Preparation method of key intermediate diol olefin compound of posaconazole

Abstract

The invention discloses a preparation method of a posaconazole key intermediate diol olefin compound, which comprises the following steps: dissolving a compound 1 in an organic solvent A, adding a mixed solution of an additive and an organic solvent B, alkali a and trioxymethylene, continuing to react, and treating to obtain a compound 2; dissolving the obtained compound 2 in an organic solvent C, adding a reducing agent, and performing heating reflux reaction to obtain a compound I; the synthesis route is as follows: the reaction process is simple, the raw materials are simple and easy to obtain, harsh reaction conditions are not needed, the route is simple and convenient, the reaction operation is simple, and the drug development potential is achieved.

Description

TECHNICAL FIELD

[0001] The application belongs to the technical field of organic chemical synthesis, and particularly relates to a preparation method of a key intermediate diol alkene compound of posaconazole. BACKGROUND

[0002] In today's world, the number of diseases caused by fungal infections is increasing. Invasive fungal infection (IFIs) refers to a disease caused by pathogenic fungi invading the human body. The main pathogenic fungi are Candida and Aspergillus, which seriously threaten the health and life safety of patients. From the development of antifungal drugs, the first generation of triazole antifungal drugs such as fluconazole and itraconazole have made some progress in the treatment of some fungal infection diseases, but they have some shortcomings, such as insufficient broad-spectrum antifungal spectrum, poor pharmacokinetic characteristics affecting drug absorption, distribution, metabolism and excretion in the body, and single dosage form.

[0003] However, the second generation of triazole antifungal drugs such as voriconazole and posaconazole show more prominent advantages. Posaconazole, as a new second-generation triazole antifungal drug, is widely used for the prevention and treatment of invasive fungal diseases, and shows excellent antibacterial activity and excellent tolerance in dealing with invasive fungal infections. Compared with other drugs of the same type, posaconazole has a wider antibacterial spectrum, stronger antibacterial activity, better economic benefit and significant advantages. Therefore, posaconazole is considered to be the first choice for the prevention of IFIs and has a wide range of applications in the prevention and treatment of IFIs.

[0004] Due to the increasing incidence of invasive fungal infections, the demand for posaconazole is also increasing worldwide. However, the current synthesis process of posaconazole faces many difficulties and challenges, such as long steps, easy degradation of intermediates or side reactions, and harsh reaction conditions for some reactions. Therefore, it is of great practical significance to develop a simple and efficient synthesis route. The synthesis of posaconazole mainly focuses on three fragments, and the most concerned is the synthesis of the intermediate containing a chiral tetrahydrofuran ring structure. Due to the characteristics of "multiple chiral centers + non-continuous chiral centers", the stereoselective synthesis of two non-continuous chiral centers is very difficult, and the effective control of diastereoselectivity is required. Complex chiral skeletons are usually needed to control the synthesis of non-continuous chiral centers by combining stereospecific, electronic and inductive effects. In view of the wide development prospects of posaconazole and the importance of the key intermediate containing a chiral tetrahydrofuran ring structure, it is necessary to develop a feasible preparation method. SUMMARY

[0005] In view of the above problems, the present application aims to provide a preparation method of a posaconazole key intermediate diol alkene compound.

[0006] The specific technical solutions are as follows:

[0007] The preparation method of the posaconazole key intermediate diol alkene compound comprises the following steps:

[0008] (1) Compound 1 is dissolved in an organic solvent A, a mixed solution of an additive and an organic solvent B, a base a and trioxane are added, and the reaction is continued, and after treatment, compound 2 is obtained;

[0009] (2) Compound 2 obtained in step (1) is dissolved in an organic solvent C, a reducing agent is added, and the reaction is carried out under heating and reflux to obtain compound I;

[0010] The synthetic route is as follows:

[0011]

[0012] Further, the base a in step (1) is any one or a combination of any plurality of pyridine, sodium hydride, sodium hydroxide, potassium hydroxide, 2,6-dimethylpyridine, 4-dimethylaminopyridine, cesium carbonate, potassium carbonate, potassium acetate, potassium tert-butoxide, sodium tert-butoxide, triethylamine, diisopropylamine, N,N-diisopropylethylamine, n-butyllithium, tert-butyllithium, lithium diisopropylamide, hexamethylphosphoric triamide, sodium amide, potassium acetate, cesium acetate and potassium phosphate.

