CN113683648A - Synthetic method and intermediate of 2 '-fluoro-2' -deoxyuridine - Google Patents
Synthetic method and intermediate of 2 '-fluoro-2' -deoxyuridine Download PDFInfo
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Abstract
The invention relates to a synthetic method of 2 '-fluoro-2' -deoxyuridine and an intermediate thereof, which are implemented by the following method.
Description
Technical Field
The invention relates to a synthetic method of 2 '-fluoro-2' -deoxyuridine and a novel intermediate thereof, belonging to the field of organic synthesis.
Background
The 2 '-fluoro-2' -deoxyuridine is an important drug intermediate. 2 '-fluoro-2' -deoxyuridine is water-soluble and has almost no crystalline compound, and most of the prior art is purified by column chromatography to be a high-purity, white crystalline powder with a high yield.
CN112500446A discloses a method for synthesizing 2 '-fluoro-2' -deoxyuridine, which comprises the following steps: step 1) adding uridine and diphenyl carbonate into dimethylformamide, heating to dissolve, clarifying the solution, adding a catalyst sodium bicarbonate under the condition of keeping the temperature, heating for reaction for the second time, naturally cooling to room temperature after the reaction is finished, stirring, filtering, and drying a filter cake to obtain a compound 2; and 2) dissolving the compound 2, anhydrous potassium fluoride and a catalyst boron trifluoride diethyl etherate in a solvent, heating for reaction, filtering and concentrating after the reaction is finished, and obtaining a compound 3, namely 2 '-fluoro-2' -deoxyuridine. However, the method has low hydroxyl conversion rate, and the 2 '-fluoro-2' -deoxyuridine is an extremely viscous compound and cannot be solidified and purified under the condition of low purity, so that column passing purification is required at the later stage of the method, and continuous industrial scale-up production cannot be used.
CN112409420A discloses a purification method of 2 '-fluoro-2' -deoxyuridine, comprising the following steps: 1) dissolving the crude product of 2 '-fluoro-2' -deoxyuridine in ethyl acetate, adding triethylamine, and dropwise adding an acylation reagent for reaction under controlled temperature; 2) after the reaction is finished, adding methanol, stirring, cooling, crystallizing, filtering, washing a filter cake with ethyl acetate, and drying the filter cake to obtain a compound 2; 3) and dissolving the compound 2 in methanol, adding sodium hydroxide, filtering after complete reaction, and drying a filter cake to obtain the 2 '-fluoro-2' -deoxyuridine. The acylation step used 4-dimethylaminopyridine, again in a yield of only 76.8%.
In a process for preparing 2 '-fluoro-2' -deoxyuridineIn the preparation process, the steps before and after the fluorination reaction are key processes, and the prior art reports that a trifluoromethanesulfonylation reagent is used for reacting with a 2' -hydroxyl to obtain trifluoromethanesulfonate, and then the fluorination reagent is used for reacting to obtain a 2' -fluoro-2 ' -deoxyuridine intermediate compound. Trifluoromethanesulfonylating agents, e.g. trifluoromethanesulfonyl fluoride (CF)3SO2F) Trifluoromethanesulfonyl Chloride (CF)3SO2Cl) and trifluoromethanesulfonic anhydride ((CF)3SO2)2O), wherein trifluoromethanesulfonyl fluoride (CF)3SO2F) The triflation reaction of the 2' -hydroxyl of 1-beta-D-arabinofuranosyl uracil which can be used as a 3 ', 5 ' -hydroxyl protected form is carried out under a temperature condition of about-60 ℃, the reaction temperature of triflyl chloride is required to be below-50 ℃, and the reaction kettle with high pressure resistance is required to be used under a higher temperature condition of the triflyl fluoride or the triflyl chloride.
Trifluoromethanesulfonic anhydride ((CF)3SO2)2O) can be used as a trifluoromethanesulfonylating agent for the hydroxyl group at the 2' -position, but trifluoromethanesulfonic anhydride ((CF) is used in view of atom utilization3SO2)2O) is not efficient.
