Preparation method of fluorobone triol intermediate

Abstract

The invention discloses a preparation method of a fluorine bone triol intermediate, which comprises the following steps: (20S)-3beta-acetoxy-20-methyl-21-iodo-pregna-5-ene as shown in a formula II is taken as a raw material, and 26, 26, 26, 27, 27, 27-hexafluoro-25-hydroxycholesterol is prepared through four steps of reaction, namely coupling, ester hydrolysis, trifluoromethyl substitution and trifluoromethyl addition, and the reaction formula is as shown in the specification. The method has the advantages of simple process, cheap and easily available reagents, and suitableness for industrial production.

Description

Technical Field

[0001] This invention belongs to the field of green preparation technology of steroidal compounds, and specifically relates to a method for preparing a fluorocalcitriol intermediate. Background Technology

[0002] Fluorostrigol was launched in Japan in 2001 for the treatment of secondary hyperthyroidism. It is an analogue of calcitriol, but with perfluorination at C-26 and C-27, enhancing its antioxidant capacity and ability to induce cell differentiation. While calcitriol readily causes hypercalcemia and hyperphosphatemia, fluorotricostrigol effectively inhibits parathyroid hormone and does not cause an increase in serum calcium and phosphorus levels.

[0003] 26,26,26,27,27,27-Hexafluoro-25-hydroxycholesterol is an important intermediate in the synthesis of fluorotriol. Patent US4248791 discloses a two-step method for the synthesis of 26,26,26,27,27,27-Hexafluoro-25-hydroxycholesterol.

[0004] The reaction process is as follows: .

[0005] The n-butyllithium (n-BuLi) used in this route is highly reactive and reacts violently with water and air. It is a flammable and explosive high-risk reagent, requiring extremely high standards for storage conditions, feeding operations, and equipment airtightness, as it can easily cause fires, explosions, and other safety accidents. Metallic potassium also has strong reducing properties and reacts violently with water, releasing flammable and explosive hydrogen gas, further amplifying the safety risks of the process. Hexafluoroacetone gas is highly toxic, and if leaked, it can damage the respiratory system and skin of operators, while also imposing stringent standards on ventilation and protective facilities in the production site.

[0006] Kobayashi et al. reported (Journal of the Chemical Society, Chemical Communications, 1980, 11(35):459-460) a method for synthesizing 26,26,26,27,27,27-hexafluoro-25-hydroxycholesterol, with the following reaction formula: .

[0007] This route uses sodium amalgam, a hazardous mercury-containing compound. It not only has strong reducing properties and readily reacts violently with many substances, but the mercury it contains is also highly toxic and bioaccumulative, posing a serious threat to the health of operators. Furthermore, the mercury-containing waste generated after the reaction is extremely difficult to dispose of and can easily cause persistent environmental pollution. Therefore, it is not suitable for industrial production. Summary of the Invention

[0008] The purpose of this invention is to provide a method for preparing a fluorotriol intermediate.

[0009] The technical solution adopted in this invention is as follows: A method for preparing a fluorotriol intermediate, using (20S)-3β-acetoxy-20-methyl-21-iodo-pregn-5-ene (as shown in Formula II) as a starting material, involves a four-step reaction process: coupling, ester hydrolysis, trifluoromethyl substitution, and trifluoromethyl addition, to prepare 26,26,26,27,27,27-hexafluoro-25-hydroxycholesterol. Specifically, the method includes the following steps: (i) Coupling reaction: using the compound (20S)-3β-acetoxy-20-methyl-21-iodine as shown in Formula II The compound shown in Formula III was synthesized in an organic solvent using 5-pregnane and acrylate as raw materials, under the synergistic effect of reducing agent zinc powder, catalyst and ligand; (ii) Ester hydrolysis reaction: Using the compound shown in Formula III as a raw material, a hydrolysis reaction is carried out in a solvent under the action of an inorganic base to obtain the compound shown in Formula IV; (iii) Trifluoromethyl substitution reaction: Using the compound shown in Formula IV as a starting material, react with a trifluoromethyl reagent in a solvent under the action of an organic base to prepare the compound shown in Formula V; (iv) Trifluoromethyl addition reaction: Using the compound shown in formula V as the starting material and (trifluoromethyl)trimethylsilane as the trifluoromethyl source, the compound shown in formula I was prepared by reaction in a solvent under the action of a catalyst. The reaction route equation is shown below: .