[0013] Further, the molar amount of the base a in step (1) is 1.0-10.0 equivalents of the molar amount of compound 1.

[0014] Further, the additive in step (1) is any one or a combination of any plurality of titanium tetrachloride, dibutylboron trifluoromethanesulfonate and lithium diisopropylamide.

[0015] Further, the molar amount of the additive in step (1) is 1.0-10.0 equivalents of the molar amount of compound 1.

[0016] Further, the organic solvent A, the organic solvent B in step (1) and the organic solvent C in step (2) are selected from any one or a combination of any plurality of ethyl acetate, N,N-dimethylformamide, acetonitrile, butyronitrile, pentanitrile, benzene, toluene, xylene, pentane, hexane, octane, cyclohexane, cyclohexanone, chlorobenzene, dichlorobenzene, dichloromethane, methanol, ethanol, isopropyl alcohol, diethyl ether, acetone, methyl butanone, ethylene glycol monomethyl ether, ethylene glycol monoethyl ether, tetrahydrofuran and water.

[0017] Further, the molar amount of the trichloromethane in step (1) is 1.0-10.0 equivalents of the amount of the compound 1.

[0018] Further, the reducing agent in step (2) is any one or a combination of any several of lithium aluminum hydride, sodium borohydride, potassium borohydride, borane, diisobutylaluminum hydride, sodium cyanoborohydride, sodium triacetoxyborohydride, sodium dimethoxyethylborohydride, and 9-BBN-H.

[0019] Further, the molar amount of the reducing agent in step (2) is 1.0-10.0 equivalents of the molar amount of the compound 2.

[0020] Further, the reaction temperature in steps (1) and (2) ranges from -78 to 100℃, and the total reaction time is at least 1 hour.

[0021] The present application has the following beneficial effects:

[0022] 1) The present application uses simple and readily available m-difluorobenzene as a raw material to introduce a prosthetic group in the structure, and then performs a hydroxymethylation reaction and a prosthetic group reduction reaction to obtain a diol olefin product, which is convenient for subsequent construction of a chiral center through an asymmetric halocyclization reaction to obtain a halocyclization product, and the introduction of halogen creates conditions for the introduction of a triazole group, thereby providing a new direction for the synthesis of the key intermediate II of posaconazole.

[0023] 2) The reaction conditions of the present application are relatively mild, the raw materials are simple and readily available, and the preparation process is simple. DETAILED DESCRIPTION

[0024] The present application will be further described in detail below in combination with the following specific examples, and the protection scope of the present application is not limited to the following examples. Changes and advantages that can be thought of by those skilled in the art without departing from the spirit and scope of the present application are included in the present application, and the appended claims are the protection scope. The process, conditions, reagents, experimental methods, etc. for implementing the present application are the general knowledge and common sense in the art, and the present application has no special limitation. The data given in the following examples include specific operations and reaction conditions and products, and the product purity is identified by nuclear magnetic resonance.

[0025] The synthesis route of 2-(2-(2,4-difluorophenyl)propylidene)propane-1,3-diol (compound I) is as follows:

[0026]

[0027] Example 1

[0028] Step (1): Preparation of 3-(4-(2,4-difluorophenyl)-2-(hydroxymethyl)pent-4-enoyl)oxazolidin-2-one

[0029] Compound 1 (4.2 mmol, 1.0 equiv.) was added to a 50 mL dry Schlenk tube under nitrogen protection, followed by 10 mL super dry DCM to dissolve it, and then a TiCl4-DCM solution (1.1 equiv., 1 M) was added dropwise at -10 °C, stirred for 15 min, DIPEA (5.46 mmol, 1.3 equiv.) was added, the mixture was stirred for 1.5 h, then trioxane (9.24 mmol, 2.2 equiv.) and TiCl4-DCM solution (1.1 equiv., 1 M) were added, the reaction was stirred for 0.5 h, and then the temperature was raised to 0 °C for continuous reaction. After the reaction was completed, saturated NH4Cl solution was added to quench the reaction, the organic layer and the aqueous layer were separated, the aqueous layer was extracted with DCM, the organic layers were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and then column chromatography was performed to obtain compound 2 (yield 71 %) (eluent polarity: petroleum ether / ethyl acetate = 5 / 1).