Furthermore chem. pharm. Bull, 1981, Vol.29, No.11, pp.3281-3285 reports the use of trifluoromethanesulphonyl chloride (CF. Pharm. Bull. RTM.) (CF. RTM. TM.)3SO2Cl), but chloride anion (Cl) is generated as a byproduct as the reaction proceeds in the synthesis of 2 '-deoxy-2' -fluoroguanosine-) A substitution reaction with the 2 '-trifluoromethanesulfonate form as a product is then caused in the reaction system to give a by-product in which the chlorine atom is substituted at the 2' -position. Due to chloride anion (Cl)-) Nucleophilic than fluoroanion (F)-) The nucleophilicity of (a) is much higher, which becomes an important side reaction. Thus, trifluoromethanesulfonyl Chloride (CF) was used3SO2Cl) are also limited.
Therefore, the invention provides a novel synthetic route which overcomes the defects of the prior art, is simple and convenient to operate, has mild reaction, high yield and good safety, does not need column chromatography, has good product quality and is very suitable for industrial production.
Disclosure of Invention
The invention provides a synthesis method of 2 '-fluoro-2' -deoxyuridine, which is a brand new synthesis route and is suitable for industrial production.
The invention also provides a novel intermediate compound 4 as an important intermediate compound.
The invention provides 2 '-fluoro-2' -deoxyuridine, which comprises the following synthetic route:
wherein R is a hydroxyl protecting group, most preferably a tetrahydropyranyl group (THP group) as the hydroxyl protecting group;
wherein R 'is a protecting group conventional in the art for hydroxy, preferably R' is Tetrahydropyranyl (THP), methoxymethyl ether (MOM), a silane group (e.g., t-butyldimethylsilyl), or an acyl group (e.g., acetyl), preferably acetyl.
The invention provides a technical scheme I: a process for the preparation of a 2 '-fluoro-2' -deoxyuridine compound, which comprises reacting compound 3 with a hydroxyl activating reagent (most preferably perfluorobutanesulfonyl fluoride reagent) in an organic solvent under the action of a base to give compound 4, and then under conditions comprising a second organic base and a fluorinating agent to give compound 5, of the formula:
wherein R is a hydroxyl protecting group, most preferably a tetrahydropyranyl group (THP group) as the hydroxyl protecting group;
compound 5 can be selectively deprotected to afford compound 6.
The invention provides a technical scheme II: the invention preferably adopts the technical scheme that the preparation method of the 2 '-fluoro-2' -deoxyuridine compound comprises the steps of reacting a compound 3 with a hydroxyl activating reagent (most preferably a perfluorobutanesulfonyl fluoride reagent) in an organic solvent under the condition of a first organic base to obtain a compound 4, and directly obtaining a compound 5 under the conditions of a second organic base and a fluorinating agent without treatment by a 'one-pot method';
wherein R is a hydroxyl protecting group, most preferably a tetrahydropyranyl group (THP group) as the hydroxyl protecting group;
compound 5 can be selectively deprotected to afford compound 6.
The invention provides a technical scheme I or a technical scheme II, wherein the molar charge ratio of a compound 3 to a hydroxyl activating reagent is 1: (1-5), preferably 1: (1-3); the hydroxyl activating reagent is selected from perfluorobutanesulfonyl fluoride; the invention provides a technical scheme that the alkali is selected from inorganic alkali or organic alkali, wherein the inorganic alkali is selected from sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide, barium hydroxide and the like; said organic base or said second organic base in the first or said first and second organic bases in the second embodiment, respectively, may be selected from diisopropylethylamine, trimethylamine, triethylamine, tri-N-butylamine, N-dimethyllaurylamine, diisopropylamine, N-dimethylaniline, dimethylbenzylamine, triethylenediamine (DABCO), 1, 8-diazabicyclo [5.4.0] undec-7-ene (DBU), 1, 5-diazabicyclo [4.3.0] non-5-ene (DBN), 1, 4-diazabicyclo [2, 2, 2] octane, 4-Dimethylaminopyridine (DMAP), pyridine, 2, 5-lutidine, 2, 6-lutidine, 3, 4-lutidine, 3, 5-lutidine, 2, 4, 6-trimethylpyridine, imidazole, pyrimidine, pyridazine, N-methylmorpholine, tetramethylethylenediamine and Tetramethylguanidine (TMG), one or any combination thereof and the like, preferably triethylamine, diisopropylethylamine and pyridine, particularly more preferably triethylamine;
the invention provides a technical scheme I, wherein the molar charge ratio of the compound 3 to the alkali is 1 (1-10), preferably 1 (1-6); the invention provides a technical scheme II, wherein the molar charge ratio of the compound 3 to the first organic base is 1 (1-10), preferably 1 (1-6);
the invention provides a technical scheme I or a technical scheme II, wherein the molar charge ratio of the fluorinating agent to the compound 4 is 1-10:1, preferably 2-4: 1; the fluorinating agent may be selected from hydrofluoric acid or a salt thereof, and the molar ratio of the second organic base to hydrofluoric acid is typically in the range of 60: 1-1:60, preferably 25:1 to 1:25, more preferably 15:1 to 1: 15. The second organic base and the fluorinating agent may be a complex, preferably pyridine fluorohydrogenate, triethylamine fluorohydrogenate, most preferably triethylamine fluorohydrogenate; "a complex comprising 1mol of triethylamine and 3mol of hydrofluoric acid (triethylamine trihydrofluoride salt)" and "a complex comprising about 30% (about 10 mol%) of pyridine and about 70% (about 90 mol%) of hydrofluoric acid can be used.
