Total synthesis of ervitsine

Abstract

The application provides a full synthesis method of Ervitsine, and the full synthesis method of the indole alkaloid Ervitsine is prepared by using a halogenated furan as a raw material through an organic full synthesis method. The full synthesis method of the indole alkaloid Ervitsine provided by the application has the advantages of cheap and easily available raw materials, mild reaction conditions, short steps, high total yield, low production cost and good prospects for industrial production.

Description

TECHNICAL FIELD

[0001] The present application relates to a method for synthesizing Ervitsine, and belongs to the technical field of organic chemical synthesis. BACKGROUND

[0002] The natural product Ervitsine is an indole alkaloid natural product isolated from Pandaca boiteaui of the Nerium genus by Professor Husson and his collaborators in 1977, and its structural formula is as follows: Ervitsine (1).

[0003]

[0004] Indole alkaloids are the largest branch of the alkaloid family, in which the indole structure fused to a seven-membered ring is called cyclohepta [b] indoles. Compounds containing this structure show a wide range of biological activities. Ervitsine is one of them, and another alkaloid Methuenine, which is very similar in structure, is an anticholinergic agent. In addition, unlike other cyclohepta [b] indole alkaloids, Ervitsine has unique C5-C7 and C6-C16 bonds in its structure, which is of great synthetic value. Due to the limitation of natural sources, the amount of this natural product isolated from nature is very small, and it is difficult to carry out further biological activity research. Therefore, it is crucial to develop an efficient synthesis method for further activity research of the natural product.

[0005] In 1993, the Bosch research group completed the biomimetic route synthesis of Ervitsine. They used 2-acetylindole as the starting material, reacted with a pyridine compound under the action of strong base, and then the obtained intermediate attacked the Eschenmoser salt to obtain the tetracyclic compound with a yield of 15%. Subsequently, oxidation with meta-chloroperbenzoic acid obtained the nitroxide, and the obtained nitroxide compound underwent Cope elimination to form a terminal double bond under toluene reflux conditions, and compound VI was obtained with a yield of 45%. Finally, the natural product Ervitsine was obtained with a yield of 65%, and the synthesis route is as follows.

[0006]

[0007] However, this synthesis route has a low yield, and it is also difficult to realize the synthesis of the diversity of the molecule. The biological activity research and drug research of the natural product in the later stage are difficult. SUMMARY

[0008] Based on the above problems, the application provides a short natural product Ervitsine synthesis method, and the structure is easy to modify, can provide sufficient material basis for future biological activity research and new drug research and development screening lead compounds, and is believed to contribute to human major diseases such as anti-inflammatory and anti-tumor.

[0009] According to a first aspect of the application, an intermediate compound for synthesizing Ervitsine is provided, and the intermediate compound comprises compound 4, compound 6, compound 7, compound 8, compound 9, compound 10, compound 11, compound 12, compound 14, compound 15, compound 16, compound 17, compound 18, compound 19, compound 20, and corresponds to the structure shown in the following:

[0010] 、 、 、 、

[0011] 、 、 、 、

[0012] 、 、 、 、 、 、 .

[0013] According to a second aspect of the application, a preparation method of the intermediate compound is provided, and the preparation method of the compound 4 comprises:

[0014] reacting a mixture containing halogenated furan, solvent 1, diisopropylaminolithium, benzyl chloromethyl ether, n-butyllithium and compound 3 to obtain the compound 4;

[0015] The compound 3 has the structure shown in the following:

[0016] .

[0017] Optionally, the halogenated furan is 3-bromofuran.

[0018] Optionally, the solvent 1 is at least one selected from ethyl ether and tetrahydrofuran.

[0019] Optionally, the molar ratio of the halogenated furan, diisopropylaminolithium, benzyl chloromethyl ether and n-butyllithium is 1: (1.1-1.3): (1.1-1.2): (1.2-1.4).

[0020] Optionally, the molar ratio of the halogenated furan to the compound 3 is 1:1.3~1.5.

[0021] Optionally, the molar volume ratio of the halogenated furan to the solvent 1 is 0.2~0.3:1 mol / L.

[0022] Optionally, the temperature of the reaction 1 is -40~-60℃, and the time of the reaction 1 is 2~5h.

[0023] According to the third aspect of the present application, a preparation method of the intermediate compound is provided, and the preparation method of the compound 6 comprises:

[0024] reacting a mixture containing the compound 4, the compound 5, the solvent 2 and potassium carbonate to obtain the compound 6 by reaction 2;

[0025] The compound 5 has the following structure:

[0026] .

[0027] Optionally, the solvent 2 is acetone.

[0028] Optionally, the molar ratio of the compound 4 to the compound 5 is 1:1.1~1.2.

[0029] Optionally, the molar ratio of the compound 4 to the potassium carbonate is 1:2.5~3.0.

[0030] Optionally, the molar volume ratio of the compound 4 to the solvent 2 is 0.1~0.2:1 mol / L.

[0031] Optionally, the temperature of the reaction 2 is 50~55℃, and the time of the reaction 2 is 10~12h.

[0032] Optionally, the preparation method of the compound 7 comprises: reacting a mixture containing the compound 6, the solvent 3 and sodium borohydride to obtain the compound 7 by reaction 3.

[0033] Optionally, the solvent 3 is a mixed solvent, and the mixed solvent is tetrahydrofuran and water, and the volume ratio of tetrahydrofuran to water is 4:1.

[0034] Optionally, the molar volume ratio of the compound 6 to the solvent 3 is 0.1~0.2:1 mol / L.

[0035] Optionally, the molar ratio of the compound 6 to the sodium borohydride is 1:1.0~1.5.

[0036] Optionally, the temperature of the reaction 3 is 0~25℃, and the time of the reaction 3 is 0.5~2h.

[0037] Optionally, the preparation method of the compound 8 comprises: mixing compound 7, solvent 4, 2.6-dimethylpyridine, triisopropylsilyl trifluoromethanesulfonate, potassium tert-butoxide to obtain the compound 8.

[0038] Optionally, the solvent 4 is tetrahydrofuran.

[0039] Optionally, the molar ratio of the compound 7, 2.6-dimethylpyridine, triisopropylsilyl trifluoromethanesulfonate, potassium tert-butoxide is 1: (2.5-3): (1.1-1.2): (1.3-1.5).

[0040] Optionally, the molar volume ratio of the compound 7 to the solvent 4 is 0.07-0.2: 1 mol / L.

[0041] Optionally, the temperature of the reaction 4 is 0-25℃, and the reaction time of the reaction 4 is 0.5-3h.

[0042] According to the fourth aspect of the present application, a preparation method of the intermediate compound is provided, and the preparation method of the compound 9 comprises:

[0043] Mixing compound 8, solvent 5 and peroxide acetone to obtain the compound 9.

[0044] Optionally, the molar ratio of the compound 8 to the peroxide acetone is 1: 2.5-3.0.

[0045] Optionally, the molar volume ratio of the compound 8 to the solvent 5 is 0.001-0.05: 1 mol / L.

[0046] Optionally, the solvent 5 is dichloromethane.

[0047] Optionally, the temperature of the reaction 5 is -78--40℃, and the reaction time of the reaction 5 is 0.2-0.5h.

[0048] Optionally, the preparation method of the compound 10 comprises: mixing compound 9, solvent 6, palladium-carbon, triphenylphosphine, imidazole and iodine under hydrogen atmosphere to obtain the compound 10.

[0049] Optionally, the molar ratio of the compound 9, palladium-carbon, triphenylphosphine, imidazole and iodine is 1: (0.1-0.15): (2.5-3): (2.5-3): (1.5-2).