[0010] Further, in step (i), the molar ratio of zinc powder to the compound shown in Formula II is 5 to 15:1, preferably 8 to 10:1.

[0011] Furthermore, in step (i), NiCl is selected as the catalyst. 2、 NiCl2·6H2O, NiBr2, NiBr2·3H2O, or CuI, preferably NiCl2·6H2O; the molar ratio of the catalyst to the compound shown in Formula II is 0.05~3:1, preferably 0.1~2:1; in step (i), the ligand is selected from pyridine, 4-dimethylaminopyridine, 2-methylpyridine, 2,4,6-trimethylpyridine, or bipyridine, preferably pyridine; the molar ratio of the ligand to the compound shown in Formula II is 30~60:1, preferably 40~50:1.

[0012] Further, the acrylate mentioned in step (i) is selected from methyl acrylate, ethyl acrylate, phenyl acrylate, or benzyl acrylate, preferably ethyl acrylate; the molar ratio of the acrylate to the compound shown in Formula II is 5~10:1, preferably 7~8.5:1; the organic solvent in step (i) is tetrahydrofuran, 2-methyltetrahydrofuran, morpholine, or... N -Methylmorpholine, preferably tetrahydrofuran; the mass-to-volume ratio of the compound shown in Formula II to the organic solvent is 0.1~0.3 g / mL, preferably 0.1~0.15 g / mL.

[0013] Further, in step (ii), the inorganic base is selected from one or more of sodium hydroxide, potassium hydroxide, potassium carbonate, and sodium carbonate, preferably sodium hydroxide; the molar ratio of the inorganic base to the compound shown in Formula III is 1~3:1, preferably 2~2.5:1.

[0014] Further, the solvent used in step (ii) is one or a mixture of two of methanol, ethanol, and tetrahydrofuran, preferably a mixture of methanol and tetrahydrofuran; the reaction temperature is 25-60°C. o C, preferably 30~40 o C; The reaction time is 1~5 h, preferably 3~4 h.

[0015] Further, in step (iii), the organic base is selected from pyridine, imidazole, 4-dimethylaminopyridine, 2,4,6-trimethylpyridine, pyrimidine, pyrazine, and quinoline, preferably pyridine; the molar ratio of the organic base to the compound shown in Formula IV is 2~6:1, preferably 3.5~4.5:1; in step (iii), the trifluoromethyl reagent is selected from trifluoroacetic anhydride or trifluoroacetyl chloride, preferably trifluoroacetic anhydride; the molar ratio of the trifluoromethyl reagent to the compound shown in Formula IV is 2~5:1, preferably 3.3~4:1.

[0016] Furthermore, the solvent used in step (iii) is chlorobenzene, toluene, N,N- One of dimethylformamide, 1,4-dioxane, dichloromethane, and ethyl acetate, preferably toluene; the reaction temperature in step (iii) is 40~120°C. o C, preferably 100~120 o C; The reaction time is 4~12 h, preferably 8~9 h.

[0017] Furthermore, the catalyst in step (iv) is preferably tetrabutylamine fluoride or cesium fluoride. The catalyst is tetrabutylamine fluoride; the molar ratio of the catalyst to the compound shown in Formula V is 0.01 to 0.4:1, preferably 0.05 to 0.15:1; in step (iv), the molar ratio of (trifluoromethyl)trimethylsilane to the compound shown in Formula V is 1 to 5:1, preferably 2.5 to 4:1.

[0018] Furthermore, the solvent used in step (iv) is selected from tetrahydrofuran, N,N - Dimethylformamide, n-pentane, n-hexane or methyl tert-butyl ether, preferably tetrahydrofuran; the reaction time of step (iv) is 0.5 to 5 h, preferably 3 to 4 h.

[0019] The 26,26,26,27,27,27-hexafluoro-25-hydroxycholesterol synthesized in this invention is a key intermediate in the synthesis of fluorotriol.

[0020] By employing the above-mentioned technology, the present invention has the following beneficial effects: the present invention is simple to operate, has mild reaction conditions, and high reaction yield, making it suitable for large-scale preparation and production. The reagents used are inexpensive, readily available, and widely sourced, significantly reducing the cost of industrial production; the reagents used are low in toxicity and corrosiveness, and have excellent safety during storage, transportation, and feeding, effectively reducing personnel operation risks and equipment maintenance costs in industrial production. Detailed Implementation

[0021] The present invention will be further described below with reference to specific embodiments. However, the present invention is not limited to the following embodiments. The implementation conditions used in the embodiments can be further adjusted according to different requirements of specific applications, and the implementation conditions not specified are conventional conditions in this industry.