[0030]

[0031] 1 H NMR (400 MHz, CDC13) δ 7.26-7.18 (m, 1H), 6.92-6.69 (m, 2H), 5.26 (s, 1H), 5.19 (s, 1H), 3.75 (dd, J = 10.8, 3.8 Hz, 2H), 3.62 (dd, J = 10.8, 7.0 Hz, 2H), 2.80-2.20 (m, 4H), 1.79-1.67 (m, 1H). 13 C NMR (100 MHz, CDC13) δ 174.3, 162.4 (dd, J = 14.6, 4.0 Hz), 159.9 (dd, J = 225.6, 12.7 Hz), 153.7, 140.3, 130.8, 125.0 (dd, J = 225.6, 12.7 Hz), 118.8, 111.2 (d, J = 20.7 Hz), 104.2 (dd, J = 52.4, 26.2 Hz), 70.1, 63.8, 57.9, 44.3, 35.1. C-F C-F C-F C-F C-F 19 F NMR (376 MHz, CDC13) δ -110.66 (d, J = 7.2 Hz), -110.86 (d, J = 7.5 Hz).

[0032] Example 2

[0033] ​​​​​Step (1): Preparation of 3-(4-(2,4-difluorophenyl)-2-(hydroxymethyl)pent-4- enoyl)oxazolidin-2-one

[0034] Compound 1 (4.2 mmol, 1.0 equiv.) was added to a 50 mL dry Schlenk tube under nitrogen protection, followed by 10 mL super dry tetrahydrofuran to dissolve it, and then cooled to -78 °C. LDA-THF solution (1.1 equiv., 1 M) was slowly added dropwise through a constant pressure dropping funnel, and stirred for 1 h after the addition was completed. A solution of hexamethylphosphoramide (6.3 mmol, 1.5 equiv.) and trioxane (5.04 mmol, 1.2 equiv.) in dichloromethane was slowly added dropwise, and the reaction was continued to stir at room temperature overnight. After the reaction was completed, saturated NH4Cl solution was slowly added to quench the reaction under ice bath, and the organic layer and the aqueous layer were separated. The aqueous layer was extracted with EA, and the organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and then column chromatography was performed to obtain compound 2 (yield 62%) (eluent polarity: petroleum ether / ethyl acetate = 5 / 1).

[0035] Example 3

[0036] Step (1): Preparation of 3-(4-(2,4-difluorophenyl)-2-(hydroxymethyl)pent-4- enoyl)oxazolidin-2-one

[0037] Compound 1 (4.2 mmol, 1.0 equiv.) was added to a 50 mL dry Schlenk tube under nitrogen protection at -78 °C, followed by 10 mL super dry DCM to dissolve it, and then TiCl4-DCM solution (1.1 equiv., 1 M) and DIPEA (10.5 mmol, 2.5 equiv.) were added. The reaction was stirred at -78 °C for 40 min, and then a solution of hexamethylphosphoramide (6.3 mmol, 1.5 equiv.) and trioxane (5.04 mmol, 1.2 equiv.) in dichloromethane was added. The reaction was continued to stir at room temperature for 1 h. After the reaction was completed, saturated NH4Cl solution was added to quench the reaction, and the organic layer and the aqueous layer were separated. The aqueous layer was extracted with DCM, and the organic layers were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and then column chromatography was performed to obtain compound 2 (yield 62%) (eluent polarity: petroleum ether / ethyl acetate = 5 / 1).

