Preparation method of sofosbuvir intermediate isomer

Abstract

The invention provides a preparation method of a sofosbuvir key intermediate isomer as shown in a formula (I), which comprises the following steps: S7, carrying out oxidation reaction on a compound 4 in the presence of a first oxidant to obtain a compound 3; s8, the compound 3 is subjected to a reduction reaction in the presence of a reducing agent, and a compound 2 is obtained; s9, the compound 2 is subjected to a cyclization reaction under the acidic condition, and a compound 1 is obtained; and S10, carrying out esterification reaction on the compound 1 and benzoyl chloride in the presence of alkali to obtain the compound shown in the formula (I). The synthesis method has great significance in research on quality and impurities of sofosbuvir, can be used for qualitative and quantitative analysis of impurities in sofosbuvir production, and provides guarantee for medication safety of sofosbuvir.

Description

Technical Field

[0001] This invention relates to the preparation of a pharmaceutical intermediate, specifically to a method for preparing a sofosbuvir intermediate isomer. Background Technology

[0002] Sofosbuvir, marketed as Sovaldi, is an antiviral drug developed by Pharmasset for the treatment of chronic hepatitis C (HCV) infection. It was approved by the U.S. FDA in December 2013. It is indicated for the treatment of chronic hepatitis C virus infection in adults aged 18 years and older, with significant efficacy against HCV genotypes 1, 2, 3, 4, 5, and 6. The drug can be used alone or in combination with other antiviral drugs, such as ribavirin (RBV) and pegylated interferon (PEG-IFN).

[0003] The existing synthetic route for sofosbuvir is as follows.

[0004]

[0005] As shown by the above route, methyl ((2R,3R,4R)-3-(benzoyloxy)-4-fluoro-4-methyl-5-oxotetrahydrofuran-2-yl)benzoate (SFB-6) is the key chiral center in the formation of the sofosbuvir intermediate. However, in the detection of sofosbuvir intermediate SFB-6, impurity isomers are difficult to distinguish. Patent WO2014196491A1 discloses the impurity isomers of sofosbuvir intermediate SFB-6. The synthesis of these impurity isomers is of great significance for the quality and impurity research of sofosbuvir, and can be used for the qualitative and quantitative analysis of impurities in sofosbuvir production, thus ensuring the safety of sofosbuvir use. Summary of the Invention

[0006] To address the aforementioned problems in the prior art, a method for preparing a sofosbuvir intermediate isomer is provided. This method can obtain the sofosbuvir intermediate impurity isomer shown in formula (I), which can be used for the quality control of sofosbuvir.

[0007] This invention provides a method for preparing the key intermediate isomer of sofosbuvir shown in formula (I), comprising the following steps:

[0008]

[0009] S7: Compound 4 undergoes an oxidation reaction in the presence of the first oxidizing agent to give compound 3;

[0010] S8: Compound 3 undergoes a reduction reaction in the presence of a reducing agent to give compound 2;

[0011] S9: Compound 2 undergoes a cyclization reaction under acidic conditions to give compound 1;

[0012] S10: Compound 1, in the presence of a base, undergoes an esterification reaction with benzoyl chloride to give compound (I).

[0013] Preferably, in step S7, the first oxidant is selected from one or more of manganese dioxide, sodium hypochlorite / tetramethylpiperidine oxide system, and Des Martin reagent.

[0014] Preferably, in step S8, the reducing agent is selected from one or more of sodium borohydride, calcium borohydride, and potassium borohydride.

[0015] Preferably, in step S9, the acidic reagent is selected from one or more of concentrated hydrochloric acid, concentrated sulfuric acid, and concentrated nitric acid.

[0016] Preferably, in step S10, the alkali is selected from organic alkali or inorganic alkali.

[0017] Preferably, the organic base is selected from one or more of pyridine, triethylamine, N,N-dimethylamine and quinoline.

[0018] Preferably, in step S10, the condensing agent for the esterification reaction is selected from 4-dimethylaminopyridine.

[0019] Preferably, the preparation method further includes the following steps:

[0020]

[0021] S6: Compound 5 undergoes a fluorination reaction with a fluorinating agent; then 2,2-dimethoxypropane is added, and under acidic conditions, a deprotection reaction is carried out to obtain compound 4.