The invention provides a technical scheme I or a technical scheme II, wherein the organic solvent is selected from one or a combination of dimethyl sulfoxide, aliphatic alkanes, aromatic hydrocarbons, halogenated hydrocarbons, ethers, esters, amides or nitrile solvents, wherein the aliphatic alkanes such as n-hexane, cyclohexane or n-heptane; aromatic hydrocarbons such as toluene and the like; halogenated hydrocarbons such as dichloromethane, chloroform or 1, 2-dichloroethane; ethers such as diethyl ether, tetrahydrofuran, methyl tert-butyl ether or dioxane; esters such as ethyl acetate or n-butyl acetate; amides such as N, N-dimethylformamide, N-dimethylacetamide or N-methylpyrrolidone; nitriles such as acetonitrile and the like. Of these, tetrahydrofuran, dichloromethane, acetonitrile, dioxane, 2-methyltetrahydrofuran, toluene, N-dimethylformamide, methyl tert-butyl ether, diethyl ether, dimethyl sulfoxide or any mixture of the above solvents is preferred, dichloromethane, N-dimethylformamide and acetonitrile are preferred, and acetonitrile is most preferred.
According to the first technical scheme or the second technical scheme, the reaction time of the compound 5 prepared by the compound 3 is 1-24 hours, preferably 1-20 hours until the detection reaction is finished.
The invention provides a technical scheme I or a scheme II, wherein the temperature conditions of each step of the reaction time for preparing the compound 5 from the compound 3 are usually-100 ℃, preferably-80-80 ℃, further preferably-60-60 ℃ and most preferably 15-40 ℃.
The invention provides a method for obtaining a compound 6 after selectively removing a protecting group from a compound 5, which comprises the step of reacting the compound 6 under an acidic condition by using the compound 5, wherein the reaction formula is as follows:
wherein R is a hydroxyl protecting group, most preferably a tetrahydropyranyl group (THP group) as the hydroxyl protecting group;
the acidic reagent is selected from formic acid, glacial acetic acid, p-toluenesulfonic acid and the like, preferably p-toluenesulfonic acid;
the molar charge ratio of the compound 5 to the acidic reagent is 1 (0.1-5)
The solvent is selected from tetrahydrofuran, dichloromethane, acetonitrile, dioxane, 2-methyltetrahydrofuran, toluene, N-dimethylformamide, methyl tert-butyl ether, diethyl ether, dimethyl sulfoxide, methanol or any mixture of the solvents, preferably methanol;
the reaction time is usually 1 to 24 hours, preferably 2 to 10 hours, until the completion of the detection reaction.
The compound 3 can be prepared by the following method, and the invention also provides a preferable technical scheme, wherein the compound 2 is not processed, and the compound 3 is prepared by a one-pot method.
Or, the compound 2 is obtained by reacting under alkaline conditions, and the reaction formula is as follows:
wherein R is a hydroxyl protecting group, and most preferably a tetrahydropyranyl group (THP group) is used as the hydroxyl protecting group.
