A method for preparing a monohydroxymethylcyclopropane nucleoside analog

Abstract

This invention discloses a method for preparing monohydroxymethylcyclopropane nucleoside analogs. The method includes: sequentially adding a vinyl nucleobase derivative and a propynyl thioacetal compound to a mixture of a gold-nitrogen heterocyclic carbene catalyst and a silver salt under inert gas protection. After reaction, a highly stereospecific and selective disulfide vinylcyclopropane nucleoside analog is obtained. Following hydrodesulfurization, a vinylcyclopropane nucleoside analog is obtained. Further oxidation, reduction, or deprotection in three steps yields the monohydroxymethylcyclopropane nucleoside analog. This invention provides a concise new route for the synthesis of vinylcyclopropane nucleoside and monohydroxymethylcyclopropane nucleoside analogs, with mild reaction conditions, overcoming the potential explosiveness and lengthy synthetic routes of traditional methods. The raw materials are readily available, and the product can be converted into various other useful potential bioactive molecules, demonstrating strong practicality.

Description

Technical Field

[0001] This invention relates to the fields of chemistry and pharmaceutical technology, specifically to a method for preparing monohydroxymethylcyclopropane nucleoside analogs. Background Technology

[0002] Nucleoside analogs play a crucial role in antiviral and antitumor chemotherapy, especially given the rapid development of this field over the past decade. Structural modification of natural nucleosides is a vital method for finding new and more effective antiviral drugs. Currently, the vast majority of marketed and clinically tested antiviral drugs are nucleoside analogs, with those possessing cyclopropane structures becoming promising lead compounds with significant antiviral potential (see CN1780643A and US20110288053A1). However, these drugs generally suffer from numerous adverse reactions, low bioavailability, easy induction of drug resistance, and rapid metabolism. Therefore, modifying various parts of nucleoside analogs to optimize the biological activity of nucleoside drugs is of great significance.

[0003] Vinyl metal carbenes are important functionalized metal carbene species, offering rapid and extensive functionalization pathways due to their diverse transformation sites, thus finding wide applications in organic synthesis (see ACS Catal. 2023, 13, 132-140; Chem Catal. 2022, 2, 563-577). However, commonly used vinyl metal carbene precursors often contain difficult-to-remove leaving substituents (alkyl, phenyl, ester groups), limiting their application in the synthesis of natural products and active pharmaceutical ingredients, or resulting in lengthy synthetic steps. Therefore, developing vinyl metal carbene precursors with easily removable leaving substituents is of great significance.

[0004] Among various synthetic schemes for cyclopropane nucleosides, the transition metal-induced decomposition of diazo compounds is a traditional and widely used method (see CN108314655A and Org. Lett., 2016, 18, 4344-4347). However, the instability, explosiveness, and toxicity of diazo compounds hinder their safe, scalable, and large-scale industrial application. Secondly, the traditional method utilizes the Simmons-Smith cyclopropane reaction to synthesize cyclopropane nucleosides, resulting in a lengthy synthetic route (11-18 steps) (see J. Org. Chem., 1997, 62, 1991-1995; Tetrahedron Lett., 1995, 36, 3499-3502), leading to high production costs. With the rapid development of international research and production of nucleoside analogues, the demand for cyclopropane nucleosides with potential antiviral activity is increasing. Therefore, research on a stable, safe, efficient and concise synthetic route for the synthesis of cyclopropane nucleosides is urgent and cannot be delayed. Summary of the Invention

[0005] To overcome the aforementioned shortcomings, this invention provides a method for preparing monohydroxymethylcyclopropane nucleoside analogs. Using a propynyl thioacetal compound as a vinyl metal carbene precursor and a vinyl nucleobase derivative as a raw material, the reaction is carried out at room temperature in the presence of a gold-nitrogen heterocyclic carbene catalyst to obtain a disulfide vinylcyclopropane nucleoside analog. Further hydrodesulfurization of the disulfide vinylcyclopropane nucleoside analog yields a vinylcyclopropane nucleoside analog. Subsequent oxidation, reduction, or deprotection processes yield the potentially biologically active monohydroxymethylcyclopropane nucleoside analog in three steps. This method provides a mild, substrate-safe, convenient, and efficient route for the synthesis of monohydroxymethylcyclopropane nucleoside analogs.