[0050] Optionally, the solvent 6 is toluene.

[0051] Optionally, the molar volume ratio of the compound 9 to the solvent 6 is 0.03-0.05:1 mol / L.

[0052] Optionally, the temperature of the reaction 6 is 20-30℃, and the reaction time is 1-2h.

[0053] Optionally, the preparation method of the compound 11 comprises: mixing the compound 10, the solvent 7, and zinc powder to obtain the compound 11.

[0054] Optionally, the solvent 7 comprises isopropyl alcohol, tert-butyl alcohol, and water, and the volume ratio of isopropyl alcohol:tert-butyl alcohol:water is 10 ml:10 ml:0.2 ml.

[0055] Optionally, the molar ratio of the compound 10 to the zinc powder is 1:10.0-12.0.

[0056] Optionally, the molar volume ratio of the compound 10 to the solvent 7 is 0.01-0.02:1 mol / L.

[0057] Optionally, the temperature of the reaction 7 is 80-95℃, and the reaction time of the reaction 7 is 2-5h.

[0058] According to the fifth aspect of the present application, a preparation method of the intermediate compound is provided, and the preparation method of the compound 12 comprises:

[0059] mixing the compound 11, the solvent 8, 2.6-dimethylpyridine, tert-butyldimethylsilyl trifluoromethanesulfonate, p-toluenesulfonyl hydrazide, and acetic acid to obtain the compound 12.

[0060] Optionally, the solvent 8 is 1.2-dichloroethane.

[0061] Optionally, the molar ratio of the compound 11, 2.6-dimethylpyridine, tert-butyldimethylsilyl trifluoromethanesulfonate, and p-toluenesulfonyl hydrazide is 1:(1.6-2.0):(1.5-1.8):(1.5-2.0).

[0062] Optionally, the molar volume ratio of the compound 11 to the solvent 8 is 0.06-0.1:1 mol / L.

[0063] Optionally, the molar volume ratio of the compound 11 to the acetic acid is 20-35:1 mol / L.

[0064] Optionally, the temperature of the reaction 8 is 0-50℃, and the reaction time of the reaction 8 is 5 min-12h.

[0065] Optionally, the preparation method of the compound 14 comprises: reacting a mixture containing the compound 12, tetrakis triphenylphosphine palladium, o-iodoaniline, potassium carbonate and toluene to obtain the compound 14.

[0066] Optionally, the molar ratio of the compound 12, tetrakis triphenylphosphine palladium, o-iodoaniline and potassium carbonate is 1: (0.1-0.12): (3.3-3.5): (4.0-5.0).

[0067] Optionally, the molar volume ratio of the compound 12 and the toluene is 0.05-0.1: 1 mol / L.

[0068] Optionally, the temperature of the reaction 9 is 110-120°C, and the reaction time of the reaction 8 is 10-18h.

[0069] According to the sixth aspect of the present application, a preparation method of the intermediate compound is provided, and the preparation method of the compound 15 comprises:

[0070] reacting a mixture containing the compound 14, solvent 9, iodobenzene trifluoroacetate and tetrabutylammonium fluoride to obtain the compound 15.

[0071] Optionally, the solvent 9 is tetrahydrofuran.

[0072] Optionally, the molar ratio of the compound 14, iodobenzene trifluoroacetate and tetrabutylammonium fluoride is 1: (1.3-1.5): (4.5-5.5).

[0073] Optionally, the molar volume ratio of the compound 14 and the solvent 9 is 0.01-0.05: 1 mol / L.

[0074] Optionally, the temperature of the reaction 10 is -20-0°C, and the reaction time of the reaction 10 is 10 min-3h.

[0075] Optionally, the preparation method of the compound 16 comprises: reacting a mixture containing the compound 15, solvent 10, lithium naphthalene, triethylamine and di-tert-butyl dicarbonate to obtain the compound 16.

[0076] Optionally, the molar ratio of the compound 15, lithium naphthalene, triethylamine and di-tert-butyl dicarbonate is 1: (5.0-10.0): (2.5-3.0): (2.5-3.0).

[0077] Optionally, the molar volume ratio of the compound 15 and the solvent 10 is 0.03-0.1: 1 mol / L.

[0078] Optionally, the solvent 10 is at least one selected from ethylene glycol dimethyl ether and tetrahydrofuran.

[0079] Optionally, the temperature of the reaction 11 is -78 ~ -40℃, and the time of the reaction 11 is 10 min ~ 0.5 h.

[0080] According to the seventh aspect of the present application, a preparation method of the intermediate compound is provided, and the preparation method of the compound 19 comprises the following steps:

[0081] S1: a mixture containing the compound 16, a solvent 11, and pyridinium dichromate is reacted to obtain a product containing the compound 17;

[0082] S2: after the product containing the compound 17 is dissolved, a mixture containing the compound 18, a solvent 12, and potassium bis(trimethylsilyl)amide is added, and reacted to obtain the compound 19.

[0083] Optionally, in the step S1, the molar ratio of the compound 16 to the pyridinium dichromate is 1: 5.0 ~ 6.0.

[0084] Optionally, in the step S1, the molar volume ratio of the compound 16 to the solvent 11 is 0.006 ~ 0.01: 1 mol / L.

[0085] Optionally, in the step S1, the solvent 11 is dichloromethane.

[0086] Optionally, in the step S1, the temperature of the reaction 12 is 0 ~ 25℃, and the time of the reaction 12 is 20 min ~ 2 h.

[0087] Optionally, in the step S2, the molar ratio of the compound 18 to the potassium bis(trimethylsilyl)amide is 1: 0.8 ~ 1.0.

[0088] Optionally, in the step S2, the molar volume ratio of the compound 18 to the solvent 12 is 0.05 ~ 0.1: 1 mol / L.

[0089] Optionally, in the step S2, the solvent 12 is tetrahydrofuran.

[0090] Optionally, in the step S2, the temperature of the reaction 13 is -78 ~ 25℃, and the time of the reaction 13 is 1 h ~ 3 h.

[0091] According to the eighth aspect of the present application, a synthesis method of Ervitsine is provided, and the synthesis method of the Ervitsine comprises the following steps:

[0092] Step a: a mixture containing the compound 19, a solvent 13, and diisobutylaluminum hydride is reacted to obtain a product containing the compound 20;

[0093] Step b: after dissolving the product containing compound 20, add tetrabutylammonium fluoride, manganese dioxide, and react for 15 to obtain the Ervitsine;

[0094] The compound 19 is consistent with the compound 19 described above.

[0095] The compound 19 is prepared by the preparation method of the compound 19 described above.

[0096] Optionally, in the step a, the molar ratio of the compound 19 to the diisobutylaluminum hydride is 1:4.0-5.0.

[0097] Optionally, in the step a, the molar volume ratio of the compound 19 to the solvent 13 is 0.001-0.02:1 mol / L.

[0098] Optionally, in the step a, the solvent 13 is tetrahydrofuran.

[0099] Optionally, in the step a, the temperature of the reaction 14 is 0-50°C, and the reaction time of the reaction 14 is 0.5 h-1 h.

[0100] Optionally, in the step b, the molar ratio of the compound 19 to the tetrabutylammonium fluoride is 1:1.2-1.5.

[0101] Optionally, in the step b, the molar ratio of the compound 19 to the manganese dioxide is 1:10.0-12.0.

[0102] Optionally, in the step b, the temperature of the reaction 15 is 20-30°C, and the reaction time of the reaction 15 is 0.5 h-1 h.

