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CN114230623A - 2-thio-N-hydroxyl cytosine ribonucleoside phosphate and antiviral drug application thereof - Google Patents

2-thio-N-hydroxyl cytosine ribonucleoside phosphate and antiviral drug application thereof Download PDF

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CN114230623A
CN114230623A CN202210168933.6A CN202210168933A CN114230623A CN 114230623 A CN114230623 A CN 114230623A CN 202210168933 A CN202210168933 A CN 202210168933A CN 114230623 A CN114230623 A CN 114230623A
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hydroxycytosine
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鲍甫义
袁仁涛
王小明
周伟
柳惠
陈锋
刘志东
杨丽
彭盛
叶小新
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Guoqing Biomedical Shanghai Co ltd
Guoqing Technology Zhuhai Hengqin Co ltd
Nanjing Yiyuan Biomedical Research Institute Co ltd
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Guoqing Technology Zhuhai Hengqin Co ltd
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Abstract

The invention discloses 2-sulfo-N-hydroxycytosine ribonucleoside phosphate, which has the structural formula:
Figure 100004_DEST_PATH_IMAGE002
the compound disclosed by the invention has a good inhibition effect on HBV DNA secreted by HepG2.2.15 cells, has anti-hepatitis virus activity, provides a good choice for treating viral hepatitis, and has an important significance for developing more ideal medicines for treating hepatitis B.

Description

2-thio-N-hydroxyl cytosine ribonucleoside phosphate and antiviral drug application thereof
Technical Field
The invention belongs to the technical field of pharmaceutical chemistry, and particularly relates to 2-thio-N-hydroxycytosine ribonucleoside phosphate and an antiviral drug application thereof.
Background
Persistent infection with HBV is a major cause of hepatitis b chronicity and can lead to the development of disease conditions, exacerbation, and HBV-associated hepatocellular carcinoma. In addition to vaccination against hepatitis B, the currently approved clinical anti-HBV drugs include two main classes, interferon and nucleoside drugs, and some marketed immunomodulators and Chinese medicines can also be used as adjuvant methods for hepatitis B treatment. The interferon is a kind of cell factor capable of regulating body's immunity and has antiviral and antitumor effect. In the aspect of resisting hepatitis B virus, interferon mainly acts on an interferon receptor of a cell, so that a large number of protein kinases are generated, and then the inhibition effect on the virus is realized through a series of biochemical processes.
In 1995, Dienstag et al used lamivudine for the first time to treat chronic hepatitis B, and started the research trend of nucleoside drugs for treating hepatitis B. (Dienstag J L, Perrillo R P, Schiff E R, et al, A preliminary three of lamivudine for viral hepatitis B infection [ J ]. N Engl J Med, 1995, 333 (25): 1657.) in addition to lamivudine, telbivudine, entecavir, adefovir, tenofovir, etc. are currently commonly used anti-hepatitis B virus drugs that competitively bind to viral DNA during viral replication and reduce viral DNA replication by inhibiting reverse transcriptase activity. Nucleoside drugs do have anti-HBV infection effects, but the greatest problems are the emergence of resistant viral strains, viral tolerance and rebound after cessation of treatment. Since the survival time of viral DNA in infected hepatocytes is relatively long, and drugs cause variation of HBV polymerase to develop drug resistance, etc., complete elimination of HBV virus becomes problematic. To solve these problems, more effective anti-hepatitis B virus drugs are developed as soon as possible, and thus it is urgent to treat hepatitis B.
The information disclosed in this background section is only for enhancement of understanding of the general background of the invention and should not be taken as an acknowledgement or any form of suggestion that this information forms the prior art already known to a person skilled in the art.
Disclosure of Invention
The present invention aims to provide a 2-thio-N-hydroxycytosine ribonucleoside phosphate compound, thereby overcoming the above-mentioned drawbacks of the prior art and providing a new technical alternative.
To achieve the above object, the present invention provides a 2-thio-N-hydroxycytosine ribonucleoside phosphate compound characterized in that: the molecular formula is as follows: c24H35N4O9PS, molecular weight 586.603, structural formula:
Figure 205532DEST_PATH_IMAGE001
。
preferably, in the above technical scheme, the 2-thio-N-hydroxycytosine ribonucleoside phosphate is a white solid with a solubility: is easily soluble in common organic solvents such as methanol, ethanol, ethyl acetate, dichloromethane, chloroform, carbon tetrachloride, dimethyl sulfoxide, N-dimethylformamide, acetone, tetrahydrofuran, etc., and is hardly soluble in water.