[0006] The present invention relates to a method for preparing vinylcyclopropane nucleoside analogs by gold-nitrogen heterocyclic carbene catalysis, comprising the following steps:

[0007] Weigh appropriate amounts of gold-nitrogen heterocyclic carbene catalyst and silver salt, introduce an inert protective gas, and stir the reaction in an organic solvent for a certain time. Weigh appropriate amounts of raw material vinyl compound 2 and raw material propynyl thioacetal compound 1, dissolve them in an organic solvent, and add them sequentially to the reaction system containing the catalyst. React at room temperature for a certain time. After the reaction is complete, quench the reaction, perform post-reaction processing, separate by column chromatography and remove the solvent by vacuum distillation to obtain the disulfide vinylcyclopropane nucleoside analog rac-3, and calculate the yield. The general formula of its reaction equation is as follows:

[0008]

[0009] In the formula, Y is a nucleobase derivative and X is a disulfide group;

[0010] Furthermore, in the above scheme, the structure of the gold-nitrogen heterocyclic carbene catalyst is as follows:

[0011]

[0012] Furthermore, in the above scheme, the silver salt is any one of AgSbF6, AgBF4, AgPF6, AgPF6, AgOTf, and AgNTf2.

[0013] Furthermore, in the above scheme, the inert protective gas is any one or a mixture of nitrogen, argon, and helium.

[0014] Furthermore, in the above scheme, the solvent is selected from one or a mixture of organic solvents such as acetonitrile, tetrahydrofuran, 1,2-dichloroethane, dioxane, dichloromethane, nitromethane, diethyl ether, or chloroform.

[0015] Furthermore, in the above scheme, the structure X of the propynyl thioacetal compound 1 is selected from any of the following substituent groups: C1-10 cycloalkyl-(CH2). 1-10 -, -CH(CH3)-, -CH(CH2CH3)-, -CH(CH3)CH2-, -CH(CH2CH3)CH2-, -CH(CH3)CH(CH3)-, -CH(CH2CH3)CH(CH2CH3)-, -CH(CH3)CH2CH2-, 1,2-substituted phenyl 1,3-substituted phenyl 1,2-Dimethylene-substituted phenyl 1,3-Dimethyl-substituted phenyl -CH2CH2OCH2CH2OCH2CH2- or -CH2CH2SCH2CH2SCH2CH2-.

[0016] Furthermore, in the above scheme, the propynyl thioacetal compound 1 is a vinyl metal carbene precursor compound.

[0017] Furthermore, in the above scheme, the structure Y of the vinyl nucleobase derivative 2 is a nucleobase derivative, including but not limited to the following structures:

[0018] (1) Among them, R 1 Selected from: -N(PG)2, -NHPG, hydrogen, halogen, methyl, methoxy, ethoxy, phenyl;

[0019] R 2Selected from: halogen, hydrogen, methoxy, -NHPG, -N(PG)2, where PG includes, but is not limited to, one of the following groups: Boc (tert-butyloxycarbonyl), Bz (benzoyl), Pac (phenoxyacetyl), Ac (acetyl) or Fmoc (9-fluorenylmethoxycarbonyl).

[0020] (2) Among them, R 3 Selected from: -N(Pg)2, -NHPG, hydrogen, halogen, methoxy, ethoxy, phenyl.

[0021] (3) Among them, R 4 Selected from: hydrogen, halogen, methyl.