[0022] Example 1 26,26,26,27,27,27-hexafluoro-25-hydroxycholesterol was prepared according to the method of the present invention, and the reaction formula is as follows: .

[0023] (i) Coupling reaction to prepare the compound shown in Formula III: In a 50 mL two-necked flask, add zinc powder (0.556 g, 8.5 mmol) and nickel chloride hexahydrate (0.357 g, 1.5 mmol), purge with nitrogen three times, then add pyridine (3.560 g, 45 mmol) and ethyl acrylate (0.850 g, 8.5 mmol), and heat to 65°C. oAt C, the reaction proceeded for 1 h, and the solution turned reddish-brown. After cooling to room temperature, the compound of formula II (0.442 g, 1 mmol) dissolved in 4 mL of tetrahydrofuran was slowly added, and the reaction proceeded for 3 h. TLC monitoring was maintained until the compound of formula II reacted completely. After the reaction was complete, insoluble substances in the reaction solution were removed by filtration. The filtrate was extracted with ethyl acetate and dilute hydrochloric acid (1 mol / L), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography (eluent was a mixture of petroleum ether and ethyl acetate in a volume ratio of 8:1) to obtain the compound of formula III (0.367 g), which was a white solid with a yield of 88.2%.

[0024] Characterization data: 1 H NMR (400 MHz, Chloroform- d )δ: 5.31~5.37 (m, 1H), 4.08~ 4.15(q, J =7.1 Hz, 2H), 3.47~3.56 (m, 1H), 2.20~2.32 (m, 4H), 1.95~2.06 (m, 2H), 1.84~1.87(m,1H), 1.80~1.84 (m, 2H), 1.79~1.84 (m, 2H),1.56~1.62 (m, 4H),1.50~1.54(m, 2H), 1.47~1.50 (m, 2H), 1.41~1.44 (m, 1H), 1.44~1.46 (m, 1H), 1.34~1.37(m, 1H), 1.23~1.26 (t, J =7.1 Hz, 3H), 1.09~1.16 (m, 2H), 1.06~1.09 (m, 2H), 1.02~1.05 (m, 1H), 1.00 (s, 3H), 0.93 (d, J =6.5 Hz, 3H), 0.67 (s, 3H). 13 C NMR (100 MHz, Chloroform-d) δ: 174.0, 140.8, 121.7, 71.8, 60.2,56.7, 55.8, 50.1, 42.3, 42.3, 39.7, 37.3, 36.5, 35.5, 35.4, 34.8, 31.9, 31.7,28.2, 24.3, 21.6, 21.1, 19.4, 18.6, 14.3, 11.9. (ii) Ester hydrolysis reaction to prepare the compound shown in formula IV: Take a 100 mL single-necked flask and add the compound shown in Formula III (0.416 g, 1 mmol), sodium hydroxide (0.08 g, 2 mmol), methanol (2.5 mL), and tetrahydrofuran (2.5 mL) sequentially. Heat to 40 °C. o At C, the reaction was carried out for 3.5 h, monitored by TLC, until the compound shown in Formula III reacted completely. After the reaction was completed, 50 mL of dilute hydrochloric acid (1 mol / L) was added dropwise to the reaction solution, and the mixture was filtered to obtain the crude product of the compound shown in Formula IV (0.381 g). The compound shown in Formula IV was a white solid, with a yield of 98.1%.