[0022] Preferably, in step S6, the fluorinating agent is selected from one or more of tetramethylammonium fluoride, ethyltrimethylammonium fluoride, tetraethylammonium fluoride, methyltriethylammonium fluoride, tetrapropylammonium fluoride, tetrabutylammonium fluoride, benzyltrimethylammonium fluoride, benzyltriethylammonium fluoride, benzyltributylammonium fluoride, tetradecyltrimethylammonium fluoride, hexadecyltrimethylammonium fluoride, dimethyldibenzylammonium fluoride, trioctylmethylammonium fluoride, tetraphenylphosphine fluoride, triphenylmethylphosphine fluoride, triphenylethylphosphine fluoride, triphenylbutylphosphine fluoride, and triphenylbenzylphosphine fluoride.

[0023] Preferably, in step S6, the acidic reagent is selected from one or more of concentrated hydrochloric acid, concentrated sulfuric acid, and concentrated nitric acid.

[0024] Preferably, the preparation method further includes the following steps:

[0025]

[0026] S5: Compound 6 undergoes a condensation reaction with thionyl chloride in the presence of a base; then it undergoes an oxidation reaction in the presence of a second oxidizing agent to give compound 5.

[0027] Preferably, in step S5, the alkali is selected from organic or inorganic alkalis.

[0028] Preferably, the organic base is selected from one or more of pyridine, triethylamine, N,N-dimethylamine, and quinoline.

[0029] Preferably, in step S5, the second oxidant is selected from one or more of sodium hypochlorite, potassium periodate, and sodium periodate.

[0030] Preferably, the preparation method further includes the following steps:

[0031]

[0032] S4: Compound 7 undergoes an oxidation reaction under alkaline conditions and in the presence of a third oxidizing agent to yield compound 6.

[0033] Preferably, in step S4, the reagent for the alkaline condition is selected from one or more of sodium bicarbonate, sodium sesquicarbonate, disodium hydrogen phosphate, sodium triphosphate, tetrasodium pyrophosphate, sodium citrate, calcium citrate, calcium carbonate, magnesium oxide, sodium gluconate, sodium lactate, sodium acetate, dipotassium hydrogen phosphate, tetrapotassium pyrophosphate, potassium bicarbonate, calcium lactate, calcium glycerophosphate, calcium gluconate, magnesium lactate, magnesium gluconate, and magnesium hydroxide.

[0034] Preferably, in step S4, the third oxidant is selected from one or more of potassium permanganate and sodium permanganate.

[0035] Preferably, the preparation method further includes the following steps:

[0036]

[0037] S3: Compound 8 reacts with phosphorus ylide reagent in a Wittig reaction to give compound 7.

[0038] Preferably, the preparation method further includes the following steps:

[0039]

[0040] S2: Compound 9 undergoes an oxidation reaction under alkaline conditions and in the presence of a fourth oxidizing agent to give compound 8.

[0041] Preferably, in step S2, the reagent for the alkaline condition is selected from one or more of sodium bicarbonate, sodium sesquicarbonate, disodium hydrogen phosphate, sodium triphosphate, tetrasodium pyrophosphate, sodium citrate, calcium citrate, calcium carbonate, magnesium oxide, sodium gluconate, sodium lactate, sodium acetate, dipotassium hydrogen phosphate, tetrapotassium pyrophosphate, potassium bicarbonate, calcium lactate, calcium glycerophosphate, calcium gluconate, magnesium lactate, magnesium gluconate, and magnesium hydroxide.

[0042] Preferably, in step S2, the fourth oxidant is selected from one or more of potassium periodate and sodium periodate.

[0043] Preferably, the preparation method further includes the following steps:

[0044]

[0045] S1: Mannitol, in the presence of a catalyst, undergoes a condensation reaction with 2,2-dimethoxypropane to give compound 9.

[0046] Preferably, in step S1, the catalyst is selected from one or more of methanesulfonic acid, toluenesulfonic acid, p-toluenesulfonic acid, and trifluoromethanesulfonic acid.

