low; 3) the phosphorus pentasulfide vulcanization method has the defects of overhigh reaction temperature and the like.
Disclosure of Invention
In order to overcome the defects of the prior art, the invention provides a high-efficiency synthesis method of a 5-halogenated-4-sulfur-2 ', 3' -O-di-tert-butyldimethylsilyl nucleoside compound. The synthesis method has the advantages of mild conditions, high reaction efficiency and simple post-treatment.
The above purpose of the invention is realized by the following technical scheme:
5-halo-4-thioxo-2 ', 3' -O-di-tert-butyldimethylsilyl nucleoside compounds; has the general formula (c):
wherein, X is F, Cl, Br and I.
The specific structural formula of the 5-halo-4-thio-2 ', 3' -O-di-tert-butyldimethylsilyl nucleoside compound is as follows:
wherein A is 5-fluoro-4-thio-2 ', 3' -O-di-tert-butyldisilyldioxysuridine, B is 5-chloro-4-thio-2 ', 3' -O-di-tert-butyldisilyldioxysuridine, C is 5-bromo-4-thio-2 ', 3' -O-di-tert-butyldisilyldioxysuridine, and D is 5-iodo-4-thio-2 ', 3' -O-di-tert-butyldisilyldioxysyldeoxyuridine.
A high-efficiency synthesis method of 5-halogeno-4-thio-2 ', 3' -O-di-tert-butyldimethylsilyl nucleoside compound; 5-halogenated deoxyuridine is used as a raw material, NaHS is used as a vulcanizing agent, and the reaction conditions are as follows: a chemical reaction in a solution of water (V: V ═ 3:1) to finally obtain a compound c represented by general formula (c);
wherein, X is F, Cl, Br and I.
Further, the efficient synthesis method of the 5-halo-4-thio-2 ', 3' -O-di-tert-butyldisilyl nucleoside compound comprises the following steps: under the protection of nitrogen, reacting a 5-halogenated 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); dissolving the compound a and 1,2, 4-triazole in anhydrous acetonitrile solvent to react to obtain a light yellow solid compound b shown in a general formula (b); final compound b with NaHS in acetone: reaction in a solution of water (V: V ═ 3:1) gave compound c represented by general formula (c) as a yellow solid.
Further, the efficient synthesis method of the 5-halo-4-thio-2 ', 3' -O-di-tert-butyldisilyl nucleoside 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, 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, 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: 1 equivalent of compound b is dissolved in acetone: adding 2 equivalents of NaHS into a solution of water (V: V ═ 3:1), stirring at room temperature for about 30 minutes, detecting by TLC to finish the reaction, adding water for dilution after the reaction is finished, extracting by dichloromethane, washing by using a saturated NaCl solution until the reaction solution is washed to be neutral, and adding anhydrous Na2SO4Drying, filtering, and evaporating under reduced pressure to remove solvent to obtainThe more pure compound c was obtained by rapid purification by column chromatography than the pure yellow solid compound c.
Compared with the prior art, the invention has the beneficial effects that:
the invention provides an efficient synthesis method for preparing the 5-halogeno-4-thio-2 ', 3' -O-di-tert-butyldimethylsilyl nucleoside compound, and the 5-halogeno-4-thio-2 ', 3' -O-di-tert-butyldimethylsilyl nucleoside compound is synthesized for the first time. In the synthesis from compound a-compound c, NaHS was used as the sulfurizing agent, acetone: water (V: V ═ 3:1) is used as a reaction solvent, NaHS is dissociated into HS-ions in a mixed solvent consisting of acetone and water, and the HS-is used as a nucleophilic reagent to attack a triazole group on the carbon at the 4-position of a pyrimidine ring of a compound b, so that the novel compound 5-halo-4-sulfur-2 ', 3' -O-di-tert-butyldisilyl nucleoside compound is efficiently and quickly synthesized. The synthetic method utilizes the solubility characteristics that NaHS and a reaction solvent are easily soluble in water and a reaction final product is hardly soluble in water and easily soluble in dichloromethane in the post-treatment process, and simplifies the purification step of post-treatment column passing. In addition, the common sulfuration reagents in the prior art, namely Lawson reagent and thioacetic acid, are avoided in the reaction process. When the Lawson reagent is used as a vulcanizing reagent, the reaction condition is harsh, the temperature is usually about 90 ℃, the post-treatment is complex, a large amount of black byproducts are generated in the product separation process, and the reaction completion time is generally 3-4 hours. However, when thioacetic acid is used as the sulfurizing agent, although the reaction temperature is room temperature, thioacetic acid is extremely smelly, the yield is low, the post-treatment is difficult, and the reaction time is usually overnight. The invention provides a high-efficiency synthesis method of a new compound 5-halo-4-thio-2 ', 3' -O-di-tert-butyldisilyl nucleoside compound, which is carried out at room temperature (26-30 ℃), has little taste in the reaction process, is quick in reaction (usually completed within 30 minutes), has high yield and is simple in post-treatment.
