Preparation method of 2 '-C alkynyl nucleoside and 2'-C alkynyl nucleoside

Abstract

The invention relates to the field of chemical medicine preparation, in particular to a preparation method of 2 '-C alkynyl nucleoside and the 2'-C alkynyl nucleoside. The invention provides a preparation method of 2 '-C alkynyl nucleoside. The preparation method comprises the following steps: firstly, oxidizing hydroxyl on a furan ring into carbonyl through a Dess Martin oxidizing agent; then alkynyl compound salt and a catalyst are added, C = O in carbonyl is opened, alkynyl is introduced to a C atom, and benzoyl is introduced to an O atom. Then adding acetamide, a basic group, anhydrous acetonitrile and stannic chloride to obtain an intermediate containing glucoside; most importantly, methanol and methoxide are added to prepare 2 '-C alkynyl nucleoside. The invention further provides the 2 '-C alkynyl nucleoside.

Description

Technical Field

[0001] The present invention relates to the field of chemical drug preparation, and in particular to a preparation method of 2'-C alkynyl nucleoside and the 2'-C alkynyl nucleoside. Background Art

[0002] Nucleosides and their derivatives have significant effects in treating malignant tumors and antiviral activities. Currently, some 2′-C branched nucleosides have shown good anticancer and antiviral activities, such as DNA cleavage and ribonucleotide reductase inactivation. 2′-C alkynyl ribonucleotides, as bio-organic tools and potential chemotherapeutic drugs, have been designed as potential ribonucleotide reductase inactivators. However, there is no clear method for synthesizing 2′-C alkynyl nucleosides. Summary of the invention

[0003] In order to solve the problems and shortcomings in the prior art, the present invention provides a method for preparing a 2′-C alkynyl nucleoside and a 2′-C alkynyl nucleoside. The specific steps of the above-mentioned preparation method include:

[0004] A catalyst and an alkynyl compound salt are added to the compound 1 to obtain a mixture of compound 2 and compound 3; the structural formulas of the compound 1, compound 2 and compound 3 are respectively:

[0005] Wherein R1 can be one of trimethylacetylene, propyne or acetylene. The synthesis route is:

[0006]

[0007] The BzCl is added to the mixture to obtain compound 4; the structural formula of compound 4 is:

[0008]

[0009] The base, acetamide or hexamethyldisilazane, anhydrous acetonitrile, tin chloride or trimethylsilyl trifluoromethanesulfonate and the compound 4 are mixed in a first preset ratio to obtain a glycoside intermediate, the structural formula of the glycoside intermediate is:

[0010] Wherein R2 is a base;

[0011] The glycoside intermediate, methanol and methanol salt are mixed in a second preset ratio to obtain a 2′-C alkynyl nucleoside, wherein the methanol salt is one of sodium methanolate or ammonia methanol, and the structural formula of the 2′-C alkynyl nucleoside is

[0012] Optionally, the preparation method further comprises: adding Dess-Martin periodinane to compound 6 to obtain compound 1; the structural formula of compound 6 is:

[0013]

[0014] Optionally, the step of adding an oxidant to compound 6 to obtain compound 1 comprises:

[0015] Dissolving Dess-Martin periodinane in dichloromethane to obtain a first solution;

[0016] Dissolving the compound 6 in dichloromethane to obtain a second solution;

[0017] Slowly adding the second solution into the first solution, reacting at a first preset temperature for a first preset time;

[0018] adding a saturated sodium thiosulfate aqueous solution, separating and drying to obtain a first reactant;

[0019] The first reactant is purified to obtain compound 1.

[0020] Optionally, the step of adding a catalyst and an alkynyl compound salt to the compound 1 to obtain a mixture of compound 2 and compound 3 comprises:

[0021] Dissolving compound 1 in tetrahydrofuran to obtain a third solution;

[0022] dissolving the alkynyl compound salt in tetrahydrofuran to obtain a fourth solution;

[0023] After adding the catalyst to the third solution, slowly adding the fourth solution to the third solution, reacting at a second preset temperature for a second preset time;

[0024] After adding saturated NH4Cl aqueous solution to the above reaction system, extraction was performed with and dried to obtain compound 2 and compound 3, wherein the extractant was one of ethyl acetate or dichloromethane.

[0025] Optionally, the step of adding BzCl to the mixture to obtain compound 4 comprises:

[0026] dissolving the mixture of the compound 2 and the compound 3 in pyridine to obtain a fifth solution;

[0027] Slowly adding BzCl to the fifth solution, and reacting at a third preset temperature for a third preset time;

[0028] The above reaction system was added with sodium bicarbonate aqueous solution, extracted with ethyl acetate, and dried to obtain the compound 4.

[0029] Optionally, the base, acetamide and anhydrous acetonitrile, tin chloride and the compound 4 are mixed in a first preset ratio to obtain a glycoside intermediate, comprising:

[0030] Mixing the base, the BSA and the anhydrous acetonitrile, and reacting at a fourth preset temperature for a fourth preset time to obtain a sixth solution;

[0031] After adding the compound 4 to the sixth solution, slowly adding tin chloride, and reacting at a fifth preset temperature for a fifth preset time;

[0032] The above reaction system was added with sodium bicarbonate aqueous solution, extracted with ethyl acetate, and dried to obtain the glycoside intermediate.

[0033] Optionally, the glycoside intermediate, methanol and sodium methoxide are mixed in a second preset ratio to obtain a 2′-C alkynyl nucleoside, comprising:

[0034] Mixing the glycoside intermediate, the methanol and the sodium methoxide, and reacting them at a sixth preset temperature for a sixth preset time;

[0035] After adding dilute hydrochloric acid to adjust to neutrality, the solution was dried and passed through a column to obtain 2′-C alkynyl nucleoside.

[0036] Optionally, the catalyst is one or more of cerium chloride, lanthanum chloride, praseodymium chloride, titanium tetrachloride or n-butyl lithium.

[0037] Optionally, the alkynyl compound salt is one of ethynyl magnesium bromide, trimethylsilylacetylene or propyne bromide.

[0038] Optionally, the base is one of uracil, cytosine or guanine.