[0025] 1H NMR (600 MHz, DMSO- d6 ) δ: 11.92 (s, 1H), 5.25 (m, 1H), 4.57 (s,1H), 3.29~3.21 (m,1H), 2.21~2.11 (m, 3H), 2.11~2.07 (m, 1H), 1.98~1.88 (m,2H), 1.80~1.72 (m, 2H), 1.70~1.64 (m, 1H), 1.57~1.50 (m, 2H), 1.50~1.45 (m,2H), 1.42~1.39 (m, 1H), 1.39~1.37 (m,2H), 1.37~ 1.34 (m, 2H), 1.34~1.28 (m, 2H), 1.23~1.12 (m, 2H), 1.12~1.04 (m, 2H), 1.04~1.02 (m, 1H), 1.00~0.96 (m,2H), 0.94 (s, 3H), 0.89 (d, J = 6.4 Hz, 3H), 0.88~0.84 (m, 1H), 0.64 (s, 3H). (iii) Trifluoromethyl substitution reaction to prepare the compound shown in formula V. In a 50 mL two-necked flask, add the compound shown in Formula IV (0.388 g, 1 mmol), purge with nitrogen three times, then add 4 mL of toluene and trifluoroacetic anhydride (0.735 g, 3.5 mmol) sequentially, and cool to 0 °C. o C, add pyridine (0.277 g, 3.5 mmol), stir for 15 min, then heat to 100°C. o C, after reacting for 10 h, the reaction is cooled to 0. oC. Slowly add 2 mL of water, then raise the temperature to 45 °C and maintain it for 2 h. After extraction with saturated brine and ethyl acetate, dry with anhydrous sodium sulfate, concentrate under reduced pressure, and then add sodium hydroxide (0.060 g, 1.5 mmol), 2 mL of methanol and 2 mL of tetrahydrofuran in sequence. After reacting for 2 h, add dilute hydrochloric acid (1 mol / L) dropwise to neutralize the reaction. After extraction with saturated brine and ethyl acetate, dry with anhydrous sodium sulfate, concentrate under reduced pressure, and purify by column chromatography (the eluent is a mixture of petroleum ether and ethyl acetate in a volume ratio of 8:1) to obtain the compound shown in Formula V (0.326 g). The compound shown in Formula V is a white solid with a yield of 74.0%.

[0026] Characterization data: 1 H NMR (400 MHz, Chloroform- d ) δ: 5.37~5.31 (m, 1H), 3.59~3.41 (m,1H), 2.76~2.58 (m, 2H), 2.34~2.17 (m, 2H), 2.03~1.91 (m, 2H), 1.86~1.82(m,1H), 1.83~1.78 (m, 2H), 1.78~1.62 (m, 2H), 1.62~1.54 (m, 2H), 1.54~1.49 (m,2H), 1.49~1.44 (m, 2H), 1.44~1.42(m, 1H), 1.42~ 1.33 (m, 2H), 1.29~1.14 (m, 2H), 1.14~1.11 (m, 1H), 1.10~1.06 (m, 2H), 1.06~1.01 (m, 1H), 1.00 (s, 3H), 0.95~0.92 (d, J = 6.6 Hz, 3H), 0.92 ~0.87 (m, 1H), 0.67 (s, 3H). 13 C NMR (100 MHz, Chloroform- d) δ:192.3, 192.0, 191.6, 191.3, 140.9,121.8, 120.1, 117.1, 114.2, 111.3, 71.9, 56.8, 55.8, 50.2, 42.5, 42.4, 39.8,37.4, 36.9, 36.6, 35.7, 35.2, 32.0, 31.7, 28.3, 24.4, 21.2, 19.5, 19.1, 18.6,11.9. 19 F NMR (376 MHz, Chloroform- d δ: -79.32. (iv) Trifluoromethyl addition reaction to prepare the compound shown in Formula I: In a 50 mL two-necked flask, add the compound shown in Formula V (0.440 g, 1 mmol), purge with nitrogen three times, then add 5 mL of tetrahydrofuran and (trifluoromethyl)trimethylsilane (0.569 g, 4 mmol) sequentially, and incubate at -78 °C. o Tetrabutylamine fluoride (0.026 g, 0.1 mmol) was added at temperature C, and the mixture was heated to 25 °C and reacted for 4 h. After the reaction was complete, 5 mL of dilute hydrochloric acid (1 mol / L) was added to the reaction solution, and the mixture was stirred for 1 h. The solution was then extracted with ethyl acetate and saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography (using a 6:1 volume ratio of petroleum ether and ethyl acetate as the eluent) to obtain the compound shown in Formula I (0.367 g). The compound shown in Formula I is a white solid with a yield of 71.9%.

