2 '-fluorodeoxyuridine compound and synthesis method thereof

Abstract

The invention relates to the technical field of synthesis of deoxyuridine compounds, and particularly discloses a 2 '-fluorodeoxyuridine compound and a synthesis method thereof. A synthesis method of a 2 '-fluorodeoxyuridine compound comprises the following steps: synthesizing a compound 10 containing two TBSO groups by taking 2'-fluorodeoxyuridine as a raw material; the compound 10 is subjected to an oxidation reaction, a Seyferth-Gilbert recarburization reaction and TBSO group deprotection, and 2 '-deoxy-4'-C-ethynyl-2 '-floxuridine is obtained; the compound 10 can also react with phenyl thiochloroformate, then a methyl compound 15 is generated under the condition of TMSS and AIBN, and then 2 '-deoxy-4'-C-methyl-2 '-floxuridine is obtained through deprotection of a TBSO group; the 2 '-fluorodeoxyuridine compound provided by the invention can be used for synthesis of drug intermediates and research on biological activity, and has the advantage of high product stability.

Description

Technical Field

[0001] This application relates to the field of deoxyuridine synthesis technology, and more specifically, to a 2′-fluorodeoxyuridine compound and a method for synthesizing the same. Background Technology

[0002] Nucleoside analogues are a class of compounds that exhibit antiviral activity both in vitro and in vivo. By structurally mimicking natural nucleosides, they can interfere with the DNA or RNA synthesis processes necessary for cell or viral replication, thereby exerting antiviral effects.

[0003] Nucleoside analogs are typically inactive compounds in vitro, but through the action of host or viral enzymes, they can be converted into their corresponding antiviral metabolites, which can participate in inhibiting viral replication or cell proliferation. The activation mechanism of antiviral metabolites involves nucleoside analogs, or nucleoside prodrugs, being orally absorbed into the bloodstream. There, they are metabolized by phosphatases into metabolites with one or more added phosphate groups. These metabolites possess strong antiviral activity, inhibiting viral replication and thus exerting a therapeutic effect.

[0004] 2′-Deoxyuridine is a natural precursor in DNA synthesis. Introducing a fluorine atom at the 2′ position of the sugar ring is an important strategy for developing new drugs. This is because the introduction of the fluorine atom significantly alters the electronic effects and spatial conformation of the molecule, enabling it to be more effectively phosphorylated by intracellular kinases. It also enhances its binding ability to target enzymes or resists degradation by nucleases, thereby improving its bioavailability and therapeutic efficacy.

[0005] 2′-Fluorodeoxyuridine is a nucleoside analogue commonly used as an intermediate in organic synthesis and a raw material in biochemical synthesis. It is frequently used in the structural modification and synthesis of drug molecules and small organic molecule inhibitors, such as as an intermediate in the synthesis of antiviral drugs. Therefore, continued research and development of 2′-fluorodeoxyuridine and its analogues is of great significance in the field of antiviral drugs. Summary of the Invention

[0006] To increase the variety of raw materials for anti-influenza virus drug intermediates, this application provides a 2′-fluorodeoxyuridine compound and its synthesis method.

[0007] In a first aspect, this application provides a method for synthesizing 2′-fluorodeoxyuridine compounds, employing the following technical solution: A 2′-fluorodeoxyuridine compound has the following structure: R is acetylene or methyl.

[0008] Secondly, this application provides a method for synthesizing 2′-fluorodeoxyuridine compounds, using the following technical solution: A method for synthesizing 2′-fluorodeoxyuridine compounds, the synthetic route is as follows: The method for synthesizing the above-mentioned 2′-fluorodeoxyuridine compounds includes the following steps: Synthesis of compound 2: Compound 1, pyridine, and 4,4'-bismethoxytriphenylmethyl chloride were mixed and stirred at 20-25°C for 3-3.5 h to obtain a reaction solution; after post-treatment of the reaction solution, compound 2 was obtained.

[0009] Synthesis of compound 3: Compound 2, N,N-dimethylformamide, imidazole, 4-dimethylaminopyridine and tert-butyldimethylchlorosilane were mixed and stirred at 20-25°C for 18-24 h to obtain a reaction solution; after post-treatment of the reaction solution, compound 3 was obtained.

[0010] Synthesis of compound 4: Compound 3, cerium ammonium nitrate and acetonitrile were mixed and stirred at 20-25°C for 18-24 h to obtain a reaction solution; after post-treatment of the reaction solution, compound 4 was obtained.

[0011] Synthesis of compound 5: Compound 4, acetonitrile and 2-iodobenzoic acid were mixed and stirred at 85-90℃ for 2-2.5 h to obtain a reaction solution; after post-treatment of the reaction solution, compound 5 was obtained. Synthesis of compound 6: Compound 5, dioxane, aqueous formaldehyde solution and aqueous sodium hydroxide solution were mixed and stirred at 20-25℃ for 2-2.5 h to obtain a reaction solution; after post-treatment of the reaction solution, compound 6 was obtained.

[0012] Synthesis of compound 7: Compound 6, ethanol and sodium borohydride were mixed and stirred at 20-25°C for 0.5-1 h to obtain a reaction solution; after post-treatment of the reaction solution, compound 7 was obtained.