[0047] The beneficial effects of this invention are as follows: It provides a method for preparing methyl benzoate ((2R,3S,4R)-3-(benzoyloxy)-4-fluoro-4-methyl-5-oxotetrahydrofuran-2-yl)benzoate, an intermediate isomer of sofosbuvir. This method can be used for the qualitative and quantitative analysis of impurities in sofosbuvir production, thereby improving the accuracy of the detection method for impurity isomers in the final sofosbuvir product and facilitating the control of this impurity, thus ensuring the safety of sofosbuvir use. Simultaneously, it allows for the study of the impact of this impurity on drug activity and toxic side effects. Furthermore, the synthetic route of this invention is simple and efficient, and the materials, solvents, and reagents used are inexpensive and readily available, improving the utilization rate of by-products and increasing the yield of the final product. Attached Figure Description

[0048] Figure 1 This is a schematic diagram of the single-crystal structure of the compound of formula I prepared in this invention. Detailed Implementation

[0049] To make the technical solutions and beneficial effects of this disclosure more apparent and understandable, a detailed description is provided below by citing specific embodiments. The accompanying drawings are not necessarily drawn to scale, and local features may be enlarged or reduced to more clearly show the details of the local features; unless otherwise defined, the technical and scientific terms used herein have the same meanings as those in the technical field to which this application pertains.

[0050] This invention provides a method for preparing the key intermediate isomer of sofosbuvir shown in formula (I), comprising the following steps:

[0051]

[0052] S7: Compound 4 undergoes an oxidation reaction in the presence of the first oxidizing agent to give compound 3;

[0053] S8: Compound 3 undergoes a reduction reaction in the presence of a reducing agent to give compound 2;

[0054] S9: Compound 2 undergoes a cyclization reaction under acidic conditions to give compound 1;

[0055] S10: Compound 1, in the presence of a base, undergoes an esterification reaction with benzoyl chloride to give compound (I).

[0056] In some embodiments, in step S7, the first oxidant is selected from one or more of manganese dioxide, sodium hypochlorite / tetramethylpiperidine oxide system, and Desmond-Martin reagent.

[0057] In some embodiments, in step S7, the first oxidant is selected from Des Martin reagents.

[0058] In some embodiments, in step S8, the reducing agent is selected from one or more of sodium borohydride, calcium borohydride, and potassium borohydride.

[0059] In some embodiments, in step S8, the reducing agent is selected from sodium borohydride.

[0060] In some embodiments, in step S9, the acidic reagent is selected from one or more of concentrated hydrochloric acid, concentrated sulfuric acid, and concentrated nitric acid.

[0061] In some embodiments, in step S9, the acidic reagent is selected from concentrated hydrochloric acid.

[0062] In some embodiments, in step S10, the base is selected from organic or inorganic bases.

[0063] In some embodiments, in step S10, the base is selected from organic bases.

[0064] In some embodiments, the organic base is selected from one or more of pyridine, triethylamine, N,N-dimethylamine, and quinoline.

[0065] In some embodiments, the organic base is selected from triethylamine.

[0066] In some embodiments, in step S10, the condensing agent for the esterification reaction is selected from 4-dimethylaminopyridine.

[0067] In some embodiments, the preparation method further includes the following steps:

[0068]

[0069] S6: Compound 5 undergoes a fluorination reaction with a fluorinating agent; then 2,2-dimethoxypropane is added, and under acidic conditions, a deprotection reaction is carried out to obtain compound 4.

[0070] In some embodiments, in step S6, the fluorinating agent is selected from one or more of tetramethylammonium fluoride, ethyltrimethylammonium fluoride, tetraethylammonium fluoride, methyltriethylammonium fluoride, tetrapropylammonium fluoride, tetrabutylammonium fluoride, benzyltrimethylammonium fluoride, benzyltriethylammonium fluoride, benzyltributylammonium fluoride, tetradecyltrimethylammonium fluoride, hexadecyltrimethylammonium fluoride, dimethyldibenzylammonium fluoride, trioctylmethylammonium fluoride, tetraphenylphosphine fluoride, triphenylmethylphosphine fluoride, triphenylethylphosphine fluoride, triphenylbutylphosphine fluoride, and triphenylbenzylphosphine fluoride.

[0071] In some embodiments, in step S6, the fluorinating agent is selected from tetraethylammonium fluoride.

[0072] In some embodiments, in step S6, the acidic reagent is selected from one or more of concentrated hydrochloric acid, concentrated sulfuric acid, and concentrated nitric acid.