The application also claims the use of 2-thio-N-hydroxycytosine ribonucleoside phosphate in the manufacture of a medicament for inhibiting hepatitis b virus, according to the preceding description.
Preferably, in the above technical scheme, the inhibition rate of 2-thio-N-hydroxycytosine ribonucleoside phosphate on HBV DNA secretion of HepG2.2.15 cells is not less than 41.36%.
Preferably, in the above technical scheme, the medicament is prepared into pharmaceutically acceptable salts and pharmaceutically acceptable any one dosage form, including tablets, capsules, granules, pills, oral liquid, injections, or other dosage forms suitable for preparation.
The synthesis method of 2-sulfo-N-hydroxycytosine ribonucleoside phosphate is characterized by comprising the following steps: the method comprises the following steps:
S1，
Figure 122673DEST_PATH_IMAGE002
mixing the compound A, hexamethyldisilazane, trimethylchlorosilane and ammonium sulfate, stirring under the protection of inert gas to react until the solution becomes clear, concentrating the reaction solution, draining, adding 1, 2-dichloroethane, the compound B and stannic chloride, and stirring at room temperature to react; after the reaction is finished, dropwise adding a saturated sodium bicarbonate solution for quenching, extracting by dichloromethane, washing an organic phase by saturated saline solution, drying by anhydrous sodium sulfate, filtering to remove the anhydrous sodium sulfate, and concentrating the filtrate to obtain a compound C;
S2，
Figure 590825DEST_PATH_IMAGE003
dissolving the compound C in methanol, adding lithium hydroxide, stirring for reaction, adjusting the pH of the solution to be 7-8 after the reaction is finished, concentrating the reaction solution until solid is separated out, filtering, washing a filter cake, and drying the filter cake to obtain a compound D;
S3，
Figure 986035DEST_PATH_IMAGE004
mixing the compound D in acetone, adding 2, 2-dimethoxypropane, p-toluenesulfonic acid monohydrate and N, N-dimethylformamide, stirring for reaction, adding a sodium bicarbonate solid after the reaction is finished, stirring, filtering, washing filter residues with dichloromethane, concentrating the filtrate, and performing column chromatography to obtain a compound E;
S4，
Figure 800407DEST_PATH_IMAGE005
dissolving the compound E and the compound F in acetonitrile, adding magnesium chloride, stirring at 50 ℃ for 10 min, then adding diisopropylethylamine, and stirring at 50 ℃ overnight; after the reaction is finished, cooling to room temperature, adding dichloromethane for dilution, washing the reaction solution with a citric acid solution, washing the organic phase with saturated ammonium chloride, then washing with saturated sodium bicarbonate and saturated salt water, drying the organic phase with anhydrous sodium sulfate, filtering to remove the anhydrous sodium sulfate, concentrating the filtrate, and separating the crude product by column chromatography to obtain a compound G;
S5，
Figure 622869DEST_PATH_IMAGE006
dissolving compound G and 4-dimethylaminopyridine in dichloromethane 0oC, sequentially adding N, N-diisopropylethylamine and 2,4, 6-triisopropylbenzenesulfonyl chloride, stirring at room temperature for 1-2H, concentrating the reaction solution, and performing column chromatography separation to obtain a product H;
S6，
Figure 827586DEST_PATH_IMAGE007
dissolving compound H in acetonitrile, 0oSequentially adding triethylamine and hydroxylamine hydrochloride at the temperature of C, stirring at room temperature for 2-12 h, concentrating the reaction solution, and performing column chromatography separation to obtain a compound I;
S7，
Figure 26486DEST_PATH_IMAGE008
dissolving the compound I in a formic acid aqueous solution, stirring overnight at room temperature, concentrating a reaction solution, and performing column chromatography separation to obtain a final product Q09.
Preferably, in the above technical solution, step S1 specifically includes: mixing the compound A, hexamethyldisilazane, trimethylchlorosilane and ammonium sulfate, and reacting the mixture N2The solution was allowed to settle by stirring at 126 ℃ for 18h under protection.