The molar charge ratio of the compound 2 to the alkaline reagent is 1: (0.1-5);
the alkaline reagent is diisopropylethylamine, triethylamine, diisopropylamine, triethylene Diamine (DABCO), 1, 8-diazabicyclo [5.4.0] undec-7-ene (DBU), 1, 5-diazabicyclo [4.3.0] non-5-ene (DBN), 4-Dimethylaminopyridine (DMAP), pyridine, N-methylmorpholine, tetramethylethylenediamine, Tetramethylguanidine (TMG), sodium hydroxide, preferably sodium hydroxide;
the solvent is tetrahydrofuran, dichloromethane, acetonitrile, dioxane, 2-methyltetrahydrofuran, toluene, N-dimethylformamide, methyl tert-butyl ether, diethyl ether, dimethyl sulfoxide, methanol or any mixture of the solvents, preferably N, N-dimethylformamide.
The reaction time is usually 1 to 24 hours, preferably 2 to 5 hours, until the completion of the detection reaction.
The reaction temperature is 0-100 ℃, preferably 20-35 ℃.
The compound 2 of the present invention can be prepared by a method comprising reacting the compound 1 with a hydroxyl activating reagent under acidic conditions, wherein the reaction formula is as follows:
the hydroxyl activating reagent can be selected from 3, 4-dihydro-2H-pyran (DHP), acetic anhydride, benzyl chloroformate, preferably 3, 4-dihydro-2H-pyran DHP;
the molar charge ratio of the compound 1 to the hydroxyl protecting group reagent is 1: (1-5);
the acidic reagent can be selected from formic acid, glacial acetic acid, p-toluenesulfonic acid and the like, and p-toluenesulfonic acid is preferred;
the solvent is tetrahydrofuran, dichloromethane, acetonitrile, dioxane, 2-methyltetrahydrofuran, toluene, N-dimethylformamide, methyl tert-butyl ether, diethyl ether, dimethyl sulfoxide or any mixture of the solvents, preferably N, N-dimethylformamide;
the reaction time is determined until the reaction is completed, and the reaction time is usually 1 to 24 hours;
the reaction temperature is 0-100 ℃, preferably 20-30 ℃.
The invention also provides a method for selectively purifying the compound 6, which comprises the following steps of reacting the compound 7 with a hydroxyl protecting group reagent under alkaline conditions, and removing the hydroxyl protecting group to obtain the compound 6, wherein the chemical formula is as follows:
wherein R 'is a protecting group conventional in the art for hydroxy, preferably R' is Tetrahydropyranyl (THP), methoxymethyl ether, a silane group (e.g., t-butyldimethylsilyl) or an acyl group (e.g., acetyl), preferably acetyl;
the hydroxyl protecting group reagent is selected from 3, 4-dihydro-2H-pyran (DHP), tert-butyldimethylchlorosilane, chloromethyl methyl ether, acetic anhydride and the like;
the base may be sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide, barium hydroxide, etc., or diisopropylethylamine, triethylamine, diisopropylamine, triethylenediamine (DABCO), 1, 8-diazabicyclo [5.4.0] undec-7-ene (DBU), 1, 5-diazabicyclo [4.3.0] non-5-ene (DBN), 4-Dimethylaminopyridine (DMAP), pyridine, N-methylmorpholine, tetramethylethylenediamine, Tetramethylguanidine (TMG), preferably triethylamine;
the molar charge ratio of the compound 6 to the hydroxyl protecting group reagent is 1: (1-5);
the molar charge ratio of the alkali to the compound 6 is (1-10) to 1, preferably (2-4) to 1;
the solvent is tetrahydrofuran, dichloromethane, acetonitrile, dioxane, 2-methyltetrahydrofuran, toluene, N-dimethylformamide, methyl tert-butyl ether, diethyl ether, dimethyl sulfoxide, or any mixture of the above solvents, preferably dichloromethane;
the reaction time is usually 1 to 24 hours, preferably 2 to 5 hours, until the completion of the detection reaction.
The methods and conditions for deprotecting the hydroxy protecting group can be conventional in the art for such reactions, and the reaction formula is as follows:
wherein R 'is a protecting group conventional in the art for hydroxy, preferably R' is Tetrahydropyranyl (THP), silyl, acyl, acylalkyl ether, preferably acetyl.