[0027] Characterization data: 1 H NMR (400 MHz, Methanol- d4) δ: 5.34~5.29 (m, 1H), 3.44~3.34 (m, 1H), 2.27~2.15 (m, 2H), 1.92~1.83 (m, 2H), 1.83~1.81 (m, 1H), 1.81 ~1.70 (m, 2H),1.66~1.56 (m, 2H), 1.56~1.53 (m, 1H), 1.53~1.49 (m,2H),1.49~1.44 (m, 2H),1.44~1.42 (m, 1H), 1.42~1.36 (m, 2H), 1.36~1.26 (m, 2H), 1.26~1.18 (m, 1H),1.17~1.10 (m, 2H), 1.10~1.05 (m, 2H), 1.05~ 1.02 (m,1H), 1.01 (s, 3H), 0.96(d, J = 6.4 Hz, 3H), 0.71 (s, 3H). 13 C NMR (100 MHz, Methanol- d 4) δ: 142.2, 129.4, 126.5, 123.6, 122.4,120.8, 77.8, 77.6, 77.3, 77.0, 76.7, 72.4, 58.2, 57.6, 51.7, 43.6, 43.0,41.2, 38.6, 37.7, 37.6, 37.1, 33.3, 33.1, 32.5, 32.3, 29.3, 25.4, 22.3, 20.0,19.9, 19.3,12.5. 19 F NMR (376 MHz, Methanol- d 4) δ: -77.40 (q, J = 9.3 Hz), -77.58(q, J =10.0, 9.5 Hz).

[0028] Example 2

[0029] Following the steps and methods of Example 1, the only difference is that in step (i), the molar mass ratio of the compound shown in Formula II to zinc powder is adjusted to 1:5, and the other operating steps are the same, resulting in a yield of 76.5% for the compound shown in Formula III.

[0030] Example 3 Following the steps and methods of Example 1, the only difference is that in step (i), the molar mass ratio of the compound shown in Formula II to zinc powder is adjusted to 1:15, and the other operating steps are the same, resulting in a yield of 88.5% for the compound shown in Formula III.

[0031] Example 4 Following the steps and methods of Example 1, the only difference being that NiCl2·6H2O in step (i) was replaced with NiBr2·3H2O, while the other operational steps remained the same, the compound shown in Formula III was obtained with a yield of 52.1%.

[0032] Example 5 Following the steps and methods of Example 1, the only difference being that NiCl2·6H2O in step (i) was replaced with NiCl2, while the other operating steps were the same, the compound shown in Formula III was obtained with a yield of 65.4%.

[0033] Example 6 Following the steps and methods of Example 1, the only difference being that in step (i), the molar mass ratio of the compound shown in Formula II to nickel chloride hexahydrate was adjusted to 1:0.05, and the other operating steps were the same, resulting in a yield of 31.0% for the compound shown in Formula III.

[0034] Example 7 The steps and methods of Example 1 are the same, except that in step (i) the expression in equation II is changed. The molar ratio of the compound to nickel chloride hexahydrate was adjusted to 1:3, and the other operating steps were the same, resulting in a yield of 88.3% for the compound shown in Formula III.

[0035] Example 8 Following the steps and methods of Example 1, except that pyridine was replaced with bipyridine in step (i), the other steps were the same, and the compound shown in Formula III was obtained in a yield of 63.4%.

[0036] Example 9 Following the steps and methods of Example 1, except that pyridine in step (i) was replaced with 2-methylpyridine, the other steps were the same, and the compound shown in Formula III was obtained in a yield of 56.9%.

[0037] Example 10 Following the steps and methods of Example 1, the only difference being that the molar ratio of the compound shown in Formula II to pyridine in step (i) was adjusted to 1:30, with all other operating steps remaining the same, the yield of the compound shown in Formula III was 73.1%.

[0038] Example 11 Following the steps and methods of Example 1, the only difference being that in step (i), the molar mass ratio of the compound shown in Formula II to pyridine was adjusted to 1:60, while the other operating steps were the same, the yield of the compound shown in Formula III was 88.1%.

[0039] Example 12 Following the steps and methods of Example 1, except that ethyl acrylate was replaced with methyl acrylate in step (i), the other steps were the same, and the compound shown in Formula III was obtained with a yield of 87.9%.

[0040] Example 13 Following the steps and methods of Example 1, except that ethyl acrylate was replaced with benzyl acrylate in step (i), all other operating steps were the same, and the compound shown in Formula III was obtained with a yield of 88.3%.

[0041] Example 14 Following the steps and methods of Example 1, the only difference being that in step (i), the molar mass ratio of the compound shown in Formula II to ethyl acrylate was adjusted to 1:5, while the other operating steps were the same, the yield of the compound shown in Formula III was 81.3%.

[0042] Example 15 Following the steps and methods of Example 1, the only difference being that in step (i), the molar mass ratio of the compound shown in Formula II to ethyl acrylate was adjusted to 1:10, while the other operating steps were the same, the yield of the compound shown in Formula III was 88.4%.