[0073] In some embodiments, in step S6, the acidic reagent is selected from concentrated hydrochloric acid.

[0074] In some embodiments, the preparation method further includes the following steps:

[0075]

[0076] S5: Compound 6 undergoes a condensation reaction with thionyl chloride in the presence of a base; then it undergoes an oxidation reaction in the presence of a second oxidizing agent to give compound 5.

[0077] In some embodiments, in step S5, the base is selected from organic or inorganic bases.

[0078] In some embodiments, in step S5, the base is selected from organic bases.

[0079] In some embodiments, the organic base is selected from one or more of pyridine, triethylamine, N,N-dimethylamine, and quinoline.

[0080] In some embodiments, in step S5, the second oxidant is selected from one or more of sodium hypochlorite, potassium periodate, and sodium periodate.

[0081] In some embodiments, in step S5, the second oxidant is selected from sodium hypochlorite.

[0082] In some embodiments, the preparation method further includes the following steps:

[0083]

[0084] S4: Compound 7 undergoes an oxidation reaction under alkaline conditions and in the presence of a third oxidizing agent to yield compound 6.

[0085] In some embodiments, in step S4, the reagent for the alkaline condition is selected from one or more of sodium bicarbonate, sodium sesquicarbonate, disodium hydrogen phosphate, sodium triphosphate, tetrasodium pyrophosphate, sodium citrate, calcium citrate, calcium carbonate, magnesium oxide, sodium gluconate, sodium lactate, sodium acetate, dipotassium hydrogen phosphate, tetrapotassium pyrophosphate, potassium bicarbonate, calcium lactate, calcium glycerophosphate, calcium gluconate, magnesium lactate, magnesium gluconate, and magnesium hydroxide.

[0086] In some embodiments, in step S4, the reagent for the alkaline condition is selected from sodium bicarbonate.

[0087] In some embodiments, in step S4, the third oxidant is selected from one or more of potassium permanganate and sodium permanganate.

[0088] In some embodiments, in step S4, the third oxidant is selected from sodium permanganate.

[0089] In some embodiments, the preparation method further includes the following steps:

[0090]

[0091] S3: Compound 8 reacts with phosphorus ylide reagent in a Wittig reaction to give compound 7.

[0092] In some embodiments, the preparation method further includes the following steps:

[0093]

[0094] S2: Compound 9 undergoes an oxidation reaction under alkaline conditions and in the presence of a fourth oxidizing agent to give compound 8.

[0095] In some embodiments, in step S2, the reagent for the alkaline condition is selected from one or more of sodium bicarbonate, sodium sesquicarbonate, disodium hydrogen phosphate, sodium triphosphate, tetrasodium pyrophosphate, sodium citrate, calcium citrate, calcium carbonate, magnesium oxide, sodium gluconate, sodium lactate, sodium acetate, dipotassium hydrogen phosphate, tetrapotassium pyrophosphate, potassium bicarbonate, calcium lactate, calcium glycerophosphate, calcium gluconate, magnesium lactate, magnesium gluconate, and magnesium hydroxide.

[0096] In some embodiments, in step S2, the reagent for the alkaline condition is selected from sodium bicarbonate.

[0097] In some embodiments, in step S2, the fourth oxidant is selected from one or more of potassium periodate and sodium periodate.

[0098] In some embodiments, in step S2, the fourth oxidant is selected from sodium periodate.

[0099] In some embodiments, the preparation method further includes the following steps:

[0100]

[0101] S1: Mannitol, in the presence of a catalyst, undergoes a condensation reaction with 2,2-dimethoxypropane to give compound 9.

[0102] In some embodiments, in step S1, the catalyst is selected from one or more of methanesulfonic acid, toluenesulfonic acid, p-toluenesulfonic acid, and trifluoromethanesulfonic acid.

[0103] In some embodiments, in step S1, the catalyst is selected from p-toluenesulfonic acid.

[0104] In some embodiments, the preparation method is carried out in an organic solvent.

[0105] In some embodiments, the organic solvent is selected from one or more of acetonitrile, dichloromethane, 2-methyltetrahydrofuran, acetone, methanol, toluene, ethylene glycol, tetrahydrofuran, anhydrous ethanol, 1,4-dioxane, ethyl acetate, isopropyl acetate, ethylene glycol dimethyl ether, isopropanol, n-hexane, and methyl tert-butyl ether.