[0013] Synthesis of compound 8: Compound 7, anhydrous pyridine and 4,4'-bismethoxytriphenylmethyl chloride were mixed and stirred at 20-25°C for 18-24 h to obtain a reaction solution; after post-treatment of the reaction solution, compound 8 was obtained.

[0014] Synthesis of compound 9: Compound 8, anhydrous N,N-dimethylformamide, imidazole, 4-dimethylaminopyridine and tert-butyldimethylchlorosilane were mixed and stirred at 20-25°C for 18-24 h to obtain a reaction solution; after post-treatment of the reaction solution, compound 9 was obtained.

[0015] Synthesis of compound 10: Compound 9, acetonitrile and cerium ammonium nitrate were mixed and stirred at 20-25°C for 18-24 h to obtain a reaction solution; after post-treatment of the reaction solution, compound 10 was obtained.

[0016] Synthesis of compound 11: Compound 10, 2-iodobenzoic acid and anhydrous acetonitrile were mixed and stirred at 90°C for 2-2.5 h to obtain a reaction solution; the reaction solution was post-treated to obtain compound 11.

[0017] Synthesis of compound 12: Compound 11, methanol, potassium carbonate and dimethyl (1-diazo-2-oxopropyl)phosphonate were mixed and stirred at 20-25°C for 2-2.5 h to obtain a reaction solution; the reaction solution was post-treated to obtain compound 12.

[0018] Synthesis of Compound 13: Compound 12, methanol, and ammonium fluoride were mixed and reacted at 75–80 °C for 4–24 h to obtain a reaction solution; after post-treatment of the reaction solution, compound 13 was obtained, specifically 2′-deoxy-4′-C-ethynyl-2′ -Fluorouracil.

[0019] Synthesis of Compound 14: Compound 10, 4-dimethylaminopyridine, phenyl thiochloroformate, and anhydrous acetonitrile were mixed and stirred at 20–25 °C for 3–3.5 h to obtain a reaction solution; the reaction solution was post-treated to obtain Compound 14. Synthesis of Compound 15: Compound 14, anhydrous toluene, tris(trimethylsilyl)silane, and azobisisobutyronitrile were mixed and stirred at 110–115 °C for 1–1.5 h to obtain a reaction solution; the reaction solution was post-treated to obtain Compound 15.

[0020] Synthesis of compound 16: Compound 15, methanol and ammonium fluoride were mixed and stirred at 75-80°C for 4-24 h to obtain a reaction solution; after post-treatment of the reaction solution, compound 16 was obtained, specifically 2′-deoxy-4′-C-methyl-2′-fluorouridine.

[0021] Preferably, in the synthesis step of compound 2, the molar ratio of compound 1 to 4,4'-bismethoxytriphenylmethyl chloride is 1:(1 to 1.1); In the synthesis step of compound 3, the molar ratio of compound 2, imidazole, 4-dimethylaminopyridine and tert-butyldimethylchlorosilane is 1:(2-2.2):(0.1-0.1-0.15):(1.2-1.3); In the synthesis step of compound 4, the molar ratio of compound 3 and cerium ammonium nitrate is 1:(1.2-1.3).

[0022] Preferably, in the synthesis step of compound 5, the molar ratio of compound 4 to 2-iodobenzoic acid is 1:(2-2.5); In the synthesis step of compound 6, the molar ratio of compound 5, formaldehyde and sodium hydroxide is 1:(4-4.5):(1.5-1.6).

[0023] Preferably, in the synthesis step of compound 7, the molar ratio of compound 6 to sodium borohydride is 1:(4-4.5); In the synthesis step of compound 8, the molar ratio of compound 7 and 4,4'-bismethoxytriphenylmethyl chloride is 1:(1-1.05); In the synthesis step of compound 9, the molar ratio of compound 8, imidazole, 4-dimethylaminopyridine and tert-butyldimethylchlorosilane is 1:(2-2.2):(0.1-0.15):(1.2-1.3); In the synthesis step of compound 10, the molar ratio of compound 9 to cerium ammonium nitrate is 1:(1.2-1.3).

[0024] Preferably, in the synthesis step of compound 11, the molar ratio of compound 10 to 2-iodobenzoic acid is 1:(2-2.5); In the synthesis step of compound 12, the molar ratio of compound 11, potassium carbonate and dimethyl (1-diazo-2-oxopropyl)phosphonate is 1:(2-2.5):(1.2-1.3).

[0025] Preferably, in the synthesis step of compound 13, the molar ratio of compound 12 to ammonium fluoride is 1:(8-10).

[0026] Preferably, in the synthesis step of compound 14, the molar ratio of compound 10, 4-dimethylaminopyridine and phenyl thiochloroformate is 1:(4-4.5):(1.5-1.6). In the synthesis step of compound 15, the molar ratio of compound 14, tris(trimethylsilyl)silane and azobisisobutyronitrile is 1:(1.25-1.3):(0.25-0.3).

