Intermediate of phainanoids compound and preparation method thereof

Abstract

The invention provides an intermediate of a phainanoids compound and a preparation method thereof, the intermediate has a chemical structure as shown in a formula I. The method comprises the following steps: performing lithium tin exchange on a compound 1, performing nucleophilic addition on the compound 1 and a compound 2 to obtain a compound 3, and performing SNAr substitution reaction on the compound 3 under an alkaline condition to obtain the compound I. According to the method, raw materials are easy to obtain, operation is easy and convenient, industrial amplification is easy, and the intermediate can be used for preparing phainanoids compounds.

Description

Technical Field

[0001] The invention belongs to the field of organic chemistry and specifically relates to an intermediate of a phainanoids compound and a preparation method thereof. Background Art

[0002] Triterpenoid natural products containing tricyclo[4.3.1.0]decane nucleus structure are a special class of tetracyclic triterpenoid compounds. Currently, these compounds are mostly found in plants of dysoxylum, aglaia, meliaceae, dichapetalum, ailanthus and phyllanthus. The main structural difference between them and common tetracyclic triterpenes is that there is a cyclopropane structure in the molecular structure, which constitutes a tricyclo[4.3.1.0]decane system.

[0003] The phainanoids natural products belong to a very complex class of compounds with a tricyclo[4.3.1.0]decane system. Among them, phainanoid F has a very good immunosuppressive activity, with an IC of 1.000 for inhibiting the proliferation activity of T lymphocytes. 50 The value is about 2.04nM; IC for B cells 50 The value is less than 1.6 nM, which is about 221 times that of CsA (cyclosporin A).

[0004] The literature (Org. Lett. 2017, 19 (11), 3017-3020.; J. Am. Chem. Soc. 2021, 143, 19311-19316; Org. Lett. 2024, 26, 8217-8221) discloses the synthesis of pentapteraspirocyclic rings of phainanoids. The literature (Org. Lett. 2017, 19 (11), 3017-3020. J. Am. Chem. Soc. 2021, 143, 19311-19316;) discloses a method for synthesizing phainanoids, which uses palladium-catalyzed olefination as a key strategy to synthesize pentapteraspirocyclic ring fragments. The literature (Org. Lett. 2024, 26, 8217-8221.) discloses a method for synthesizing phananoids, which utilizes the nucleophilic addition of benzyl Grignard reagent to ketone and the intramolecular S N Ar arylation reaction synthesized the five-four spirocyclic fragment.

[0005] As immunosuppressants, phainanoids have very good application prospects in the future, but their structures are complex and their preparation methods are difficult. Considering that the synthesis of the five-four-spirocyclic fragment is also very challenging, the fragment is prepared in the early stage of the synthesis of phainanoids natural products. This may avoid the difficulty in constructing the spirocyclic five-four-structure fragment due to the complexity of the substrate and the increase of functional groups in the later stage of phainanoids synthesis. In addition to the reported synthesis of the five-four-spirocyclic route, the development of other new synthetic routes is also of scientific value and practical significance for exploring the final synthesis of phainanoids. Summary of the invention

[0006] The object of the present invention is to provide an intermediate of a phainanoids compound and a method for preparing the same. The method uses an alkenyl anion formed by exchanging alkenyl tin with butyl lithium to perform nucleophilic addition on a ketone, and then reacts with an intramolecular S N Arylation reaction synthesized the five-four spirocyclic fragment. In addition, the method also used the chiral source reagent verbenone to derive the chiral cyclohexene ring in two steps as the starting material.

[0007] To achieve the purpose of the present invention, the following embodiments are provided.

[0008] In one embodiment, the present invention provides an intermediate of a phainanoids compound, wherein the intermediate is a compound of formula I,

[0009]

[0010] In formula I, R is selected from a hydroxyl group or a hydroxyl protecting group.

[0011] In some embodiments, in the compound of formula I, R is a hydroxyl protecting group selected from formyl, acetyl, trifluoroacetyl, pivaloyl, substituted or unsubstituted benzoyl, p-toluenesulfonyl, methoxy or ethoxy or tert-butyloxy or isobutyloxy or trichloroethoxycarbonyl or fluorenylmethoxycarbonyl, substituted or unsubstituted benzyloxycarbonyl, substituted or unsubstituted silicon, tert-butyl, methyl, allyl, propargyl, benzyl, p-methoxybenzyl, methoxymethyl and methylthiomethyl.

[0012] Preferably, in the intermediate of the present invention, the compound represented by formula I, the hydroxyl protecting group R is benzyl.

