CN115448896A - Preparation method of sofosbuvir intermediate - Google Patents
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Abstract
The invention relates to a preparation method of a sofosbuvir intermediate, belonging to the technical field of drug synthesis. In order to solve the problem of reducing the production process, the preparation method of the sofosbuvir intermediate is provided, and the method comprises the steps of reacting D-glucose with dimethylamine in an acidic environment, adjusting pH after nitrogen replacement, heating, concentrating, filtering and recrystallizing to obtain a compound shown in a formula 3, dissolving the compound shown in the formula 3 in an organic solvent, adding an organic base into the solution to perform esterification reaction with benzoyl chloride to generate a compound shown in a formula 2, dissolving the compound shown in the formula 2 in the organic solvent, and adding the organic base into the solution to perform fluorination reaction with a fluorination reagent to generate a compound shown in the formula 1; the invention has the advantages of short production route, no need of excessive use of high-risk catalyst in the production process and easy production on the whole.
Description
Technical Field
The invention relates to a preparation method of a sofosbuvir intermediate, belonging to the field of preparation of pharmaceutical intermediates.
Background
Sofosbuvir (Sofosbuvir) is a novel drug for treating chronic hepatitis C disease, which is developed by the American Gilidard scientific company and approved by the FDA to be marketed in 2013, is also the first drug capable of treating part of hepatitis C diseases without combined use of interferon, is also a revolutionary therapy against HCV, and the appearance of Sofosbuvir makes the cure of hepatitis C possible.
The chemical name of the sofosbuvir intermediate is (2R) -2-deoxy-2-fluoro-2-methyl-D-erythro pentosan gamma-lactone 3, 5-dibenzoate, and the structural formula is as follows:
in patent US20130324709, it is disclosed that (R) -glyceraldehyde is used as a starting material, diol is obtained through Wittig reaction and dihydroxylation reaction, then diol is reacted with thionyl chloride and is oxidized to obtain sultone sulfate, the sultone sulfate is fluorinated through reaction with triethylamine trihydrofluoride, cyclization reaction is performed under the action of hydrochloric acid and ethanol to obtain bishydroxy lactone, two hydroxyls of bishydroxy lactone are protected by benzoyl to obtain an intermediate compound of formula 1, and the synthetic route is as follows:
in patent CN109438397B, a process for preparing sofosbuvir intermediate from compound (2s,3r) -ethyl-3- ((R) -2,2-dimethyl-1,3-dioxolan-4-yl) -2,3-dihydroxy-2-methylpropionate is disclosed, which comprises cyclization, oxidation, fluorination and hydrolysis, and the synthetic route is shown as follows:
the above patent documents have the common disadvantages of complicated production steps and consumption of manpower and material resources in the large-scale production process.
Therefore, a preparation method with a short reaction route and easy production is needed.
Disclosure of Invention
Aiming at the defects in the prior art, the invention provides a preparation method of a sofosbuvir intermediate, and solves the problem of how to realize the preparation method for improving the product purity.
The invention aims to realize the preparation method of the sofosbuvir intermediate by adopting the following technical scheme, and the method comprises the following steps:
s1: reacting D-glucose with dimethylamine in an acidic environment, adjusting pH after nitrogen replacement, heating, concentrating, filtering and recrystallizing to obtain a compound shown in a formula 3;
s2: dissolving the compound shown in the formula 3 in an organic solvent, and adding organic base and benzoyl chloride into the solution to perform esterification reaction to generate a compound shown in the formula 2;
s3: dissolving the compound shown in the formula 2 in an organic solvent, adding an organic base into the solution, and carrying out a fluorination reaction with a fluorination reagent to generate the compound shown in the formula 1.
The total synthetic route is as follows:
the compound of formula 1 has the structural formula:
the compound of formula 2 has the structural formula:
the compound of formula 3 has the structural formula:
the compound of formula 4 has the structural formula:
the method comprises the steps of taking D-glucose as a starting material, reacting with dimethylamine in an anhydrous environment, adding water for dissolving, then replacing with nitrogen, then adding calcium oxide for drying and heating, cooling and crystallizing after the reaction is finished to obtain a compound in a formula 3, carrying out esterification reaction on the compound in the formula 3 and 3-bromobenzoyl chloride in an organic solvent, carrying out reduced pressure concentration to obtain a compound in a formula 2, slowly dripping a thionyl chloride solution in the presence of the organic solvent and a fluorination reagent in the reaction process, so that the steric hindrance of a hydroxyl protecting group in the 3 is large and cannot be protected, wherein in the fluorination reaction, the steric hindrance of fluorine atoms is small and can be replaced, the compound in the formula 2 is dissolved in the organic solvent, and in the presence of the organic solvent and the fluorination reagent, the compound in the formula 4 is generated in the reaction process, the compound in the formula 4 is not required to be separated, the fluorination reaction system is directly finished to generate the compound in the formula 1, the Sofosbuvir intermediate, the reaction process is brief, a large amount of manpower and material resources are not required, the production cost is reduced, excessive catalyst which is difficult to treat is not used in the reaction process, and the environmental pollution difficulty of the environment is reduced.