[0039] The present invention also provides a 2′-C alkynyl nucleoside, which is prepared by any of the above-mentioned methods for preparing 2′-C alkynyl nucleoside.

[0040] Beneficial effects: The present invention uses compound 1 as a raw material, and introduces an alkynyl group to the furan ring in compound 1 under the action of a catalyst. Then, BzCl is added to complete the substitution of H in the hydroxyl group by the benzoyl group, and finally a 2′-C alkynyl nucleoside is prepared through a glycoside intermediate. A short and flexible synthesis route for 2′-C alkynyl nucleoside is clarified.

[0041] Based on the following detailed description of specific embodiments of the present invention in conjunction with the accompanying drawings, those skilled in the art will become more aware of the above and other objects, advantages and features of the present invention. BRIEF DESCRIPTION OF THE DRAWINGS

[0042] Hereinafter, some specific embodiments of the present invention will be described in detail in an exemplary and non-limiting manner with reference to the accompanying drawings. The same reference numerals in the accompanying drawings indicate the same or similar components or parts. It should be understood by those skilled in the art that these drawings are not necessarily drawn to scale. In the accompanying drawings:

[0043] Figure 1 is a process flow chart of 2′-C alkynyl nucleoside according to one embodiment of the present invention;

[0044] Figure 2 is a process flow chart of 2′-C alkynyl nucleoside according to another embodiment of the present invention. DETAILED DESCRIPTION

[0045] Refer to the following Figure 1 to Figure 2 To describe a method for preparing a 2′-C alkynyl nucleoside and a 2′-C alkynyl nucleoside according to an embodiment of the present invention. In the description of this embodiment, it should be understood that the terms “first” and “second” are used for descriptive purposes only and cannot be understood as indicating or implying relative importance or implicitly indicating the number of technical features indicated. Thus, the features defined as “first” and “second” may explicitly or implicitly include at least one of the features, that is, include one or more of the features. In the description of the present invention, the meaning of “multiple” is at least two, such as two, three, etc., unless otherwise clearly and specifically defined. When a feature “includes or contains” one or some of the features it covers, unless otherwise specifically described, this indicates that other features are not excluded and may further include other features.

[0046] In the description of the present embodiment, the description with reference to the terms "one embodiment", "some embodiments", "illustrative embodiments", "examples", "specific examples", or "some examples" means that the specific features, structures, materials, or characteristics described in conjunction with the embodiment or example are included in at least one embodiment or example of the present invention. In this specification, the schematic representation of the above terms does not necessarily refer to the same embodiment or example. Moreover, the specific features, structures, materials, or characteristics described may be combined in any one or more embodiments or examples in a suitable manner.

[0047] Figure 1 FIG. 2 is a process flow chart of a 2′-C alkynyl nucleoside according to an embodiment of the present invention. Figure 1 As shown, combined with Figure 2 The present invention provides a method for preparing a 2′-C alkynyl nucleoside and a 2′-C alkynyl nucleoside, wherein the preparation method comprises the following steps:

[0048] Step S20, adding cerium oxide and ethynyl magnesium bromide to compound 1 to obtain a mixture of compound 2 and compound 3;

[0049] Step S30, adding BzCl to a mixture of compound 2 and compound 3 to obtain compound 4;

[0050] Step S40, mixing the base, acetamide, anhydrous acetonitrile, tin chloride and compound 4 in a first preset ratio to obtain a glycoside intermediate;

[0051] Step S50, mixing the glycoside intermediate, methanol and sodium methoxide in a second preset ratio to obtain a 2′-C alkynyl nucleoside.

[0052] In this example, the synthesis route of 2′-C alkynyl nucleoside is:

[0053]

[0054] Among them, R1 represents an alkynyl group, and R2 represents a base.

[0055] It should be noted that in other embodiments of the present invention, one or more of lanthanum chloride, praseodymium chloride, titanium tetrachloride or n-butyl lithium can be used to replace cerium oxide in step S20. Trimethylsilyl acetylene or propyne bromide can also be used to replace ethynyl magnesium bromide. In step S40, hexamethyldisilazane is used to replace acetamide, and trimethylsilyl trifluoromethanesulfonate is used to replace tin chloride. In step S50, ammonia methanol is used to replace sodium methoxide.

[0056] In the above embodiment, first, an alkynyl compound salt and a catalyst are added to compound 1, so that C=O on the furan ring in compound 1 is changed to CO, and an alkynyl group is introduced into the position corresponding to C on the furan ring to obtain a mixture containing an alkynyl group. Secondly, BzCl is added to the mixture to achieve the substitution of H in the hydroxyl group by the benzoyl group. Thirdly, compound 5 and tin chloride are added to a mixture of a base, acetamide and anhydrous acetonitrile in sequence to obtain a nucleoside intermediate. Finally, the nucleoside intermediate is mixed with methanol and methoxide for reaction, and the pH value is adjusted to neutral, and the mixture is dried and filtered to obtain a 2′-C alkynyl nucleoside.

[0057] In the above embodiments, the synthesis pathway of 2′-C alkynyl nucleoside is short and the yield is high, so that 2′-C alkynyl nucleoside can be prepared using a short and flexible synthesis pathway.

[0058] like Figure 2 As shown, in some embodiments of the present invention, the method for preparing 2′-C alkynyl nucleoside further includes: step S10, adding Dess-Martin periodinane to compound 6 to obtain compound 1.

[0059] In this example, Dess-Martin periodinane is added to compound 6 to prepare compound 1, which is a simple method.

[0060] In some embodiments of the present invention, the above-mentioned addition of Dess-Martin periodinane to compound 6 to obtain compound 1 comprises:

[0061] Step S11, dissolving Dess-Martin periodinane in dichloromethane to obtain a first solution;

[0062] Step S12, dissolving compound 6 in dichloromethane to obtain a second solution;

[0063] Step S13, slowly adding the second solution into the first solution, and reacting at a first preset temperature for a first preset time;

[0064] Step S14, adding a saturated sodium thiosulfate aqueous solution, separating and drying to obtain a first reactant;

[0065] Step S15, purifying the first reactant to obtain compound 1.