[0022] (4) Among them, R 5 Selected from: hydrogen, halogen, methyl, ethyl;

[0023] R 6 Selected from: hydrogen, methyl, ethyl, halogen, trifluoromethyl, acetoxy;

[0024] R 7 Selected from: hydrogen, methyl, Boc, Bz or Ac.

[0025] (5) Among them, R 8 Selected from: hydrogen, halogen, methyl, trifluoromethyl, -NHPG, -N(PG)2;

[0026] R 9 Selected from: hydrogen, halogen, methyl, methoxy, methoxycarbonyl, -NHPG, -N(PG)2;

[0027] R 10 Selected from: hydrogen, halogen, methyl, methoxy, methoxycarbonyl, -NHPG, -N(PG)2;

[0028] R 11 Selected from: hydrogen, halogen, methyl, methoxy, methoxycarbonyl, -NHPG, -N(PG)2;

[0029] R 12 Selected from: hydrogen, halogen, methyl, methoxy, methoxycarbonyl, -NHPG, -N(PG)2.

[0030] (6) Among them, R 13 Selected from: hydrogen, halogen, methyl, -NHPG, -N(PG)2;

[0031] R 14 Selected from: hydrogen, halogen, methyl, -NHPG, -N(PG)2;

[0032] R 15 Selected from: hydrogen, halogen, methyl, -NHPG, -N(PG)2;

[0033] R 16 Selected from: hydrogen, halogen, methyl, -NHPG, -N(PG)2.

[0034] (7) Among them, R 17 Selected from: hydrogen, halogen, methyl, -NHPG, -N(PG)2;

[0035] R 18 Selected from: hydrogen, halogen, methyl, methoxycarbonyl, -NHPG, -N(PG)2;

[0036] R 19 Selected from: hydrogen, halogen, methyl, -NHPG, -N(PG)2.

[0037] (8) Among them, R 20 Selected from: hydrogen, halogens.

[0038] Furthermore, in the above scheme, the concentration of the propynyl thioacetal compound 1 in the organic solvent is 0.05-0.3 mol / L.

[0039] Furthermore, in the above scheme, the amount of propynyl thioacetal compound 1 is calculated as 1 equivalent, the amount of vinyl compound 2 is 1.5-5.0 equivalent, the amount of gold-nitrogen heterocyclic carbene catalyst is 1-10 mol%, and the corresponding amount of silver salt is 1-10 mol.

[0040] Furthermore, in the above scheme, the reaction temperature is selected from 0℃ to 90℃, and the reaction time is 6-36h.

[0041] Furthermore, in the above scheme, the reaction operation is as follows: the gold-nitrogen heterocyclic carbene catalyst and the silver salt are first stirred in a solvent for 5-10 minutes, then the vinyl nucleobase derivative 2 is added and stirred for 2-5 minutes, and finally the propynyl thioacetal compound 1 dissolved in the solvent is slowly added dropwise.

[0042] Furthermore, in the above scheme, if propynyl thioacetal compound 1 is found to be incompletely converted, the temperature can be raised to 60-90°C until propynyl thioacetal compound 1 is found to be fully converted.

[0043] Furthermore, in the above scheme, after the reaction is completed, the reaction system is restored to room temperature, triethylamine is added to quench the reaction, the mixture is filtered, washed with ethyl acetate, the filtrates are combined, the solvent is evaporated under reduced pressure, petroleum ether and ethyl acetate are used as the mobile phase, and the disulfide vinylcyclopropane nucleoside analog rac-3 is obtained by silica gel column chromatography.

[0044] Furthermore, in the above scheme, the synthesis yielded a disulfide vinylcyclopropane nucleoside analog rac-3, the structure of which includes, but is not limited to, the following structural compounds:

[0045]

[0046] Or its corresponding and non-corresponding isomers, or pharmaceutically acceptable salts or solvent compounds, or their crystal forms.