Preferably, in the above technical solution, step S6 specifically includes: dissolving compound H in acetonitrile, 0oAnd C, sequentially adding triethylamine and hydroxylamine hydrochloride, stirring at room temperature for 2-12 h, pouring the reaction solution into a saturated sodium bicarbonate solution, extracting with dichloromethane, washing an organic phase with saturated saline solution, drying with anhydrous sodium sulfate, filtering to remove the anhydrous sodium sulfate, concentrating the reaction solution, and performing column chromatography separation to obtain the compound I.
Preferably, in the above technical scheme, both steps S2 and S3 are room temperature reactions; the reactions of steps S5 and S6 are both in N2Under protection.
Preferably, in the above technical scheme, the compound C, the compound D, the compound E, the compound F, the compound G, the compound H and the compound I are all white solids.
Compared with the prior art, the invention has the following beneficial effects:
the invention discloses 2-sulfo-N-hydroxycytosine ribonucleoside phosphate and designs a synthetic method route thereof, wherein the route has simple steps and high product yield. The invention also verifies through experiments that the compound 2-sulfo-N-hydroxycytosine ribonucleoside phosphate disclosed by the invention has good inhibition effect on HBV DNA secreted by HepG2.2.15 cells, has anti-hepatitis virus activity and provides a good choice for treating viral hepatitis.
Drawings
FIG. 1 is a nuclear magnetic resonance bopomogram of Compound E;
FIG. 2 is a nuclear magnetic resonance bopomogram of Compound H;
FIG. 3 is a nuclear magnetic resonance bopom plot of Compound Q09.
Detailed Description
The following detailed description of specific embodiments of the invention is provided, but it should be understood that the scope of the invention is not limited to the specific embodiments.
Throughout the specification and claims, unless explicitly stated otherwise, the word "comprise", or variations such as "comprises" or "comprising", will be understood to imply the inclusion of a stated element or component but not the exclusion of any other element or component.
It will be appreciated by those skilled in the art that the 2-thio-N-hydroxycytosine ribonucleoside phosphate of the invention is a white solid, soluble: the compound is easily soluble in common organic solvents such as methanol, ethanol, ethyl acetate, dichloromethane, chloroform, carbon tetrachloride, dimethyl sulfoxide, N-dimethylformamide, acetone, tetrahydrofuran and the like, is hardly soluble in water, can be prepared into pharmaceutically acceptable salts according to a specific application mode, and can be prepared into pharmaceutically acceptable any dosage form including tablets, capsules, granules, pills, oral liquid, injection or other dosage forms suitable for preparation.
Example 1
The synthesis process of N-hydroxy 2-sulfo-N-hydroxyl cytosine ribonucleoside phosphate includes the following steps:
Figure 695365DEST_PATH_IMAGE009
compound A (10 g), hexamethyldisilazane (300 mL), trimethylchlorosilane (7.71 g), and ammonium sulfate (412 mg) were mixed, N2The reaction mixture was stirred at 126 ℃ for 18 hours under protection to clarify the solution, the reaction mixture was concentrated, then the reaction mixture was pumped to dryness with an oil pump, 1, 2-dichloroethane (200 mL) and compound B (27.6 g) were added to the reaction mixture, and finally tin tetrachloride (27.0 g) was added and stirred at room temperature for 1 hour. Saturated sodium bicarbonate solution was added dropwise to quench, dichloromethane was extracted, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered to remove anhydrous sodium sulfate, the filtrate was concentrated and pumped dry with an oil pump to give compound C (33.7 g, white solid) which was used in the next step without further purification.
Compound C (4 g) was dissolved in methanol (50 mL), lithium hydroxide (843 mg) was added at room temperature, stirred at room temperature for 30 min, hydrochloric acid solution (3N) was added dropwise, solution pH =7 was adjusted, concentrated until solids precipitated, filtered, the filter cake was washed with dichloromethane, the filter cake was pumped off by an oil pump to give compound D (1.71 g, white solid), which was used in the next step without further treatment.
Compound D (1.7 g) was mixed with acetone (30 mL), and the compound 2, 2-dimethoxypropane (3.4 g), p-toluenesulfonic acid monohydrate (1.3 g) and N, N-dimethylformamide (10 mL) were added at room temperature, stirred at room temperature for 2h, solid sodium bicarbonate (1.5 g) was added, stirred at room temperature for 1h, the insoluble matter was removed by filtration, the residue was washed with dichloromethane, and the filtrate was concentrated and column-chromatographed to give Compound E (1.5 g, white solid).