[0066] Specifically, dichloromethane is used as a solvent to dissolve the Dess-Martin periodinant and compound 6 into a solution. Then, the solution of the compound is slowly added dropwise into the solution of the oxidant, and after the reaction is complete, compound 1 is obtained by extraction, separation, drying and purification.

[0067] In this embodiment, Dess-Martin periodinane and compound 6 are prepared into solutions respectively, which is convenient for controlling the dropping speed and the reaction is more complete.

[0068] In some embodiments of the present invention, the above-mentioned step of adding the catalyst and the alkynyl compound salt to compound 1 to obtain a mixture of compound 2 and compound 3 comprises:

[0069] Step S21, dissolving compound 1 in tetrahydrofuran to obtain a third solution;

[0070] Step S22, dissolving ethynylmagnesium bromide in tetrahydrofuran to obtain a fourth solution;

[0071] Step S23, after adding cerium chloride to the third solution, slowly adding the fourth solution to the third solution, reacting at a second preset temperature for a second preset time;

[0072] Step S24, adding saturated NH4Cl aqueous solution to the above reaction system, extracting with ethyl acetate, and drying to obtain a mixture of compound 2 and compound 3.

[0073] In other words, in order to prepare a mixture of compound 2 and compound 3, compound 1 and ethynyl magnesium bromide are first dissolved in tetrahydrofuran to obtain a solution containing compound 1 and a solution containing compound ethynyl magnesium bromide. Next, cerium oxide and the solution containing ethynyl magnesium bromide are sequentially added dropwise to the solution containing compound 1 to react fully. Finally, the above reaction system is added with a saturated NH4Cl aqueous solution, extracted with ethyl acetate, and dried.

[0074] In this embodiment, since tetrahydrofuran has the characteristics of low viscosity and good chemical stability, it can provide good fluidity for the third solution and the fourth solution, while ensuring stability and reliability during the chemical synthesis process.

[0075] In other embodiments of the present invention, in step S22, one or more of lanthanum chloride, praseodymium chloride, titanium tetrachloride or n-butyl lithium can be used to replace cerium oxide. In step S22, trimethylsilyl acetylene or propyne bromide can be used to replace ethynyl magnesium bromide. In step S24, dichloromethane can be used as an extractant instead of ethyl acetate. In this embodiment, dichloromethane is used as an extractant, which has the advantages of strong dissolving power, fast extraction speed and high environmental protection.

[0076] In some embodiments of the present invention, the above-mentioned adding the alkynyl compound salt to the mixture to obtain compound 5 comprises:

[0077] Step S31, dissolving a mixture of compound 2 and compound 3 in pyridine to obtain a fifth solution;

[0078] Step S32, slowly adding BzCl into the fifth solution, and reacting at a third preset temperature for a third preset time;

[0079] Step S33, adding sodium bicarbonate aqueous solution to the above reaction system, extracting with ethyl acetate, and drying to obtain compound 4.

[0080] In this embodiment, BzCl is added to the fifth solution so that the benzoyl group completely replaces the H atom in the hydroxyl group.

[0081] In some embodiments of the present invention, the above-mentioned mixing of the base, acetamide and anhydrous acetonitrile, tin chloride and compound 4 in a first preset ratio to obtain a glycoside intermediate comprises:

[0082] Step S41, mixing the base, BSA and anhydrous acetonitrile, and reacting at a fourth preset temperature for a fourth preset time to obtain a sixth solution;

[0083] Step S42, after adding compound 4 to the sixth solution, slowly adding tin chloride, and reacting at a fifth preset temperature for a fifth preset time;

[0084] Step S43, adding sodium bicarbonate aqueous solution to the above reaction system, extracting with ethyl acetate, and drying to obtain a glycoside intermediate.

[0085] In some embodiments of the present invention, the above-mentioned mixing of the glycoside intermediate, methanol and sodium methoxide in a second preset ratio to obtain a 2′-C alkynyl nucleoside comprises:

[0086] Step S51, mixing the glycoside intermediate, methanol and sodium methoxide, and reacting them at a sixth preset temperature for a sixth preset time;

[0087] Step S52, adding dilute hydrochloric acid to adjust to neutrality, drying, and column passing to obtain 2'-C alkynyl nucleoside.

[0088] In some other embodiments of the present invention, in step S51, ammonia methanol is used instead of sodium methoxide. In some embodiments of the present invention, the base is one of uracil, cytosine or guanine.

[0089] The present invention also provides a 2′-C alkynyl nucleoside, which is prepared by the preparation method in any one of the above embodiments.

[0090] The present invention is specifically explained below using several embodiments, and the technical solutions in the embodiments of the present invention are clearly and completely described. The described embodiments are only a part of the embodiments of the present invention, rather than all the embodiments.

[0091] Example 1

[0092] A method for preparing a 2′-C alkynyl nucleoside, comprising the following specific steps:

[0093] Step 101, (201 g, 47.4 mmol) Dess-Martin periodinane was placed in a 2 L round-bottom flask, 1000 mL of dry dichloromethane was added as solvent to obtain a first solution, which was placed in a cold well at 0°C;

[0094] Step 102, dissolving (150 g, 32.5 mmol) of compound 6 in 500 mL of dichloromethane to obtain a second solution;

[0095] Step 103, slowly adding the second solution to the first solution, and moving to room temperature to react for 2 hours after the addition;

[0096] Step 104, after the reaction is complete as detected by TLC, 600 ml of saturated sodium thiosulfate aqueous solution is added to quench the reaction, the organic phase is separated, and the organic phase is dried to obtain the first reactant;

[0097] Step 105, evaporating to dryness and then purifying by column to obtain 95 g of compound 1 with a yield of 70%;

[0098] Step 106, place (95 g, 20.7 mmol) of compound 1 in a 2 L round-bottom flask, add 500 mL of dry THF as solvent, and place in a -78°C cold well to obtain a third solution;

[0099] Step 107, dissolving ethynylmagnesium bromide in tetrahydrofuran to obtain a fourth solution;

[0100] Step 108, add (20.41 g, 82.8 mmol) of cerium chloride to the third solution, then slowly dropwise add (830 mL, 41.4 mmol) of the fourth solution, and react at 25° C. for 3 h after the reaction is complete;

[0101] Step 109, after TLC detection of the completion of the reaction, the above reaction system was slowly poured into 1L of saturated NH4Cl aqueous solution, and then extracted with 1L of ethyl acetate, dried, and passed through a silica gel column to obtain 75g of a mixture of compound 2 and compound 3 with a yield of 75%.