[0043] Example 16 Following the steps and methods of Example 1, except that tetrahydrofuran was replaced with 2-methyltetrahydrofuran in step (i), the other operating steps were the same, and the compound shown in Formula III was obtained in a yield of 80.2%.

[0044] Example 17 The steps and methods of Example 1 are the same, except that in step (i) the expression in equation II is changed. The mass-to-volume ratio of the compound to the solvent was adjusted to 0.1 g / mL, and the other operating steps were the same, resulting in a yield of 86.6% for the compound shown in Formula III.

[0045] Example 18 The steps and methods of Example 1 are the same, except that in step (i) the expression in equation II is changed. The mass-to-volume ratio of the compound to the solvent was adjusted to 0.3 g / mL, and other operating steps were the same, resulting in a yield of 83.1% for the compound shown in Formula III.

[0046] Example 19 Following the steps and methods of Example 1, except that sodium hydroxide is replaced with potassium hydroxide in step (ii), all other steps are the same, yielding the compound shown in Formula IV. It is 97.7%.

[0047] Example 20 Following the steps and methods of Example 1, except that sodium hydroxide was replaced with sodium carbonate in step (ii), the other steps were the same, and the compound shown in Formula IV was obtained with a yield of 83.3%.

[0048] Example 21 Following the steps and methods of Example 1, the only difference being that in step (ii), the molar ratio of the compound shown in Formula III to sodium hydroxide was adjusted to 1:1, while the other operating steps were the same, the yield of the compound shown in Formula IV was 81.4%.

[0049] Example 22 Following the steps and methods of Example 1, the only difference being that in step (ii), the molar ratio of the compound shown in Formula III to sodium hydroxide was adjusted to 1:3, while the other operating steps were the same, the yield of the compound shown in Formula IV was 98.3%.

[0050] Example 23 Following the steps and methods of Example 1, except that methanol was replaced with ethanol in step (ii), the other operating steps were the same, and the compound shown in Formula IV was obtained with a yield of 92.5%.

[0051] Example 24 The steps and methods of Example 1 are followed, except that the reaction temperature is adjusted to 25°C in step (ii). o C, with the other steps being the same, yielded the compound shown in Formula IV in 91.4%.

[0052] Example 25 The steps and methods of Example 1 are followed, except that the reaction temperature is adjusted in step (ii). The degree was adjusted to 60. o C, with the other steps being the same, yielded the compound shown in Formula IV in 96.8%.

[0053] Example 26 Following the steps and methods of Example 1, except that trifluoroacetic anhydride was replaced with trifluoroacetyl chloride in step (iii), the other operating steps were the same, and the compound shown in Formula V was obtained with a yield of 43.9%.

[0054] Example 27 The steps and methods of Example 1 are the same, except that in step (iii), the molar ratio of the compound shown in Formula IV to trifluoroacetic anhydride is adjusted to 1:2; all other steps are the same. Similarly, the compound shown in formula V was obtained in a yield of 56.6%.

[0055] Example 28 The steps and methods of Example 1 are the same, except that in step (iii), the molar ratio of the compound shown in Formula IV to trifluoroacetic anhydride is adjusted to 1:5; all other steps are the same. Similarly, the compound shown in formula V was obtained in a yield of 65.9%.

[0056] Example 29 Following the steps and methods of Example 1, except that pyridine was replaced with imidazole in step (iii), the other steps were the same, and the compound shown in Formula V was obtained in a yield of 33.6%.

[0057] Example 30 Following the steps and methods of Example 1, except that pyridine was replaced with quinoline in step (iii), the other steps were the same, and the compound shown in Formula V was obtained in 32.5% yield.

[0058] Example 31 The steps and methods of Example 1 are followed, except that in step (iii) formula IV is used instead. The molar mass ratio of the compound shown to pyridine was adjusted to 1:2, and the other operating steps were the same, resulting in a 51.2% yield of the compound shown in formula V.

[0059] Example 32 Following the steps and methods of Example 1, the only difference being that in step (iii), the molar mass ratio of the compound shown in Formula IV to pyridine is adjusted to 1:6; all other operational steps are the same, yielding... The yield of the compound shown in formula V was 49.3%.

[0060] Example 33 Following the steps and methods of Example 1, except that toluene was replaced with chlorobenzene in step (iii), the other operating steps were the same, and the compound shown in Formula V was obtained with a yield of 65.9%.