[0013] In another embodiment, a method for preparing a compound of formula I is provided, comprising the following steps:

[0014]

[0015] In formula I, R is a hydroxyl group or a hydroxyl protecting group,

[0016] 1) exchanging compound 1 with lithium tin and subjecting it to nucleophilic addition with compound 2 to obtain compound 3;

[0017] 2) Compound 3 is subjected to SNAr2 reaction under alkaline conditions to obtain compound I,

[0018]

[0019] The definition of R in Formula 2 and Formula 3 is the same as that in Formula 1.

[0020] Preferably, in the above method of the present invention, the hydroxyl protecting group is selected from formyl, acetyl, trifluoroacetyl, pivaloyl, substituted or unsubstituted benzoyl, p-toluenesulfonyl, methoxy or ethoxy or tert-butyloxy or isobutyloxy or trichloroethoxycarbonyl or fluorenylmethoxycarbonyl, substituted or unsubstituted benzyloxycarbonyl, substituted or unsubstituted silicon, tert-butyl, methyl, allyl, propargyl, benzyl, p-methoxybenzyl, methoxymethyl and methylthiomethyl, more preferably benzyl.

[0021] Preferably, in the above method of the present invention, the base is selected from one or more of potassium tert-butoxide, sodium tert-butoxide, potassium carbonate, sodium carbonate, potassium hydroxide, sodium hydroxide, methyl lithium, methyl magnesium chloride, methyl magnesium bromide, ethyl magnesium chloride, ethyl magnesium bromide, n-propyl magnesium chloride, n-propyl magnesium bromide, isopropyl magnesium chloride, isopropyl magnesium bromide, n-butyl lithium, sec-butyl lithium, tert-butyl lithium and 1,8-diazacyclo[5,4,0]undecene-7.

[0022] In some embodiments, the present invention provides a method for preparing a compound of formula I, wherein compound 2 is prepared by the following method, which comprises the following steps:

[0023] (1) converting compound 4 into compound 5, comprising dissolving compound 4 in an organic solvent, reacting with sodium borohydride in the presence of potassium carbonate to convert the compound 4 into compound 5, preferably, the organic solvent contains methanol;

[0024] (2) converting compound 5 into compound 6, comprising dissolving compound 5 in an organic solvent, adding sodium hydride, tetrabutylammonium iodide, and benzyl bromide under argon protection, and heating to obtain compound 6, wherein R is benzyl, and preferably, the organic solvent is tetrahydrofuran;

[0025] (3) converting compound 6 into compound 7 comprises dissolving compound 6 in an organic solvent, adding trichloroacetyl chloride, methanol and ammonium chloride under argon protection, and reacting to obtain compound 7, preferably, the organic solvent is diethyl ether;

[0026] (4) converting compound 7 into compound 8, comprising dissolving compound 7 in an organic solvent, adding ethylene glycol and p-toluenesulfonic acid, and reacting to obtain compound 8, preferably, the organic solvent is benzene;

[0027] (5) converting compound 8 into compound 9, comprising dissolving compound 8 in an organic solvent, adding a borane tetrahydrofuran solution, adding a sodium hydroxide aqueous solution and hydrogen peroxide under ice-water cooling, extracting with ethyl acetate and spinning dryness, dissolving in acetone and water, and adding p-toluenesulfonic acid to react to obtain compound 9, preferably, the organic solvent comprises tetrahydrofuran;

[0028] (6) converting compound 9 into compound 10, comprising dissolving compound 9 in an organic solvent, adding triphenylphosphine and carbon tetrabromide, and reacting to obtain compound 9, preferably, the organic solvent comprises dichloromethane;

[0029] (7) converting compound 10 into compound 11, comprising dissolving compound 10 in an organic solvent, adding potassium tert-butoxide under ice-water cooling to react to obtain compound 11, preferably, the organic solvent is a mixture of tetrahydrofuran and tert-butanol;

[0030] (8) converting compound 11 into compound 2, comprising dissolving compound 11 in an organic solvent, cooling under argon gas, adding triethylamine and trimethylsilyl trifluoromethanesulfonate, adding phenylselenium bromide after the raw materials disappear, and then adding hydrogen peroxide to obtain compound 2, preferably, the organic solvent comprises tetrahydrofuran

[0031]

[0032] In formula 6-11, the definition of R is the same as that of formula I, and preferably R is benzyl.