[0102] Step 110, dissolving a mixture of compound 2 and compound 3 (75 g, 154 mmol) in 800 mL of dry pyridine to obtain a fifth solution;

[0103] Step 111, slowly drop BzCl (22 mL, 185 mmol) into the fifth solution at 0°C, and after the dropwise addition is complete, move the mixture to 25°C for reaction for 2 hours;

[0104] Step 112, after TLC shows that the reaction is complete, the reaction system in step 111 is slowly poured into 1L of sodium bicarbonate aqueous solution, and then 1L of ethyl acetate is added for extraction, dried, and the sample is mixed with silica gel and passed through a column to obtain 70g of compound 4 with a yield of 80%;

[0105] Step 113, adding 3 g uracil (2 eq), 11 g BSA (4 eq) and 50 mL anhydrous acetonitrile into a 100 mL round-bottom flask, mixing, and reacting at 60° C. for 30 min to obtain a sixth solution;

[0106] Step 114, add 8 g of compound 4 to the sixth solution, slowly add 4.8 mL of SnCl4 (3 eq) at 0° C., and after the addition is complete, move to 80° C. and continue the reaction for 48 h. TLC detection shows that the reaction is complete.

[0107] Step 115, pour the reaction system in step 113 into a sodium bicarbonate aqueous solution, extract with ethyl acetate, evaporate to dryness, mix with silica gel, and pass through a column with PE:EA=2:1 to obtain 4.3 g of glycoside intermediate with a yield of 55%;

[0108] Step 116, add 4.3 g of the glycoside intermediate to 50 mL of methanol to obtain a seventh mixed solution; add 1.4 g of sodium methoxide (3.5 eq) to the seventh mixed solution, react at 25° C. for 10 min, and detect the completion of the reaction by TLC. Adjust the mixture to neutral with dilute hydrochloric acid, evaporate to dryness, mix the sample with silica gel and pass it through a column to obtain 1.38 g of alkynyl nucleoside with a yield of 72%.

[0109] Example 2

[0110] A method for preparing a 2′-C alkynyl nucleoside, comprising the following specific steps:

[0111] The difference from Example 1 is that

[0112] Step 106, place (57 g, 12.4 mmol) of compound 1 in a 2 L round-bottom flask, add 300 mL of dry THF as solvent, and place in a -78°C cold well to obtain a third solution;

[0113] Step 107, dissolving ethynylmagnesium bromide in tetrahydrofuran to obtain a fourth solution;

[0114] Step 108, add (12.16 g, 49.6 mmol) of lanthanum chloride to the third solution, then slowly dropwise add (498 mL, 24.8 mmol) of the fourth solution, and react at 25° C. for 3 h after the dropwise addition is complete;

[0115] Step 109, after TLC detection of the reaction is complete, the above reaction system is slowly poured into 600 mL of saturated NH4Cl aqueous solution, and then extracted with 600 mL of dichloromethane, dried, and passed through a silica gel column to obtain 30.7 g of a mixture of compound 2 and compound 3, with a yield of 51%.

[0116] Example 3

[0117] A method for preparing a 2′-C alkynyl nucleoside, comprising the following specific steps:

[0118] The difference from Example 1 is that

[0119] Step 106, place (38 g, 8.28 mmol) of compound 1 in a 2 L round-bottom flask, add 200 mL of dry THF as solvent, and place in a -78 ° C cold well to obtain a third solution;

[0120] Step 107, dissolving ethynylmagnesium bromide in tetrahydrofuran to obtain a fourth solution;

[0121] Step 108, add (8.18 g, 33.1 mmol) of praseodymium chloride to the third solution, then slowly dropwise add (332 mL, 16.56 mmol) of the fourth solution, and react at 25° C. for 3 h after the dropwise addition is complete;

[0122] Step 109, after TLC detection of the completion of the reaction, the above reaction system was slowly poured into 400 mL of saturated NH4Cl aqueous solution, and then extracted with 400 mL of ethyl acetate, dried, and passed through a silica gel column to obtain 19.27 g of a mixture of compound 2 and compound 3, with a yield of 48%.

[0123] Example 4

[0124] A method for preparing a 2′-C alkynyl nucleoside, comprising the following specific steps:

[0125] The difference from Example 1 is

[0126] Step 106, placing (28.5 g, 6.21 mmol) of compound 1 in a 2 L round-bottom flask, adding 1500 mL of dry THF as a solvent, and placing in a -78°C cold well to obtain a third solution;

[0127] Step 107, dissolving ethynylmagnesium bromide in tetrahydrofuran to obtain a fourth solution;

[0128] Step 108, add (4.71 g, 2.72 ml, 24.84 mmol) of titanium tetrachloride to the third solution, then slowly dropwise add (249 mL, 12.42 mmol) of 0.5 M fourth solution, and react at 25° C. for 3 h after the dropwise addition is complete;

[0129] Step 109, after TLC detection of the reaction is complete, the above reaction system is slowly poured into 400 mL of saturated NH4Cl aqueous solution, and then extracted with 400 mL of ethyl acetate, dried, and passed through a silica gel column to obtain 16.26 g of a mixture of compound 2 and compound 3, with a yield of 54%.

[0130] The structural formula of the 2′-C alkynyl nucleoside obtained in Examples 1 to 4 is

[0131] Example 5

[0132] A method for preparing a 2′-C alkynyl nucleoside, comprising the following specific steps:

[0133] The difference from Example 1 is

[0134] Step 113, adding 3 g of cytosine (2 eq), 11 g of BSA (4 eq) and 60 mL of anhydrous acetonitrile into a 100 mL round-bottom flask, mixing, and reacting at 60° C. for 30 min to obtain a sixth solution;

[0135] Step 114, add 8 g of compound 4 to the sixth solution, slowly add 4.8 mL of SnCl4 (3 eq) at 0° C., and after the addition is complete, move to 80° C. and continue the reaction for 48 h. TLC detection shows that the reaction is complete.