[0038] Example 4

[0039] Step (1): Preparation of 3-(4-(2,4-difluorophenyl)-2-(hydroxymethyl)pent-4- enoyl)oxazolidin-2-one

[0040] Compound 1 (4.2 mmol, 1.0 equiv.) was added to a 50 mL dry Schlenk tube under nitrogen protection, followed by 10 mL super dry DCM to dissolve it, and then cooled to 0 °C. A solution of dibutylboron trifluoromethanesulfonate in dichloromethane (1.1 equiv., 1 M) and DIPEA (6.3 mmol, 1.5 equiv.) were added dropwise at 0 °C, and the mixture was stirred for 30 min, then cooled to -78 °C, followed by the addition of trioxane (6.3 mmol, 1.5 equiv.) in batches, and the reaction was continued to stir for 2 h, and then warmed to 0 °C for further reaction. After the reaction was completed, a methanol / hydrogen peroxide solution (5:1) was added at -78 °C to quench for 10 min, followed by treatment at 0 °C for 30 min, and then the mixture was concentrated under reduced pressure and diluted with DCM and saturated sodium bicarbonate solution, and the organic layer was separated, and the aqueous layer was extracted with DCM, and the combined organic layers were dried over anhydrous sodium sulfate, and then concentrated under reduced pressure, and then column chromatography was performed to obtain compound 2 (yield 58%) (eluent polarity: petroleum ether / ethyl acetate = 5 / 1).

[0041] Example 5

[0042] Step (2): Preparation of 2-(2-(2,4-difluorophenyl)propylidene)propane-1,3-diol

[0043] Under nitrogen protection, lithium aluminum hydride (2 mmol, 2.0 equiv.) was added to a dry three-necked round-bottom flask equipped with a high-efficiency reflux condenser (with a drying tube at the top) and a constant-pressure dropping funnel, and then 2 mL of super dry tetrahydrofuran was added as a solvent. Dry compound 2 (1 mmol, 1.0 equiv.) was dissolved in super dry tetrahydrofuran under vigorous stirring, and then slowly and dropwise added to the mixture through the constant-pressure dropping funnel (ice bath cooling was necessary). After the addition was completed, the temperature was raised to 55 °C and heating reflux was started, and the reaction was continued for 2 h. After the reaction was completed, the reaction flask was immersed in an ice water bath to cool to 0-5 °C, and stirring was maintained. Saturated sodium sulfate solution was added extremely slowly and dropwise under vigorous stirring and ice bath cooling, and then 1 N aqueous hydrochloric acid solution was added until the pH of the mixture was 1.0, and then the mixture was separated, and the aqueous layer was extracted with DCM, and the combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure and column chromatography was performed to obtain compound I (yield 75%) (eluent polarity: petroleum ether / ethyl acetate = 4 / 1).

[0044]

[0045] 1H NMR (400 MHz, CDC13) δ 7.21 - 7.00 (m, 1H), 6.80 - 6.57 (m, 2H), 5.19 (s, 1H), 5.10 (s, 1H), 3.68 (dd, J = 10.7, 3.8 Hz, 2H), 3.55 (dd, J = 10.8, 7.0 Hz, 2H), 2.40 (d, J = 7.4 Hz, 4H), 1.77 - 1.48 (m, 1H). 13 C NMR (100 MHz, CDC13) δ 161.3 (dd, J = 225.9, 11.9 Hz), 158.8 (dd, J = 225.9, 11.9 Hz), 140.6 (d, J = 1.6 Hz), 129.7 (dd, J = 9.5, 5.9 Hz), 124.2 (dd, J = 14.4, 3.9 Hz), 117.1, 110.3 (dd, J = 21.3, 3.5 Hz), 103.2 (dd, J = 26.0, 13.0 Hz), 64.5, 39.0, 33.9. C-F C-F C NMR (100 MHz, CDC13) δ 161.3 (dd, J = 225.9, 11.9 Hz), 158.8 (dd, J = 225.9, 11.9 Hz), 140.6 (d, J = 1.6 Hz), 129.7 (dd, J = 9.5, 5.9 Hz), 124.2 (dd, J = 14.4, 3.9 Hz), 117.1, 110.3 (dd, J = 21.3, 3.5 Hz), 103.2 (dd, J = 26.0, 13.0 Hz), 64.5, 39.0, 33.9. C-F C-F C NMR (100 MHz, CDC13) δ 161.3 (dd, J = 225.9, 11.9 Hz), 158.8 (dd, J = 225.9, 11.9 Hz), 140.6 (d, J = 1.6 Hz), 129.7 (dd, J = 9.5, 5.9 Hz), 124.2 (dd, J = 14.4, 3.9 Hz), 117.1, 110.3 (dd, J = 21.3, 3.5 Hz), 103.2 (dd, J = 26.0, 13.0 Hz), 64.5, 39.0, 33.9. C-F C-F C NMR (100 MHz, CDC13) δ 161.3 (dd, J = 225.9, 11.9 Hz), 158.8 (dd, J = 225.9, 11.9 Hz), 140.6 (d, J = 1.6 Hz), 129.7 (dd, J = 9.5, 5.9 Hz), 124.2 (dd, J = 14.4, 3.9 Hz), 117.1, 110.3 (dd, J = 21.3, 3.5 Hz), 103.2 (dd, J = 26.0, 13.0 Hz), 64.5, 39.0, 33.9. C-F 19 F NMR (376 MHz, CDC13) δ -110.81 (d, J = 7.6 Hz), -111.34.