1H NMR (400 MHz, DMSO-d 6) δ 12.71 (s, 1H), 7.98 (d, 1H), 6.87 (d, 1H), 6.02 (d, 1H), 5.31 (t, 1H), 4.85 – 4.73 (m, 2H), 4.17 – 4.06 (m, 1H), 3.65 (qdd, 2H), 1.51 (s, 3H), 1.29 (s, 3H)。
Compound E (4.62 g) and compound F (20.78 g) were dissolved in acetonitrile (100 mL), diisopropylethylamine (4.97 g), 50 g was added oCAdding MgCl2 (1.46 g)， 50 oStir overnight at C. The reaction solution was diluted with dichloromethane, washed twice with citric acid (1M), once with saturated ammonium chloride solution, once with saturated sodium bicarbonate solution, and once with saturated brine. The organic phase was dried over anhydrous sodium sulfate, filtered to remove anhydrous sodium sulfate, the filtrate was concentrated, and separated by column chromatography to give compound G (3.53G, white solid).
Compound G (3.53G) was dissolved in dichloromethane (100 mL) with 4-dimethylaminopyridine (71 mg) at 0oAnd C, adding N, N-diisopropylethylamine (3.73 g) and 2,4, 6-triisopropylbenzenesulfonyl chloride (3.5 g) in sequence, stirring at room temperature for 1H, concentrating the reaction solution, and performing column chromatography to separate the reaction product to obtain a compound H (3.93 g, white solid).
1H NMR (400 MHz, DMSO-d 6) δ 12.77 (d, 1H), 7.66 (dd,1H), 7.38 (dd,2H), 7.26 – 7.13 (m, 3H), 6.96 (s, 2H), 6.91 (d,1H), 6.19 – 6.09 (m, 1H), 5.87 (dd,1H), 4.86 – 4.75 (m, 2H), 4.55 (hept,2H), 4.28 – 4.17 (m, 2H), 4.08 – 3.84 (m, 3H), 2.80 (p,1H), 1.54 – 1.39 (m, 3H), 1.36 – 1.20 (m, 10H), 1.20 – 1.09 (m, 13H), 1.10 (s, 6H), 0.83 (t,6H)。
Compound H (3.93 g) was dissolved in acetonitrile (200 mL), 0oTriethylamine (1.36 g) and hydroxylamine hydrochloride (0.93 g) were added successively under C, stirred at room temperature for 2h, the reaction solution was poured into a saturated sodium bicarbonate solution, extracted with dichloromethane, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered to remove anhydrous sodium sulfate, the filtrate was concentrated, and separated by column chromatography to give compound I (2.16 g, white solid).
Compound I (2.16 g) was dissolved in aqueous formic acid (100 mL, V/V = 80%), stirred at room temperature overnight, the reaction was concentrated, and isolated by column chromatography to give compound Q09 (1.27 g, white solid).
1H NMR (400 MHz, DMSO-d 6) δ 10.53 (s, 1H), 9.69 (d, J = 12.5 Hz, 1H), 7.38 (t, J = 7.9 Hz, 2H), 7.23 (s, 1H), 7.21 (s, 1H), 7.18 (t, J = 7.4 Hz, 1H), 6.90 (d, J = 8.3 Hz, 1H), 6.59 (d, J = 5.0 Hz, 1H), 6.21 – 6.05 (m, 1H), 5.80 (d, J = 8.2 Hz, 1H), 5.45 (d, J = 5.6 Hz, 1H), 5.28 (d, J = 5.0 Hz, 1H), 4.25 – 4.08 (m, 2H), 4.03 – 3.96 (m, 2H), 3.96 (d, J = 5.6 Hz, 1H), 3.96 – 3.89 (m, 2H), 3.92 – 3.82 (m, 1H), 1.46 (p, J = 6.3 Hz, 1H), 1.35 – 1.22 (m, 7H), 0.82 (t, J = 7.4 Hz, 6H)。
Example 2 in vitro anti-HBV Activity Studies
The prepared compound, positive control drugs of telbivudine and lamivudine are used as in vitro anti-HBV virus efficacy evaluation tests.