[0047] Furthermore, in the above scheme, the following is stated:

[0048] (1) The disulfide vinylcyclopropane nucleoside analog rac-3 was obtained by hydrogenation desulfurization with Raney nickel to obtain the vinylcyclopropane nucleoside analog.

[0049] (2) Subsequently, ozone oxidation was performed, followed by reduction with NaBH4, and finally deprotection was performed to obtain a monohydroxymethylcyclopropane nucleoside analog.

[0050] (3) Its reaction formula is:

[0051]

[0052] The structures of Y described above are all consistent with the structure of Y in vinyl nucleobase derivative 2.

[0053] Furthermore, in the above scheme, the synthesis yielded the vinylcyclopropane nucleoside analog rac-4, which includes, but is not limited to, the following structural compounds:

[0054]

[0055] Or its corresponding and non-corresponding isomers, or pharmaceutically acceptable salts or solvent compounds, or their crystal forms.

[0056] Furthermore, in the above scheme, the synthesis yielded a monohydroxymethylcyclopropane nucleoside analog rac-5, which includes, but is not limited to, the following structural compounds:

[0057]

[0058] Or its corresponding and non-corresponding isomers, or pharmaceutically acceptable salts or solvent compounds, or their crystal forms.

[0059] Furthermore, in the above-described scheme, the monohydroxymethylcyclopropane nucleoside analog rac-5 further comprises a therapeutically effective amount of an AIDS treatment agent selected from HIV inhibitors, anti-infective agents, and immunomodulators for use as antiviral drugs.

[0060] Furthermore, in the above scheme, the HIV inhibitor is a non-nucleoside reversal rate enzyme inhibitor.

[0061] The prefix "Cx-y" (where x and y are integers) used in this invention refers to the number of carbon atoms in a given group. Therefore, C 1-7 Cycloalkyl groups contain 1 to 7 carbon atoms, C 1-10 Alkyl groups contain 1 to 10 carbon atoms, etc.

[0062] Unless otherwise indicated or clearly stated from the context, the term "halogen" as a group or part of a group is generally used for fluorine, chlorine, bromine, and iodine.

[0063] Some compounds of this invention are, in stereochemistry, designated by the prefix "rac" to indicate a racemic mixture with 50%:50% enantiomers, indicated by bonds shown as either solid or virtual wedges. Enantiomers are stereoisomers that are mirror images of each other and do not overlap. As an example:

[0064] instruct It is a 1:1 mixture.

[0065] Salts of the compounds described in this invention and their solvates may be those in which the counterions are pharmaceutically acceptable. The term "pharmaceutically acceptable salt" means that, to a reliable medical judgment, it is suitable for contact with the tissues of humans and lower animals without excessive toxicity, irritation, allergic reactions, etc., and in proportion to a reasonable benefit / risk ratio. Salts of non-pharmaceutically acceptable acids and bases may also be used, for example, for the preparation or purification of pharmaceutically acceptable compounds.

[0066] All salts, whether pharmaceutically acceptable or unacceptable, are included within the scope of this invention. Pharmaceutically acceptable salts include acid addition salts and base addition salts. Such salts can be formed by conventional means, for example by reacting a free acid or base with one or more equivalents of a suitable acid or base, optionally in a solvent or a medium in which the salt is insoluble, followed by removal of the solvent or medium using standard techniques (e.g., in a vacuum, by freeze-drying or by filtration). Salts can also be prepared by exchanging the counterion of a compound of the invention in salt form with another counterion, for example using a suitable ion exchange resin.

[0067] Beneficial effects of the invention:

[0068] This invention provides a concise and efficient new synthetic route for vinylcyclopropane nucleoside analogs and monohydroxymethylcyclopropane nucleoside analogs. The reaction conditions are mild, overcoming the disadvantages of potential explosiveness and lengthy synthetic routes of traditional methods. The starting materials are readily available, the reaction has high stereospecificity and selectivity (cis,dr:one diast.), the yield is moderate to excellent, and the product can be converted into a variety of other useful potential bioactive molecules, making it highly practical. Attached Figure Description

[0069] Figure 1 It is the disulfide vinylcyclopropane nucleoside analog rac-3-1 1 H hydrogen spectrum.