[0103] According to the ninth aspect of the present application, a total synthesis method for synthesizing Ervitsine is provided, and the synthesis route of the total synthesis method for synthesizing Ervitsine is as follows:

[0104] ;

[0105] The compound 4, the compound 6, the compound 7, the compound 8, the compound 9, the compound 10, the compound 11, the compound 12, the compound 14, the compound 15, the compound 16, the compound 17, the compound 18, the compound 19, and the compound 20 in the synthesis route are consistent with the compound 4, the compound 6, the compound 7, the compound 8, the compound 9, the compound 10, the compound 11, the compound 12, the compound 14, the compound 15, the compound 16, the compound 17, the compound 18, the compound 19, and the compound 20 described above.

[0106] The beneficial effects that this application can produce include:

[0107] This invention provides a concise method for synthesizing the natural product Ervitsine. Employing total organic synthesis, it achieves high efficiency in obtaining the indole alkaloid Ervitsine, with a yield exceeding 60%. Furthermore, its structure can be easily modified, providing a sufficient material basis for future bioactivity research and lead compound screening in new drug development. It is believed that this method will contribute to the treatment of major human diseases such as inflammation and tumors. The synthetic method of this invention uses inexpensive and readily available raw materials, employs mild reaction conditions, has a short procedure time, high overall yield, and low production cost, showing promising prospects for industrial-scale production. Detailed Implementation

[0108] The present application is described in detail below with reference to the embodiments, but the present application is not limited to these embodiments.

[0109] Unless otherwise specified, all raw materials used in the embodiments of this application were purchased through commercial channels.

[0110] Example 1

[0111] Synthesis of Compound 4

[0112]

[0113] Compound 2 (30 g, 211 mmol, 1.0 equiv.) was dissolved in diethyl ether (800 mL). Diisopropylaminolithium (2.0 M tetrahydrofuran / n-heptane / ethylbenzene solution, 126 mL, 253.2 mmol, 1.2 equiv.) was slowly added at -78 ºC, and the mixture was stirred at this temperature for one hour. Then, benzylchloromethyl ether (34.1 mL, 232 mmol, 1.1 equiv.) was added at this temperature, and the mixture was brought to room temperature and stirred for one hour. The temperature was then lowered to -40 °C, and n-butyllithium (2.5 M n-hexane solution, 118 mL, 295 mmol, 1.4 equiv.) was slowly added. The mixture was stirred at this temperature for one hour, followed by the slow addition of compound 3 (43.4 g, 316.5 mmol, 1.5 equiv.). The reaction was carried out at this temperature for two hours, quenched with saturated ammonium chloride solution, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the crude product obtained by rotary evaporation was concentrated. This crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate 10:1 → 5:1) to give a pale yellow oily product 4 (37.8 g, yield 68%).

[0114] R f = 0.6 (petroleum ether / ethyl acetate = 3 / 1);

[0115] IR (film) λ max 2933, 2862, 1697, 1558, 1087, 1066, 740, 698 cm -1 ;

[0116] 1 H NMR (600 MHz, CDCl3) δ 7.43 (d, J = 2.0 Hz, 1H), 7.34 (d, J = 4.4Hz, 4H), 7.29 (ddd, J = 8.7, 5.0, 3.8 Hz, 1H), 6.70 (d, J = 2.0 Hz, 1H), 4.84(s, 2H), 4.60(s, 2H), 4.45(s, 2H);

[0117] 13 C NMR (150 MHz, CDCl3) δ 187.0, 158.1, 142.8, 137.5, 128.6, 128.1,128.1, 120.8, 109.9, 73.3, 63.4, 47.5;

[0118] HRMS (ESI) calculation of molecular weight C 14 H 13 ClO3 [M+Na] + : 287.0445; Measured molecular weight: 287.0442.

[0119] Example 2

[0120] Synthesis of Compound 6

[0121]

[0122] Compound 4 (23 g, 87 mmol, 1.0 equiv) and compound 5 (19.9 g, 95.7 mmol, 1.1 equiv) were dissolved in 800 ml of acetone. Anhydrous potassium carbonate (36 g, 261 mmol, 3.0 equiv) was then added to the system. The system was heated to 50 °C and kept incubated overnight. After cooling to room temperature, the mixture was filtered through diatomaceous earth and concentrated. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate 10:1 → 4:1) to give a brown oily product 6 (30.4 g, yield 80%).

[0123] R f= 0.45 (petroleum ether / ethyl acetate = 3 / 1);

[0124] IR (film) λ max 3284, 2924, 1691, 1348, 1161, 902, 659 cm -1 ;

[0125] 1 H NMR (600 MHz, CDCl3) δ 7.77 – 7.72 (m, 2H), 7.41 (d, J = 2.0 Hz,1H), 7.33 (d, J = 4.4 Hz, 4H), 7.31 – 7.27 (m, 3H), 6.77 (d, J = 2.0 Hz, 1H), 4.81 (s, 2H), 4.58 (s, 2H), 4.53 (s, 2H), 4.24 (d, J = 2.5 Hz, 2H), 2.42 (s, 3H), 2.08 (t, J = 2.5 Hz, 1H);

[0126] 13 C NMR (150 MHz, CDCl3) δ 189.4, 157.7, 144.0, 142.7, 137.6, 136.1,129.8, 128.6, 128.1, 128.0, 127.8, 121.1, 109.6, 76.6, 74.6, 73.2, 63.5,53.2, 37.5, 21.7;

[0127] HRMS (ESI) calculation of molecular weight C 24 H 23 NO5S [M+Na] + : 460.1189; Measured molecular weight: 460.1185.

[0128] Example 3

[0129] Synthesis of Compound 7

[0130]

[0131] Compound 6 (5 g, 11.4 mmol, 1.0 equiv.) was dissolved in 100 mL of a mixed solvent (tetrahydrofuran / water = 4:1) and cooled to 0 °C. Sodium borohydride (431 mg, 11.4 mmol, 1.0 equiv.) was then added in portions. After the reaction was complete, the mixture was quenched with saturated ammonium chloride solution, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to obtain a crude product with a concentrated organic phase. This crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate 8:1 → 3:1) to give a pale yellow oil product 4 (4.3 g, yield 86%).

[0132] R f = 0.3 (petroleum ether / ethyl acetate = 3 / 1);

[0133] IR (film) λ max 3516, 3290, 2924, 1330, 1159, 813, 661 cm -1 ;

[0134] 1 H NMR (600 MHz, CDCl3) δ 7.73 – 7.69 (m, 2H), 7.37 – 7.29 (m, 5H), 7.29 (ddt, J = 8.5, 5.4, 2.8 Hz, 1H), 7.24 (d, J = 8.1 Hz, 2H), 6.44 (d, J =1.9 Hz, 1H), 5.01 (dd, J = 8.8, 3.7 Hz, 1H), 4.56 (t, J = 3.0 Hz, 4H), 4.23(dd, J = 18.4, 2.5 Hz, 1H), 4.11 (dd, J = 18.4, 2.5 Hz, 1H), 3.43 (dd, J =14.6, 8.8 Hz, 1H), 3.30 (dd, J = 14.6, 3.7 Hz, 1H), 2.91 (s, 1H), 2.40 (s,3H), 1.99 (t, J = 2.5 Hz, 1H);

[0135] 13C NMR (150 MHz, CDCl3) δ 148.4, 144.0, 142.5, 137.8, 135.6, 129.7,128.6, 128.1, 128.0, 127.9, 124.0, 109.6, 77.0, 74.1, 72.6, 65.9, 62.9, 53.4,38.7, 21.7;

[0136] HRMS (ESI) calculation of molecular weight C 24 H 25 NO5S [M+Na] + : 462.1346; Measured molecular weight: 462.1341.