[0033] In a specific embodiment, the preparation of compound 2 comprises the following steps:

[0034] (1) dissolving compound 4 in an organic solvent, stirring at room temperature, adding potassium carbonate, cooling in an ice-water bath after the raw material disappears, and adding sodium borohydride to obtain compound 5, preferably, the organic solvent comprises methanol;

[0035] (2) dissolving compound 5 in an organic solvent, preferably, R is benzyl, stirring at room temperature, adding sodium hydride, tetrabutylammonium iodide, benzyl bromide under argon protection, and then heating to obtain compound 6;

[0036] Preferably, the organic solvent comprises tetrahydrofuran;

[0037] (3) Compound 6 was dissolved in an organic solvent, heated and stirred, and trichloroacetyl chloride was added under argon protection. After the starting material disappeared, methanol and ammonium chloride were added to obtain compound 7;

[0038] Preferably, the organic solvent comprises diethyl ether;

[0039] (4) dissolving compound 7 in an organic solvent, adding ethylene glycol and p-toluenesulfonic acid, heating and stirring to obtain compound 8;

[0040] Preferably, the organic solvent comprises benzene;

[0041] (5) Compound 8 was dissolved in an organic solvent, and a borane tetrahydrofuran solution was added under ice-water cooling, and then the temperature was raised to room temperature with stirring. After the raw material disappeared, the mixture was cooled under ice-water cooling, and a sodium hydroxide aqueous solution and hydrogen peroxide were added. The mixture was extracted with ethyl acetate and dried by spin drying, and then dissolved in acetone and water. p-Toluenesulfonic acid was added and heated to obtain compound 9;

[0042] Preferably, the organic solvent comprises tetrahydrofuran;

[0043] (6) dissolving compound 9 in an organic solvent, adding triphenylphosphine and carbon tetrabromide at room temperature to obtain compound 9, preferably, the organic solvent comprises dichloromethane;

[0044] (7) Compound 10 was dissolved in an organic solvent, and potassium tert-butoxide was added under ice-water cooling to obtain compound 11;

[0045] Preferably, the organic solvent comprises a mixture of tetrahydrofuran and tert-butyl alcohol;

[0046] (8) Compound 11 was dissolved in an organic solvent, cooled in an ice-water bath under argon protection, triethylamine and trimethylsilyl trifluoromethanesulfonate were added, and after the starting material disappeared, phenylselenium bromide was added, followed by hydrogen peroxide to obtain compound 2;

[0047] Preferably, the organic solvent comprises tetrahydrofuran.

[0048] Beneficial effects of the present invention: The method of the present invention provides an efficient and convenient chemical synthesis method for the five-four-spirocyclic fragment of phainanoids compounds, with easy-to-obtain raw materials, simple operation, easy scale-up and convenient implementation. BRIEF DESCRIPTION OF THE DRAWINGS

[0049] Figure 1 is the hydrogen spectrum of compound 5;

[0050] Figure 2 is the carbon spectrum of compound 5;

[0051] Figure 3 is the hydrogen spectrum of compound 6 (R is benzyl);

[0052] Figure 4 is the carbon spectrum of compound 6;

[0053] Figure 5 is the hydrogen spectrum of compound 7;

[0054] Figure 6 is the carbon spectrum of compound 7;

[0055] Figure 7 is the hydrogen spectrum of compound 8;

[0056] Figure 8 is the carbon spectrum of compound 8;

[0057] Fig. 9 is the hydrogen spectrum of compound 9;

[0058] Fig.10 is the carbon spectrum of compound 9;

[0059] Fig.11 is the hydrogen spectrum of compound 2;

[0060] Fig.12 is the carbon spectrum of compound 2;

[0061] Fig.13 is the hydrogen spectrum of compound 3;

[0062] Fig.14 is the carbon spectrum of compound 3;

[0063] Fig.15 is the hydrogen spectrum of compound I;

[0064] Fig.16 is the carbon spectrum of compound I. DETAILED DESCRIPTION

[0065] In order to enable those skilled in the art to more clearly understand the technical solution of the present invention, the technical solution of the present invention will be described in detail below in conjunction with specific embodiments.

[0066] Example 1 Preparation of Compound 2

[0067] 1.1 The synthetic route of compound 2 (R is preferably benzyl) is as follows:

[0068]

[0069] In formula 2 and 6-11, R is benzyl.