[0070] Figure 2 It is the disulfide vinylcyclopropane nucleoside analog rac-3-1 13 C64 carbon spectrum.

[0071] Figure 3 It is the disulfide vinylcyclopropane nucleoside analog rac-3-21 1 H hydrogen spectrum.

[0072] Figure 4 It is the vinylcyclopropane nucleoside analog rac-4-1 1 H hydrogen spectrum.

[0073] Figure 5 This is the reaction formula of the preparation method of the present invention. Detailed Implementation

[0074] The present invention will now be described in detail with reference to the embodiments.

[0075] Example 1

[0076] This embodiment provides a method for preparing a propynyl thioacetal compound, a method for preparing a compound as shown in the formula.

[0077]

[0078] The preparation steps are as follows: Diethyl acetal of propyne (1 equiv, 6 mmol), 1,3-propanedithiol (1.07 equiv.), and 250 mL of dry dichloromethane were added to a 500 mL round-bottom flask. An inert protective gas was introduced, and the mixture was stirred at room temperature for 10 minutes. After cooling to 0 °C, boron trifluoride ethyl ester ether (0.4 equiv.) was slowly added dropwise to the mixed reaction system. After reacting at room temperature for 72 h, 50 mL of saturated sodium carbonate solution was added to quench the reaction, and the organic solvent was removed by rotary evaporation under reduced pressure. The organic phase was washed with saturated sodium carbonate aqueous solution (3 × 30 mL), and the aqueous phase was extracted with n-pentane (3 × 30 mL). The organic phase was collected, washed with brine, dried over anhydrous sodium sulfate, and concentrated by rotary evaporation under reduced pressure. Purification was performed by silica gel chromatography with the eluent (0.2% petroleum ether diethyl ether) to obtain the target product 1a (0.52 g, 60%). Its structure is characterized as follows: a pale yellow oily liquid; 1 H NMR (400MHz, CDCl3): δ = 4.53 (d, J = 1.7Hz, 1H), 3.26 (ddd, J = 13.6, 9.8, 3.0Hz, 2H), 2.78 (ddd, J = 6 .4,3.0,0.8Hz,1H),2.74(ddd,J=6.2,3.2,0.9Hz,1H),2.71(d,J=2.4Hz,1H),2.13-1.97(m,2H); 13 C NMR (100MHz, CDCl3): δ = 80.0, 73.8, 32.0, 27.3 (2×C), 25.7; GCMS (EI): majorpeak (at 6.07): m / z 144 (M +· ,100),102(M +· -C2H4,40),97(M +· -CH3S,47),74(M +· -C3H2S,41),69(M +· -C3H7S,58),45(M +· -C5H7S,54).

[0079] Example 2

[0080]

[0081] In a dry round-bottom flask, add IPr*OMeAuCl (5% equivalent), AgSbF6 (5% equivalent), and 0.5 mL of dry 1,2-dichloroethane. After stirring the mixture for 10 minutes, add vinyl adenine 2-1a (3 equivalent) to the reaction system, followed by slow dropwise addition of propynyl thioacetal compound 1b (1 equivalent, 0.3 mmol) dissolved in 1.5 mL. Stir the reaction overnight at room temperature. Monitor by TLC until the starting propynyl thioacetal compound is completely consumed. Quench the reaction with 0.5 mL of triethylamine. Filter, then concentrate by rotary evaporation under reduced pressure. Column chromatography (eluent: 60% ethyl acetate in petroleum ether, +1% triethylamine) purified the product rac-3-1 (127 mg, 86%). Its structure is characterized as follows: brown solid; 1 H NMR (400MHz, CDCl3): δ = 8.87 (s, 1H), 8.14 (s, 1H), 5.94 (d, J = 1.0Hz, 1H; S-CH = C), 3.72 (td, J = 7.4 × (2), 4.5Hz, 1H; N-CH-CH2-CH), 2.93-2.85 (band ,4H; S-CH2-CH2-S), 2.18(dtd,J=9.2,7.1×(2),1.1Hz,1H;N-CH-CH2-CH),1.94(td,J=7.1×(2),4.5Hz,1H;N-CH-CHH-CH),1.61(dt,J=9.2,7.5×(2) Hz, 1H; N-CH-CHH-CH), 1.41 (s, 18H; 2 × C(CH3)3); 13 CNMR (100 MHz, CDCl3): δ= 154.8,152.0,150.3,150.2,145.4,128.8,121.2,114.3,83.5(2×C),30.7,27.8(6×C),27.4,26.2,25.4,9.1; NOESY:3.72×2.18;MS(EI):m / z 492(M ·+ +H + ,100).