[0027] In summary, this application has the following beneficial effects: First, compound 1 reacts sequentially with DMTrCl and TBSCl to protect the two hydroxyl groups, followed by removal of the DMTr group with cerium ammonium nitrate to obtain monohydroxy compound 4. Second, compound 4 undergoes oxidation, alkylation, and reduction reactions to generate dihydroxy compound 7. Third, compound 7 reacts sequentially with DMTrCl and TBSCl, followed by removal of the DMTr group with cerium ammonium nitrate to obtain monohydroxy compound 10 containing two TBSO groups. Finally, compound 10 undergoes oxidation, a Seyferth-Gilbert carbonization reaction, and deprotection of the TBSO group to obtain 2′-deoxy-4′-C-ethynyl- 2′-Fluorouracil; simultaneously, compound 10 can also react with phenyl thiochloroformate, and then generate methyl compound 15 under TMSS and AIBN conditions, which is then deprotected by the TBSO group to obtain 2′-deoxy-4′-C-methyl-2′-fluorouracil; the 2′-deoxy-4′-C-ethynyl-2′-fluorouracil and 2′-deoxy-4′-C-methyl-2′-fluorouracil of this application belong to the deoxyuridine class of compounds, which can be used for the synthesis of pharmaceutical intermediates and the study of biological activity. They have the advantage of high product stability, and their synthesis methods are simple to operate, safe and environmentally friendly, and suitable for large-scale industrial production. Attached Figure Description

[0028] Figure 1 This is the HNMR spectrum of compound 4 in Example 1 of this application; Figure 2 This is the HNMR spectrum of compound 7 in Example 1 of this application; Figure 3 This is the FNMR spectrum of compound 7 in Example 1 of this application; Figure 4 This is the HNMR spectrum of compound 10 in Example 1 of this application; Figure 5 This is the HNMR spectrum of compound 13 in Example 2 of this application; Figure 6 This is the FNMR spectrum of compound 13 in Example 2 of this application; Figure 7 This is the HNMR spectrum of compound 14 in Example 3 of this application; Figure 8 This is the HNMR spectrum of compound 15 in Example 3 of this application; Figure 9 This is the HNMR spectrum of compound 16 in Example 3 of this application; Figure 10 This is the FNMR spectrum of compound 16 in Example 3 of this application. Detailed Implementation

[0029] The present application will be further described in detail below with reference to the accompanying drawings and embodiments.

[0030] The raw materials used in the embodiments of this application are all commercially available. Example

[0031] Example 1 A synthetic method for 1-((2R,3R,4R,5R)-4-((tert-butyldimethylsilyl)oxy)-5-(((tert-butyldimethylsilyl)oxy)methyl)-3-fluoro-5-(hydroxymethyl)tetrahydrofuran-2-yl)pyrimidine-2,4(1H,3H)-dione is provided, and the synthetic route is as follows:

[0032] The above-mentioned method for synthesizing 1-((2R,3R,4R,5R)-4-((tert-butyldimethylsilyl)oxy)-5-(((tert-butyldimethylsilyl)oxy)methyl)-3-fluoro-5-(hydroxymethyl)tetrahydrofuran-2-yl)pyrimidine-2,4(1H,3H)-dione includes the following steps: Synthesis of Compound 2: Compound 1 (1125 g, 4569.560 mmol), pyridine (5 L), and 4,4'-bismethoxytriphenylmethyl chloride (1703.13 g, 5026.516 mmol) were added sequentially to a 10 L three-necked flask and mixed. The mixture was stirred at 20–25 °C for 3 h. The reaction mixture was monitored by TLC until the starting materials were consumed, and the reaction solution was obtained. After removing most of the pyridine from the reaction solution by rotary evaporation using an oil pump, DCM (10 L) and water (10 L) were added for extraction once, and the organic phases were combined. The organic phases were then washed twice with saturated sodium chloride solution (5 L), and finally anhydrous sodium sulfate was added to dry the organic phase. The organic phase was concentrated by rotary evaporation to obtain crude compound 2 (3240 g), which was directly used for the next step.

[0033] Synthesis of Compound 3: Compound 2 (3240 g), N,N-dimethylformamide (15 L), imidazole (622.19 g, 9139.120 mmol), 4-dimethylaminopyridine (55.83 g, 456.956 mmol) and tert-butyldimethylchlorosilane (826.47 g, 5483.472 mmol) were sequentially added to a 50 L reactor and mixed to obtain a mixture; the mixture was stirred at 20–25 °C for 24 h, and the reactants were monitored by TLC until the reactants were consumed, yielding a reaction solution; After removing most of the N,N-dimethylformamide from the reaction solution by rotary evaporation using an oil pump, DCM (15L) and water (15L) were added for extraction once, and the organic phases were combined. The organic phases were then washed twice with saturated sodium chloride solution (5L), and finally anhydrous sodium sulfate was added to dry the organic phase, yielding crude compound 3 (3300g), which was directly used for the next step.

[0034] Synthesis of compound 4: Compound 3 (3300 g), acetonitrile (15 L) and cerium ammonium nitrate (3006.15 g, 5483.472 mmol) were added sequentially to a 50 L reactor and mixed to obtain a mixture; the mixture was stirred at 20-25 °C for 24 h, and the reactants were monitored by TLC until the reactants were consumed, and the reaction solution was obtained; After removing acetonitrile by rotary evaporation of the reaction solution, ethyl acetate (10 L) and water (10 L) were added for extraction twice, and the organic phases were combined. Then, anhydrous sodium sulfate was added to dry the organic phase, and the organic phase was concentrated by rotary evaporation to obtain the crude product.