[0136] Step 115, pouring the reaction system in step 113 into a sodium bicarbonate aqueous solution, extracting with ethyl acetate, evaporating to dryness, mixing with silica gel, and passing through a column with PE:EA=2:1 to obtain 3.5 g of a glycoside intermediate with a yield of 48%;

[0137] Step 116, add 3.5 g of the glycoside intermediate to 40 mL of methanol to obtain a seventh mixed solution; add 1.3 g of sodium methoxide (3.5 eq) to the seventh mixed solution, react at 25° C. for 10 min, and detect the completion of the reaction by TLC. Adjust the mixture to neutral with dilute hydrochloric acid, evaporate to dryness, mix the sample with silica gel and pass it through a column to obtain 0.74 g of alkynyl nucleoside with a yield of 50%.

[0138] Example 6

[0139] A method for preparing a 2′-C alkynyl nucleoside, comprising the following specific steps:

[0140] The difference from Example 2 is

[0141] Step 113, adding 3 g of cytosine (2 eq), 11 g of hexamethyldisilazane (4 eq) and 60 mL of anhydrous acetonitrile into a 100 mL round-bottom flask, mixing, and reacting at 60° C. for 30 min to obtain a sixth solution;

[0142] Step 114, add 8 g of compound 4 to the sixth solution, slowly add 4.8 mL of trimethylsilyl trifluoromethanesulfonate (3 eq) at 0° C., after the addition is complete, move to 80° C. and continue the reaction for 48 h. TLC detection shows that the reaction is complete.

[0143] Step 115, pouring the reaction system in step 113 into a sodium bicarbonate aqueous solution, extracting with ethyl acetate, evaporating to dryness, mixing with silica gel, and passing through a column with PE:EA=2:1 to obtain 3.5 g of a glycoside intermediate with a yield of 48%;

[0144] Step 116, add 3.5 g of the glycoside intermediate to 40 mL of methanol to obtain a seventh mixed solution; add 1.3 g of sodium methoxide (3.5 eq) to the seventh mixed solution, react at 25° C. for 10 min, and detect the completion of the reaction by TLC. Adjust the mixture to neutral with dilute hydrochloric acid, evaporate to dryness, mix the sample with silica gel and pass it through a column to obtain 0.74 g of alkynyl nucleoside with a yield of 50%.

[0145] Example 7

[0146] A method for preparing a 2′-C alkynyl nucleoside, comprising the following specific steps:

[0147] The difference from Example 3 is

[0148] Step 113, adding 3 g of cytosine (2 eq), 11 g of BSA (4 eq) and 60 mL of anhydrous acetonitrile into a 100 mL round-bottom flask, mixing, and reacting at 60° C. for 30 min to obtain a sixth solution;

[0149] Step 114, add 8 g of compound 4 to the sixth solution, slowly add 4.8 mL of SnCl4 (3 eq) at 0° C., and after the addition is complete, move to 80° C. and continue the reaction for 48 h. TLC detection shows that the reaction is complete.

[0150] Step 115, pouring the reaction system in step 113 into a sodium bicarbonate aqueous solution, extracting with ethyl acetate, evaporating to dryness, mixing with silica gel, and passing through a column with PE:EA=2:1 to obtain 3.5 g of a glycoside intermediate with a yield of 48%;

[0151] Step 116, add 3.5 g of the glycoside intermediate to 40 mL of methanol to obtain a seventh mixed solution; add 1.3 g of ammonia methanol (3.5 eq) to the seventh mixed solution, react at 25° C. for 10 min, and detect the completion of the reaction by TLC. Adjust the mixture to neutral with dilute hydrochloric acid, evaporate to dryness, mix the sample with silica gel and pass it through a column to obtain 0.74 g of alkynyl nucleoside with a yield of 50%.

[0152] Example 8

[0153] A method for preparing a 2′-C alkynyl nucleoside, comprising the following specific steps:

[0154] The difference from Example 4 is

[0155] Step 113, adding 3 g of cytosine (2 eq), 11 g of BSA (4 eq) and 60 mL of anhydrous acetonitrile into a 100 mL round-bottom flask, mixing, and reacting at 60° C. for 30 min to obtain a sixth solution;

[0156] Step 114, add 8 g of compound 4 to the sixth solution, slowly add 4.8 mL of SnCl4 (3 eq) at 0° C., and after the addition is complete, move to 80° C. and continue the reaction for 48 h. TLC detection shows that the reaction is complete.

[0157] Step 115, pouring the reaction system in step 113 into a sodium bicarbonate aqueous solution, extracting with ethyl acetate, evaporating to dryness, mixing with silica gel, and passing through a column with PE:EA=2:1 to obtain 3.5 g of a glycoside intermediate with a yield of 48%;

[0158] Step 116, add 3.5 g of the glycoside intermediate to 40 mL of methanol to obtain a seventh mixed solution; add 1.3 g of sodium methoxide (3.5 eq) to the seventh mixed solution, react at 25° C. for 10 min, and detect the completion of the reaction by TLC. Adjust the mixture to neutral with dilute hydrochloric acid, evaporate to dryness, mix the sample with silica gel and pass it through a column to obtain 0.74 g of alkynyl nucleoside with a yield of 50%.

[0159] The structural formula of the 2′-C alkynyl nucleoside obtained in Examples 5 to 8 is

[0160] Example 9

[0161] A method for preparing a 2′-C alkynyl nucleoside, comprising the following specific steps:

[0162] The difference from Example 1 is

[0163] Step 113, adding 4.2 g 6-chloropurine (2 eq), 11 g BSA (4 eq) and 60 mL anhydrous acetonitrile into a 100 mL round-bottom flask, mixing, and reacting at 60° C. for 30 min to obtain a sixth solution;

[0164] Step 114, add 8 g of compound 4 to the sixth solution, slowly add 4.8 mL of SnCl4 (3 eq) at 0° C., and after the addition is complete, move to 80° C. and continue the reaction for 48 h. TLC detection shows that the reaction is complete.