In the preparation method of the sofosbuvir intermediate, preferably, the D-glucose in the S1 step does not need to be reacted with dimethylamine under anhydrous conditions, the reaction solvent can be selected from alcohol solutions, and the byproducts are less in favor of post-treatment when the alcohol solvent is used as the reaction environment.
In the preparation method of the sofosbuvir intermediate, preferably, one of methanol and ethanol can be used as a solvent in the step S1. Most preferably, anhydrous ethanol is selected as the reaction solvent to increase the reaction stability.
In the preparation method of the sofosbuvir intermediate, preferably, calcium oxide is added after nitrogen replacement in the step S1 to dry the reaction environment, so that the water content of the product is reduced, and the subsequent reaction is facilitated.
In the above preparation method of the sofosbuvir intermediate, preferably, the organic solution in the steps S2 and S3 is one of dichloromethane, 2-methyltetrahydrofuran or acetone. Most preferably, 2-methyltetrahydrofuran is used as a reaction solvent, so that the generation of byproducts can be reduced, and the recovery and the utilization are convenient.
In the preparation method of the sofosbuvir intermediate, the organic base in the steps S2 and S3 can be one of triethylamine, pyridine or lithium diisopropylamide. Most preferably, the product of the pyridine reaction is easier to handle.
In the above preparation method of sofosbuvir intermediate, preferably, the fluorination reagent in the step S3 may be triethylamine trihydrofluoride, triethylamine pentahydrofluoric acid or [ bis (2-methoxyethyl) amine ] sulfur trifluoride. And most preferably, triethylamine pentahydrofluoric acid is selected as a fluorination reagent, so that the risk is low, and the operation and the production are convenient.
In the above preparation method of the sofosbuvir intermediate, the catalyst in the step S3 can be preferably one of thionyl chloride and sulphuryl chloride. Most preferably, the material consumption is relatively complete when the thionyl chloride is used as a reaction catalyst, so that the production cost can be reduced.
In the above preparation method of the sofosbuvir intermediate, the catalyst solvent in the S3 step may be preferably one of acetone and acetonitrile. Most preferably, the solvent using acetone as a catalyst is highly safe and easy to produce.
In the above preparation method of the sofosbuvir intermediate, preferably, the intermediate compound formula 4 produced in the S3 step is directly subjected to a fluorination reaction without isolation. Most preferably, the intermediate compound shown in the formula 4 can directly perform a fluorination reaction with a fluorination reagent, so that the production flow is reduced, and the cost is reduced.
In summary, compared with the prior art, the invention has the following advantages:
1. the method has the advantages of short reaction route, no need of complicated reaction process, occupation of manpower and material resources, reduction of production cost, simple production process and contribution to industrial production.
2. Most of the catalysts used in the invention can not generate byproducts which are difficult to treat, and catalysts which are highly polluted and difficult to treat, such as triphenylphosphine, potassium permanganate and the like, are not used, so that the post-treatment difficulty is reduced, and the production cost is reduced.
Drawings
FIG. 1 is a synthetic scheme of the present invention;
FIG. 2 is a structural formula of a compound of formula 1 according to the present invention;
FIG. 3 is a structural formula of a compound of formula 2 according to the present invention;
FIG. 4 is a structural formula of a compound of formula 3 according to the present invention;
FIG. 5 shows the structural formula of the compound of formula 4 according to the present invention.
Detailed Description
The technical solution of the present invention is further specifically described below by way of specific examples, but the present invention is not limited to these examples.
Example 1
Preparation of a compound of formula 3:
under the anhydrous condition, 180.0g (1.0 mol) of D-glucose is added into 250ml of anhydrous ethanol, 60.0g (1.0 mol) of glacial acetic acid is added, stirred for 30min, then 139.4g (1.02 mol) of ethanol solution of 33% dimethylamine is added dropwise, and the temperature is controlled not to exceed 20 ℃. Heating the reaction solution to 75 ℃ for reaction for 2 hours, cooling to 55 ℃, preserving the temperature for reaction for 2h, and concentrating under reduced pressure at 50 ℃ to obtain brown oily substance.