[0137] Example 4

[0138] Synthesis of Compound 8

[0139]

[0140] Compound 7 (6.8 g, 15 mmol, 1.0 equiv.) was dissolved in 200 mL of tetrahydrofuran and cooled to 0 °C. Then, 2,6-dimethylpyridine (5.2 mL, 45 mmol, 3.0 equiv.) and triisopropylsilyltrifluoromethanesulfonate (4.4 mL, 16.5 mmol, 1.1 equiv.) were added sequentially, and the reaction was carried out at this temperature for 2 hours. Then, potassium tert-butoxide (1.0 M tetrahydrofuran solution, 22.5 mL, 22.5 mmol, 1.5 equiv.) was added to the system, and the reaction was carried out at this temperature for 30 minutes. The reaction was quenched with saturated ammonium chloride aqueous solution, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered and concentrated, and the crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate 20:1 → 10:1) to give a yellow oily product 8 (6.7 g, yield 75%).

[0141] R f = 0.5 (petroleum ether / ethyl acetate = 10 / 1);

[0142] IR (film) λ max 2943, 2866, 1346, 1163, 1093, 927, 665 cm -1 ;

[0143] 1H NMR (600 MHz, CDCl3) δ 7.64 – 7.60 (m, 2H), 7.40 – 7.36 (m, 2H), 7.36 – 7.31 (m, 3H), 7.31 – 7.27 (m, 1H), 7.24 (d, J = 8.1 Hz, 2H), 6.68 (t,J = 6.2 Hz, 1H), 6.41 (d, J = 1.9 Hz, 1H), 5.21 – 5.12 (m, 3H), 4.60 – 4.55(m, 3H), 4.46 (d, J = 12.5 Hz, 1H), 3.33 (dd, J = 13.9, 6.8 Hz, 1H), 3.06(dd, J = 13.9, 7.1 Hz, 1H), 2.40 (s, 3H), 1.13 – 0.95 (m, 21H);

[0144] 13 C NMR (150 MHz, CDCl3) δ 201.4, 147.8, 143.8, 142.2, 138.3, 134.9,129.8, 128.5, 128.0, 127.7, 127.4, 125.2, 110.0, 101.3, 88.4, 72.7, 66.1,62.7, 53.2, 21.7, 18.1, 18.0, 12.4;

[0145] HRMS (ESI) calculation of molecular weight C 33 H 45 NO5SSi [M+H] + : 596.2860; Measured molecular weight: 596.2857.

[0146] Example 5

[0147] Synthesis of Compound 9

[0148]

[0149] Compound 8 (290 mg, 0.48 mmol, 1.0 equiv.) was dissolved in 50 mL of dichloromethane and cooled to -78 °C. Then, peroxyacetone (0.085 M acetone solution, 10 mL, 0.85 mmol, 2.5 equiv.) was added, and the mixture was reacted for 10 minutes. The mixture was then filtered through a sintered glass funnel, the filtrate was evaporated to dryness, and purified by silica gel column chromatography (petroleum ether / ethyl acetate 10:1 → 5:1) to give a pale yellow oily product 9 (210 mg, 70% yield).

[0150] R f = 0.5 (petroleum ether / ethyl acetate = 5 / 1);

[0151] IR (film) λ max 2954, 2910, 2850, 1653, 1558, 1458 cm -1 ;

[0152] 1 H NMR (600 MHz, CDCl3) δ 7.75 – 7.70 (m, 2H), 7.42 – 7.38 (m, 2H), 7.35 (t, J = 7.6 Hz, 2H), 7.29 (dd, J = 7.7, 4.9 Hz, 3H), 5.99 (t, J = 1.3Hz, 1H), 5.10 (dd, J = 4.5, 1.5 Hz, 1H), 4.71 (d, J = 11.2 Hz, 2H), 4.62 (d,J = 11.9 Hz, 1H), 4.58 (ddt, J = 9.3, 6.4, 1.6 Hz, 1H), 3.94 (s, 2H), 3.93 –3.86 (m, 1H), 2.71 (dd, J = 16.5, 4.5 Hz, 1H), 2.42 (s, 3H), 2.30 (d, J =16.5 Hz, 1H), 2.15 (dd, J = 11.8, 9.0 Hz, 1H), 1.12 – 0.92 (m, 21H);

[0153] 13C NMR (150 MHz, CDCl3) δ 202.8, 147.3, 143.6, 137.8, 137.1, 129.5,128.5, 128.2, 127.8, 127.7, 125.9, 88.1, 77.4, 74.2, 68.7, 67.2, 65.9, 53.3,46.6, 21.7, 18.0, 12.1;

[0154] HRMS (ESI) calculation of molecular weight C 33 H 45 NO6SSi [M+Na] + : 634.2629; Measured molecular weight: 634.2625.

[0155] Example 6

[0156] Synthesis of Compound 10

[0157]

[0158] Compound 9 (210 mg, 0.34 mmol, 1.0 equiv) was dissolved in 10 mL of toluene, followed by the addition of palladium on carbon (10% palladium on carbon, 36 mg, 0.034 mmol, 0.1 equiv.). A hydrogen balloon was then inserted and purged three times with hydrogen. After reacting at room temperature for 12 hours, the hydrogen balloon was removed. Triphenylphosphine (244 mg, 0.93 mmol, 3.0 equiv.), imidazole (63 mg, 0.93 mmol, 3.0 equiv.), and elemental iodine (158 mg, 0.62 mmol, 2.0 equiv.) were added sequentially to the system. Argon gas was introduced into the system, and the temperature was raised to 80 °C. After reacting for 1 hour, the reaction was quenched with saturated sodium thiosulfate solution. The mixture was filtered through diatomaceous earth and extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate. After filtration and concentration, the crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate 10:1 →). The product was diluted 5:1 to give 10 (161 mg, 75% yield) of white solid.

[0159] R f = 0.45 (petroleum ether / ethyl acetate = 5 / 1);

[0160] IR (film) λ max 2943, 2866, 1728, 1342, 1157 cm -1 ;

[0161] 1H NMR (600 MHz, CDCl3) δ 7.74 (d, J = 8.3 Hz, 2H), 7.31 (d, J = 8.2Hz, 2H), 4.69 – 4.64 (m, 1H), 4.43 (d, J = 1.6 Hz, 1H), 4.06 (dt, J = 10.8,6.0 Hz, 1H), 3.72 (d, J = 11.4 Hz, 1H), 3.67 (d, J = 11.4 Hz, 1H), 3.52 (ddd,J = 13.4, 6.1, 1.5 Hz, 1H), 2.87 – 2.80 (m, 1H), 2.79 – 2.72 (m, 1H), 2.54 –2.45 (m, 1H), 2.43 (s, 3H), 2.34 (dddd, J = 14.4, 11.7, 8.5, 1.5 Hz, 1H), 1.64 – 1.56 (m, 1H), 1.09 – 0.99 (m, 21H);

[0162] 13 C NMR (150 MHz, CDCl3) δ 203.7, 143.7, 136.9, 129.6, 127.7, 81.4,71.8, 65.7, 63.5, 49.7, 49.6, 43.2, 30.4, 21.7, 18.0, 18.0, 12.2, 10.5;

[0163] HRMS (ESI) calculation of molecular weight C 26 H 40 INO5SSi [M+H] + : 634.1514; Measured molecular weight: 634.1511.

[0164] Example 7

[0165] Synthesis of Compound 11

[0166]

[0167] Compound 10 (161 mg, 0.25 mmol, 1.0 equiv.) was dissolved in a mixed solvent (isopropanol: tert-butanol: water = 10 ml: 10 ml: 0.2 ml). The system was heated to 90 °C. After the substrate was completely dissolved, activated zinc powder (160 mg, 2.5 mmol, 10.0 equiv.) was added to the system. After reacting for 2 hours, the mixture was cooled to room temperature. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate 8:1 → 3:1) after filtration through diatomaceous earth to give a colorless oily product 11 (80 mg, yield 63%).