[0165] Step 115, pouring the reaction system in step 113 into a sodium bicarbonate aqueous solution, extracting with ethyl acetate, evaporating to dryness, mixing with silica gel, passing through a column, and crystallizing with ethanol to obtain 3.0 g of a glycoside intermediate with a yield of 38%;

[0166] Step 116, 3.0 g of the glycoside intermediate was placed in a 100 mL jar, and 20 mL of ammonia methanol was added to obtain a seventh mixed solution; the mixture was sealed at 70° C. for 12 h, and after TLC detection, the reaction was complete, the mixture was evaporated to dryness, the sample was mixed and passed through a column, and the mixture was recrystallized from methanol to obtain 0.91 g of alkynyl nucleoside, with a yield of 64%.

[0167] Example 10

[0168] A method for preparing a 2′-C alkynyl nucleoside, comprising the following specific steps:

[0169] The difference from Example 2 is

[0170] Step 113, adding 4.2 g 6-chloropurine (2 eq), 11 g BSA (4 eq) and 60 mL anhydrous acetonitrile into a 100 mL round-bottom flask, mixing, and reacting at 60° C. for 30 min to obtain a sixth solution;

[0171] Step 114, add 8 g of compound 4 to the sixth solution, slowly add 4.8 mL of SnCl4 (3 eq) at 0° C., and after the addition is complete, move to 80° C. and continue the reaction for 48 h. TLC detection shows that the reaction is complete.

[0172] Step 115, pouring the reaction system in step 113 into a sodium bicarbonate aqueous solution, extracting with ethyl acetate, evaporating to dryness, mixing with silica gel, passing through a column, and crystallizing with ethanol to obtain 3.0 g of a glycoside intermediate with a yield of 38%;

[0173] Step 116, 3.0 g of the glycoside intermediate was placed in a 100 mL jar, and 20 mL of ammonia methanol was added to obtain a seventh mixed solution; the mixture was sealed at 70° C. for 12 h, and after TLC detection, the reaction was complete, the mixture was evaporated to dryness, the sample was mixed and passed through a column, and the mixture was recrystallized from methanol to obtain 0.91 g of alkynyl nucleoside, with a yield of 64%.

[0174] Embodiment 11

[0175] A method for preparing a 2′-C alkynyl nucleoside, comprising the following specific steps:

[0176] The difference from Example 3 is

[0177] Step 113, adding 4.2 g 6-chloropurine (2 eq), 11 g BSA (4 eq) and 60 mL anhydrous acetonitrile into a 100 mL round-bottom flask, mixing, and reacting at 60° C. for 30 min to obtain a sixth solution;

[0178] Step 114, add 8 g of compound 4 to the sixth solution, slowly add 4.8 mL of SnCl4 (3 eq) at 0° C., and after the addition is complete, move to 80° C. and continue the reaction for 48 h. TLC detection shows that the reaction is complete.

[0179] Step 115, pouring the reaction system in step 113 into a sodium bicarbonate aqueous solution, extracting with ethyl acetate, evaporating to dryness, mixing with silica gel, passing through a column, and crystallizing with ethanol to obtain 3.0 g of a glycoside intermediate with a yield of 38%;

[0180] Step 116, placing 3.0 g of the glycoside intermediate in a 100 mL sealed container, adding 20 mL of ammonia methanol to obtain a seventh mixed solution; sealing at 70° C. for 12 h, evaporating to dryness after TLC detection of the reaction completion, mixing the sample and passing it through a column, and recrystallizing with methanol to obtain 0.91 g of alkynyl nucleoside with a yield of 64%.

[0181] Example 12

[0182] A method for preparing a 2′-C alkynyl nucleoside, comprising the following specific steps:

[0183] The difference from Example 4 is

[0184] Step 113, adding 4.2 g 6-chloropurine (2 eq), 11 g BSA (4 eq) and 60 mL anhydrous acetonitrile into a 100 mL round-bottom flask, mixing, and reacting at 60° C. for 30 min to obtain a sixth solution;

[0185] Step 114, add 8 g of compound 4 to the sixth solution, slowly add 4.8 mL of SnCl4 (3 eq) at 0° C., and after the addition is complete, move to 80° C. and continue the reaction for 48 h. TLC detection shows that the reaction is complete.

[0186] Step 115, pouring the reaction system in step 113 into a sodium bicarbonate aqueous solution, extracting with ethyl acetate, evaporating to dryness, mixing with silica gel, passing through a column, and crystallizing with ethanol to obtain 3.0 g of a glycoside intermediate with a yield of 38%;

[0187] Step 116, placing 3.0 g of the glycoside intermediate in a 100 mL sealed container, adding 20 mL of ammonia methanol to obtain a seventh mixed solution; sealing at 70° C. for 12 h, evaporating to dryness after TLC detection of the reaction completion, mixing the sample and passing it through a column, and recrystallizing with methanol to obtain 0.91 g of alkynyl nucleoside with a yield of 64%.

[0188] The structural formula of the 2′-C alkynyl nucleoside obtained in Examples 9 to 12 is

[0189] Embodiment 13

[0190] A method for preparing a 2′-C alkynyl nucleoside, comprising the following specific steps:

[0191] Step 201, (201 g, 47.4 mmol) Dess-Martin periodinane is placed in a 2 L round-bottom flask, 1000 mL of dry dichloromethane is added as a solvent to obtain a first solution, which is placed in a cold well at 0°C;

[0192] Step 202, dissolving (150 g, 32.5 mmol) of compound 6 in 500 mL of dichloromethane to obtain a second solution;

[0193] Step 203, slowly adding the second solution to the first solution, and moving to room temperature to react for 2 hours after the addition;

[0194] Step 204, after the reaction is complete as detected by TLC, 600 ml of saturated sodium thiosulfate aqueous solution is added to quench the reaction, the organic phase is separated, and the organic phase is dried to obtain the first reactant;

[0195] Step 205, evaporating to dryness and then purifying by column to obtain 95 g of compound 1 with a yield of 70%;

[0196] Step 206, dissolve (0.72 mL, 0.50 g, 5.1 mmol) of trimethylsilylacetylene in 25 ml of dry tetrahydrofuran, cool to -78°C, then slowly dropwise add (1.6 M in hexanes, 3.12 mL, 5.0 mmol) of n-butyllithium solution, and stir for 30 minutes to obtain a third solution;

[0197] Step 207, dissolving (2.04 g 5.48 mmol) CeCl3 in 10 ml dry tetrahydrofuran to obtain a fourth solution;

[0198] Step 208, dissolve (530 mg, 1.15 mmol) of compound 1 in 10 ml of tetrahydrofuran to obtain a fifth solution.