[0106] The method of the present invention will be described below through specific embodiments. It should be understood that these embodiments are used to illustrate the basic principles, main features and advantages of the present invention, and the present invention is not limited to the scope of the following embodiments. The implementation conditions used in the embodiments can be further adjusted according to specific requirements, and the implementation conditions not specified are usually the conditions in conventional experiments.

[0107] In the following examples, unless otherwise specified, all temperatures are in Celsius, and unless otherwise specified, all starting materials and reagents are commercially available or synthesized according to known methods. Commercially available materials and reagents are used directly without further purification.

[0108] Unless otherwise specified in the examples, the solution in the reaction refers to an aqueous solution.

[0109] Unless otherwise specified in the examples, the reaction temperature is room temperature, which is 20℃~30℃.

[0110] The following embodiments are provided to better understand the present invention and are not limited to the preferred embodiments described. They do not constitute a limitation on the content and scope of protection of the present invention. Any product that is the same as or similar to the present invention, derived by any person under the guidance of the present invention or by combining the features of the present invention with other prior art, falls within the protection scope of the present invention.

[0111] Main instruments

[0112] Waters Q-TOF micro mass spectrometer; Bruker TENSOR 27 infrared spectrometer (KBr pellet method); BRUKER AV-500 nuclear magnetic resonance spectrometer (CDCl3 as solvent, TMS as internal standard); Bruker Smart Apex II X-ray single crystal diffractometer.

[0113] Example 1: Synthesis of 1,2-bis(2,2-dimethyl-1,3-dioxapentan-4-yl)ethane-1,2-diol (compound 9)

[0114]

[0115] 110 g of dimethyl sulfoxide was added to a 500 mL reaction flask and stirred. Then, 100 g (0.55 mol) of mannitol, 0.5 g of p-toluenesulfonic acid, and 135.5 g of 2,2-dimethoxypropane were added. The reaction was allowed to proceed to completion at room temperature. The reaction solution was neutralized with 0.4 g of triethylamine and stirred. 200 g of water was added, and the mixture was extracted with 400 mL of ethyl acetate. The extract was separated, and then extracted again with 200 mL of ethyl acetate. The extracts were combined and washed successively with 200 mL of water and 200 mL of saturated sodium chloride solution. The mixture was separated, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure at 50 °C to obtain a white solid. 216 g of methyl tert-butyl ether was added, and the mixture was stirred at 50 °C for 1 h. The temperature was lowered to 30 °C, and 297 g of n-hexane was added dropwise. The mixture was stirred for 1 h, and then cooled to 10 °C to crystallize. The crystals were filtered and dried under blast at 50 °C to obtain 50.3 g of white solid compound 9.

[0116] Example 2: Synthesis of (S,E)-3-(2,2-dimethyl-1,3-dioxapentan-4-yl)-2-methylacrylate (Compound 7)

[0117]

[0118] Add 250 mL of dichloromethane and 50 g of compound 9 to a 500 mL reaction flask, stir, add 25 mL of saturated sodium bicarbonate solution, cool to 2 °C, add 49 g of sodium periodate in portions, maintaining the temperature at 15-20 °C. After the addition is complete, control the temperature and react for 2 hours. After the reaction is complete, add 31 g of anhydrous sodium sulfate, stir and dry for 10 min, filter, wash the filter cake with a small amount of dichloromethane, and dry under vacuum to obtain compound 8. Combine the filtrate and add it to a reaction flask, stir, add 145.2 g of phosphorus ylide, react at room temperature and pass through the solution. After the reaction is complete, concentrate under reduced pressure at 40 °C, distill twice with 100 mL of n-hexane, concentrate, wash twice with 400 mL of n-hexane, filter, combine the filtrate and concentrate under reduced pressure at 50 °C to obtain 73.8 g of oily compound 7.