[0082] Example 3

[0083]

[0084] In a dry round-bottom flask, add IPr*OMeAuCl (5% equivalent), AgSbF6 (5% equivalent), and 0.5 mL of dry 1,2-dichloroethane. After stirring the mixture for 10 minutes, add vinyluracil 2-4a (3 equivalent) to the reaction system, followed by slow dropwise addition of propynylthioacetal compound 1b (1 equivalent, 0.3 mmol) dissolved in 1.5 mL. Stir the reaction overnight at room temperature. Monitor by TLC until the starting propynylthioacetal compound is completely consumed. Quench the reaction with 0.5 mL of triethylamine. Filter, then concentrate by rotary evaporation under reduced pressure. Column chromatography (eluent: 55% ethyl acetate in petroleum ether, +1% triethylamine) to purify the target product rac-3-21 (67 mg, 83%). Its structure is characterized as follows: brown solid; 1 H NMR (400MHz, CDCl3): δ = 8.75 (br, 1H), 7.21 (d, J = 8.0Hz, 1H; N-CH = CH), 6.03 (d, J = 0.6Hz, 1H; S-CH=C),5.63(d,J=7.9Hz,1H;N-CH=CH),3.32(td,J=7.8×(2),4.8Hz,1H;N-CH-CH2-CH),3. 10-3.03(band,4H;S-CH2-CH2-S),2.07(tdd,J=9.2×(2),7.0,1.0Hz,1H;N-CH-CH2-CH),1.5 1(td,J=7.2×(2),4.8Hz,1H;N-CH-CHH-CH), 1.37(dt,J=9.2,7.7×(2)Hz,1H;N-CH-CHH-CH); 13 CNMR (100MHz, CDCl3): δ = 163.3, 151.5, 144.3, 121.2, 114.3, 101.1, 35.6, 27.7, 26.6, 25.6, 9.2; NOESY: 3.22×2.07; MS (EI): m / z 269 (M ·+ +H + ,100).

[0085] Example 4

[0086]