The alkali is inorganic alkali or organic alkali, the inorganic alkali is selected from sodium hydroxide, sodium bicarbonate and sodium phosphate, and the organic alkali is selected from ammonia gas/ammonia water, methylamine solution, ethylenediamine or triethylamine; the molar ratio of the alkali to the compound 7 is 5-40: 1; the reaction solvent is acetonitrile, tetrahydrofuran, methanol, dichloromethane, dioxane, 2-methyltetrahydrofuran, toluene, N-dimethylformamide, methyl tert-butyl ether, diethyl ether, dimethyl sulfoxide or any mixture of the solvents; the reaction temperature is 0-100 ℃.
The invention also provides a new 2 '-fluoro-2' -deoxyuridine intermediate compound 4, which has the following structural formula:
wherein R is a hydroxyl protecting group, most preferably a tetrahydropyranyl group (THP group) as the hydroxyl protecting group, of the formula:
the method of the invention has the following advantages:
1. the invention provides a brand-new industrialized route for synthesizing 2 '-fluoro-2' -deoxyuridine;
2. the synthetic route is as follows: the method has the advantages of short route, good conversion rate, high yield, total yield of 65 percent, avoidance of trifluoromethanesulfonyl chloride, no need of column treatment, high purity of product derivatives and easy crystallization;
3. the synthetic route is as follows: the method is simple to operate, environment-friendly and suitable for industrial production;
4. a novel intermediate 4 for the synthesis of 2 '-fluoro-2' -deoxyuridine is disclosed;
5. providing a methodological reference for the synthesis of analogous compounds;
6. the method does not need low-temperature reaction or reaction in a high-pressure reaction kettle, has moderate production cost, and is suitable for industrial production.
DETAILED DESCRIPTION OF EMBODIMENT (S) OF INVENTION
The invention will be further illustrated with reference to the following specific examples. It should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention. The experimental methods in the following examples, which are not specified under specific conditions, are generally carried out under conventional conditions.
The starting materials or reagents used in the examples are, unless otherwise specified, commercially available.
The room temperatures stated in the examples are from 20 to 35 ℃. Unless otherwise indicated, the reagents were used without purification. All solvents were purchased from commercial suppliers, such as Aldrich (Aldrich), and used without treatment.
Example 1
Compound 1(50.00g) and DMF (500mL), 3, 4-dihydro-2H-pyran (55.80g,663.3 mmol) were charged in a 1L three-necked flask, and p-toluenesulfonic acid (1.90g, 11.0mmol) was added with stirring at room temperature. The reaction solution was stirred at room temperature for 18 hours, the reaction was quenched and completely inverted, cooled to 5-10 deg.C, and sodium hydroxide solution (2N, 115mL) was added dropwise, raising the system temperature to 27 deg.C. After stirring at room temperature for two hours, glacial acetic acid (39.84g,663.4mmol) was added, the mixture was stirred uniformly at pH 7, extracted with EA phase (200mL × 3), the organic phases were combined and concentrated under reduced pressure to obtain solid compound 3-1(82.00g, yield: 89.9%, HPLC purity: 90%) which was used directly in the next step.
Example 2
A1L three-necked flask was charged with the compound 3-1(50g) obtained in example 1, acetonitrile (500mL), triethylamine (73.59g,727.2 mmol) and perfluorobutylsulfonyl fluoride (54.92g,181.8mmol), the system was stirred at room temperature for 2 hours, the starting material was completely converted by TLC, triethylamine trihydrofluoride salt (58.62g,363.6mmol) was added to the system, and the reaction system was reacted at room temperature for 18 hours. Saturated sodium bicarbonate solution (500.0mL) was added, stirred for half an hour, extracted with ethyl acetate (300.0mL x 3), the organic phases were combined, washed once with saturated brine, and the compound 5-1 concentrated under reduced pressure was dried over anhydrous sodium sulfate to give an oil (45.23g, yield: 90.1%, HPLC purity: 90%) which was used directly in the next step.