[0046] Example 6

[0047] Step (2): Preparation of 2-(2-(2,4-difluorophenyl)propylidene)propane-1,3-diol

[0048] Under nitrogen protection, dry compound 2 (1 mmol, 1.0 equiv.) was dissolved in 2 mL of super dry tetrahydrofuran, and then added to a dry three-necked flask. Under stirring, a tetrahydrofuran solution (1 M) of borane (2.5 mmol, 2.5 equiv.) was slowly injected into the mixture (if necessary, ice bath cooling). After injection, heating to 65°C and starting heating reflux, reaction for 6 h. After the reaction was completed, cooling to room temperature, under stirring and ice water bath cooling, methanol was added dropwise to quench the reaction very slowly, concentrated under reduced pressure, then a small amount of 3M hydrochloric acid was added and stirred for 15 min, the aqueous layer was extracted with DCM, and the combined organic layers were washed with saturated sodium bicarbonate solution and then saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and column chromatography to obtain compound I (yield 67%) (eluent polarity: petroleum ether / ethyl acetate = 4 / 1).

[0049] Example 7

[0050] ​​​​Step (2): Preparation of 2-(2-(2,4-difluorophenyl)propylidene)propane-1,3-diol

[0051] Under nitrogen protection, dry compound 2 (1 mmol, 1.0 equiv.) was dissolved in 2 mL of super dry tetrahydrofuran, and then added to a dry three-neck flask, which was placed in an ice bath environment. Under stirring condition, sodium borohydride (4.0 mmol, 4.0 equiv.) was added to the reaction vessel. Then, I2 (2.0 mmol, 2.0 equiv.) was dissolved in a small amount of super dry tetrahydrofuran, and slowly added to the three-neck flask by a constant pressure dropping funnel. At this time, the temperature was maintained at ≤5°C, and after the addition was completed, it was stirred at 0°C for 30 min. Then, the temperature was raised to room temperature, and the reaction was carried out for 6 h. After the reaction was completed, it was cooled to 0°C, and methanol was slowly added dropwise to quench the reaction under stirring. Then, a small amount of 3M NaOH solution was added and stirred for 30 min, and the organic layer was separated by liquid-liquid extraction. The water layer was extracted with ethyl acetate, and the combined organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to obtain compound I (yield 65%) (eluent polarity: petroleum ether / ethyl acetate = 4 / 1).