[0199] Step 209, slowly add the fourth solution to the third solution, react for 1.5 hours, then dropwise add the fifth solution, and react at 25° C. for 2 hours after the dropwise addition is complete;

[0200] Step 210, after TLC detection of the reaction is complete, the reaction system is slowly poured into ice water to quench, and then 1 L of ethyl acetate is added for extraction, dried, and the sample is mixed with silica gel and passed through a column to obtain 0.377 g of a mixture of compound 2 and compound 3, with a yield of 59%.

[0201] Step 211, dissolving a mixture of (7.5 g, 15.4 mmol) of compound 2 and compound 3 in 80 mL of dry pyridine to obtain a fifth solution;

[0202] Step 212, slowly drip (2.2 mL, 18.5 mmol) BzCl into the fifth solution at 0° C., and after the dripping is complete, move to 25° C. to react for 2 h;

[0203] Step 213, after TLC shows that the reaction is complete, the reaction system in step 111 is slowly poured into 100 mL of sodium bicarbonate aqueous solution, and then 100 mL of ethyl acetate is added for extraction, dried, and the sample is mixed with silica gel and passed through a column to obtain 7.0 g of compound 4;

[0204] Step 214, adding 0.33 g uracil (2 eq), 1.1 g BSA (4 eq) and 5 mL anhydrous acetonitrile into a 100 mL round-bottom flask, mixing, and reacting at 60° C. for 30 min to obtain a sixth solution;

[0205] Step 215, add 0.88 g of compound 4 to the sixth solution, slowly add 0.5 mL of SnCl4 (3 eq) at 0° C., and after the addition is complete, move to 80° C. and continue the reaction for 48 h. TLC detection shows that the reaction is complete.

[0206] Step 216, pour the reaction system in step 113 into a sodium bicarbonate aqueous solution, extract with ethyl acetate, evaporate to dryness, mix with silica gel, and pass through a column with PE:EA=2:1 to obtain 0.43 g of a glycoside intermediate;

[0207] Step 217, add 4.3 g of the glycoside intermediate to 50 mL of methanol to obtain a seventh mixed solution; add 1.4 g of sodium methoxide (3.5 eq) to the seventh mixed solution, react at 25° C. for 10 min, and detect the completion of the reaction by TLC. Adjust the mixture to neutral with dilute hydrochloric acid, evaporate to dryness, mix the sample with silica gel and pass it through a column to obtain 1.38 g of alkynyl nucleoside.

[0208] The structural formula of the 2′-C alkynyl nucleoside obtained in Example 13 is

[0209] Embodiment 14

[0210] A method for preparing a 2′-C alkynyl nucleoside, comprising the following specific steps:

[0211] Step 301, (201 g, 47.4 mmol) Dess-Martin periodinane is placed in a 2 L round-bottom flask, 1000 mL of dry dichloromethane is added as a solvent to obtain a first solution, which is placed in a cold well at 0°C;

[0212] Step 302, dissolving (150 g, 32.5 mmol) of compound 6 in 500 mL of dichloromethane to obtain a second solution;

[0213] Step 303, slowly adding the second solution to the first solution, and moving to room temperature to react for 2 hours after the addition;

[0214] Step 304, after the reaction is complete as detected by TLC, 600 ml of saturated sodium thiosulfate aqueous solution is added to quench the reaction, the organic phase is separated, and the organic phase is dried to obtain the first reactant;

[0215] Step 305, evaporating to dryness and then purifying by column to obtain 95 g of compound 1 with a yield of 70%;

[0216] Step 306, taking (5 g, 10.87 mmol) of compound 1 and dissolving it in 40 ml of dry tetrahydrofuran, cooling the reaction system to -78°C, slowly adding (6.79 ml of 1.6 M, 16.31 mmol) of n-butyl lithium solution, stirring for 0.5 hours, to obtain a third solution;

[0217] Step 307, (1.41 ml, 16.31 mmol) Propyl bromide Add the third solution, and react at 25°C for 2h after the addition is complete;

[0218] Step 308, after TLC detection of the reaction is complete, the reaction system is slowly poured into ice water to quench, and then 1 L of ethyl acetate is added for extraction, dried, and the sample is mixed with silica gel and passed through a column to obtain 2.28 g of a mixture of compound 2 and compound 3, with a yield of 42%.

[0219] Step 309, dissolving (7.5 g, 15.4 mmol) of a mixture of compound 2 and compound 3 in 80 mL of dry pyridine to obtain a fifth solution;

[0220] Step 310, slowly drip (2.2 mL, 18.5 mmol) BzCl into the fifth solution at 0°C, and after the dripping is complete, move to 25°C to react for 2 hours;

[0221] Step 311, after TLC shows that the reaction is complete, the reaction system in step 111 is slowly poured into 100 mL of sodium bicarbonate aqueous solution, and then 100 mL of ethyl acetate is added for extraction, dried, and the sample is mixed with silica gel and passed through a column to obtain 7.0 g of compound 4;

[0222] Step 312, adding 0.65 g 6-chloropurine (2 eq), 1.1 g BSA (4 eq) and 5 mL anhydrous acetonitrile into a 100 mL round-bottom flask, mixing, and reacting at 60° C. for 30 min to obtain a sixth solution;

[0223] Step 313, add 0.88 g of compound 4 to the sixth solution, slowly add 0.5 mL of SnCl4 (3 eq) at 0° C., and after the addition is complete, move to 80° C. and continue the reaction for 48 h. TLC detection shows that the reaction is complete.