Example 3
To a 500mL three-necked flask were added the compound 5-1(40g) obtained in example 2, methanol (200mL), p-toluenesulfonic acid (1.66g, 9.64mmol) and, while the system was stirred at room temperature for 10 hours, the TLC spot plate starting material was completely converted and the system was concentrated under reduced pressure to give oil 6(26g), HPLC purity: 91.20%, the recovery of the crude product is beyond the theoretical yield and is used directly in the next step.
Example 4
A500 mL three-necked flask was charged with the compound 6(26g) obtained in example 3, methylene chloride (300mL), acetic anhydride (26.95g, 264.0mmol) and triethylamine (26.71g,264.0mmol) and stirred at room temperature for 10 hours, the TLC plate was completely converted, the system was concentrated under reduced pressure, ethanol (400mL) was added to the system and stirred for 3 hours to precipitate a large amount of solid, which was then filtered, collected and recrystallized from glacial acetic acid and ethanol to obtain a white solid (19.50g, yield in two steps: 61.2%, purity: 99.92%).
Example 5
A500 mL three-necked flask was charged with the compound 7-1(19.5g) obtained in example 4 and methanolic ammonia (7M/L,140mL), and the system was stirred at room temperature for 10 hours, TLC plates were used for complete conversion of the starting material, the system was concentrated under reduced pressure, methanol/n-heptane (40 mL/150mL) was added to the system and stirred at 70 ℃ for 3 hours to precipitate a large amount of solid, which was then filtered to collect the solid, thereby obtaining a white solid 6(13.65g, yield: 93.9%, purity: 99.95%).
Claims (10)
1. A method for preparing a 2 '-fluoro-2' -deoxyuridine compound 6, the structural formula is as follows:
the method comprises the following steps of reacting a compound 3 with a perfluorobutyl sulfonyl fluoride reagent in an organic solvent under the action of an inorganic base or an organic base to obtain a compound 4, and then reacting under the conditions of a second organic base and a fluorinating agent to obtain a compound 5, wherein the reaction formula is as follows:
wherein R is a hydroxyl protecting group, preferably a tetrahydropyranyl group THP group as the hydroxyl protecting group;
and removing the protecting group of the compound 5 to obtain a compound 6.
2. A method for preparing a 2 '-fluoro-2' -deoxyuridine compound 6, the structural formula is as follows:
the method comprises the steps of reacting a compound 3 with a perfluorobutyl sulfonyl fluoride reagent in an organic solvent under the condition of a first organic base to obtain a compound 4, and directly obtaining a compound 5 under the conditions of a second organic base and a fluorinating agent without treatment by a one-pot method;
wherein R is a hydroxyl protecting group, preferably a tetrahydropyranyl group THP group as the hydroxyl protecting group;
and removing the protecting group of the compound 5 to obtain a compound 6.
3. The production method according to claim 1 or 2, characterized in that: the compound 5 is subjected to deprotection to obtain a compound 6, and the compound 6 is obtained by reacting the compound 5 under an acidic condition, wherein the reaction formula is as follows:
wherein R is a hydroxyl protecting group, preferably a tetrahydropyranyl group THP group as the hydroxyl protecting group;
the acidic reagent is selected from formic acid, glacial acetic acid, p-toluenesulfonic acid and the like, preferably p-toluenesulfonic acid;
the molar charge ratio of the compound 5 to the acidic reagent is 1 (0.1-5);
the reaction is carried out in a solvent selected from tetrahydrofuran, dichloromethane, acetonitrile, dioxane, 2-methyltetrahydrofuran, toluene, N-dimethylformamide, methyl tert-butyl ether, diethyl ether, dimethyl sulfoxide, methanol or any mixture thereof, preferably methanol;
the reaction time is 1 to 24 hours, preferably 2 to 10 hours.