[0070] 1.2 Synthesis of compound 5:

[0071] Compound 4 (4.16 g, 18.888 mmol) was dissolved in methanol (30 mL), potassium carbonate (7.76 g, 56.110 mmol) was added at room temperature, and the reaction was continued to be stirred at room temperature until the raw material disappeared completely by TLC (about 10 min), the reaction bottle was transferred to an ice-water bath for cooling, sodium borohydride (2.12 g, 56.110 mmol) was weighed and added to the reaction bottle in batches, and the reaction was continued to be stirred in an ice-water bath until the raw material disappeared completely by TLC (about 30 min), and saturated ammonium chloride solution (10 mL) was added to quench; ethyl acetate (30 mL × 3) was used for extraction, the organic phases were combined and dried over anhydrous sodium sulfate, filtered, and chromatographed on a freshly filled silica gel column (petroleum ether / ethyl acetate = 3:1) to obtain a light yellow oily compound 4 (2.80 g, 82%). 1 H NMR (400MHz, CDCl3) δ5.84-5.70(m,1H),4.93(s,1H),4.89(dd,J=6.7,1.1Hz,1H),4.85-4.80(m,1H),4.67(d,J=1.1Hz,1H),4.10(p, J=4.0Hz,1H),2.02-1.90(m,2H),1.85-1.77(m,1H),1.74(dd,J=1.2,0.7Hz,3H),1.67-1.53(m,3H),1.50-1.40(m,1H),1.17(s,3H). 13 C NMR (101MHz, CDCl3) δ150.45,147.69,112.62,110.44,67.19,52.03,44.92,40.09,33.15,25.10,22.86,21.05.

[0072] 1.3 Synthesis of compound 6:

[0073] Under argon protection, sodium hydride (133.2 mg, 3.329 mmol) and TBAI (82.0 mg, 0.222 mmol) were weighed into a reaction flask, and dry tetrahydrofuran (3 mL) was added under ice-water bath. Compound 5 (200.0 mg, 1.110 mmol) was dissolved in dry tetrahydrofuran (2 mL) and added dropwise to the reaction system. Benzyl bromide (0.2 mL, 1.665 mmol) was added 10 minutes after the addition. The mixture was heated to 50 °C and stirred in an oil bath until the raw material disappeared completely by TLC detection (about 2 h). Saturated ammonium chloride solution (5 mL) was added under ice-water bath to quench the mixture; the mixture was extracted with ethyl acetate (20 mL × 3), the organic phases were combined and dried over anhydrous sodium sulfate, filtered, and chromatographed on a freshly filled silica gel column (petroleum ether / ethyl acetate = 30:1) to obtain compound 6 (322.0 mg, 100%) as a colorless oil. 1HNMR (400MHz, CDCl3) δ7.39-7.16(m,5H),5.87-5.71(m,1H),4.92(dd,J=3.0,1.2Hz,1H),4. 88(dd,J=4.2,1.2Hz,1H), 4.83(dq,J=3.0,1.4Hz,1H), 4.65(d,J=1.3Hz,1H), 4.54(d,J=12. 0Hz,1H),4.46(d,J=12.0Hz,1H),3.71(p,J=3.5Hz,1H),2.05-1.92(m,3H),1.80(ddd,J=14. 4,3.7,2.0Hz,1H),1.73(d,J=0.5Hz,3H),1.56-1.45(m,2H),1.45-1.36(m,1H),1.19(s,3H). 13 C NMR (101MHz, CDCl3) δ150.82,147.77,139.44,128.43,127.38,127.35,112. 52,110.19,73.81,70.17,52.65,41.18,40.28,30.72,24.97,23.25,19.79.

[0074] 1.4 Synthesis of compound 7:

[0075] Under argon protection, zinc copper couple (758.7 mg, 11.604 mmol) was weighed, compound 6 (1.05 g, 3.868 mmol) and dry ether (15 mL) were added, and a mixed solution of trichloroacetyl chloride (0.65 mL, 5.803 mmol) in ether (5 mL) was added dropwise at 40°C reflux condition, and the reaction was carried out for 4 hours. After that, silica gel was padded and filtered, the mixture was spin-dried, and dissolved in methanol (30 mL). Solid ammonium chloride (620.7 mg, 11.604 mmol) was added at room temperature, and zinc powder (1.264 g, 19.340 mmol) was added in batches. Exotherm was obvious. After the addition was completed, the mixture was stirred overnight in an oil bath at 50°C, filtered, and spin-dried. After column chromatography on a freshly filled silica gel column (petroleum ether / ethyl acetate = 10:1), a colorless oily compound 7 (596.4 mg, 50%) was obtained. 1H NMR (400MHz, CDCl3) δ7.40-7.22(m,5H),5.85(dd,J=17.5,10.7Hz,1H),4.95(ddd,J=14.1,11.7,0 .9Hz,2H),4.54(d,J=12.0Hz,1H),4.46(d,J=12.0Hz,1H),3.71(p,J=3.4Hz,1H),3.14(d,J=17.1H z,1H),2.94(s,1H),2.66-2.52(m,1H),2.50-2.41(m,1H),2.12-2.00(m,1H),1.98-1.86(m,1H),1 .70-1.59(m,2H),1.58-1.45(m,2H),1.41(ddt,J=14.5,7.3,3.6Hz,1H),1.35(s,3H),1.26(s,3H). 13 CNMR(101MHz,CDCl3)δ208.91,151.40,139.28,128.45,127.41,127.34,110.57 ,73.73,70.25,61.47,59.61,54.96,44.05,41.97,33.97,31.30,24.72,20.48.