[0035] The crude product was purified by column chromatography using ethyl acetate:petroleum ether = 1:5 → 1:0 (v / v) as the eluent. After purification, the solvent was evaporated to dryness, yielding compound 4 (800 g, 2219.402 mmol, 3-step yield 48.5%), as a pale yellow solid.

[0036] Depend on Figure 1 It can be seen that the NMR of compound 4 is: 1 H NMR (400MHz, DMSO) δ11.40(s,1H),7.88(d,J=8.1Hz,1H),5.89(dd,J=17.9,1. 9Hz,1H),5.64(d,J=8.1Hz,1H),5.22(t,J=4.8Hz,1H),5.11(ddd,J=53.3,4.2 ,2.1Hz,1H),4.33(ddd,J=18.8,7.1,4.5Hz,1H),3.87(d,J=6.9Hz,1H),3.74( dd,J=6.5,4.1Hz,1H),3.60–3.49(m,1H),0.87(s,9H),0.10(d,J=1.8Hz,6H).

[0037] Synthesis of compound 5: Compound 4 (800 g, 2219.402 mmol), acetonitrile (5 L) and 2-iodobenzoic acid (1553.69 g, 5548.506 mmol) were added sequentially to a 10 L three-necked flask and mixed to obtain a mixture; the mixture was stirred at 90 °C for 2 h, and the reactants were monitored by TLC until they were completely consumed, yielding a reaction solution; The reaction solution was cooled to 0°C and stirred for 30 minutes. After a large amount of solid precipitated in the reaction solution, the solid-liquid mixture was filtered, and the solid residue was washed with ethyl acetate (2 L). The filtrate was collected and evaporated to dryness to obtain crude compound 5 (730 g), which was directly used for the next step.

[0038] Synthesis of compound 6: Compound 5 (730 g), dioxane (3 L), 37% formaldehyde aqueous solution (655.024 mL, 8877.608 mmol) and 2M sodium hydroxide aqueous solution (1664.552 mL, 3329.103 mmol) were mixed to obtain a mixture; the mixture was stirred at 20-25 °C for 2 h, and the reactants were monitored by TLC until the reactants were consumed, thus obtaining the reaction solution; Acetic acid was added to adjust the pH of the reaction solution to 7, yielding a crude reaction solution of compound 6, which was directly used for the next step.

[0039] Synthesis of compound 7: Ethanol (1 L) and sodium borohydride (335.84 g, 8877.608 mmol) were added sequentially to the crude reaction solution of compound 6 to obtain a mixture; the mixture was stirred at 20-25 °C for 0.5 h, and the reaction solution was obtained after the raw materials were consumed by TLC monitoring. Add 500 mL of saturated NH4Cl aqueous solution to the reaction solution slowly, which will release heat and gas to quench the reaction. Then adjust the pH of the reaction solution to 7. After evaporating the solvent in the reaction solution, a mixed solution is obtained. Add ethyl acetate (5 L) and water (5 L) to extract twice and combine the organic phases. Then add anhydrous sodium sulfate to dry the organic phase and concentrate the organic phase by rotary evaporation to obtain the crude product.

[0040] The crude product was purified by column chromatography using ethyl acetate:petroleum ether = 1:2 → 1:0 (v / v) as the eluent. After purification, the solvent was evaporated to dryness, yielding compound 7 (275 g, 704.255 mmol, 3-step yield 31.7%) as a white solid.

[0041] Depend on Figure 2 and Figure 3 It can be seen that the NMR of compound 7 is: 1H NMR (400MHz, DMSO) δ11.41(d,J=1.7Hz,1H),7.92(d,J=8.1Hz,1H),6.06(dd,J=1 4.3,4.6Hz,1H),5.69(dd,J=8.1,2.1Hz,1H),5.31–5.08(m,2H),4.59(dd,J=6.5 ,5.0Hz,1H),4.48(dd,J=11.9,5.0Hz,1H),3.69(d,J=4.9Hz,1H),3.59(s,1H),3 .54(d,J=5.0Hz,1H), 3.46(d,J=6.7Hz,1H), 0.89(s,9H), 0.09(d,J=5.9Hz,6H).

[0042] Synthesis of compound 8: Compound 7 (275 g, 704.255 mmol), anhydrous pyridine (3 L), and 4,4'-bismethoxytriphenylmethyl chloride (250.55 g, 739.468 mmol) were added sequentially to a 5 L three-necked flask and mixed to obtain a mixture; the mixture was stirred at 20–25 °C for 24 h, and the reaction solution was obtained after the starting materials were consumed by TLC monitoring; Most of the pyridine was removed by rotary evaporation of the reaction solution using an oil pump. Dichloromethane (2L) and water (2L) were added for extraction once, and the organic phases were combined. The organic phase was then washed twice with saturated sodium chloride solution (1L). Finally, anhydrous sodium sulfate was added to dry the organic phase, and the organic phase was concentrated by rotary evaporation to obtain the crude product.