4. The production method according to claim 1 or 2, characterized in that: the alkali is selected from inorganic alkali or organic alkali, wherein the inorganic alkali is selected from sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide or barium hydroxide;
the organic base or first or second organic base is selected from the group consisting of diisopropylethylamine, trimethylamine, triethylamine, tri-N-butylamine, N-dimethyllaurylamine, diisopropylamine, N-dimethylaniline, dimethylbenzylamine, triethylenediamine, 1, 8-diazabicyclo [5.4.0] undec-7-ene, 1, 5-diazabicyclo [4.3.0] non-5-ene, 1, 4-diazabicyclo [2, 2, 2] octane, 4-dimethylaminopyridine, pyridine, 2, 5-dimethylpyridine, 2, 6-dimethylpyridine, 3, 4-dimethylpyridine, 3, 5-dimethylpyridine, 2, 4, 6-trimethylpyridine, imidazole, pyrimidine, pyridazine, N-methylmorpholine, tetramethylethylenediamine and tetramethylguanidine TMG, or any combination thereof, and the like, triethylamine, diisopropylethylamine and pyridine are preferred, and triethylamine is particularly more preferred.
5. The production method according to claim 1 or 2, characterized in that: the molar charge ratio of the compound 3 to the fluorobutylsulfonyl fluoride reagent is 1: (1-5), preferably 1: (1-3); the molar charge ratio of the fluorinating agent to the compound 4 is 1-10:1, preferably 2-4: 1; said fluorinating agent may be selected from hydrofluoric acid or a salt thereof, preferably said second organic base and fluorinating agent is a complex, preferably pyridine hydrogen fluoride, triethylamine hydrogen fluoride, most preferably triethylamine hydrogen fluoride; it is further preferred that the molar ratio of said second organic base to hydrofluoric acid is generally in the range of from 60: 1 to 1:60, preferably in the range of from 25:1 to 1:25, particularly more preferably in the range of from 15:1 to 1: 15;
preferably, the organic solvent is selected from one or a combination of dimethyl sulfoxide, aliphatic alkanes, aromatic hydrocarbons, halogenated hydrocarbons, ethers, esters, amides or nitrile solvents, wherein the aliphatic alkanes are selected from n-hexane, cyclohexane or n-heptane; the aromatic hydrocarbon is selected from toluene and the like; the halogenated hydrocarbon is selected from dichloromethane, chloroform or 1, 2-dichloroethane; the ether solvent is selected from diethyl ether, tetrahydrofuran, methyl tert-butyl ether or dioxane; the ester solvent is selected from ethyl acetate or n-butyl acetate; the amide solvent is selected from N, N-dimethylformamide, N, N-dimethylacetamide or N-methylpyrrolidone; the nitrile solvent is selected from acetonitrile, further preferably tetrahydrofuran, dichloromethane, acetonitrile, dioxane, 2-methyltetrahydrofuran, toluene, N-dimethylformamide, methyl tert-butyl ether, diethyl ether, dimethyl sulfoxide or any mixture of the above solvents, further preferably dichloromethane, N-dimethylformamide and acetonitrile, most preferably acetonitrile;
it is preferable that the temperature conditions at each step of the reaction time for obtaining the compound 5 by the preparation of the compound 3 are usually-100 ℃ to 100 ℃, preferably-80 ℃ to 80 ℃, further preferably-60 ℃ to 60 ℃, most preferably 15 ℃ to 40 ℃; the reaction time is preferably 1 to 24 hours, more preferably 1 to 20 hours.
6. The production method according to claim 1 or 2, characterized in that: the compound 3 can be prepared by the following method, comprising the step of preparing the compound 3 by a one-pot method without processing the compound 2, wherein the reaction formula of the first step and the second step is as follows:
or compound 2 under alkaline conditions, and the reaction formula of the step two is as follows:
wherein R is a hydroxyl protecting group, most preferably a tetrahydropyranyl group (THP group) as the hydroxyl protecting group;
the molar charge ratio of the compound 2 to the alkaline reagent in the second step is 1: (0.1-5);
the alkaline reagent in the second step is diisopropylethylamine, triethylamine, diisopropylamine, triethylene diamine, 1, 8-diazabicyclo [5.4.0] undec-7-ene, 1, 5-diazabicyclo [4.3.0] non-5-ene, 4-dimethylaminopyridine, pyridine, N-methylmorpholine, tetramethylethylenediamine, tetramethylguanidine and sodium hydroxide, preferably sodium hydroxide;
the solvent in the second step is tetrahydrofuran, dichloromethane, acetonitrile, dioxane, 2-methyltetrahydrofuran, toluene, N-dimethylformamide, methyl tert-butyl ether, diethyl ether, dimethyl sulfoxide, methanol or any mixture of the solvents, preferably N, N-dimethylformamide;
the reaction time of the second step is 1 to 24 hours, preferably 2 to 5 hours;
the reaction temperature of the second step is 0-100 ℃, and preferably 20-35 ℃.