[0168] R f = 0.3 (petroleum ether / ethyl acetate = 3 / 1);

[0169] IR (film) λ max 2943, 2866, 1718, 1342, 1159, 1118, 956, 883 cm -1 ;

[0170] 1 H NMR (400 MHz, CDCl3) δ 7.71 (d, J = 8.0 Hz, 2H), 7.30 (d, J = 8.0Hz, 2H), 5.24 (d, J = 5.6 Hz, 2H), 4.65 (s, 1H), 4.31 (dt, J = 9.3, 4.7 Hz,1H), 3.98 (dt, J = 8.2, 6.1 Hz, 1H), 3.29 (dd, J = 13.7, 5.7 Hz, 1H), 3.02(q, J = 6.2 Hz, 1H), 2.94 (dd, J = 13.3, 8.7 Hz, 1H), 2.90 – 2.68 (m, 2H),2.46 (t, J = 4.1 Hz, 1H), 2.42 (s, 3H), 1.80 (s, 1H), 1.74 (ddd, J = 15.0,9.2, 6.7 Hz, 1H), 1.03 (s, 21H);

[0171] 13C NMR (100 MHz, CDCl3) δ 205.6, 143.9, 141.7, 135.8, 129.7, 127.9,118.0, 69.0, 67.9, 66.3, 50.7, 47.4, 44.0, 36.8, 21.7, 18.1, 18.1, 12.2;

[0172] HRMS (ESI) calculation of molecular weight C 26 H 41 NO5SSi [M+H] + : 508.2547; Measured molecular weight: 508.2543.

[0173] Example 8

[0174] Synthesis of Compound 12

[0175]

[0176] Compound 11 (630 mg, 1.24 mmol, 1.0 equiv.) was dissolved in 20 mL of 1,2-dichloroethane and the system was cooled to 0 °C. Then, 2,6-dimethylpyridine (0.23 mL, 1.98 mmol, 1.6 equiv.) and tert-butyldimethylsilyltrifluoromethanesulfonate (0.45 mL, 1.86 mmol, 1.5 equiv.) were added sequentially. After reacting at this temperature for 5 minutes, p-toluenesulfonyl hydrazine (460 mg, 2.48 mmol, 2.0 equiv.) and 0.04 mL of acetic acid were added, and the system was heated to 50 °C. The reaction was allowed to proceed overnight, then cooled to room temperature, quenched with saturated ammonium chloride solution, and extracted with dichloromethane. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate 10:1 → 5:1) to give a yellow oily product 12. (812 mg, yield 83%).

[0177] R f = 0.5 (petroleum ether / ethyl acetate = 5 / 1);

[0178] IR (film) λ max 3219, 2947, 2866, 1558, 1340, 1091, 1047, 837 cm -1 ;

[0179] 1H NMR (600 MHz, CD2Cl2) δ 7.9 – 7.8 (m, 2H), 7.7 – 7.6 (m, 2H), 7.4(s, 1H), 7.3 (dd, J = 13.2, 8.1 Hz, 4H), 5.0 (dd, J = 7.8, 1.3 Hz, 2H), 5.0(s, 1H), 4.0 (tt, J = 7.9, 3.9 Hz, 1H), 3.7 (dt, J = 9.7, 5.8 Hz, 1H), 3.3(dd, J = 13.8, 5.7 Hz, 1H), 2.8 (dt, J = 7.3, 5.2 Hz, 1H), 2.6 (dd, J = 13.9,9.7 Hz, 1H), 2.4 (s, 3H), 2.4 (s, 3H), 2.4 (dd, J = 14.9, 4.5 Hz, 1H), 2.3(dd, J = 14.9, 8.2 Hz, 1H), 2.0 (dt, J = 14.7, 4.0 Hz, 1H), 1.5 (dd, J =14.8, 7.6 Hz, 1H), 1.0 (q, J = 3.3, 2.7 Hz, 21H), 0.8 (s, 9H), 0.0 (s, 3H), -0.0 (s, 3H);

[0180] 13 C NMR (150 MHz, CD2Cl2) δ 155.5, 144.8, 144.0, 142.7, 137.1, 135.6, 130.0, 130.0, 128.6, 128.0, 117.0, 69.4, 67.7, 63.5, 46.0, 44.4, 36.3, 35.8,25.8, 21.7, 21.6, 18.1, 18.1, 12.5, -4.7, -4.7;

[0181] HRMS (ESI) calculation of molecular weight C 39 H 63 N3O6S2Si2 [M+H] + : 790.3770; Measured molecular weight: 790.3760.

[0182] Example 9

[0183] Synthesis of Compound 14

[0184]

[0185] Compound 12 (817 mg, 1.04 mmol, 1.0 equiv.), tetratetraphenylphosphine palladium (115 mg, 0.1 mmol, 0.1 equiv.), o-iodoaniline 13 (800 mg, 4.16 mmol, 3.5 equiv.), and anhydrous potassium carbonate (575 mg, 4.16 mmol, 4.0 equiv.) were added sequentially to a flask. After purging with argon, 20 mL of toluene was added, and the system was heated to 110 °C and stirred overnight. After the reaction was complete, the mixture was cooled to room temperature, diluted with 20 mL of ethyl acetate, and filtered through diatomaceous earth. The concentrated crude product was purified by column chromatography (petroleum ether / ethyl acetate 15:1 → 10:1) to give a yellow oily product 15 (565.0 mg, 78% yield).

[0186] R f = 0.65 (petroleum ether / ethyl acetate = 5 / 1);

[0187] IR (film) λ max 2947, 2866, 1558, 1338, 1161, 1066, 837 cm -1 ;

[0188] 1H NMR (600 MHz, CD2Cl2) δ 7.4 – 7.4 (m, 2H), 7.1 (d, J = 8.0 Hz, 2H), 7.1 (td, J = 7.6, 1.6 Hz, 1H), 6.9 (d, J = 7.8 Hz, 1H), 6.7 – 6.6 (m, 2H),5.8 – 5.8 (m, 1H), 5.2 (s, 1H), 5.1 (d, J = 1.5 Hz, 1H), 4.9 (d, J = 1.5 Hz,1H), 4.9 (ddd, J = 9.9, 5.4, 2.9 Hz, 1H), 3.8 (dt, J = 11.7, 6.0 Hz, 3H), 3.6(dd, J = 14.5, 5.9 Hz, 1H), 3.1 (dd, J = 14.4, 11.3 Hz, 1H), 2.5 (dt, J =13.6, 5.1 Hz, 1H), 2.4 (s, 3H), 1.8 (ddd, J = 14.1, 9.9, 4.6 Hz, 1H), 1.1 –0.9 (m, 21H), 0.9 (s, 9H), 0.0 (d, J = 5.7 Hz, 6H);

[0189] 13 C NMR (150 MHz, CD2Cl2) δ 146.4, 143.8, 143.6, 141.4, 138.0, 137.8,130.4, 130.0, 129.7, 128.7, 127.7, 118.6, 115.6, 112.6, 70.6, 69.2, 45.4,45.4, 38.0, 25.9, 21.6, 18.3, 18.2, 18.2, 12.5, -4.6, -4.6;

[0190] HRMS (ESI) calculation of molecular weight C 38 H 60 N₂O₄SSi₂ [M+H] + : 697.3885; Measured molecular weight: 697.3884.