Drawings
FIG. 1 shows Compound a of example 1 of the present invention1The nuclear magnetism characterization map of (1).
FIG. 2 shows Compound b of example 1 of the present invention1The nuclear magnetism characterization map of (1).
FIG. 3 shows Compound c of example 1 of the present invention1The 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
5-fluoro-4-thio-2 ', 3' -O-di-tert-butyldisilyldimethoxyuridine, the structural formula of which is shown as the general formula (c)1) As shown in the drawings, the above-described,
s1. Compound a1The 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 a1As a white solid, 9.54g, yield 99%, the next step S2 was carried out without purification.1H NMR(CDCl3,500MHz)δ: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 b1The 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 charged1White solid (3g), stirred at rt overnight. After TLC detection, the reaction solution was filtered, the organic phase was diluted with dichloromethane and saturated NaHCO3Solutions ofWashing with saturated NaCl solution and anhydrous Na2SO4Drying, filtering, and vacuum evaporating to remove solvent to obtain compound b1As a pale yellow solid, 3.28g, yield 99%, and was directly subjected to the next step S3 without purification.1H 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. Compound c1The synthesis of (2): compound b1(300mg) was dissolved in 1.15ml of acetone: to a solution of water (V: V ═ 3:1), 64.5mg of NaHS was added after sufficient dissolution, the reaction solution changed from the initially turbid solution to a clear, light yellow solution and finally to a dark brown, transparent solution, and after about 30 minutes the reaction was detected by TLC (PE: EA ═ 3:1) and found to be complete. Diluting with water to obtain a large amount of yellow solid (as impurity), extracting with dichloromethane, washing with saturated NaCl, and removing anhydrous Na2SO4Drying, and evaporating the solvent under reduced pressure to obtain a yellow oily solid c1Solidify overnight into yellow syrup, 251.9mg, 90% yield.1H NMR(CDCl3,500MHz)δ: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)。
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 (3)
1. A 5-halo-4-thio-2 ', 3' -O-di-tert-butyldisilyl nucleoside compound; it is characterized in that the utility model is characterized in that,
has the general formula (c):
wherein, X is F, Cl, Br and I.
2. The process for efficiently synthesizing a 5-halo-4-thio-2 ', 3' -O-di-tert-butyldimethylsilyl nucleoside compound according to claim 1, wherein 5-halodeoxyuridine is used as the starting material, NaHS is used as a vulcanizing agent, and the ratio of the starting material to the starting material in acetone: a chemical reaction in a solution of water (V: V ═ 3:1) to finally obtain a compound c represented by general formula (c);
wherein, X is F, Cl, Br and I;
the synthesis steps are as follows: under the protection of nitrogen, reacting the 5-halogenated 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); dissolving the compound a and 1,2, 4-triazole in anhydrous acetonitrile solvent to react to obtain a light yellow solid b shown in a general formula (b); compound b with NaHS in acetone: reacting in a solution with the volume ratio of water being 3:1 to obtain a yellow solid compound c shown as a general formula (c).
3. The efficient synthesis method of 5-halo-4-thio-2 ', 3' -O-di-tert-butyldimethylsilyl nucleoside compound as claimed in claim 2, characterized by comprising 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; 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 vacuum evaporating to remove solvent to obtain compoundThe material a, which is a white solid, was 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: 1 equivalent of compound b is dissolved in acetone: adding 2 equivalents of NaHS into a solution with the water volume ratio of 3:1, stirring at room temperature for about 30 minutes, detecting by TLC to finish the reaction, adding water for dilution after the reaction is finished, extracting by dichloromethane, washing by using a saturated NaCl solution until the reaction solution is washed to be neutral, and adding anhydrous Na2SO4Drying, filtering, and evaporating the solvent under reduced pressure to obtain a pure yellow solid compound c, and further purifying the compound c by column chromatography.
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