[0119] Example 3: Synthesis of ethyl ((3R)-3-((R)-2,2-dimethyl-1,3-dioxapentan-4-yl)-2,3-dihydroxy-2-methylpropionate (compound 6)

[0120]

[0121] 21.4 g of compound 7 and 24.8 g of ethylene glycol were added to a 1 L reaction flask along with 623 mL of acetone. The mixture was stirred, and 24.8 g of sodium bicarbonate was added. The mixture was cooled to -15 °C, and 41.6 g of 36% sodium permanganate was added dropwise. After the addition was complete, the temperature was controlled to ensure the reaction was complete. The reaction was then extinguished by slowly adding saturated sodium sulfite solution. The mixture was filtered, and the filter cake was washed with acetone and dried. The filtrates were combined and concentrated under reduced pressure at 50 °C. The residue was extracted with 100 mL of ethyl acetate, separated, combined, washed with water, separated, and concentrated under reduced pressure at 50 °C. 50 g of toluene was added, and the mixture was heated to 27 °C. 200 g of n-hexane was added dropwise, and the mixture was cooled to -10 °C to crystallize. The crystals were filtered and dried under blast air at 50 °C to obtain 15.2 g of white solid compound 6.

[0122] Example 4: Synthesis of ethyl (3R)-3-((R)-2,2-dimethyl-1,3-dioxapentan-4-yl)-2-fluoro-3-hydroxy-2-methylpropionate (compound 4)

[0123]

[0124] 15 g of compound 6, 75 mL of isopropyl acetate (IPAC), 15 mL of acetonitrile, and 21.4 g of triethylamine were added to a 500 mL reaction flask. The mixture was stirred and cooled to 0-5 °C. 10.78 g of thionyl chloride was added dropwise. After the addition was complete, the mixture was kept at 0-10 °C until the reaction was complete. 70 mL of purified water was added to quench the reaction. The mixture was separated, and the organic layer was washed successively with 70 mL of saturated sodium bicarbonate solution and saturated sodium chloride solution. The organic layer was added back to the reaction flask, stirred, and then 8.5 g of sodium bicarbonate and 10 mL of acetonitrile were added. The mixture was cooled to 0-5 °C, and then 110 g of sodium hypochlorite solution was added dropwise. After the addition was complete, the mixture was kept at 0-10 °C until the reaction was complete. 70 mL of saturated sodium sulfite solution was added, the mixture was stirred, filtered, and the filtrate was separated. The filtrate was washed again with 30 mL of saturated sodium bicarbonate solution, separated, dried over anhydrous sodium bicarbonate, filtered, and concentrated under reduced pressure at 50 °C to obtain compound 5. Add 260 mL of dioxane, stir, add 19 g of tetraethylammonium fluoride, heat to reflux, react for 2 h, cool to room temperature, add 260 mL of 2,2-dimethoxypropane, stir for 3 h, add 16 mL of concentrated hydrochloric acid, stir for 1 h, slowly add 500 mL of saturated sodium bicarbonate solution in portions, stir at room temperature, concentrate the filtrate under reduced pressure at 50 °C, add 160 mL of ethyl acetate to the residue, stir for 10 min, separate the liquid and extract with 150 mL of ethyl acetate, combine the organic phases, dry with anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure at 50 °C to obtain 8.48 g of pale yellow oily compound 4.

[0125] Example 5: Synthesis of (3R,4S,5R)-3-fluoro-4-hydroxy-5-(hydroxymethyl)-3-methyldihydrofuran-2(3H)-one (Compound 1)

[0126]

[0127] 4 g of compound 4 and 60 mL of dichloromethane were added to a 250 mL reaction flask and stirred. 13.6 g of Des Martin oxidant was added, and the reaction was allowed to proceed to completion at room temperature. The mixture was then concentrated under reduced pressure at 40 °C, and the residue was purified by column chromatography to give 3.52 g of a colorless oily compound 3. The mixture was returned to the 250 mL reaction flask, and 40 mL of anhydrous ethanol was added. The mixture was stirred, and 7 g of sodium borohydride was added in portions. After the addition was complete, the mixture was allowed to react overnight at room temperature. After the reaction was complete, the mixture was concentrated under reduced pressure at 50 °C, and the residue was purified by column chromatography to give 3.2 g of a colorless oily compound 2. The mixture was then returned to the 250 mL reaction flask, and 50 mL of anhydrous ethanol was added. The mixture was stirred, and then 1 mL of concentrated hydrochloric acid was added. The reaction was allowed to proceed overnight, and after the reaction was complete, the mixture was concentrated under reduced pressure at 50 °C, and the residue was purified by column chromatography to give 1.8 g of a colorless oily compound 1.