[0076] 1.5 Synthesis of compound 8:

[0077] Compound 7 (551.2 mg, 1.764 mmol) was dissolved in benzene (10 mL), ethylene glycol (1 mL) and p-toluenesulfonic acid monohydrate (33.6 mg, 0.176 mmol) were added at room temperature, and the mixture was refluxed and stirred at 90°C until the raw material disappeared completely according to TLC detection (about 2 h). After cooling to room temperature, a saturated sodium bicarbonate solution (5 mL) was added to quench the mixture; the mixture was extracted with ethyl acetate (20 mL × 3), and the organic phases were combined and dried over anhydrous sodium sulfate, filtered, and spin-dried; the mixture was chromatographed on a freshly filled silica gel column (petroleum ether / ethyl acetate = 10:1) to obtain a colorless oily compound 8 (510.7 mg, 81%). 1HNMR (400MHz, CDCl3) δ7.39-7.21(m,5H),5.85(dd,J=17.5,10.7Hz,1H),4.89(ddd,J=14.1,11.9,1 .1Hz,2H),4.53(d,J=12.0Hz,1H),4.45(d,J=12.0Hz,1H),3.93-3.84(m,2H),3.82-3.76(m,2H),3. 69-3.63(m,1H),2.43(d,J=12.9Hz,1H),2.20-2.12(m,1H),2.05-1.88(m,3H),1.84-1.72(m,1H),1 .62(ddd,J=14.3,4.0,2.1Hz,1H),1.55-1.39(m,3H),1.35-1.30(m,1H),1.28(s,3H),1.26(s,3H). 13 C NMR (101MHz, CDCl3) δ151.68,139.45,128.42,127.36,127.34,109.71,105.80,74.09,70 .15,63.77,63.56,55.71,50.16,49.08,43.83,41.91,33.65,31.35,23.87,21.08,19.56.

[0078] 1.6 Synthesis of compound 9:

[0079] Under argon protection, compound 8 (510.7 mg, 1.433 mmol) was dissolved in dry tetrahydrofuran (14 mL), cooled in an ice-water bath, and then borane tetrahydrofuran (1 mol / L, 2.2 mL) was added dropwise. After the addition, the mixture was heated to room temperature and stirred overnight. Sodium hydroxide solution (4 mol / L, 1.0 mL) and hydrogen peroxide (50%, 1.0 mL) were carefully added in an ice-water bath, and the mixture was stirred for two hours in an ice-water bath. A saturated sodium thiosulfate solution (10 mL) was added dropwise to quench the mixture. The mixture was extracted with ethyl acetate (50 mL × 3), and the organic phases were combined and washed with anhydrous sulfuric acid. The mixture was dried over sodium sulfate, filtered and spin-dried, redissolved in acetone (10 mL) and water (5 mL), and p-toluenesulfonic acid (29.1 mg, 0.152 mmol) was added at room temperature. After the addition, the temperature was raised to 50 ° C and stirred to react until the raw material disappeared completely by TLC detection (about 4 h), and saturated sodium bicarbonate solution (10 mL) was added under ice-water bath to quench; extracted with ethyl acetate (20 mL × 3), the organic phases were combined and dried over anhydrous sodium sulfate, filtered and spin-dried, and then chromatographed on a silica gel column filled with petroleum ether / ethyl acetate = 2:1 to obtain compound 9 (249.5 mg, 99%) as a colorless oil. 1HNMR (400MHz, CDCl3) δ7.42-7.22(m,5H),4.51(s,2H),3.82-3.63(m,3H),3.13-2.97(m,1H),2.84(dd,J=11.5,6.5Hz,1H) ,2.73-2.57(m,2H),1.95-1.83(m,2H),1.81-1.74(m,1H),1.71-1.61(m,3H),1.56-1.42(m,3H),1.30(s,3H),1.21(s,3H). 13 C NMR (101MHz, CDCl3) δ208.35,139.24,128.47,127.47,127.38,74.13,70.29,62. 45,60.64,59.28,54.68,46.72,42.38,38.76,34.23,30.96,24.21,23.75,21.61.