[0224] Step 314, pour the reaction system in step 113 into a sodium bicarbonate aqueous solution, extract with ethyl acetate, evaporate to dryness, mix with silica gel, and pass through a column with PE:EA=2:1 to obtain 0.43 g of glycoside intermediate;

[0225] Step 315, add 4.3 g of the glycoside intermediate to 50 mL of methanol to obtain a seventh mixed solution; add 1.4 g of sodium methoxide (3.5 eq) to the seventh mixed solution, react at 25° C. for 10 min, and detect the completion of the reaction by TLC. Adjust the mixture to neutral with dilute hydrochloric acid, evaporate to dryness, mix the sample with silica gel and pass it through a column to obtain 1.38 g of alkynyl nucleoside.

[0226] The structural formula of the 2′-C alkynyl nucleoside obtained in Example 14 is

[0227] At this point, those skilled in the art should recognize that, although multiple exemplary embodiments of the present invention have been shown and described in detail herein, many other variations or modifications that conform to the principles of the present invention can still be directly determined or derived based on the content disclosed in the present invention without departing from the spirit and scope of the present invention. Therefore, the scope of the present invention should be understood and recognized as covering all these other variations or modifications.

Claims

1. A method for preparing a 2'-C alkynyl nucleoside, characterized in that: The preparation method comprises the following steps: A catalyst and an alkynyl compound salt are added to the compound 1 to obtain a mixture of compound 2 and compound 3; the structural formulas of the compound 1, compound 2 and compound 3 are respectively: Wherein R1 can be one of trimethylethynyl, propynyl or ethynyl, and the synthesis route is: The BzCl is added to the mixture to obtain compound 4; the structural formula of compound 4 is: The base, acetamide or hexamethyldisilazane, anhydrous acetonitrile, tin chloride or trimethylsilyl trifluoromethanesulfonate and the compound 4 are mixed in a first preset ratio to obtain a glycoside intermediate; the structural formula of the glycoside intermediate is: Wherein R2 is a base; The glycoside intermediate, methanol and methanol salt are mixed in a second preset ratio to obtain a 2'-C alkynyl nucleoside, wherein the methanol salt is one of sodium methanolate or ammonia methanol, and the structural formula of the 2'-C alkynyl nucleoside is 2. The method for preparing 2'-C alkynyl nucleoside according to claim 1, characterized in that: Also includes: Dess-Martin periodinane is added to compound 6 to obtain compound 1; the structural formula of compound 6 is:

3. The method for preparing 2'-C alkynyl nucleoside according to claim 2, characterized in that: The method of adding a Dess-Martin oxidant to compound 6 to obtain compound 1 comprises: Dissolving Dess-Martin periodinane in dichloromethane to obtain a first solution; Dissolving the compound 6 in dichloromethane to obtain a second solution; Slowly adding the second solution into the first solution, reacting at a first preset temperature for a first preset time; adding a saturated sodium thiosulfate aqueous solution, separating and drying to obtain a first reactant; The first reactant is purified to obtain compound 1.

4. The method for preparing 2'-C alkynyl nucleoside according to claim 1, characterized in that: The step of adding a catalyst and an alkynyl compound salt to the compound 1 to obtain a mixture of compound 2 and compound 3 comprises: Dissolving compound 1 in tetrahydrofuran to obtain a third solution; dissolving the alkynyl compound salt in tetrahydrofuran to obtain a fourth solution; After adding the catalyst to the third solution, slowly adding the fourth solution to the third solution, reacting at a second preset temperature for a second preset time; After adding saturated NH4Cl aqueous solution to the above reaction system, extraction is performed with an extractant, and drying is performed to obtain a mixture of compound 2 and compound 3, wherein the extractant is ethyl acetate or dichloromethane.

5. The method for preparing 2'-C alkynyl nucleoside according to claim 1, characterized in that: The step of adding BzCl to the mixture to obtain compound 4 comprises: dissolving the mixture of the compound 2 and the compound 3 in pyridine to obtain a fifth solution; Slowly adding BzCl to the fifth solution, and reacting at a third preset temperature for a third preset time; The above reaction system was added with sodium bicarbonate aqueous solution, extracted with ethyl acetate, and dried to obtain the compound 4.

6. The method for preparing 2'-C alkynyl nucleoside according to claim 1, characterized in that: The base, acetamide, anhydrous acetonitrile, tin chloride and the compound 4 are mixed in a first preset ratio to obtain a glycoside intermediate, comprising: Mixing the base, the BSA and the anhydrous acetonitrile, and reacting at a fourth preset temperature for a fourth preset time to obtain a sixth solution; After adding the compound 4 to the sixth solution, slowly adding tin chloride, and reacting at a fifth preset temperature for a fifth preset time; The above reaction system was added with sodium bicarbonate aqueous solution, extracted with ethyl acetate, and dried to obtain the glycoside intermediate.

7. The method for preparing 2'-C alkynyl nucleoside according to claim 1, characterized in that: The step of mixing the glycoside intermediate, methanol and sodium methoxide in a second preset ratio to obtain a 2'-C alkynyl nucleoside comprises: Mixing the glycoside intermediate, the methanol and the sodium methoxide, and reacting them at a sixth preset temperature for a sixth preset time; Dilute hydrochloric acid was added to adjust to neutrality, and then dried and passed through a column to obtain 2'-C alkynyl nucleoside.

8. The method for preparing 2'-C alkynyl nucleoside according to claim 4, characterized in that: The catalyst is one or more of cerium chloride, lanthanum chloride, praseodymium chloride, titanium tetrachloride or n-butyl lithium.

9. The method for preparing a 2'-C alkynyl nucleoside according to any one of claims 1 to 7, characterized in that: The base is one of uracil, cytosine or guanine.

10. A 2'-C alkynyl nucleoside, which is prepared by the method for preparing a 2'-C alkynyl nucleoside according to any one of claims 1 to 9.

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