[0043] The crude product was purified by column chromatography using ethyl acetate:petroleum ether = 1:5 → 1:1 (v / v) as the eluent. After purification, the solvent was evaporated to dryness, yielding compound 8 (274.71 g, 396.489 mmol, yield 56.3%) as a yellow solid.

[0044] Synthesis of compound 9: Compound 8 (274.71 g, 396.489 mmol), anhydrous N,N-dimethylformamide (2 L), imidazole (53.99 g, 792.978 mmol), 4-dimethylaminopyridine (4.84 g, 39.649 mmol) and tert-butyldimethylchlorosilane (71.71 g, 475.787 mmol) were added sequentially to a 5 L three-necked flask and mixed to obtain a mixture; the mixture was stirred at 20–25 °C for 24 h, and the reactants were monitored by TLC until the reactants were consumed, yielding the reaction solution; After removing most of the DMF by rotary evaporation of the reaction solution using an oil pump, dichloromethane (2L) and water (2mL) were added for extraction once, and the organic phases were combined. The organic phases were then washed twice with saturated sodium chloride solution (1L), and finally anhydrous sodium sulfate was added to dry the organic phase, yielding crude compound 9 (314g), which was directly used for the next step.

[0045] Synthesis of compound 10: Compound 9 (314 g), acetonitrile (2 L) and cerium ammonium nitrate (260.84 g, 475.787 mmol) were added sequentially to a 5 L three-necked flask and mixed to obtain a mixture; the mixture was stirred at 20-25 °C for 24 h, and the reaction solution was obtained after the starting materials were consumed by TLC monitoring; Acetonitrile was removed from the reaction solution by rotary evaporation to obtain the crude product. The crude product was purified by column chromatography using ethyl acetate:petroleum ether = 1:8 → 1:1 (v / v) as the eluent. After purification, the solvent was evaporated to dryness to give compound 10 (109.87 g, 217.672 mmol, 2-step yield 54.9%), as a pale yellow solid.

[0046] Depend on Figure 4 It is known that compound 10 is a 1-((2R,3R,4R,5R)-4-((tert-butyldimethylsilyl)oxy)-5-(((tert-butyldimethylsilyl)oxy)methyl)-3-fluoro-5-(hydroxymethyl)tetrahydrofuran-2-yl)pyrimidine-2,4(1H,3H)-dione, NMR: 1 H NMR (400MHz, DMSO) δ11.44(s,1H),7.73(d,J=8.1Hz,1H),6.03(dd,J=15.9,3.2 Hz, 1H), 5.60 (d, J=8.1Hz, 1H), 5.19 (ddd, J=53.6, 4.9, 3.5Hz, 1H), 4.64 (dd, J= 6.8,4.9Hz,1H),4.46(dd,J=16.9,5.1Hz,1H),3.94–3.86(m,1H),3.70–3.60(m ,2H),3.45(dd,J=12.2,7.0Hz,1H),0.92–0.86(m,18H),0.09(d,J=4.5Hz,12H).

[0047] Example 2 A method for synthesizing 2′-deoxy-4′-C-ethynyl-2′-fluorouridine, the synthetic route is as follows:

[0048] The above-mentioned method for synthesizing 2′-deoxy-4′-C-ethynyl-2′-fluorouridine includes the following steps: Synthesis of compound 11: Compound 10 (50 g, 99.060 mmol), anhydrous acetonitrile (500 mL), and 2-iodobenzoic acid (69.35 g, 247.649 mmol) were added sequentially to a 2 L three-necked flask and mixed to obtain a mixture; the mixture was stirred at 90 °C for 2 h, and the reaction solution was obtained by TLC monitoring after the starting materials were consumed; The reaction solution was cooled to 0°C and stirred for 30 minutes. After a large amount of solid precipitated in the reaction solution, the solid-liquid mixture was filtered, and the solid residue was washed with ethyl acetate (500 mL). The filtrate was collected and evaporated to dryness to obtain crude compound 11 (57 g), which was directly used for the next step.

[0049] Synthesis of compound 12: Compound 11 (57 g), methanol (500 mL), potassium carbonate (27.38 g, 198.120 mmol), and dimethyl phosphonate (1-diazo-2-oxopropyl)phosphonate (22.84 g, 118.872 mmol) were added sequentially to a 2 L three-necked flask and mixed to obtain a mixture; the mixture was stirred at 20–25 °C for 2 h, and the reaction solution was obtained after the starting materials were consumed by TLC monitoring; Methanol was removed from the reaction solution by rotary evaporation. Ethyl acetate (500 mL) and water (500 mL) were added and extracted twice. The organic phases were combined. Anhydrous sodium sulfate was added to dry the organic phase. The mixture was filtered and concentrated by rotary evaporation to obtain the crude product.

[0050] The crude product was purified by column chromatography using ethyl acetate:petroleum ether = 1:10 → 1:5 (v / v) as the eluent. After purification, the solvent was evaporated to dryness, yielding compound 12 (30 g, 60.129 mmol, 2-step yield 60.7%) as a pale yellow solid.

[0051] Synthesis of compound 13: Compound 12 (10 g, 20.050 mmol), methanol (100 mL) and ammonium fluoride (5.94 g, 160.403 mmol) were added sequentially to a 500 mL three-necked flask and mixed to obtain a mixture; the mixture was stirred at 80 °C for 4 h, and the reactants were monitored by TLC until they were completely consumed, and the reaction solution was obtained; The methanol in the reaction solution is removed by rotary evaporation, resulting in the crude product.