[0080] 1.7 Synthesis of compound 10:

[0081] Compound 9 (249.5 mg, 0.755 mmol) was dissolved in dry dichloromethane (8 mL), and carbon tetrabromide (300.5 mg, 0.906 mmol) was added under an ice-water bath, and then triphenylphosphine (297.0 mg, 1.132) was added. After the addition, the temperature was raised to room temperature and stirred to react until the raw material disappeared completely according to TLC detection (about 1 h). The reaction solution was directly spin-dried and chromatographed on a freshly filled silica gel column (petroleum ether / ethyl acetate = 10:1) to obtain a colorless oily compound 10 (251.2 mg, 85%).

[0082] 1.8 Synthesis of compound 11:

[0083] Compound 10 (300.0 mg, 0.763 mmol) was dissolved in dry tetrahydrofuran (16 mL) and tert-butanol (2 mL), cooled in an ice-water bath, and potassium tert-butoxide (171.2 mg, 1.525 mmol) was weighed. After the addition, the reaction was continued to stir in an ice-water bath until the raw material disappeared completely according to TLC detection (about 0.5 h), and saturated ammonium chloride solution (5 mL) was added in an ice-water bath to quench; extracted with ethyl acetate (20 mL×3), the organic phases were combined and dried over anhydrous sodium sulfate, filtered, and spin-dried, and then chromatographed on a freshly filled silica gel column (petroleum ether / ethyl acetate=12:1) to obtain a colorless oily compound 11 (156.1 mg, 65%). 1HNMR (400MHz, CDCl3) δ7.41-7.20(m,5H),4.60-4.35(m,2H),3.71(ddd,J=14.7,5.7,2.9Hz,1H),3.18-3.00(m,1H),2.90-2.79(m,1H ),2.74-2.39(m,1H),2.14(ddd,J=16.5,9.3,6.7Hz,1H),1.91-1.71(m,3H),1.70-1.51(m,2H),1.50-1.23(m,6H),1.23-1.02(m,5H). 13 C NMR (101MHz, CDCl3) δ214.42,209.55,139.45,139.37,128.44,128.42,127.37,127.34,74.55,74.40,70.27,70.21,63.85,61.43,60.90 ,53.33,51.18,50.90,45.32,44.74,39.04,38.21,33.77,33.12,32.28,31.82,31.40,31.07,24.26,19.02,18.70,18.61,18.04,16.68.

[0084] 1.9 Synthesis of Compound 2:

[0085] Compound 11 (17.2 mg, 0.057 mmol) was dissolved in dry tetrahydrofuran (1.5 mL) under argon protection, cooled in an ice-water bath, triethylamine (79 μL, 0.57 mmol) was added dropwise, and then TMSOTf (52 μL, 0.285 mmol) was added. After the addition, the reaction was continued to stir in an ice-water bath until the raw material disappeared completely by TLC detection (about 1 h), and then a solution of phenylselenium bromide (24.5 mg, 0.104 mmol) in dry tetrahydrofuran (0.5 mL) was added dropwise. After the addition, TLC detection showed that the raw material was completely reacted. A saturated sodium bicarbonate solution (2 mL) was added in an ice-water bath to quench; extraction with ethyl acetate (20 mL×3) was performed. , the organic phases were combined and dried over anhydrous sodium sulfate, filtered and dried by suction, and then chromatographed on a silica gel column (petroleum ether / ethyl acetate = 15:1). The product of the previous step was dissolved in tetrahydrofuran (2 mL), cooled in an ice-water bath, and hydrogen peroxide (50%, 0.1 mL) was added dropwise. After the addition, the mixture was stirred and reacted for 0.5 hours in an ice-water bath, and then heated to room temperature and stirred and reacted for 10 minutes. A saturated sodium thiosulfate solution (2 mL) was carefully added in an ice-water bath to quench; extracted with ethyl acetate (20 mL × 3), the organic phases were combined and dried over anhydrous sodium sulfate, filtered and dried by suction, and then chromatographed on a silica gel column (petroleum ether / ethyl acetate = 15:1) to obtain a colorless oily compound 2 (9.1 mg, 51%).1 H NMR (400MHz, CDCl3) δ7.38-7.27(m,5H),6.19-6.11(m,1H),4.60-4.47(m,2H),3.70-3.60(m, 1H),2.67(d,J=15.1Hz,1H),2.26(s,1H),2.19(ddd,J=15.1,1.8,1.0Hz,1H),2.02(dd,J=15.1 ,8.2Hz,1H),1.97-1.90(m,1H),1.84(dd,J=15.0,3.0Hz,1H),1.78-1.70(m,1H),1.55(t,J=6. 1Hz,1H),1.39-1.34(m,1H),1.33(d,J=4.1Hz,3H),1.27(dd,J=18.3,7.4Hz,2H),0.75(s,3H). 13 C NMR (101MHz, CDCl3) δ197.51,154.09,139.04,128.52,127.67,123.12,74.15, 70.39,50.75,50.43,47.08,40.57,40.29,39.66,33.13,28.47,21.28,17.87.