[0191] Example 10

[0192] Synthesis of Compound 15

[0193]

[0194] Compound 14 (41 mg, 0.059 mmol, 1.0 equiv.) was dissolved in 5 mL of tetrahydrofuran and cooled to 0 °C. Iodobenzene trifluoroacetate (40 mg, 0.088 mmol, 1.5 equiv.) was then added, and the reaction was allowed to proceed for 10 minutes. The temperature was then lowered to -20 °C, and tetrabutylammonium fluoride (1.0 M tetrahydrofuran solution, 0.29 mL, 0.29 mmol, 5.0 equiv.) was added. After reacting for 3 hours, the reaction was quenched with saturated ammonium chloride solution and extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, and the crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate 10:1 → 5:1) to give a pale yellow oily product 15 (18.7 mg, 59% yield).

[0195] R f = 0.4 (petroleum ether / ethyl acetate = 5 / 1);

[0196] IR (film) λ max 3471, 2951, 2854, 1653, 1596, 1155, 1072, 837 cm -1 ;

[0197] 1H NMR (600 MHz, (CD3)2CO) δ 9.6 (s, 1H), 7.9 – 7.9 (m, 1H), 7.7 – 7.7(m, 2H), 7.4 (dd, J = 7.1, 1.8 Hz, 1H), 7.3 (d, J = 8.0 Hz, 2H), 7.1 (pd, J =7.1, 1.4 Hz, 2H), 6.0 (s, 1H), 5.6 (dd, J = 9.9, 4.3 Hz, 1H), 5.0 (d, J = 1.6Hz, 1H), 4.8 (d, J = 1.6 Hz, 1H), 4.6 (d, J = 3.7 Hz, 1H), 3.8 (ddt, J =11.9, 6.2, 2.9 Hz, 1H), 3.7 (dd, J = 14.2, 6.0 Hz, 1H), 3.0 (q, J = 5.5 Hz,1H), 2.9 (dd, J = 14.2, 11.5 Hz, 1H), 2.6 (dt, J = 13.5, 4.9 Hz, 1H), 2.4 (s,3H), 1.9 (ddd, J = 14.1, 10.0, 4.6 Hz, 1H), 0.9 (s, 9H), 0.2 (s, 3H), 0.2 (s,3H);

[0198] 13 C NMR (150 MHz, (CD3)2CO) δ 146.6, 143.9, 140.9, 139.3, 135.7,130.2, 129.1, 128.4, 122.5, 120.3, 119.8, 112.3, 112.1, 109.2, 69.2, 68.2,55.9, 45.9, 45.4, 38.8, 26.5, 21.4, 18.8, -4.4;

[0199] HRMS (ESI) calculation of molecular weight C 29 H 38 N₂O₄SSi [M+H] + : 539.2394; Measured molecular weight: 539.2392.

[0200] Example 11

[0201] Synthesis of Compound 16

[0202]

[0203] Compound 15 (180 mg, 0.33 mmol, 1.0 equiv.) was dissolved in 10 mL of ethylene glycol dimethyl ether. The system was cooled to -78 °C, and then lithium naphthalene solution (0.5 M ethylene glycol dimethyl ether solution, 3.3 mL, 1.65 mmol, 5.0 equiv.) was added. The system was stirred for 10 minutes while maintaining a dark green color, and then quenched with 1.0 mL of methanol. Triethylamine (0.14 mL, 0.99 mmol, 3.0 equiv.) and di-tert-butyl dicarbonate (0.23 mL, 0.99 mmol, 3.0 equiv.) were added sequentially to the system. The system was then heated to room temperature and stirred for 1 hour. Finally, the system was quenched with saturated ammonium chloride solution and extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, and the crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate 15:1 → 10:1) after filtration and concentration to give a white solid product 16 (138.9 mg, yield 87%).

[0204] R f = 0.6 (petroleum ether / ethyl acetate = 5 / 1);

[0205] [α]25 D = +16.1 (c = 0.31 in MeOH);

[0206] IR (film) λ max 3473, 2927, 2856, 1664, 1558, 1417, 1159, 1072 cm -1 ;

[0207] 1H NMR (600 MHz, (CD3)2CO) δ 9.5 (d, J = 17.0 Hz, 1H), 7.9 – 7.7 (m,1H), 7.4 (dd, J = 15.0, 6.9 Hz, 1H), 7.2 – 6.9 (m, 2H), 6.1 (d, J = 76.5 4.1 – 3.9 (m, 2H), 3.2(t, J = 5.5 Hz, 1H), 2.8 (dd, J = 13.2, 11.1 Hz, 1H), 2.8 – 2.5 (m, 1H), 2.0– 1.8 (m, 1H), 1.5 (d, J = 91.5 Hz, 9H), 1.0 (d, J = 8.0 Hz, 9H), 0.3 – 0.1(m, 6H);

[0208] 13 C NMR (150 MHz, (CD3)2CO) δ 154.4, 154.3, 148.7, 148.2, 140.7,140.6, 135.7, 129.3, 129.2, 122.3, 120.1, 120.1, 120.0, 119.4, 112.2, 112.0,111.3, 110.6, 110.5, 110.0, 80.2, 79.7, 70.1, 69.7, 69.3, 69.3, 54.7, 53.1,45.8, 44.8, 43.9, 39.2, 38.7, 28.8, 28.6, 26.5, 26.4, 26.3, 18.8, -4.3, -4.4, -4.4;

[0209] HRMS (ESI) calculation of molecular weight C 27 H 40 N₂O₄Si [M+Na] + : 507.2650; Measured molecular weight: 507.2648.

[0210] Example 12

[0211] Synthesis of Compound 19

[0212]

[0213] Compound 16 (20 mg, 0.034 mmol, 1.0 equiv.) was dissolved in 5.0 mL of dichloromethane. 60 mg of diatomaceous earth was added to the system and the temperature was lowered to 0 °C. Then, pyridinium dichromate (65 mg, 0.17 mmol, 5.0 equiv.) was added. After reacting for 20 minutes, 5.0 mL of petroleum ether, 5.0 mL of ethyl acetate, and 100 mg of diatomaceous earth were added. The mixture was brought to room temperature and stirred for 10 minutes. The mixture was then filtered through diatomaceous earth and evaporated to dryness. The crude product was then directly used for the next step.

[0214] Compound 18 (40 mg, 0.17 mmol, 5.0 equiv.) was dissolved in 3.0 mL of tetrahydrofuran. The system was cooled to -78 °C, and then potassium bis(trimethylsilyl)amino (1 M in THF, 0.13 mL, 0.13 mmol, 4.0 equiv.) was added. After stirring for 1 hour, the crude product of compound 17 obtained in the previous step was dissolved in 1.0 mL of tetrahydrofuran and slowly added to the system. The reaction was then carried out at -78 °C for 2 hours, followed by stirring at room temperature for 30 minutes. The reaction was then quenched with saturated ammonium chloride solution and extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, and the concentrated crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate 20:1 → 15:1) to give a yellow oily product 19 (9.5 mg, yield 57%).