[0052] Example 8

[0053] Step (2): Preparation of 2-(2-(2,4-difluorophenyl)propylidene)propane-1,3-diol

[0054] Under nitrogen protection, dry compound 2 (1 mmol, 1.0 equiv.) was dissolved in 2 mL of super dry tetrahydrofuran, and then added to a dry three-neck flask, which was placed in an ice bath environment. Under stirring condition, sodium borohydride (4.0 mmol, 4.0 equiv.) was added to the reaction vessel. Then, I2 (2.0 mmol, 2.0 equiv.) was dissolved in a small amount of super dry tetrahydrofuran, and slowly added to the three-neck flask by a constant pressure dropping funnel. At this time, the temperature was maintained at ≤5°C, and after the addition was completed, it was stirred at 0°C for 30 min. Then, the temperature was raised to room temperature, and the reaction was carried out for 6 h. After the reaction was completed, it was cooled to 0°C, and methanol was slowly added dropwise to quench the reaction under stirring. Then, a small amount of 3M NaOH solution was added and stirred for 30 min, and the organic layer was separated by liquid-liquid extraction. The water layer was extracted with ethyl acetate, and the combined organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to obtain compound I (yield 65%) (eluent polarity: petroleum ether / ethyl acetate = 4 / 1).

[0055] Example 9

[0056] Step (2): Preparation of 2-(2-(2,4-difluorophenyl)propylidene)propane-1,3-diol

[0057] Under nitrogen protection, dry compound 2 (1 mmol, 1.0 equiv.) was dissolved in 5 mL super dry tetrahydrofuran, and then added into a dry three-neck flask. Under stirring condition, sodium borohydride (3 mmol, 3.0 equiv.) in super dry tetrahydrofuran (1.0 M) was added into the reaction vessel. After stirring at 0 °C for 1 h, the temperature was increased to room temperature and stirred for 1 h, then the temperature was increased to 65 °C and heated to reflux, and the reaction was stirred overnight. After the reaction was completed, the temperature was cooled to 0 °C, and methanol was slowly added dropwise to quench the reaction under stirring, then a small amount of 3 M NaOH solution was added, and then a small amount of 30% aqueous H2O2 solution was added dropwise, and stirred at room temperature for 1 h until no flocculent precipitate was formed. The liquid was separated, and the aqueous layer was extracted with ethyl acetate. The organic layers were combined and washed with saturated Na2S2O3 solution and saturated brine successively. After drying over anhydrous sodium sulfate, the mixture was concentrated under reduced pressure and purified by column chromatography to obtain compound I (yield 60%) (eluent polarity: petroleum ether / ethyl acetate = 4 / 1, plus 0.5% triethylamine).

[0058] Example 10

[0059] Step (2): Preparation of 2-(2-(2,4-difluorophenyl)propylidene)propane-1,3-diol

[0060] Under nitrogen protection, dry compound 2 (1 mmol, 1.0 equiv.) was dissolved in 5 mL super dry tetrahydrofuran, and then added into a dry three-neck flask. Under stirring condition, sodium borohydride (3 mmol, 3.0 equiv.) in super dry tetrahydrofuran (1.0 M) was added into the reaction vessel. After stirring at 0 °C for 1 h, the temperature was increased to room temperature and stirred for 1 h, then the temperature was increased to 65 °C and heated to reflux, and the reaction was stirred overnight. After the reaction was completed, the temperature was cooled to 0 °C, and methanol was slowly added dropwise to quench the reaction under stirring, then a small amount of 3 M NaOH solution was added, and then a small amount of 30% aqueous H2O2 solution was added dropwise, and stirred at room temperature for 1 h until no flocculent precipitate was formed. The liquid was separated, and the aqueous layer was extracted with ethyl acetate. The organic layers were combined and washed with saturated Na2S2O3 solution and saturated brine successively. After drying over anhydrous sodium sulfate, the mixture was concentrated under reduced pressure and purified by column chromatography to obtain compound I (yield 60%) (eluent polarity: petroleum ether / ethyl acetate = 4 / 1, plus 0.5% triethylamine).