[0087] Prepare 1.2g in a 25mL double-necked round-bottom flask. -Nickel(ACROS TMThe activated W-3 ​​grade 50% suspension (washed three times with water) was added to 3 mL of THF. The mixture was refluxed for 10 minutes under an argon atmosphere, then cooled to room temperature. Subsequently, 0.3 mL of 20% sodium hydroxide aqueous solution and rac-3-1 (147 mg) dissolved in 3 mL of THF solution were added, and the mixture was stirred for 10 minutes at room temperature. Then, 2.4 g of [the solution] was added. -Nickel(ACROS TM The activated W-3 ​​grade 50% suspension was washed three times with water. After stirring at -10°C for 2 min, the starting material was no longer detectable by TLC. The reaction mixture was filtered through diatomaceous earth and washed with ethyl acetate. The organic phase was collected and the solvent was removed by rotary evaporation under reduced pressure. Column chromatography (eluent: 30% ethyl acetate in petroleum ether, +1% triethylamine) was performed to purify the target product rac-4-1 (72 mg, 60%). Its structure was characterized as follows: white solid; 1 H NMR (400MHz, CDCl3): δ=8.88(s,1H),8.03(s,1H),5.17-5.14(m,2H),4.94-4.91(m,1H),3.66(td,J=7.3×(2),4.5Hz,1H),2. 21-2.14(m,1H),1.66(ddd,J=8.9,7.5,6.7Hz,1H),1.53(td,J=6.7×(2),4.5Hz,1H; N-CH-CHH-CH), 1.41(s,18H;2×C(CH3)3); 13 C NMR (100MHz, CDCl3): δ=154.6,152.3,150.4(2×C),150.4,145.8,133.0,129.0,11 7.7,83.7(2×C),30.9,27.8(6×C),21.1,11.5;NOESY:3.66×2.21-2.14;MS(EI):m / z 402(M ·+ +H + ,43),250(M ·+ -H2O,59).

[0088] Example 5

[0089]

[0090] In a dry round-bottom flask, vinylcyclopropane adenine rac-4-1 (152 mg, 1 equiv.) and 5 mL of dry dichloromethane were added, and the mixture was cooled to -78 °C. Ozone was bubbled into the reaction system until it turned blue. After reacting for 3 h, sodium borohydride (1.1 equiv.) was added, and the reaction was continued at room temperature for 2 h. Subsequently, a dioxane solution with an appropriate amount of hydrogen chloride was slowly added dropwise, and the reaction was continued for 1 h. The solvent was removed by rotary evaporation under reduced pressure, and the mixture was extracted with ethyl acetate. Saturated sodium bicarbonate solution was added, and the organic phase was collected. The phase was washed with brine, dried over anhydrous sodium sulfate, and concentrated by rotary evaporation under reduced pressure. The product was purified by silica gel chromatography using eluent (2% methanol in dichloromethane, +1% triethylamine) to give the target product rac-5-1 (52 mg, 67%). Its structure is characterized as follows: white solid; 1 H NMR (400MHz, CDCl3): δ = 8.14 (s, lH), 8.11 (s, 1H), 7.25 (br, 2H, NH2), 4.72 (dd, J = 6.5, 4.6Hz, 1H), 3.46 (ddd, J = 7.2, 7.2, 4.3Hz, lH), 3.27 (ddd, J=11.7, 6.5, 5.6Hz, lH), 2.99 (ddd, J=11.7, 8.2, 4.6Hz, lH), 1.51 (m, lH), 1.27 (m, lH), 1.18 (m, 1H); HRMS: calcd for C9H 11 N5O + [M+H + ]:206.1042,found:206.1046.

[0091] In summary, this invention provides a concise method for the synthesis of vinylcyclopropane nucleoside analogs. Using propynyl thioacetal compounds and vinyl nucleobase derivatives as starting materials, a highly stereospecific and selective disulfide vinylcyclopropane nucleoside analog is obtained at room temperature in the presence of a gold-nitrogen heterocyclic carbene catalyst. Furthermore, hydrodesulfurization yields the vinylcyclopropane nucleoside analog, followed by oxidation, reduction, or deprotection, resulting in a potentially biologically active monohydroxymethylcyclopropane nucleoside analog in three steps. Compared to previously reported synthetic methods requiring 11-18 steps, the synthetic route disclosed here is more concise and efficient.

[0092] In various cyclopropane nucleoside synthesis schemes, the traditional method utilizes transition metal-induced decomposition of diazo compounds. However, diazo compounds are unstable, explosive, and toxic. Furthermore, commonly used vinyldiazo metal carbene precursors often contain difficult-to-remove substituent groups (alkyl, phenyl, ester groups), limiting their application in the synthesis of natural products and active pharmaceutical molecules. Additionally, disulfide substituents can be removed via hydrodesulfurization. This method overcomes the potential explosiveness and lengthy synthetic routes of traditional methods, offering milder conditions, readily available starting materials, high stereospecificity and selectivity, and the ability to convert the product into various other useful potential bioactive molecules, making it highly practical.