[0052] The crude product was purified by column chromatography using ethyl acetate:petroleum ether = 1:2 → 1:0 (v / v) as the eluent. After purification, the solvent was evaporated to dryness, yielding compound 13 (5 g, 18.486 mmol, yield 92.2%) as a white solid.

[0053] Depend on Figure 5 and Figure 6 It can be seen that compound 13 is 2′-deoxy-4′-C-ethynyl-2′-fluorouridine, NMR: 1HNMR (400MHz, DMSO) δ11.42(s,1H),7.78(d,J=8.1Hz,1H),5.99(dd,J=19.4,1.9Hz,1H),5.83(d,J=6.8Hz,1H),5.64(d,J=8.1Hz,1 H),5.55(t,J=5.9Hz,1H),5.11(ddd,J=53.6,5.2,1.9Hz,1H),4.39–4.27(m,1H),3.68(dd,J=12.2,5.5Hz,1H),3.62–3.50(m,2H).

[0054] Example 3 A method for synthesizing 2′-deoxy-4′-C-methyl-2′-fluorouridine, the synthetic route is as follows:

[0055] The above method for synthesizing 2′-deoxy-4′-C-methyl-2′-fluorouridine includes the following steps: Synthesis of Compound 14: Compound 10 (50 g, 99.060 mmol), anhydrous acetonitrile (500 mL), 4-dimethylaminopyridine (500 mL), and phenyl thiochloroformate (25.65 g, 148.589 mmol) were added sequentially to a 2 L three-necked flask and mixed to obtain a mixture. The mixture was stirred at 20–25 °C for 3 h. The reaction mixture was monitored by TLC until the starting materials were consumed, and the reaction solution was obtained. The reaction solution was removed by rotary evaporation to remove acetonitrile. Ethyl acetate (500 mL) and water (500 mL) were added and extracted twice. The organic phases were combined, dried with anhydrous sodium sulfate, filtered, and concentrated by rotary evaporation to obtain the crude product.

[0056] The crude product was purified by column chromatography using ethyl acetate:petroleum ether = 1:10 → 1:4 (v / v) as the eluent. After purification, the solvent was evaporated to dryness, yielding compound 14 (46.16 g, 72.022 mmol, yield 72.7%) as a pale yellow solid.

[0057] Depend on Figure 7 It can be seen that the NMR of compound 14 is: 1H NMR (400MHz, DMSO) δ11.48(s,1H),7.72(d,J=8.1Hz,1H),7.48(dd,J=10.8,5. 1Hz,2H),7.33(t,J=7.4Hz,1H),7.17–7.09(m,2H),6.09(dd,J=16.2,3.9Hz,1H ),5.71–5.60(m,1H),5.53–5.30(m,1H),4.75–4.50(m,3H),3.79(q,J=10.8Hz, 2H), 1.37–1.21 (m, 2H), 0.90 (d, J = 5.4Hz, 18H), 0.11 (dd, J = 15.2, 3.5Hz, 12H).

[0058] Synthesis of compound 15: Compound 14 (46.16 g, 72.022 mmol), anhydrous toluene (500 mL), tris(trimethylsilyl)silane (22.39 g, 90.028 mmol) and azobisisobutyronitrile (2.96 g, 18.006 mmol) were added sequentially to a 2 L three-necked flask and mixed to obtain a mixture; the mixture was stirred at 115 °C for 1 h, and the reactants were monitored by TLC until the reactants were consumed, yielding the reaction solution; Toluene was removed from the reaction solution by rotary evaporation to obtain the crude product. The crude product was purified by column chromatography using ethyl acetate:petroleum ether = 1:10 → 1:5 (v / v) as the eluent. After purification, the solvent was evaporated to dryness to give compound 15 (25.84 g, 52.864 mmol, yield 73.4%) as a white solid.

[0059] Depend on Figure 8 It can be seen that the NMR of compound 15 is: 1 H NMR (400MHz, DMSO) δ11.42(s,1H),7.75(d,J=8.1Hz,1H),5.94(dd,J=17.6,2.2Hz,1H),5.56(d,J=8.0Hz,1H),5.17(ddd,J=53.7,5.1,2.2Hz,1 H), 4.36 (dd, J = 20.3, 5.1Hz, 1H), 3.68 (d, J = 11.3Hz, 1H), 3.49 (d, J = 11.3Hz, 1H), 1.13 (s, 3H), 0.89 (d, J = 1.4Hz, 18H), 0.08 (d, J = 12.3Hz, 12H).

[0060] Synthesis of compound 16: Compound 15 (14 g, 28.645 mmol), methanol (140 mL) and ammonium fluoride (8.49 g, 229.157 mmol) were added sequentially to a 500 mL three-necked flask and mixed to obtain a mixture; the mixture was stirred at 80 °C for 24 h, and the reactants were monitored by TLC until they were completely consumed, and the reaction solution was obtained; The methanol in the reaction solution is removed by rotary evaporation, resulting in the crude product.