[0061] Example 11

[0062] Step (3): Preparation of ((3R,5R)-5-(bromomethyl)-5-(2,4-difluorophenyl)tetrahydrofuran-3-yl)methanol

[0063] In the dark, diol alkene compound I (0.05 mmol, 1.0 equiv.) and C2 symmetric cyclization sulfide catalyst (0.0025 mmol, 0.05 equiv.) were dissolved in dichloromethane, respectively, added to a dry Schlenk tube and cooled to -78°C, then MsOH (0.05 mmol, 1.0 equiv.) in dichloromethane (0.05M) and NBS (0.06 mmol, 1.2 equiv.) were quickly added to the mixture, then the reaction was continued to be stirred at -78°C in the dark. After the reaction was completed, 1 mL of saturated Na2SO3 solution was added to quench the reaction, then diluted with 3 mL of deionized water, separated, and the aqueous layer was extracted with dichloromethane. The combined organic layers were dried with anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to obtain compound 3 (yield 91%, 81:19 er) (eluent polarity: n-hexane / ethyl acetate = 1 / 3).

[0064]

[0065] Example 12

[0066] Step (4) and Step (5): Preparation of ((3S,5R)-5-((1H-1,2,4-triazol-1-yl)methyl)-5-(2,4- difluorophenyl)tetrahydrofuran-3-yl)methyl 4-methylbenzenesulfonate

[0067] Compound 3 (5.0 mmol, 1.0 equiv.) was dissolved in DMF at room temperature, then sodium triazole (25 mmol, 5.0 equiv.) was added, stirred for 5 min, then DMPU (3.75 mmol, 0.75 equiv.) was added dropwise, and stirred at 110°C for 24 h. After the reaction was completed, it was cooled to room temperature, quenched with water, and the aqueous phase was extracted with EA, and the organic phase was extracted with 1N HCl aqueous solution until the EA phase thin layer chromatography showed no product color spots, the aqueous phase was adjusted to pH 7-8 with sodium hydroxide solution, and then extracted with EA. The combined organic phases were dried with anhydrous sodium sulfate, concentrated under reduced pressure to obtain compound 4, which was directly used in the next step.

[0068]

[0069] The crude compound 4 obtained in the previous step was dissolved in DCM at room temperature under nitrogen protection, TEA (1.2 equiv.) and DMAP (0.1 equiv.) were added and stirred for 5 min, TsCl (1.0 equiv.) was added at 0 °C at once, and the reaction was carried out at room temperature overnight. After the reaction was completed, water was added for washing, the organic phase was separated, the aqueous phase was extracted with DCM, the combined organic phase was dried over anhydrous sodium sulfate, and then concentrated under reduced pressure to obtain the crude product. Isopropanol was added, the temperature was raised to 50-60 °C, and then n-heptane was added dropwise. The mixture was cooled to room temperature and stirred for crystallization for 1.5 h. Filtration was performed, and the filter cake was washed with n-heptane to obtain the posaconazole intermediate II (51% yield for two-step continuous reaction).

[0070] Example 13

[0071] Step (6): Preparation of posaconazole

[0072] The other key fragment III of posaconazole (0.64 mmol, 1.0 equiv.) was added to a 25 mL reaction bottle at room temperature, 2.5 mL of DMSO was added, the key intermediate II (0.70 mmol, 1.1 equiv.) was added, 25 wt% aqueous NaOH solution (0.70 mmol, 1.1 equiv.) was added dropwise, and the reaction was carried out at 45 °C for 36 h. After the reaction was completed, 2 mL of ice water was added to the reaction system, and a large amount of solid was precipitated. Filtration was performed, and the filter cake was washed with water to obtain a brown solid. The solid was dissolved in DCM, decolorized with activated carbon, and then concentrated under reduced pressure to obtain a white solid, which was the crude posaconazole. The crude product was added to methanol, heated to reflux for 30 min, naturally cooled to 20-25 °C, and then crystallized for 2 h. Filtration was performed, and the filter cake was washed with pre-cooled MeOH. The filter cake was air-dried at 40-45 °C for 6 h to obtain the final product posaconazole (75% yield).