[0061] Example 34 Following the steps and methods of Example 1, except that toluene was replaced with dichloromethane in step (iii), the other steps were the same, and the compound shown in Formula V was obtained in a yield of 38.4%.

[0062] Example 35 The steps and methods of Example 1 are followed, except that the reaction temperature is adjusted to 40°C in step (iii). o C, with the other steps being the same, yielded the compound shown in formula V with a yield of 39.8%.

[0063] Example 36 The steps and methods of Example 1 are followed, except that the reaction temperature is adjusted to 110°C in step (iii). o C, with the other steps being the same, yielded the compound shown in formula V with a yield of 67.7%.

[0064] Example 37 Following the steps and methods of Example 1, except that the reaction time was adjusted to 4 h in step (iii), the other operating steps were the same, and the yield of the compound shown in Formula V was 56.8%.

[0065] Example 38 Following the steps and methods of Example 1, except that the reaction time was adjusted to 12 h in step (iii), the other operating steps were the same, and the yield of the compound shown in Formula V was 61.2%.

[0066] Example 39 Following the steps and methods of Example 1, except that tetrabutylamine fluoride was replaced with cesium fluoride in step (iv), the other operating steps were the same, and the compound shown in Formula I was obtained with a yield of 69.8%.

[0067] Example 40 Following the steps and methods of Example 1, the only difference being that in step (iv) the molar mass ratio of the compound shown in Formula V to tetrabutylamine fluoride was adjusted to 1:0.01, and the other operating steps were the same, the yield of the compound shown in Formula I was 61.2%.

[0068] Example 41 Following the steps and methods of Example 1, the only difference being that in step (iv) the molar mass ratio of the compound shown in Formula V to tetrabutylamine fluoride was adjusted to 1:0.4, and the other operating steps were the same, the yield of the compound shown in Formula I was 64.8%.

[0069] Example 42 Following the steps and methods of Example 1, the only difference being that in step (iv) the molar mass ratio of the compound shown in Formula V to (trifluoromethyl)trimethylsilane was adjusted to 1:1, and the other operating steps were the same, the yield of the compound shown in Formula I was 43.5%.

[0070] Example 43 The steps and methods of Example 1 are followed, except that in step (iv) the expression V is changed. The molar ratio of the compound to (trifluoromethyl)trimethylsilane was adjusted to 1:5, and the other operating steps were the same, resulting in a 54.8% yield of the compound shown in Formula I.

[0071] Example 44 The steps and methods of Example 1 are followed, except that in step (iv) four Hydrofuran was replaced with n-pentane, and the other steps were the same, yielding the compound shown in Formula I. It is 31.5%.

[0072] Example 45 Following the steps and methods of Example 1, except that tetrahydrofuran was replaced with methyl tert-butyl ether in step (iv), the other operating steps were the same, and the compound shown in Formula I was obtained in a yield of 30.8%.

[0073] Example 46 The steps and methods of Example 1 are followed, except that the reaction time is changed in step (iv). The time interval was adjusted to 0.5 h, and other operating steps were the same, resulting in a 56.7% yield of the compound shown in Formula I.

[0074] Example 47 Following the steps and methods of Example 1, except that the reaction time was adjusted to 5 h in step (iv), the other operating steps were the same, and the yield of the compound shown in Formula I was 71.7%.

[0075] The contents described in this specification are merely an enumeration of the implementation forms of the inventive concept, and the scope of protection of this invention should not be regarded as limited to the specific forms described in the embodiments.

Claims

1. A method for preparing a fluorotriol intermediate, characterized in that, Includes the following steps: (i) Coupling reaction: Using the compound (20S)-3β-acetoxy-20-methyl-21-iodo-pregn-5-ene shown in Formula II and acrylate as raw materials, the compound shown in Formula III was synthesized in an organic solvent under the synergistic effect of reducing agent zinc powder, catalyst and ligand; (ii) Ester hydrolysis reaction: Using the compound shown in Formula III as a raw material, a hydrolysis reaction is carried out in a solvent under the action of an inorganic base to obtain the compound shown in Formula IV; (iii) Trifluoromethyl substitution reaction: Using the compound shown in Formula IV as a starting material, react with a trifluoromethyl reagent in a solvent under the action of an organic base to prepare the compound shown in Formula V; (iv) Trifluoromethyl addition reaction: Using the compound shown in formula V as the starting material and (trifluoromethyl)trimethylsilane as the trifluoromethyl source, the compound shown in formula I was prepared by reaction in a solvent under the action of a catalyst. The reaction route equation is shown below: 。 2. The method for preparing a fluorotriol intermediate according to claim 1, characterized in that, In step (i), the molar ratio of zinc powder to the compound shown in Formula II is 5 to 15:1, preferably 8 to 10:

1.