[0061] The crude product was purified by column chromatography using ethyl acetate:petroleum ether = 1:2 → 1:0 (v / v) as the eluent. After purification, the solvent was evaporated to dryness, yielding compound 16 (6 g, 23.057 mmol, yield 80.4%) as a white solid.

[0062] Depend on Figure 9 and Figure 10 It is known that compound 16 is 2′-deoxy-4′-C-methyl-2′-fluorouridine, NMR: 1 HNMR (400MHz, DMSO) δ11.36(s,1H),7.95(d,J=8.1Hz,1H),5.99(dd,J=16.0,3.3Hz,1H),5.62(dd,J=16.0,7.0Hz,2H),5.29( t, J=5.1Hz, 1H), 5.08 (ddd, J=53.6, 5.0, 3.4Hz, 1H), 4.19 (dt, J=17.9, 5.5Hz, 1H), 3.42 (qd, J=11.8, 5.1Hz, 2H), 1.10 (s, 3H).

[0063] Example 4 A method for synthesizing 1-((2R,3R,4R,5R)-4-((tert-butyldimethylsilyl)oxy)-5-(((tert-butyldimethylsilyl)oxy)methyl)-3-fluoro-5-(hydroxymethyl)tetrahydrofuran-2-yl)pyrimidine-2,4(1H,3H)-dione, differing from Example 1 in that, in the synthesis of compound 4: compound 3 (1g), acetonitrile (10mL), water (10mL), and cerium ammonium nitrate (0.99g, 1.810mmol) were sequentially added to a 100mL three-necked flask and mixed to obtain a mixture; the mixture was stirred at 20–25°C for 24h, and TLC and LC-MS showed no reaction.

[0064] A comparison of Examples 1 and 4 shows that in the synthesis of compound 4, excess water inhibits the reaction.

[0065] Example 5 A method for synthesizing 1-((2R,3R,4R,5R)-4-((tert-butyldimethylsilyl)oxy)-5-(((tert-butyldimethylsilyl)oxy)methyl)-3-fluoro-5-(hydroxymethyl)tetrahydrofuran-2-yl)pyrimidine-2,4(1H,3H)-dione differs from Example 1 in that the synthesis of compound 8 involves the following steps: compound 7 (1 g, 2.561 mmol), pyridine (10 mL, non-ultra-dry solvent), and 4,4'-bismethoxytriphenylmethyl chloride (0.91 g, 2.689 mmol) are sequentially added to a 100 mL three-necked flask and mixed to obtain a mixture. The mixture is stirred at 20–25 °C for 24 h, and TLC and LC-MS show no reaction.

[0066] A comparison of Examples 1 and 5 shows that a strictly anhydrous environment is required for the synthesis of Compound 8.

[0067] Example 6 A method for synthesizing 2′-deoxy-4′-C-methyl-2′-fluorouridine, differing from Example 3 in that the synthesis of compound 15 is as follows: Compound 14 (1 g, 1.560 mmol), anhydrous dioxane (10 mL), tri-n-butyltin hydride (0.57 g, 1.950 mmol), and azobisisobutyronitrile (0.06 g, 0.390 mmol) are sequentially added to a 100 mL three-necked flask and mixed to obtain a mixture; the mixture is stirred at 115 °C for 1 h, and TLC and LC-MS show no reaction.

[0068] A comparison of Examples 1 and 6 shows that in the synthesis of compound 15, tris(trimethylsilyl)silane is used to react with compound 14 in order to synthesize compound 15.

[0069] This specific embodiment is merely an explanation of this application and is not intended to limit it. After reading this specification, those skilled in the art can make modifications to this embodiment without contributing any inventive step, but such modifications are protected by patent law as long as they fall within the scope of the claims of this application.

Claims

1. A 2′-fluorodeoxyuridine compound, characterized in that, The structural formula is shown below: R is acetylene or methyl.

2. The method for synthesizing the 2′-fluorodeoxyuridine compound according to claim 1, characterized in that, The synthesis route is as follows: The method for synthesizing the above-mentioned 2′-fluorodeoxyuridine compounds includes the following steps: The compound of formula I, methanol and ammonium fluoride were mixed and stirred at 75-80°C for 4-24 h to obtain a reaction solution; after post-treatment of the reaction solution, 2′-fluorodeoxyuridine compounds were obtained. In the compounds of Formula I and 2′-fluorodeoxyuridine compounds, R is ethynyl or methyl.

3. The method for synthesizing 2′-fluorodeoxyuridine compounds according to claim 2, characterized in that, In the compound of formula I, R is an acetylene group, and its structural formula is shown in compound 12; the synthetic route of compound 12 is as follows: The method for synthesizing compound 12 includes the following steps: Synthesis of compound 11: Compound 10, 2-iodobenzoic acid and anhydrous acetonitrile were mixed and stirred at 90°C for 2-2.5 h to obtain a reaction solution; the reaction solution was post-treated to obtain compound 11. Synthesis of compound 12: Compound 11, methanol, potassium carbonate and dimethyl (1-diazo-2-oxopropyl)phosphonate were mixed and stirred at 20-25°C for 2-2.5 h to obtain a reaction solution; the reaction solution was post-treated to obtain compound 12.