[0086] Example 2 Preparation of Compound I

[0087] 2.1 The synthetic route of compound I is as follows:

[0088]

[0089] In the formula, R is benzyl.

[0090] 2.2 Synthesis of compound 3:

[0091] Under argon protection, compound 1 (52.6 mg, 0.128 mmol) was dissolved in dry tetrahydrofuran (2 mL), the reaction bottle was cooled at -78 ° C, and then n-butyl lithium (39 μL, 0.097 mmol) was added dropwise. After the addition, the mixture was stirred at -78 ° C for 0.5 h. Compound 2 (10.0 mg, 0.032 mmol) was dissolved in dry tetrahydrofuran (0.6 mL) and added dropwise to the reaction system. The reaction was stirred at this temperature until the raw material disappeared completely by TLC detection (about 1 h), and a saturated ammonium chloride solution (2 mL) was added to quench the mixture; ethyl acetate (20 mL × 3) was used for extraction, the organic phases were combined and dried over anhydrous sodium sulfate, filtered, and spin-dried, and then chromatographed on a silica gel column filled with petroleum ether / ethyl acetate = 10:1 to obtain a colorless oily compound 3 (7.1 mg, 51%). 1HNMR(400MHz, CDCl3)δ7.51(td,J=7.6,1.7Hz,1H),7.35-7.30(m,5H),7.29-7.26(m,1H),7.25-7.22(m,1H),7.12 (dd,J=7.5,1.2Hz,1H),5.81(dd,J=10.1,3.8Hz,2H),5.52(t,J=1.3Hz,1H),4.54(s,2H),3.70-3.59(m,1H),2.46( d,J=3.5Hz,1H),2.24-2.16(m,1H),1.93(s,2H),1.89(ddd,J=12.2,4.4,1.8Hz,1H),1.82(d,J=6.2Hz,2H),1.78-1 .63(m,1H),1.51(dd,J=7.2,5.0Hz,1H),1.30(dd,J=6.3,3.4Hz,1H),1.26-1.23(m,1H),1.21(s,3H),0.88(s,3H). 13 C NMR(101MHz,CDCl3)δ160.1(d,J F =245.8Hz),151.8,145.3,139.3,131.2(d,J F =3.6Hz),129.1(d,J F =8.5Hz),128.5,127.7,127.5,123.9(d,J F =3.4Hz),121.3(d,J F =3.8Hz),117.2,115.9(d,J F =23.8Hz),84.3,74.6,70.3,52.4,47.4,42.8,42.7,39.9,38.9,33.3,27.4,20.2,17.8.

[0092] 2.3 Synthesis of Compound I:

[0093] Under argon protection, compound 3 (22.5 mg, 0.052 mmol), potassium tert-butoxide (17.5 mg, 0.156 mmol) and 18-crown-6 (41.2 mg, 0.156 mmol) were weighed and dissolved in dry tetrahydrofuran (2 mL), and then stirred in an oil bath at 60 ° C for overnight reaction, and saturated ammonium chloride solution (2 mL) was added to quench; ethyl acetate (20 mL × 3) was used for extraction, and the organic phases were combined and dried over anhydrous sodium sulfate, filtered, and spin-dried. After column chromatography on a freshly filled silica gel column (petroleum ether / ethyl acetate = 15:1), a colorless oily compound I (12.9 mg, 60%) was obtained. 1HNMR(400MHz, CDCl3)δ7.37-7.34(m,5H),7.30-7.27(m,1H),7.22-7.17(m,1H),6.90(dd, J=7.5,0.8Hz,1H),6.80(d,J=8.0Hz,1H),5.88(dd,J=8.1,4.7Hz,1H),5.51(s,1H),5.43( s,1H),4.60(t,J=12.2Hz,1H),4.56(s,2H),2.38(d,J=11.4Hz,1H),2.32-2.15(m,3H),2. 06(d,J=11.4Hz,1H),1.96-1.77(m,5H),1.49(s,3H),1.31(d,J=1.9Hz,1H),0.98(s,3H).