[0093] The foregoing has shown and described the basic principles, main features, and advantages of the present invention. Those skilled in the art should understand that the present invention is not limited to the above embodiments. The embodiments and descriptions in the specification are merely illustrative of the principles of the invention. Various changes and modifications can be made to the invention without departing from its spirit and scope, and all such changes and modifications fall within the scope of the present invention as claimed. The scope of protection of this invention is defined by the claims and their equivalents.

Claims

1. A method for preparing a monohydroxymethylcyclopropane nucleoside analog, characterized in that, Includes the following steps: (1) Weigh an appropriate amount of gold-nitrogen heterocyclic carbene catalyst and silver salt, introduce an inert protective gas, and stir the reaction in an organic solvent for a certain period of time. The structure of the gold-nitrogen heterocyclic carbene catalyst is as follows: ; The silver salt is AgSbF6; (2) Weigh out appropriate amounts of raw material vinyl nucleobase derivative 2 and raw material propynyl thioacetal compound 1 and dissolve them in an organic solvent. Then add them sequentially to the reaction system containing a gold-nitrogen heterocyclic carbene catalyst and react at a certain temperature for a certain time. (3) After the reaction is complete, the reaction is quenched, the solvent is removed by separation and vacuum distillation to obtain the disulfide vinylcyclopropane nucleoside analog rac-3, whose general reaction equation is as follows: ； The disulfide vinylcyclopropane nucleoside analog rac-3 is selected from the following structures: ; (4) Desulfurization yields the vinylcyclopropane nucleoside analog rac-4: ; (5) Oxidation with ozone, followed by reduction with NaBH4, and finally deprotection to obtain the monohydroxymethylcyclopropane nucleoside analog rac-5; the monohydroxymethylcyclopropane nucleoside analog rac-5 is selected from the following structural compounds: 。 2. The preparation method according to claim 1, characterized in that, In step (1): The organic solvent is selected from one or more of acetonitrile, tetrahydrofuran, 1,2-dichloroethane, dioxane, dichloromethane, nitromethane, diethyl ether, or chloroform.

3. The preparation method according to claim 1, characterized in that, The propynyl thioacetal compound 1 mentioned in step (2) is a vinyl metal carbene precursor compound, and its preparation method includes: Weigh appropriate amounts of raw material propyne aldehyde diethyl acetal and raw material dithiol compound and dissolve them in an organic solvent of a certain concentration. Inert protective gas is introduced, and then a catalytic equivalent of Lewis acid is added as a catalyst. The reaction is carried out at a suitable temperature for a certain time. After the reaction is completed, the reaction is quenched, and post-reaction treatment is performed. The solvent is removed by column chromatography and vacuum distillation to obtain propyne thioacetal compound 1.

4. The preparation method according to claim 1, characterized in that: The concentration of propynyl thioacetal compound 1 in the organic solvent in step (2) is 0.05-0.3 mol / L; based on the amount of propynyl thioacetal compound 1 being 1 equivalent, the amount of vinyl nucleobase derivative 2 is 1.5-5.0 equivalents, the amount of gold-nitrogen heterocyclic carbene catalyst is 1-10 mol%, and the corresponding amount of silver salt is 1-10 mol%. The reaction temperature in step (2) is 0℃-90℃, and the reaction time is 6-36h; After the reaction in step (3) is completed, the reaction system is restored to room temperature, triethylamine is added to quench the reaction, the mixture is filtered, washed with ethyl acetate, the filtrates are combined, the solvent is evaporated under reduced pressure, petroleum ether and ethyl acetate are used as the mobile phase, and the disulfide vinylcyclopropane nucleoside analog rac-3 is obtained by silica gel column chromatography.

Images