7. The method according to claim 6, wherein: the compound 2 can be prepared by the following method, comprising the step of reacting a hydroxyl activating reagent of the compound 1 under an acidic condition, wherein the reaction formula of the step one is as follows:
the hydroxyl activating reagent can be selected from 3, 4-dihydro-2H-pyran (DHP), acetic anhydride, benzyl chloroformate, preferably 3, 4-dihydro-2H-pyran DHP;
the molar charge ratio of the compound 1 to the hydroxyl protecting group reagent is 1: (1-5);
the acidic reagent can be selected from formic acid, glacial acetic acid or p-toluenesulfonic acid, preferably p-toluenesulfonic acid;
the solvent is tetrahydrofuran, dichloromethane, acetonitrile, dioxane, 2-methyltetrahydrofuran, toluene, N-dimethylformamide, methyl tert-butyl ether, diethyl ether, dimethyl sulfoxide or any mixture of the solvents, preferably N, N-dimethylformamide;
the reaction time is 1-24 hours;
the reaction temperature is 0-100 ℃, preferably 20-30 ℃.
8. The production method according to claim 1 or 2, characterized in that: the compound 6 is purified by the following method, comprising the following steps of reacting the compound 7 with a hydroxyl protecting group reagent under alkaline conditions, and removing the hydroxyl protecting group to obtain the compound 6, wherein the chemical formula is as follows:
wherein R 'is a protecting group conventional in the art for hydroxy, preferably R' is tetrahydropyranyl THP, methoxymethyl ether, silyl, or acyl, preferably t-butyldimethylsilyl, acetyl, or tetrahydropyranyl THP;
the hydroxyl protecting group reagent is selected from 3, 4-dihydro-2H-pyran (DHP), tert-butyldimethylchlorosilane, chloromethyl methyl ether or acetic anhydride;
the base is selected from sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide, barium hydroxide, or diisopropylethylamine, triethylamine, diisopropylamine, triethylenediamine (DABCO), 1, 8-diazabicyclo [5.4.0] undec-7-ene (DBU), 1, 5-diazabicyclo [4.3.0] non-5-ene (DBN), 4-Dimethylaminopyridine (DMAP), pyridine, N-methylmorpholine, tetramethylethylenediamine, Tetramethylguanidine (TMG), preferably triethylamine.
9. The method of claim 8, wherein: the molar charge ratio of the compound 6 to the hydroxyl protecting group reagent is 1-5: 1; the molar charge ratio of the alkali to the compound 6 is 1-10:1, preferably 2-4: 1; the solvent is tetrahydrofuran, dichloromethane, acetonitrile, dioxane, 2-methyltetrahydrofuran, toluene, N-dimethylformamide, methyl tert-butyl ether, diethyl ether, dimethyl sulfoxide, or any mixture of the above solvents, preferably dichloromethane; the reaction time is 1 to 24 hours, preferably 2 to 5 hours;
the method for removing the hydroxyl protecting group has the following reaction formula:
wherein R 'is a protecting group conventional in the art for hydroxy, preferably R' is Tetrahydropyranyl (THP), silyl, acyl, acylalkyl ether, preferably acetyl;
the alkali is inorganic alkali or organic alkali, the inorganic alkali is selected from sodium hydroxide, sodium bicarbonate and sodium phosphate, and the organic alkali is selected from ammonia gas or ammonia water, methylamine solution, ethylenediamine and triethylamine; the molar ratio of the alkali to the compound 7 is 5-40: 1; the reaction solvent is acetonitrile, tetrahydrofuran, methanol, dichloromethane, dioxane, 2-methyltetrahydrofuran, toluene, N-dimethylformamide, methyl tert-butyl ether, diethyl ether, dimethyl sulfoxide or any mixture of the solvents; the reaction temperature is 0-100 ℃.
10. A2 '-fluoro-2' -deoxyuridine intermediate compound 4 having the following structural formula:
wherein R is a hydroxy protecting group, preferably the tetrahydropyranyl group THP, of the formula:
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