[0094] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions and improvements made within the spirit and principles of the present invention should be included in the protection scope of the present invention.

Claims

1. An intermediate of a phainanoids compound, which is a compound of formula I, In formula I, R is selected from a hydroxyl group or a hydroxyl protecting group.

2. A method for preparing a compound of formula I, comprising the following steps: In formula I, R is a hydroxyl group or a hydroxyl protecting group, 1) exchanging compound 1 with lithium tin and reacting with compound 2 to produce compound 3; 2) Compound 3 is subjected to SNAr2 reaction under alkaline conditions to obtain compound I, The definition of R in Formula 2 and Formula 3 is the same as that in Formula 1.

3. The method of claim 2, wherein the hydroxy protecting group is selected from formyl, acetyl, trifluoroacetyl, pivaloyl, substituted or unsubstituted benzoyl, p-toluenesulfonyl, methoxy or ethoxy or tert-butyloxy or isobutyloxy or trichloroethoxycarbonyl or fluorenylmethoxycarbonyl, substituted or unsubstituted benzyloxycarbonyl, substituted or unsubstituted silicon, tert-butyl, methyl, allyl, propargyl, benzyl, p-methoxybenzyl, methoxymethyl and methylthiomethyl. The method according to claim 3 , wherein the hydroxy protecting group is benzyl or p-methoxybenzyl.

5. The method of claim 2, wherein the alkali is selected from one or more of potassium tert-butoxide, sodium tert-butoxide, potassium carbonate, sodium carbonate, potassium hydroxide, sodium hydroxide, methyl lithium, methyl magnesium chloride, methyl magnesium bromide, ethyl magnesium chloride, ethyl magnesium bromide, n-propyl magnesium chloride, n-propyl magnesium bromide, isopropyl magnesium chloride, isopropyl magnesium bromide, n-butyl lithium, sec-butyl lithium, tert-butyl lithium and 1,8-diazacyclo[5,4,0]undecene-7.

6. The method of claim 5, wherein the base is selected from potassium tert-butoxide, sodium tert-butoxide, potassium carbonate or sodium carbonate.

7. The method according to claim 2, wherein the compound 2 is prepared by the following method, which comprises the following steps: (1) converting compound 4 into compound 5; (2) converting compound 5 into compound 6; (3) converting compound 6 into compound 7; (4) converting compound 7 into compound 8; (5) converting compound 8 into compound 9; (6) converting compound 9 into compound 10; (7) converting compound 10 into compound 11; (8) converting compound 11 into compound 2, In formula 6-11, the definition of R is the same as that of formula I.

8. The method of claim 7, comprising: (1) Compound 4 is dissolved in an organic solvent and reacted with sodium borohydride in the presence of potassium carbonate to convert into compound 5; (2) Compound 5 is dissolved in an organic solvent, sodium hydride, tetrabutylammonium iodide and benzyl bromide are added under argon protection, and heated to obtain compound 6, wherein: R is benzyl; (3) Compound 6 is dissolved in an organic solvent, and trichloroacetyl chloride, methanol and ammonium chloride are added under argon protection to react to obtain compound 7; (4) dissolving compound 7 in an organic solvent, adding ethylene glycol and p-toluenesulfonic acid, and reacting to obtain compound 8; (5) Compound 8 was dissolved in an organic solvent, a borane tetrahydrofuran solution was added, and an aqueous sodium hydroxide solution and hydrogen peroxide were added under ice-water cooling. The mixture was extracted with ethyl acetate and then spin-dried. The mixture was dissolved in acetone and water, and p-toluenesulfonic acid was added to react to obtain compound 9; (6) dissolving compound 9 in an organic solvent, adding triphenylphosphine and carbon tetrabromide, and reacting to obtain compound 9; (7) Compound 10 was dissolved in an organic solvent, and potassium tert-butoxide was added under ice-water cooling to obtain compound 11; (8) Compound 11 was dissolved in an organic solvent, and triethylamine and trimethylsilyl trifluoromethanesulfonate were added under argon protection and ice-water bath cooling. After the starting materials disappeared, phenylselenium bromide was added, and then hydrogen peroxide was added to obtain compound 2.

9. The method according to claim 8, wherein the organic solvent in step (1) contains methanol; the organic solvent in step (2) is tetrahydrofuran; the organic solvent in step (3) is ether; the organic solvent in step (4) is benzene; the organic solvent in step (5) includes tetrahydrofuran; the organic solvent in step (6) includes dichloromethane; the organic solvent in step (7) is a mixture of tetrahydrofuran and tert-butyl alcohol; the organic solvent in step (8) includes tetrahydrofuran.

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