4. The method for synthesizing 2′-fluorodeoxyuridine compounds according to claim 3, characterized in that, In the synthesis step of compound 11, the molar ratio of compound 10 and 2-iodobenzoic acid is 1:(2-2.5); In the synthesis step of compound 12, the molar ratio of compound 11, potassium carbonate and dimethyl (1-diazo-2-oxopropyl)phosphonate is 1:(2-2.5):(1.2-1.3).

5. The method for synthesizing 2′-fluorodeoxyuridine compounds according to claim 3, characterized in that, The molar ratio of compound 12 to ammonium fluoride is 1:(8-10).

6. The method for synthesizing 2′-fluorodeoxyuridine compounds according to claim 2, characterized in that, In the compound of formula I, R is a methyl group; its structural formula is shown in compound 15; the synthetic route of compound 15 is as follows: The method for synthesizing compound 15 includes the following steps: Synthesis of compound 14: Compound 10, 4-dimethylaminopyridine, phenyl thiochloroformate and anhydrous acetonitrile were mixed and stirred at 20-25°C for 3-3.5 h to obtain a reaction solution; the reaction solution was post-treated to obtain compound 14. Synthesis of compound 15: Compound 14, anhydrous toluene, tris(trimethylsilyl)silane and azobisisobutyronitrile were mixed and stirred at 110-115 °C for 1-1.5 h to obtain a reaction solution; the reaction solution was post-treated to obtain compound 15.

7. The method for synthesizing 2′-fluorodeoxyuridine compounds according to claim 6, characterized in that, In the synthesis step of compound 14, the molar ratio of compound 10, 4-dimethylaminopyridine and phenyl thiochloroformate is 1:(4-4.5):(1.5-1.6). In the synthesis step of compound 15, the molar ratio of compound 14, tris(trimethylsilyl)silane and azobisisobutyronitrile is 1:(1.25-1.3):(0.25-0.3).

8. The method for synthesizing 2′-fluorodeoxyuridine compounds according to claim 6, characterized in that, The molar ratio of compound 15 to ammonium fluoride is 1:(8-10).

9. The method for synthesizing 2′-fluorodeoxyuridine compounds according to claim 3 or 6, characterized in that, The synthetic route for compound 10 is as follows: The method for synthesizing compound 10 includes the following steps: Synthesis of compound 2: Compound 1, pyridine, and 4,4'-bismethoxytriphenylmethyl chloride were mixed and stirred at 20-25°C for 3-3.5 h to obtain a reaction solution; after post-treatment of the reaction solution, compound 2 was obtained. Synthesis of compound 3: Compound 2, N,N-dimethylformamide, imidazole, 4-dimethylaminopyridine and tert-butyldimethylchlorosilane were mixed and reacted at 20-25°C for 18-24 h to obtain a reaction solution; after post-treatment of the reaction solution, compound 3 was obtained. Synthesis of compound 4: Compound 3, cerium ammonium nitrate and acetonitrile were mixed and stirred at 20-25°C for 18-24 h to obtain a reaction solution; after post-treatment of the reaction solution, compound 4 was obtained. Synthesis of compound 5: Compound 4, acetonitrile and 2-iodobenzoic acid were mixed and stirred at 85-90℃ for 2-2.5 h to obtain a reaction solution; after post-treatment of the reaction solution, compound 5 was obtained. Synthesis of compound 6: Compound 5, dioxane, aqueous formaldehyde solution and aqueous sodium hydroxide solution were mixed and stirred at 20-25℃ for 2-2.5 h to obtain a reaction solution; after post-treatment of the reaction solution, compound 6 was obtained. Synthesis of compound 7: Compound 6, ethanol and sodium borohydride were mixed and stirred at 20-25°C for 0.5-1 h to obtain a reaction solution; after post-treatment of the reaction solution, compound 7 was obtained. Synthesis of compound 8: Compound 7, anhydrous pyridine and 4,4'-bismethoxytriphenylmethyl chloride were mixed and reacted at 20-25°C for 18-24 h to obtain a reaction solution; after post-treatment of the reaction solution, compound 8 was obtained. Synthesis of compound 9: Compound 8, anhydrous N,N-dimethylformamide, imidazole, 4-dimethylaminopyridine and tert-butyldimethylchlorosilane were mixed and reacted at 20-25°C for 18-24 h to obtain a reaction solution; after post-treatment of the reaction solution, compound 9 was obtained. Synthesis of compound 10: Compound 9, acetonitrile and cerium ammonium nitrate were mixed and stirred at 20-25°C for 18-24 h to obtain a reaction solution; after post-treatment of the reaction solution, compound 10 was obtained.

10. The method for synthesizing 2′-fluorodeoxyuridine compounds according to claim 9, characterized in that, In the synthesis step of compound 2, the molar ratio of compound 1 and 4,4'-bismethoxytriphenylmethyl chloride is 1:(1-1.1); In the synthesis step of compound 3, the molar ratio of compound 2, imidazole, 4-dimethylaminopyridine and tert-butyldimethylchlorosilane is 1:(2-2.2):(0.1-0.1-0.15):(1.2-1.3); In the synthesis step of compound 4, the molar ratio of compound 3 and cerium ammonium nitrate is 1:(1.2-1.3).

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