400ml of water was added to the oily substance, and after 3 times of replacement with nitrogen, 73.1g (1.3 mol) of calcium oxide was added while controlling the temperature not to exceed 20 ℃, and after completion of the addition, the mixture was stirred at 20 ℃ for 20min and then heated to 40 ℃ to react for 4 hours.
Cooling the temperature of the reaction solution to below 3 ℃, and dropwise adding concentrated sulfuric acid to adjust the pH value to be between 3.0 and 3.2. After the pH adjustment is finished, heating the reaction solution to 45 ℃, stirring and reacting for 12 hours, and then cooling to 25 ℃. Filtering, washing filter cake with proper amount of water, and concentrating filtrate to dryness. After refluxing the residue with 1L of acetone-water solution (V/V = 10) for 30min, heating was stopped, filtration was performed, and the cake was extracted with 500ml of acetone-water solution (V/V = 10) 2 times with reflux each. The filtrates were combined and concentrated, and the residue was added to 200ml of acetone, dissolved by heating, filtered with heat, and crystallized by stirring at room temperature to give 105g of the compound of formula 3 as an off-white solid with a yield of 65%.
Example 2
Preparation of a compound of formula 2:
under the protection of nitrogen, 100g of the compound of formula 3, 500ml of 2-methyltetrahydrofuran and 190g of pyridine are added into a reaction flask, and stirred to dissolve to form a clear solution. The reaction solution was cooled to 5 ℃ and 150g of benzoyl chloride was slowly added dropwise. When the solution is dripped, the reaction temperature is controlled to be 10-15 ℃. After the completion of the dropwise addition, the reaction mixture was stirred at 15 ℃ for 30 minutes. After completion of the reaction was confirmed by high performance liquid chromatography, 1000ml of hydrochloric acid (6.0N) and 2L of dichloromethane were added. Standing for layering, and taking an organic phase. The aqueous phase is extracted twice with 1000ml of dichloromethane. The organic phases are combined, washed once with 500ml of hydrochloric acid (1.0N) and twice with 500ml of saturated sodium bicarbonate solution. The organic phase was dried over anhydrous sodium sulfate for one hour. Filter with buchner and wash the filter cake twice with dichloromethane. The filtrate was concentrated to dryness under reduced pressure. And (3) using a mixed solvent of ethyl acetate and petroleum ether as an eluent, and purifying the obtained crude product by a quick column brushing method. The product containing solution was concentrated to dryness under reduced pressure to give 219g of the compound of formula 2 in 63% yield.
Example 3
Preparation of a compound of formula 1:
50g of the compound of formula 2 and 600ml of acetone are added to the reaction flask and dissolved with stirring to form a clear solution. 124.76ml of triethylamine pentahydrofluoric acid and 53.16g of pyridine were added. The reaction mixture was cooled to 0 ℃ and 100ml of an acetone solution of thionyl chloride (13.3 g) was slowly added dropwise with stirring, and after the addition was complete, the temperature was maintained for reaction for 2h. After completion of the reaction was confirmed by high performance liquid chromatography, the reaction was also concentrated to dryness under reduced pressure. To the crude product was added 250ml of isopropanol, warmed to 55 ℃ and stirred to dissolve the supernatant. Stirring was continued overnight, during which time the temperature was slowly reduced to room temperature. The temperature was further reduced to 0 ℃ and stirred for one hour. The solid formed was filtered with buchner and the filter cake was washed twice with pre-cooled isopropanol. The resulting solid was dried to give 42.86g of the compound of formula 1 as a white solid in 84.7% yield.
Example 4
Under anhydrous condition, adding 180.0g (1.0 mol) of D-glucose into 250ml of methanol, adding 60.0g (1.0 mol) of glacial acetic acid, stirring for 30min, dropwise adding 139.4g (1.02 mol) of ethanol solution of 33% dimethylamine, and controlling the temperature to be not more than 20 ℃. Heating the reaction solution to 75 ℃ for reaction for 2 hours, cooling to 55 ℃, preserving the temperature for reaction for 2h, and concentrating under reduced pressure at 50 ℃ to obtain brown oily substance.
Finally, 105g of the compound of formula 3 was produced as an off-white solid in a yield of 65%.