3. The method for preparing a fluorotriol intermediate according to claim 1, wherein... The characteristic is that the catalyst used in step (i) is NiCl. 2、 NiCl2·6H2O, NiBr2, NiBr2·3H2O, or CuI, preferably NiCl2·6H2O; the molar ratio of the catalyst to the compound shown in Formula II is 0.05~3:1, preferably 0.1~2:1; in step (i), the ligand is selected from pyridine, 4-dimethylaminopyridine, 2-methylpyridine, 2,4,6-trimethylpyridine, or bipyridine, preferably pyridine; the molar ratio of the ligand to the compound shown in Formula II is 30~60:1, preferably 40~50:

1.

4. The method for preparing a fluorotriol intermediate according to claim 1, characterized in that, The acrylate mentioned in step (i) is selected from methyl acrylate, ethyl acrylate, phenyl acrylate, or benzyl acrylate, preferably ethyl acrylate; the molar ratio of the acrylate to the compound shown in Formula II is 5~10:1, preferably 7~8.5:1; the organic solvent in step (i) is tetrahydrofuran, 2-methyltetrahydrofuran, morpholine, or... N -Methylmorpholine, preferably tetrahydrofuran; the mass-to-volume ratio of the compound shown in Formula II to the organic solvent is 0.1~0.3 g / mL, preferably 0.1~0.15 g / mL.

5. The method for preparing a fluorotriol intermediate according to claim 1, characterized in that, In step (ii), the inorganic base is selected from one or more of sodium hydroxide, potassium hydroxide, potassium carbonate, and sodium carbonate, preferably sodium hydroxide; the molar ratio of the inorganic base to the compound shown in Formula III is 1~3:1, preferably 2~2.5:

1.

6. The method for preparing a fluorotriol intermediate according to claim 1, characterized in that, The solvent used in step (ii) is one or a mixture of two of methanol, ethanol, and tetrahydrofuran, preferably a mixture of methanol and tetrahydrofuran; the reaction temperature is 25-60°C. o C, preferably 30~40 o C; The reaction time is 1~5 h, preferably 3~4 h.

7. The method for preparing a fluorotriol intermediate according to claim 1, characterized in that, In step (iii), the organic base is selected from pyridine, imidazole, 4-dimethylaminopyridine, 2,4,6-trimethylpyridine, pyrimidine, pyrazine, and quinoline, preferably pyridine; the molar ratio of the organic base to the compound shown in Formula IV is 2~6:1, preferably 3.5~4.5:1; in step (iii), the trifluoromethyl reagent is selected from trifluoroacetic anhydride or trifluoroacetyl chloride, preferably trifluoroacetic anhydride; the molar ratio of the trifluoromethyl reagent to the compound shown in Formula IV is 2~5:1, preferably 3.3~4:

1.

8. The method for preparing a fluorotriol intermediate according to claim 1, characterized in that, The solvent used in step (iii) is chlorobenzene, toluene, N,N- One of dimethylformamide, 1,4-dioxane, dichloromethane, and ethyl acetate, preferably toluene; the reaction temperature in step (iii) is 40~120°C. o C, preferably 100~120 o C; The reaction time is 4~12h, preferably 8~9h.

9. The method for preparing a fluorotriol intermediate according to claim 1, characterized in that, In step (iv), the catalyst is tetrabutylamine fluoride or cesium fluoride, preferably tetrabutylamine fluoride; the molar ratio of the catalyst to the compound shown in Formula V is 0.01 to 0.4:1, preferably 0.05 to 0.15:1; in step (iv), the molar ratio of (trifluoromethyl)trimethylsilane to the compound shown in Formula V is 1 to 5:1, preferably 2.5 to 4:

1.

10. The method for preparing a fluorotriol intermediate according to claim 1, characterized in that, The solvent used in step (iv) is selected from tetrahydrofuran, N,N - Dimethylformamide, n-pentane, n-hexane or methyl tert-butyl ether, preferably tetrahydrofuran; the reaction time of step (iv) is 0.5 to 5 h, preferably 3 to 4 h.

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