Telbivudine (shanghai taitake technologies, ltd.), lamivudine (shanghai taitake technologies, ltd.), hepg2.2.15 cells (provided by the antiviral drug research laboratory of the institute of pharmacy, university of fudan), Fetal Bovine Serum (FBS) (semer feishi biochemicals ltd.), DMEM medium (semer feishi biochemicals ltd.), carbon dioxide incubator (semer feishi biochemicals ltd.), fluorescent quantitative PCR (semer feishi biochemicals ltd.).
And (3) detecting the antiviral activity of the medicine: collecting HepG2.2.15 cell 1 bottle with good growth, digesting with pancreatin to obtain single cell suspension, counting with cell counting plate, adjusting cell density to 2 × 10 with DMEM medium containing 10% FBS serum5 one/mL, inoculated in culture plates (96 wells, 100uL per well). Placing in carbon dioxide incubator under 5% CO2，37oC incubate to 80% contact inhibition. Sucking the supernatant, adding culture solution containing test drug, adding culture solution containing positive control drugs of telbivudine and lamivudine with corresponding concentrations, and setting blank control hole for cell. 3 replicate wells were set for each concentration and cell blank. Placing in carbon dioxide incubator at 37oC culturing for 3d/6d/9d, sucking supernatant, centrifuging, and detecting the HBV-DNA content in the supernatant by a fluorescent quantitative PCR method, wherein the result is shown in Table 1.
TABLE 1
Figure DEST_PATH_IMAGE011
。
According to the results in the table 1, the compounds in the table have good inhibitory action on HBV DNA secretion of HepG2.2.15 cells, and the inhibitory rate of the compound Q09 is higher than that of positive control drugs of telbivudine and lamivudine, so the compound has better application prospect.
The foregoing descriptions of specific exemplary embodiments of the present invention have been presented for purposes of illustration and description. It is not intended to limit the invention to the precise form disclosed, and obviously many modifications and variations are possible in light of the above teaching. The exemplary embodiments were chosen and described in order to explain certain principles of the invention and its practical application to enable one skilled in the art to make and use various exemplary embodiments of the invention and various alternatives and modifications as are suited to the particular use contemplated. It is intended that the scope of the invention be defined by the claims and their equivalents.

Claims (10)

  1. A 2-thio-N-hydroxycytosine ribonucleoside phosphate characterized by: the molecular formula is as follows: c24H35N4O9PS, molecular weight 586.603, structural formula:
    Figure DEST_PATH_IMAGE002
    。
  2. 2. a 2-thio-N-hydroxycytosine ribonucleoside phosphate in accordance with claim 1, wherein: 2-thio-N-hydroxycytosine ribonucleoside phosphate is a white solid, solubility: is easily soluble in methanol, ethanol, ethyl acetate, dichloromethane, chloroform, carbon tetrachloride, dimethyl sulfoxide, N-dimethylformamide, acetone and tetrahydrofuran, and is hardly soluble in water.
  3. 3. Use of the 2-thio-N-hydroxycytosine ribonucleoside phosphate ester of claim 1 in the manufacture of a medicament for inhibiting hepatitis b virus.
  4. 4. The use of 2-thio-N-hydroxycytosine ribonucleoside phosphate in the preparation of a medicament for inhibiting hepatitis B virus according to claim 3, wherein the inhibition rate of 2-thio-N-hydroxycytosine ribonucleoside phosphate on HBV DNA secretion from HepG2.2.15 cells is not less than 41.36%.
  5. 5. The use of 2-thio-N-hydroxycytosine ribonucleoside phosphate in the manufacture of a medicament for inhibiting hepatitis b virus according to claim 3, wherein the 2-thio-N-hydroxycytosine ribonucleoside phosphate is manufactured as a pharmaceutically acceptable salt and in any pharmaceutically acceptable dosage form, including tablets, capsules, granules, pills, oral liquid, injections, or other dosage forms suitable for manufacture.