[0073]

[0074] 1H NMR(400MHz,CDCl3)δ8.12(s,1H),7.80(s,1H),7.67(s,1H),7.46-7.32(m,3H),7.08-6.93(m,2H),6.90-6.72(m,4H),4.65(d,J=14.4Hz,1H),4.51(d,J=14.4Hz,1H),4.15-3.97(m,3H),3.77(dd,J=8.8,6.6Hz,1H),3.69(dd,J=9.0,5.5Hz,1H),3.60(dd,J=9.0,7.1Hz,1H),3.41(s,4H),3.26(s,4H),3.14(d,J=8.9Hz,1H),2.68-2.49(m,2H),2.07(dd,J=12.6,8.0Hz,1H),1.98(m,1H),1.88(m,1H),1.21(d,J=6.2Hz,3H),0.93(t,J=7.4Hz,3H). 13 C NMR(100MHz,CDCl3)δ162.8(dd,J C-F =249.5,11.9Hz),159.0(dd,J C-F =247.2,11.8Hz),153.1,151.1,150.7,144.6,134.6,128.6(d,J C-F =10.2Hz),125.5,125.4,125.3,123.6,118.6,116.7,115.1,111.5,111.3,104.8(d,J C-F =26.2Hz),104.5(d,J C-F =25.5Hz),84.1(d,J C-F =4.3Hz),70.8,69.0(d,J C-F =9.6Hz),63.5,56.0,50.7,49.1,38.8,37.4,23.5,21.0,10.7. 19 F NMR(376MHz,CDCl3)δ-108.92(d,J=7.8Hz),-110.37(d,J=8.0Hz)。

Claims

1. A method for preparing a diol olefin compound, a key intermediate of posaconazole, characterized in that, The preparation method comprises the following steps: (1) dissolving compound 1 in an organic solvent A, adding a mixed solution of an additive and an organic solvent B, a base a, and trioxane, continuing to react, and obtaining compound 2 after treatment; (2) dissolving compound 2 obtained in step (1) in an organic solvent C, adding a reducing agent, and heating to reflux to obtain compound I; The synthesis route is as follows:

2. The production method according to claim 1, wherein The base a in step (1) is any one or a combination of any number of pyridine, sodium hydride, sodium hydroxide, potassium hydroxide, 2,6-dimethylpyridine, 4-dimethylaminopyridine, cesium carbonate, potassium carbonate, potassium acetate, potassium tert-butoxide, sodium tert-butoxide, triethylamine, diisopropylamine, N,N-diisopropylethylamine, n-butyllithium, tert-butyllithium, lithium diisopropylamide, hexamethylphosphoric triamide, sodium amide, potassium acetate, cesium acetate, and potassium phosphate.

3. The production method according to claim 2, wherein The molar amount of the base a in step (1) is 1.0-10.0 equivalents of the molar amount of compound 1.

4. The production method according to claim 1, wherein The additive in step (1) is any one or a combination of any number of titanium tetrachloride, dibutylboron trifluoromethanesulfonate, and lithium diisopropylamide.

5. The production method according to claim 4, wherein The molar amount of the additive in step (1) is 1.0-10.0 equivalents of the molar amount of compound 1.

6. The production method according to claim 1, wherein The organic solvent A, the organic solvent B in step (1), and the organic solvent C in step (2) are selected from any one or a combination of any number of ethyl acetate, N,N-dimethylformamide, acetonitrile, butyronitrile, pentanitrile, benzene, toluene, xylene, pentane, hexane, octane, cyclohexane, cyclohexanone, chlorobenzene, dichlorobenzene, dichloromethane, methanol, ethanol, isopropyl alcohol, diethyl ether, acetone, methylbutanone, ethylene glycol monomethyl ether, ethylene glycol monoethyl ether, tetrahydrofuran, and water.

7. The production method according to claim 1, wherein The molar amount of trioxane in step (1) is 1.0-10.0 equivalents of the amount of compound 1.

8. The production method according to claim 1, wherein The reducing agent in step (2) is any one or a combination of any number of lithium aluminum hydride, sodium borohydride, potassium borohydride, borane, diisobutylaluminum hydride, sodium cyanoborohydride, sodium triacetoxyborohydride, sodium dimethoxyethylborohydride, and 9-BBN-H.

9. The production method according to claim 8, wherein The molar amount of the reducing agent in step (2) is 1.0-10.0 equivalents of the molar amount of compound 2.

10. The production method according to claim 1, wherein The reaction temperature in steps (1) and (2) ranges from -78 to 100℃, and the total reaction time is at least 1 hour.

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