Example 5
Under the protection of nitrogen, 100g of the compound of formula 3, 500ml of dichloromethane and 243g of triethylamine are added into a reaction bottle and stirred to dissolve to form a clear solution. The reaction solution was cooled to 5 ℃ and 150g of benzoyl chloride was slowly added dropwise. When the solution is dripped, the reaction temperature is controlled to be 10-15 ℃. After the completion of the dropwise addition, the reaction mixture was stirred at 15 ℃ for 30 minutes. After completion of the reaction was confirmed by high performance liquid chromatography, 1000ml of hydrochloric acid (6.0N) and 2L of dichloromethane were added. Standing for layering, and taking an organic phase. The aqueous phase is extracted twice with 1000ml of dichloromethane. The organic phases are combined, washed once with 500ml of hydrochloric acid (1.0N) and twice with 500ml of saturated sodium bicarbonate solution. The organic phase was dried over anhydrous sodium sulfate for one hour. Filter with buchner and wash the filter cake twice with dichloromethane. The resulting filtrate was concentrated to dryness under reduced pressure. And (3) using a mixed solvent of ethyl acetate and petroleum ether as an eluent, and purifying the obtained crude product by a quick column brushing method. The product containing solution was concentrated to dryness under reduced pressure to give 205.4g of the compound of formula 2 in 59.1% yield.
Example 6
100g of the compound of formula 3, 500ml of 2-methyltetrahydrofuran and 257.3g of lithium diisopropylamide are added to a reaction flask under nitrogen protection, and dissolved with stirring to form a clear solution. The reaction solution was cooled to 5 ℃ and 150g of benzoyl chloride was slowly added dropwise. When the solution is dripped, the reaction temperature is controlled to be 10-15 ℃. After the completion of the dropwise addition, the reaction mixture was stirred at 15 ℃ for 30 minutes. After completion of the reaction was confirmed by high performance liquid chromatography, 1000ml of hydrochloric acid (6.0N) and 2L of methylene chloride were added. Standing for layering, and taking an organic phase. The aqueous phase is extracted twice with 1000ml of dichloromethane. The organic phases are combined, washed once with 500ml of hydrochloric acid (1.0N) and twice with 500ml of saturated sodium bicarbonate solution. The organic phase was dried over anhydrous sodium sulfate for one hour. Filter with buchner and wash the filter cake twice with dichloromethane. The filtrate was concentrated to dryness under reduced pressure. And (3) using a mixed solvent of ethyl acetate and petroleum ether as an eluent, and purifying the obtained crude product by a quick column brushing method. The product containing solution was concentrated under reduced pressure to dryness to give 212.7g of the compound of formula 2 in 61.2% yield.
Example 7
50g of the compound of formula 2 and 600ml of acetone are added to the reaction flask and dissolved with stirring to form a clear solution. 100ml of triethylamine trihydrofluoride salt and 68g of triethylamine were added. The reaction mixture was cooled to 0 ℃ and 100ml of acetone solution of thionyl chloride (13.3 g) was slowly added dropwise with stirring, and after the addition was complete, the temperature was maintained for reaction for 2h. After completion of the reaction was confirmed by high performance liquid chromatography, the reaction was also concentrated to dryness under reduced pressure. To the crude product was added 250ml of isopropanol, warmed to 55 ℃ and stirred to dissolve the supernatant. Stirring was continued overnight, during which time the temperature was slowly reduced to room temperature. Continue to cool to 0 ℃ and stir for one hour. The solid formed was filtered with a buchner filter and the filter cake was washed twice with pre-cooled isopropanol. The resulting solid was dried to give 40.3g of the compound of formula 1 as a white solid in 79.8% yield.
Example 8
50g of the compound of formula 2 and 600ml of acetone are added to the reaction flask and dissolved with stirring to form a clear solution. 137.2ml of [ bis (2-methoxyethyl) amine ] sulfur trifluoride and 92.1g of lithium diisopropylamide were added. The reaction mixture was cooled to 0 ℃ and 100ml of acetone solution of thionyl chloride (13.3 g) was slowly added dropwise with stirring, and after the addition was complete, the temperature was maintained for reaction for 2h. After completion of the reaction was confirmed by high performance liquid chromatography, the reaction was also concentrated to dryness under reduced pressure. To the crude product was added 250ml of isopropanol, warmed to 55 ℃ and stirred to dissolve the supernatant. Stirring was continued overnight, during which time the temperature slowly dropped to room temperature. The temperature was further reduced to 0 ℃ and stirred for one hour. The solid formed was filtered with a buchner filter and the filter cake was washed twice with pre-cooled isopropanol. The resulting solid was dried to give 37.7g of the compound of formula 1 as a white solid in 74.5% yield.