  6. A method for synthesizing 2-thio-N-hydroxycytosine ribonucleoside phosphate, which is characterized in that: the method comprises the following steps:
    S1，
    Figure DEST_PATH_IMAGE004
    mixing the compound A, hexamethyldisilazane, trimethylchlorosilane and ammonium sulfate, stirring under the protection of inert gas to react until the solution becomes clear, concentrating the reaction solution, draining, adding 1, 2-dichloroethane, the compound B and stannic chloride, and stirring at room temperature to react; after the reaction is finished, dropwise adding a saturated sodium bicarbonate solution for quenching, extracting by dichloromethane, washing an organic phase by saturated saline solution, drying by anhydrous sodium sulfate, filtering to remove the anhydrous sodium sulfate, and concentrating the filtrate to obtain a compound C;
    S2，
    Figure DEST_PATH_IMAGE006
    dissolving the compound C in methanol, adding lithium hydroxide, stirring for reaction, adjusting the pH of the solution to be 7-8 after the reaction is finished, concentrating the reaction solution until solid is separated out, filtering, washing a filter cake, and drying the filter cake to obtain a compound D;
    S3，
    Figure DEST_PATH_IMAGE008
    mixing the compound D in acetone, adding 2, 2-dimethoxypropane, p-toluenesulfonic acid monohydrate and N, N-dimethylformamide, stirring for reaction, adding a sodium bicarbonate solid after the reaction is finished, stirring, filtering, washing filter residues with dichloromethane, concentrating the filtrate, and performing column chromatography to obtain a compound E;
    S4，
    Figure DEST_PATH_IMAGE010
    dissolving the compound E and the compound F in acetonitrile, adding magnesium chloride, stirring at 50 ℃ for 10 min, then adding diisopropylethylamine, and stirring at 50 ℃ overnight; after the reaction is finished, cooling to room temperature, adding dichloromethane for dilution, washing the reaction solution with a citric acid solution, washing the organic phase with saturated ammonium chloride, then washing with saturated sodium bicarbonate and saturated salt water, drying the organic phase with anhydrous sodium sulfate, filtering to remove the anhydrous sodium sulfate, concentrating the filtrate, and separating the crude product by column chromatography to obtain a compound G;
    S5，
    Figure DEST_PATH_IMAGE012
    dissolving compound G and 4-dimethylaminopyridine in dichloromethane 0oC, sequentially adding N, N-diisopropylethylamine and 2,4, 6-triisopropylbenzenesulfonyl chloride, stirring at room temperature for 1-2H, concentrating the reaction solution, and performing column chromatography separation to obtain a product H;
    S6，
    Figure DEST_PATH_IMAGE014
    dissolving compound H in acetonitrile, 0oSequentially adding triethylamine and hydroxylamine hydrochloride at the temperature of C, stirring at room temperature for 2-12 h, concentrating the reaction solution, and performing column chromatography separation to obtain a compound I;
    S7，
    Figure DEST_PATH_IMAGE016
    dissolving the compound I in a formic acid aqueous solution, stirring overnight at room temperature, concentrating a reaction solution, and performing column chromatography separation to obtain a final product Q09.
  7. 7. The method of synthesizing a 2-thio-N-hydroxycytosine ribonucleoside phosphate in accordance with claim 6, wherein: step S1 specifically includes: mixing the compound A, hexamethyldisilazane, trimethylchlorosilane and ammonium sulfate, and reacting the mixture N2The solution was allowed to settle by stirring at 126 ℃ for 18h under protection.
  8. 8. The method of synthesizing a 2-thio-N-hydroxycytosine ribonucleoside phosphate in accordance with claim 6, wherein: step S6 specifically includes: dissolving compound H in acetonitrile, 0oAnd C, sequentially adding triethylamine and hydroxylamine hydrochloride, stirring at room temperature for 2-12 h, pouring the reaction solution into a saturated sodium bicarbonate solution, extracting with dichloromethane, washing an organic phase with saturated saline solution, drying with anhydrous sodium sulfate, filtering to remove the anhydrous sodium sulfate, concentrating the reaction solution, and performing column chromatography separation to obtain the compound I.
  9. 9. The method of synthesizing a 2-thio-N-hydroxycytosine ribonucleoside phosphate in accordance with claim 6, wherein: both steps S2 and S3 are room temperature reactions; the reactions of steps S5 and S6 are both in N2Under protection.
  10. 10. The method of synthesizing a 2-thio-N-hydroxycytosine ribonucleoside phosphate in accordance with claim 6, wherein: the compound C, the compound D, the compound E, the compound F, the compound G, the compound H and the compound I are all white solids.
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CN116199730A (en) * 2023-04-24 2023-06-02 南京颐媛生物医学研究院有限公司 4-thiouracil ribonucleoside phosphate compound, and preparation method and application thereof

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