[0128] Example 6: Synthesis of methyl benzoate ((2R,3S,4R)-3-(benzoyloxy)-4-fluoro-4-methyl-5-oxotetrahydrofuran-2-yl)benzoate (compound of formula (I))

[0129]

[0130] 1.8 g of compound 1 and 20 mL of acetonitrile were added to a 250 mL reaction flask and stirred. 3.86 g of benzoyl chloride and 0.1 g of 4-dimethylaminopyridine were added, and 4.44 g of triethylamine was added dropwise. The mixture was stirred until the reaction was complete, concentrated under reduced pressure at 50 °C, and purified by column chromatography to give 3.2 g of white solid. 3 mL of isoyrol was added, and the mixture was heated to reflux and stirred until dissolved. 15 mL of n-hexane was added, the heating was turned off, the mixture was cooled, filtered, and dried at 50 °C to give 2.4 g of white solid of compound (I).

[0131] HNMR (CDCl3, 500MHz) δ: 8.08-7.89 (t, J=9.20Hz, 4H), 7.68~7.60 (t, J=7.45Hz, 1H),

[0132] 7.60-7.52 (t, J=7.45Hz, 1H), 7.51-7.44 (t, J=7.85Hz, 2H), 7.44-7.37 (t, J=7.70Hz, 2H), 6.04-5.93 ( dd, J1=8.95Hz, J2=4.50Hz, 1H), 5.33-5.23 (m, 1H), 4.74-4.52 (m, 2H), 1.73-1.60 (d, J=24.15Hz, 3H). 13 C NMR (CDCl3, 500MHz) δ: 169.99, 169.81, 165.78, 164.54, 134.34, 133.47, 129.91, 129.75, 129.02, 12 8.87, 128.47, 127.78, 94.62, 93.19, 77.27, 77.25, 77.00, 76.74, 73.33, 73.06, 61.28, 15.59, 15.40. ESI-MS, m / z: 373.15[M+H] + 395.38 [M+Na] + .

[0133] Example 7: Identification of the structure of compound (I)

[0134] The obtained compound of formula (I) was subjected to X-ray single-crystal diffraction test, and the Flack constant was measured to be 0.13 (7), and its absolute configuration was determined to be 9R, 10R, 11S, as shown in the figure. Figure 1 The specific crystal data is shown in Table 1 below.

[0135] Table 1 Crystal data for compound (I)

[0136]

[0137] It should be understood that the above embodiments are exemplary and are not intended to encompass all possible implementations included in the claims. Various modifications and changes can be made to the above embodiments without departing from the scope of this disclosure. Similarly, the various technical features of the above embodiments can be arbitrarily combined to form other embodiments of the present invention that may not be explicitly described. Therefore, the above embodiments only illustrate several implementations of the present invention and do not limit the scope of protection of this patent.

Claims

1. A method for preparing a sofosbuvir intermediate isomer of formula (I), characterized in that, Includes the following steps: S7: Compound 4 undergoes an oxidation reaction in the presence of the first oxidizing agent to give compound 3; S8: Compound 3 undergoes a reduction reaction in the presence of a reducing agent to give compound 2; S9: Compound 2 undergoes a cyclization reaction under acidic conditions to give compound 1; S10: Compound 1, in the presence of a base, undergoes an esterification reaction with benzoyl chloride to give compound (I).

2. The preparation method according to claim 1, characterized in that, In step S7, the first oxidant is selected from one or more of manganese dioxide, sodium hypochlorite / tetramethylpiperidine oxide system, and Desmond-Martin reagent; and / or, In step S8, the reducing agent is selected from one or more of sodium borohydride, calcium borohydride, and potassium borohydride.

3. The preparation method according to claim 1, characterized in that, In step S9, the acidic reagent is selected from one or more of concentrated hydrochloric acid, concentrated sulfuric acid, and concentrated nitric acid.

4. The preparation method according to claim 1, characterized in that, In step S10, the base is selected from organic or inorganic bases; and / or, The organic base is selected from one or more of pyridine, triethylamine, N,N-dimethylamine, and quinoline; and / or, In step S10, the condensing agent for the esterification reaction is selected from 4-dimethylaminopyridine.