Example 9
50g of the compound of formula 2 and 600ml of acetone are added to the reaction flask and dissolved with stirring to form a clear solution. 124.76ml of triethylamine pentahydrofluoric acid and 53.16g of pyridine were added. The reaction mixture was cooled to 0 ℃ and 100ml of acetone solution of sulfonyl chloride (15.09 g) was slowly added dropwise with stirring, after the addition was complete, the temperature was maintained and the reaction was allowed to proceed for 2h. After completion of the reaction was confirmed by high performance liquid chromatography, the reaction was also concentrated to dryness under reduced pressure. To the crude product was added 250ml of isopropanol, warmed to 55 ℃ and stirred to dissolve the clear. Stirring was continued overnight, during which time the temperature was slowly reduced to room temperature. The temperature was further reduced to 0 ℃ and stirred for one hour. The solid formed was filtered with buchner and the filter cake was washed twice with pre-cooled isopropanol. The resulting solid was dried to give 41.24g of the compound of formula 1 as a white solid in a yield of 81.5%.
Example 10
50g of the compound of formula 2 and 600ml of acetone are added to the reaction flask and dissolved with stirring to form a clear solution. 124.76ml of triethylamine pentahydrofluoric acid and 53.16g of pyridine were added. The reaction mixture was cooled to 0 ℃ and 100ml of an acetonitrile solution of thionyl chloride (13.3 g) was slowly added dropwise with stirring, and after the addition was completed, the temperature was maintained for reaction for 2 hours. After completion of the reaction was confirmed by high performance liquid chromatography, the reaction was also concentrated to dryness under reduced pressure. To the crude product was added 250ml of isopropanol, warmed to 55 ℃ and stirred to dissolve the clear. Stirring was continued overnight, during which time the temperature was slowly reduced to room temperature. Continue to cool to 0 ℃ and stir for one hour. The solid formed was filtered with buchner and the filter cake was washed twice with pre-cooled isopropanol. Drying the obtained solid to obtain 41.69g of compound of formula 1 as white solid with yield of 82.4%
Example 11
This example is the example of the published patent CN105085445B
A1000 mL three-necked flask was charged with α -configuration compound (2R, 3R,4R, 5S) -5- (4-benzoylamino-2-oxopyrimidin-1 (2H) -yl) -2- ((benzoyloxy) methyl) -4-fluoro-4-methyltetrahydrofuran-3-benzoic acid ester (50g, 0.088mmol), and then to the reaction system was added acetonitrile 300mL, followed by full stirring and addition of (NH 4) 2Ce (NO 3) 6 (24g, 0.044mmol, 0.5eq) in one portion. After the addition was completed, the reaction system was irradiated with a 100W high-pressure mercury lamp for 12 hours under sufficient stirring, during which time spot analysis was performed by TLC at 2-hour intervals. After the reaction is finished, the system is naturally cooled to room temperature, the organic solvent is removed by decompression on a rotary evaporator, water (200 mL) and dichloromethane (200 mL) are added into the residue, an organic phase is separated, an aqueous phase is extracted by dichloromethane (2 x 100mL), the organic phases are combined, and after the organic phase is concentrated, isopropanol is used for recrystallization to obtain 13.5g (41.2%) of the lactone product 3, 5-bis-O-benzoyl-2-deoxy-2-fluoro-2-C-methyl-D-ribono-gamma-lactone.
Compared with the preparation method of the invention, the yield in the embodiment is lower, which causes higher preparation cost and is not beneficial to expanding production.
The embodiments of the present invention are not limited to the above-described examples, and various changes and modifications in form and detail may be made by those skilled in the art without departing from the spirit and scope of the present invention, and these are considered to fall within the scope of the present invention.
Claims (10)
1. A preparation method of a sofosbuvir intermediate is characterized by comprising the following steps:
s1: reacting D-glucose with dimethylamine in an acidic environment, adjusting pH after nitrogen replacement, heating, concentrating, filtering and recrystallizing to obtain a compound shown in a formula 3;
s2: dissolving the compound shown in the formula 3 in an organic solvent, and adding organic base and benzoyl chloride into the solution to perform esterification reaction to generate a compound shown in the formula 2;
s3: dissolving the compound shown in the formula 2 in an organic solvent, adding an organic base into the solution, and carrying out a fluorination reaction with a fluorination reagent to generate the compound shown in the formula 1.