[0215] R f = 0.65 (petroleum ether / ethyl acetate = 10 / 1);

[0216] IR (film) λ max 3473, 2927, 2854, 1683, 1558,1163, 1095, 881, 837 cm -1 ;

[0217] 1H NMR (400 MHz, CD2Cl2) δ 8.4 (s, 1H), 7.9 – 7.7 (m, 1H), 7.3 (t, J =7.8 Hz, 1H), 7.1 (q, J = 7.1 Hz, 2H), 6.1 (d, J = 55.2 Hz, 1H), 5.6 (t, J =7.6 Hz, 1H), 5.3 (d, J = 4.8 Hz, 1H), 5.1 – 4.7 (m, 2H), 4.3 (dd, J = 44.2,15.6 Hz, 1H), 3.9 (d, J = 6.3 Hz, 1H), 3.6 (dd, J = 38.5, 15.9 Hz, 1H), 2.4(ddd, J = 11.7, 6.5, 4.8 Hz, 1H), 2.1 – 2.0 (m, 1H), 1.7 (dt, J = 9.2, 4.6Hz, 3H), 1.5 (dd, J = 48.4, 25.6 Hz, 9H), 1.0 (d, J = 2.3 Hz, 9H), 0.2 (d, J= 14.6 Hz, 6H);

[0218] 13 C NMR (100 MHz, CD2Cl2) δ 153.6, 148.0, 139.3, 134.4, 133.9, 121.7,121.3, 119.5, 118.6, 110.7, 108.3, 79.8, 68.5, 52.2, 47.3, 45.9, 44.6, 40.4,28.3, 28.2, 28.1, 25.7, 25.7, 18.1, 12.0, -4.7, -5.1;

[0219] HRMS (ESI) calculation of molecular weight C 29 H 42 N₂O₃Si [M+H] + : 495.3037; Measured molecular weight: 495.3034.

[0220] Example 13

[0221] Synthesis of Compound 1

[0222]

[0223] Compound 19 (9.5 mg, 0.019 mmol, 1.0 equiv.) was dissolved in 2.0 mL of tetrahydrofuran. The system was cooled to 0 °C and diisobutylaluminum hydride (1.0 M tetrahydrofuran solution, 0.1 mL, 0.1 mmol, 5.2 equiv.) was added. The temperature was then raised to 50 °C and stirred for 30 minutes. The mixture was then cooled to 0 °C, and 60 μL of water, 60 μL of 15% sodium hydroxide solution, and 150 μL of water were added sequentially. The mixture was stirred at room temperature for 30 minutes, and then 20 mg of anhydrous magnesium sulfate was added. After stirring for 10 minutes, the mixture was filtered through diatomaceous earth and evaporated to dryness to obtain the crude product of compound 20, which was then directly used for the next step.

[0224] The crude product obtained in the previous step was dissolved in 2.0 ml of dichloromethane, and then tetrabutylammonium fluoride trihydrate (7.9 mg, 0.028 mmol, 1.5 equiv.) was added to the system. After reacting at room temperature for 5 hours, activated manganese dioxide (17 mg, 0.19 mmol, 10.0 equiv.) was added to the system. After reacting for 30 minutes, the mixture was filtered with diatomaceous earth, and the crude product was purified by silica gel column chromatography (ethyl acetate / methanol 20:1 → 10:1) after evaporation to obtain a white solid product 1 (2.8 mg, yield 61%).

[0225] R f = 0.5 (ethyl acetate / methanol = 10 / 1);

[0226] IR (film) λ max 2692, 2924, 1653, 1558, 1261, 1093, 1020, 798 cm -1 ;

[0227] 1H NMR (600 MHz, CD3CN) δ 9.8 (s, 1H), 7.8 (dt, J = 8.2, 1.0 Hz, 1H), 7.5 (dt, J = 8.4, 1.0 Hz, 1H), 7.3 (ddd, J = 8.2, 6.9, 1.1 Hz, 1H), 7.2 (ddd,J = 8.0, 6.9, 1.0 Hz, 1H), 5.4 – 5.3 (m, 1H), 5.1 – 5.1 (m, 2H), 5.0 (s, 1H),3.8 (t, J = 4.6 Hz, 1H), 3.0 – 2.9 (m, 2H), 2.8 (dd, J = 16.8, 3.9 Hz, 1H), 2.8 (d, J = 14.5 Hz, 1H), 2.1 (s, 3H), 1.7 (dd, J = 6.9, 2.2 Hz, 3H);

[0228] 13 C NMR (150 MHz, CD3CN) δ 194.5, 147.5, 137.6, 137.2, 135.2, 128.7,126.9, 122.6, 121.3, 121.0, 117.8, 113.1, 111.0, 62.1, 54.0, 51.3, 42.5,39.8, 12.1;

[0229] HRMS (ESI) calculation of molecular weight C 19 H 20 N2O [M+H] + : 293.1648; Measured molecular weight: 293.1646.

[0230] The above description is merely a few embodiments of this application and is not intended to limit this application in any way. Although this application discloses preferred embodiments as described above, it is not intended to limit this application. Any changes or modifications made by those skilled in the art without departing from the scope of the technical solution of this application using the disclosed technical content are equivalent to equivalent implementation cases and fall within the scope of the technical solution.

Claims

1. A method for preparing an intermediate compound of Ervitsine, characterized in that, Includes the following steps: S1: Preparation of compound 15: The mixture containing compound 14... A mixture of solvent 9, iodobenzene trifluoroacetate, and tetrabutylammonium fluoride was reacted with solvent 10 to obtain compound 15. ; S2: Preparation of Compound 16: A mixture containing Compound 15, Solvent 10, lithium naphthalene, triethylamine, and di-tert-butyl dicarbonate was subjected to reaction 11 to obtain Compound 16. ; S3: Preparation of Compound 17: A mixture containing Compound 16, Solvent 11, and pyridinium dichromate was subjected to reaction 12 to obtain a mixture containing Compound 17. Products; S4: Preparation of Compound 19: Dissolve the product containing Compound 17 and then add the product containing Compound 18. In a mixture of solvent 12 and potassium bis(trimethylsilyl)amino, compound 19 was obtained by reaction 13. ; S5: Preparation of Compound 20: A mixture containing Compound 19, Solvent 13, and diisobutylaluminum hydride was subjected to reaction 14 to obtain a mixture containing Compound 20. The product of.

2. The preparation method according to claim 1, characterized in that, In step S1, solvent 9 is tetrahydrofuran; and / or, The molar ratio of compound 14, iodobenzene trifluoroacetate, and tetrabutylammonium fluoride is 1:(1.3~1.5):(4.5~5.5); and / or, The molar volume ratio of compound 14 to solvent 9 is 0.01~0.05:1 mol / L; and / or, The temperature of reaction 10 is -20~0℃, and the reaction time is 10min~3h.

3. The preparation method according to claim 1, characterized in that, In step S2, the molar ratio of compound 15, lithium naphthalene, triethylamine, and di-tert-butyl dicarbonate is 1:(5.0~10.0):(2.5~3.0):(2.5~3.0); and / or, The molar volume ratio of compound 15 to solvent 10 is 0.03~0.1:1 mol / L; and / or, The solvent 10 is selected from at least one of ethylene glycol dimethyl ether and tetrahydrofuran; and / or, The temperature of reaction 11 is -78 to -40°C, and the reaction time is 10 min to 0.5 h.

4. The preparation method according to claim 1, characterized in that, In step S3, the molar ratio of compound 16 to pyridinium dichromate is 1:5.0~6.0; and / or, The molar volume ratio of compound 16 to solvent 11 is 0.006~0.01:1 mol / L; and / or, The solvent 11 is dichloromethane; and / or, The temperature of reaction 12 is 0~25℃, and the reaction time is 20min~2h.

5. The preparation method according to claim 1, characterized in that, In step S4, the molar ratio of compound 18 to potassium bis(trimethylsilyl)amino is 1:0.8~1.0; and / or, The molar volume ratio of compound 18 to solvent 12 is 0.05~0.1:1 mol / L; and / or, The solvent 12 is tetrahydrofuran; and / or, The temperature of reaction 13 is -78~25℃, and the reaction time is 1h~3h.