5. The preparation method according to claim 1, characterized in that, The preparation method further includes the following steps: S6: Compound 5 undergoes a fluorination reaction with a fluorinating agent; then 2,2-dimethoxypropane is added, and under acidic conditions, a deprotection reaction is carried out to obtain compound 4; In step S6, the fluorinating agent is selected from one or more of tetramethylammonium fluoride, ethyltrimethylammonium fluoride, tetraethylammonium fluoride, methyltriethylammonium fluoride, tetrapropylammonium fluoride, tetrabutylammonium fluoride, benzyltrimethylammonium fluoride, benzyltriethylammonium fluoride, benzyltributylammonium fluoride, tetradecyltrimethylammonium fluoride, hexadecyltrimethylammonium fluoride, dimethyldibenzylammonium fluoride, trioctylmethylammonium fluoride, tetraphenylphosphine fluoride, triphenylmethylphosphine fluoride, triphenylethylphosphine fluoride, triphenylbutylphosphine fluoride, and triphenylbenzylphosphine fluoride; and / or, In step S6, the acidic reagent is selected from one or more of concentrated hydrochloric acid, concentrated sulfuric acid, and concentrated nitric acid.

6. The preparation method according to claim 5, characterized in that, The preparation method further includes the following steps: S5: Compound 6 undergoes a condensation reaction with thionyl chloride in the presence of a base; then it undergoes an oxidation reaction in the presence of a second oxidizing agent to give compound 5. In step S5, the base is selected from organic or inorganic bases; and / or, The organic base is selected from one or more of pyridine, triethylamine, N,N-dimethylamine, and quinoline; and / or, In step S5, the second oxidant is selected from one or more of sodium hypochlorite, potassium periodate, and sodium periodate.

7. The preparation method according to claim 6, characterized in that, The preparation method further includes the following steps: S4: Compound 7 undergoes an oxidation reaction under alkaline conditions and in the presence of a third oxidizing agent to give compound 6; In step S4, the reagent for the alkaline condition is selected from one or more of sodium bicarbonate, sodium sesquicarbonate, disodium hydrogen phosphate, sodium triphosphate, tetrasodium pyrophosphate, sodium citrate, calcium citrate, calcium carbonate, magnesium oxide, sodium gluconate, sodium lactate, sodium acetate, dipotassium hydrogen phosphate, tetrapotassium pyrophosphate, potassium bicarbonate, calcium lactate, calcium glycerophosphate, calcium gluconate, magnesium lactate, magnesium gluconate, and magnesium hydroxide; and / or, In step S4, the third oxidant is selected from one or more of potassium permanganate and sodium permanganate.

8. The preparation method according to claim 7, characterized in that, The preparation method further includes the following steps: S3: Compound 8 reacts with phosphorus ylide reagent in a Wittig reaction to give compound 7.

9. The preparation method according to claim 8, characterized in that, The preparation method further includes the following steps: S2: Compound 9 undergoes an oxidation reaction under alkaline conditions and in the presence of a fourth oxidizing agent to give compound 8; In step S2, the reagent for the alkaline condition is selected from one or more of sodium bicarbonate, sodium sesquicarbonate, disodium hydrogen phosphate, sodium triphosphate, tetrasodium pyrophosphate, sodium citrate, calcium citrate, calcium carbonate, magnesium oxide, sodium gluconate, sodium lactate, sodium acetate, dipotassium hydrogen phosphate, tetrapotassium pyrophosphate, potassium bicarbonate, calcium lactate, calcium glycerophosphate, calcium gluconate, magnesium lactate, magnesium gluconate, and magnesium hydroxide; and / or, In step S2, the fourth oxidant is selected from one or more of potassium periodate and sodium periodate.

10. The preparation method according to claim 9, characterized in that, The preparation method further includes the following steps: S1: Mannitol, in the presence of a catalyst, undergoes a condensation reaction with 2,2-dimethoxypropane to give compound 9; In step S1, the catalyst is selected from one or more of methanesulfonic acid, toluenesulfonic acid, p-toluenesulfonic acid, and trifluoromethanesulfonic acid.

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