2. The preparation method of the sofosbuvir intermediate as claimed in claim 1, characterized in that: in the step S1, D-glucose is required to react with dimethylamine under anhydrous condition, and the reaction solvent can be alcohol solution.
3. The preparation method of the sofosbuvir intermediate as claimed in claim 2, wherein: in the step S1, one of methanol and ethanol can be used as a solvent.
4. The preparation method of the sofosbuvir intermediate as claimed in claim 1, wherein: and in the step S1, after nitrogen replacement, adding calcium oxide to dry the reaction environment.
5. The preparation method of the sofosbuvir intermediate as claimed in claim 1, wherein: and the organic solution in the S2 and S3 steps is one of dichloromethane, 2-methyltetrahydrofuran or acetone.
6. The preparation method of the sofosbuvir intermediate as claimed in claim 1, characterized in that: the organic base in the S2 and S3 steps can be one of triethylamine, 2-methylpyridine or lithium diisopropylamide.
7. The preparation method of the sofosbuvir intermediate as claimed in claim 1, characterized in that: the fluorinating reagent in the step S3 can be one of triethylamine trihydrofluoride, triethylamine pentahydrofluoric acid or [ bis (2-methoxyethyl) amine ] sulfur trifluoride.
8. The preparation method of the sofosbuvir intermediate as claimed in claim 1, wherein: the catalyst in the step S3 can be one of thionyl chloride and sulfuryl chloride.
9. The preparation method of the sofosbuvir intermediate as claimed in claim 8, wherein: the catalyst solvent in the step S3 can be one of acetone and acetonitrile.
10. The preparation method of the sofosbuvir intermediate as claimed in claim 1, characterized in that: the intermediate compound formula 4 produced in the S3 step is directly subjected to a fluorination reaction without isolation.
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| CN102695698A (en) * | 2010-01-08 | 2012-09-26 | 杏林制药株式会社 | Method for producing 3,4-disubstituted pyrrolidine derivative and production intermediate thereof |
| CN104693157A (en) * | 2015-02-15 | 2015-06-10 | 上海应用技术学院 | Preparation method of 2-C-methyl-D-ribotide-1,4-lactone |
| CN105693661A (en) * | 2014-12-15 | 2016-06-22 | 苏州旺山旺水生物医药有限公司 | Preparation method and intermediate body of (2S, 3R, 4R)-3,5-bis-sustituted-2-deoxy-2-hydroxy-2-methyl-D-ribose-gamma-lactone |
| CN106366057A (en) * | 2016-08-25 | 2017-02-01 | 上海同昌生物医药科技有限公司 | Synthetic method of sofosbuvir intermediate |
| CN108373458A (en) * | 2017-11-29 | 2018-08-07 | 江西国化实业有限公司 | The synthetic method of the fluoro- 2 methyl-D-ribos-gamma lactones of 3,5- dibenzoyl -2- deoxidations -2- |
| CN109422710A (en) * | 2017-08-28 | 2019-03-05 | 常州制药厂有限公司 | A kind of preparation method of Suo Feibuwei fluorine lactone intermediate |
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2022
- 2022-10-24 CN CN202211303939.6A patent/CN115448896A/en active Pending
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102695698A (en) * | 2010-01-08 | 2012-09-26 | 杏林制药株式会社 | Method for producing 3,4-disubstituted pyrrolidine derivative and production intermediate thereof |
| CN105693661A (en) * | 2014-12-15 | 2016-06-22 | 苏州旺山旺水生物医药有限公司 | Preparation method and intermediate body of (2S, 3R, 4R)-3,5-bis-sustituted-2-deoxy-2-hydroxy-2-methyl-D-ribose-gamma-lactone |
| CN104693157A (en) * | 2015-02-15 | 2015-06-10 | 上海应用技术学院 | Preparation method of 2-C-methyl-D-ribotide-1,4-lactone |
| CN106366057A (en) * | 2016-08-25 | 2017-02-01 | 上海同昌生物医药科技有限公司 | Synthetic method of sofosbuvir intermediate |
| CN109422710A (en) * | 2017-08-28 | 2019-03-05 | 常州制药厂有限公司 | A kind of preparation method of Suo Feibuwei fluorine lactone intermediate |
| CN108373458A (en) * | 2017-11-29 | 2018-08-07 | 江西国化实业有限公司 | The synthetic method of the fluoro- 2 methyl-D-ribos-gamma lactones of 3,5- dibenzoyl -2- deoxidations -2- |
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