6. The preparation method according to claim 1, characterized in that, In step S5, the molar ratio of compound 19 to diisobutylaluminum hydride is 1:4.0~5.0; and / or, The molar volume ratio of compound 19 to solvent 13 is 0.001~0.02:1 mol / L; and / or, The solvent 13 is tetrahydrofuran; and / or, The temperature of reaction 14 is 0~50℃, and the reaction time is 0.5h~1h.

7. The preparation method according to claim 1, characterized in that, The preparation method of compound 14 includes the following steps: Containing compound 12 A mixture of tetraphenylphosphine, palladium, o-iodoaniline, potassium carbonate, and toluene, reacted in reaction 9 to give compound 14; and / or, The molar ratio of compound 12, tetra(triphenylphosphine)palladium, o-iodoaniline, and potassium carbonate is 1:(0.1~0.12):(3.3~3.5):(4.0~5.0); and / or, The molar volume ratio of compound 12 to toluene is 0.05~0.1:1 mol / L; and / or, The temperature of reaction 9 is 110~120℃, and the reaction time of reaction 8 is 10~18h.

8. The preparation method according to claim 7, characterized in that, The preparation method of compound 12 includes the following steps: Containing compound 11 A mixture of solvent 8, 2,6-dimethylpyridine, tert-butyldimethylsilyltrifluoromethanesulfonate, p-toluenesulfonylhydrazine, and acetic acid, reacted with reaction 8 to give compound 12; and / or, The solvent 8 is 1,2-dichloroethane; and / or, The molar ratio of compound 11, 2,6-dimethylpyridine, tert-butyldimethylsilyltrifluoromethanesulfonate, and p-toluenesulfonylhydrazine is: 1:(1.6~2.0):(1.5~1.8):(1.5~2.0); and / or, The molar volume ratio of compound 11 to solvent 8 is 0.06~0.1:1 mol / L; and / or, The molar volume ratio of compound 11 to acetic acid is 20-35:1 mol / L; and / or, The temperature of reaction 8 is 0~50℃, and the reaction time is 5min~12h.

9. The preparation method according to claim 8, characterized in that, The preparation method of compound 11 includes the following steps: Containing compound 10 A mixture of solvent 7 and zinc powder is reacted with reaction 7 to obtain compound 11; and / or, The solvent 7 includes isopropanol, tert-butanol, and water, wherein isopropanol:tert-butanol:water = 10 ml:10 ml:0.2 ml; and / or, The molar ratio of compound 10 to zinc powder is 1:10.0~12.0; and / or, The molar volume ratio of compound 10 to solvent 7 is 0.01~0.02:1 mol / L; and / or, The temperature of reaction 7 is 80~95℃, and the reaction time is 2~5h.

10. The preparation method according to claim 9, characterized in that, The preparation method of compound 10 includes the following steps: In a hydrogen atmosphere, compound 9 will be... A mixture of solvent 6, palladium on carbon, triphenylphosphine, imidazole, and elemental iodine, reacted with solvent 6 to give compound 10; and / or, The molar ratio of compound 9, palladium on carbon, triphenylphosphine, imidazole, and elemental iodine is: 1:(0.1~0.15):(2.5~3):(2.5~3):(1.5~2); and / or, The solvent 6 is toluene; and / or, The molar volume ratio of compound 9 to solvent 6 is 0.03~0.05:1 mol / L; and / or, The temperature of reaction 6 is 20~30℃, and the reaction time is 1~2h.

11. The preparation method according to claim 10, characterized in that, The preparation method of compound 9 includes the following steps: Containing compound 8 A mixture of solvent 5 and peroxyacetone, reacted with reaction 5, yields compound 9; and / or, The molar ratio of compound 8 to peroxyacetone is 1:2.5~3.0; and / or, The molar volume ratio of compound 8 to solvent 5 is 0.001~0.05:1 mol / L; and / or, The solvent 5 is dichloromethane; and / or, The temperature of reaction 5 is -78 to -40°C, and the reaction time is 0.2 to 0.5 hours.

12. The preparation method according to claim 11, characterized in that, The preparation method of compound 8 includes the following steps: Containing compound 7 A mixture of solvent 4, 2,6-dimethylpyridine, triisopropylsilyltrifluoromethanesulfonate, and potassium tert-butoxide is reacted with solvent 4 to give compound 8; and / or, Solvent 4 is tetrahydrofuran; and / or, The molar ratio of compound 7, 2,6-dimethylpyridine, triisopropylsilyltrifluoromethanesulfonate, and potassium tert-butoxide is 1:(2.5~3):(1.1~1.2):(1.3~1.5); and / or, The molar volume ratio of compound 7 to solvent 4 is 0.07~0.2:1 mol / L; and / or, The temperature of reaction 4 is 0~25℃, and the reaction time is 0.5~3h.

13. The preparation method according to claim 12, characterized in that, The preparation method of compound 7 includes the following steps: Containing compound 6 A mixture of solvent 3 and sodium borohydride, reacted with reaction 3, yields compound 7; and / or, Solvent 3 is a mixed solvent, consisting of tetrahydrofuran and water, with a volume ratio of tetrahydrofuran to water of 4:1; and / or, The molar volume ratio of compound 6 to solvent 3 is 0.1~0.2:1 mol / L; and / or, The molar ratio of compound 6 to sodium borohydride is 1:1.0~1.5; and / or, The temperature of reaction 3 is 0~25℃, and the reaction time is 0.5~2h.

14. The preparation method according to claim 13, characterized in that, The preparation method of compound 6 includes the following steps: Containing compound 4 Compound 5 A mixture of solvent 2 and potassium carbonate, reacted in reaction 2, yields compound 6; and / or, Solvent 2 is acetone; and / or, The molar ratio of compound 4 to compound 5 is 1:1.1~1.2; and / or, The molar ratio of compound 4 to potassium carbonate is 1:2.5~3.0; and / or, The molar volume ratio of compound 4 to solvent 2 is 0.1~0.2:1 mol / L; and / or, The temperature of reaction 2 is 50~55℃, and the reaction time is 10~12h.

15. The preparation method according to claim 14, characterized in that, The preparation method of compound 4 includes the following steps: The mixture contains 3-bromofuran, solvent 1, lithium diisopropylamino, benzylchloromethyl ether, n-butyllithium, and compound 3. The mixture, after reaction 1, yields compound 4; and / or, Solvent 1 is selected from at least one of diethyl ether and tetrahydrofuran; and / or, The molar ratio of 3-bromofuran, diisopropylaminolithium, benzylchloromethyl ether, and n-butyllithium is 1:(1.1~1.3):(1.1~1.2):(1.2~1.4); and / or, The molar ratio of the 3-bromofuran to compound 3 is 1:1.3~1.5; and / or, The molar volume ratio of the 3-bromofuran to solvent 1 is 0.2~0.3:1 mol / L; and / or, The temperature of reaction 1 is -40 to -60°C, and the reaction time is 2 to 5 hours.

16. A method for synthesizing ervitsine, characterized in that, The method for synthesizing Ervitsine includes the following steps: The product containing compound 20 was prepared by any one of the methods described in claims 1-15, dissolved, and tetrabutylammonium fluoride and manganese dioxide were added. After reaction 15, Ervitsine was obtained. The molar ratio of compound 19 to tetrabutylammonium fluoride is 1:1.2~1.5; and / or, The molar ratio of compound 19 to manganese dioxide is 1:10.0~12.0; and / or, The temperature of reaction 15 is 20~30℃, and the reaction time is 0.5h~1h.

17. A total synthesis method for ervitsine, characterized in that, The synthetic route for the total synthesis of Ervitsine is as follows: 。

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