WO2017080292A1

WO2017080292A1 - Trifluoromethyl-modified (+)-patulolide c and preparation method thereof

Info

Publication number: WO2017080292A1
Application number: PCT/CN2016/098188
Authority: WO
Inventors: 徐军; 蒋信义; 肖方亮; 周宇; 张敏华
Original assignee: 雅本化学股份有限公司
Priority date: 2015-11-13
Filing date: 2016-09-06
Publication date: 2017-05-18
Also published as: CN105218508A; CN105218508B

Abstract

A trifluoromethyl-modified (+)-Patulolide C. By adding a trifluoromethyl group to (+)-Patulolide C, it is expected that favorable antibacterial and anti-inflammatory activity can be obtained.

Description

FIELD OF THE INVENTION The present invention relates to a trifluoromethyl modified compound, and more particularly to a trifluoromethyl modified (+) -Patulolide C and its manufacturing method. BACKGROUND OF THE INVENTION The history of organofluorine chemistry dates back to the end of the 19th century. In 1886, H. Moissan first synthesized elemental fluorine by electrolysis, which truly opened the door to fluorine chemistry. In 1896, F. Swarts et al. synthesized ethyl fluoroacetate, which opened the curtain for the study of organofluorine chemistry. Since then, organic fluorine chemistry has made great progress, and has penetrated into many disciplines such as medical science, life science, and materials science, and has received increasing attention and application in many fields such as industry, medicine, and aerospace.

Research on fluorine-containing physiologically active substances began in 1954. At that time, J. Fried et al found that 9«-fluoroacetic acid cortisone was the corresponding glucocorticoid as the glucocorticoid, and its anti-inflammatory activity was 10-12 times higher. The first time to show the introduction of fluorine atoms into the An important role in organic molecules for improving their physiological activity. In 1957, the synthesis of 5-fluorouracil created a new situation in the history of cancer treatment, allowing people to once again appreciate the unique charm of fluorine atoms in drug design. Nowadays, many organic chemists and pharmacologists have invested in the corresponding work, and a large number of physiologically active fluorine-containing organic compounds have been synthesized. According to a recent statistic, only one to three fluorochemicals were marketed each year before the 1980s. However, since the 1973 selective fluorination reagent DAST (Diethylamino)sulfur trifluoride, after 1982, The number of listed fluorochemicals increased significantly (see Figure 1).

Fludrocortisone acetate

In 2006, the American Chemical Society's Chemical & Engineering News introduced the application of fluorine in medical science in the form of Cover Story. The article pointed out that 30-40% of the currently listed pesticides contain fluorine, while fluorine-containing drugs account for 20% of the listed drugs. In 2007, Science published a review of fluorinated drugs by analyzing the effects of crystal structure and protein structure of fluorochemicals from two databases, Cambridge Structural Database and The Protein Data Bank. The effect of fluorine atoms on biological activity.

In 2008, Professor JT Njardarson of Cornell University in the United States summarized the top 200 drugs in the world in that year, of which 33 were fluorine-containing drugs, accounting for 16.5%. Among the top 50 drugs in the sales volume, fluorine-containing drugs accounted for 1/5. The first place was occupied by LIPITOR (Lipitor), a fluorine-containing drug for the treatment of hyperlipemia and hypercholesterolemia in the United States. Its sales volume was US$13.6 billion, which was higher than that of the second American Squibb company. The drug PLAVIX (; Bao Shutong, $ 8.6 billion) was 58% more (see Table 1 below).

Table 1. Fluorine-containing drugs in the top 50 drugs in global sales in 2008 *

* According to the original data of the JT Njardarson group of the University of Cornell, a large number of facts show that the selective introduction of fluorine atoms or fluorine-containing groups into organic molecules can significantly change the physiological activity of the original molecules, so the fluorine-containing compounds in the field of medicine More and more widely used, mainly due to the unique properties below the fluorine atom:

1. The van der Waals radius of the fluorine atom and the hydrogen atom is very close (r _F = 1.47 A, r _H = 1.20 A), so that the fluorine atom replaces the hydrogen atom in the molecule, and the volume of the whole molecule does not change much, so it is not easily affected by the living body. Recognized by the enzyme receptor, it can smoothly replace the metabolic process of the non-fluorine matrix into the organism, that is, the so-called "pseudo-effect".

2. In addition to the replacement of a hydrogen atom by fluorine, other atoms and functional groups in the organic active molecule can also be modeled by a fluorine atom or a fluorine-containing group. This is the so-called "biological allotment" principle. It can be geometrically simulated for another functional group, as well as the polarity and static charge distribution of the parent molecule. In general, the structure of a biological target molecule does not distinguish between the same genus and the biological allele. For example, the radius of the fluorine atom is very close to that of the hydroxyl group, so the fluorine atom is often used to simulate the hydroxyl group and exhibits a "pseudo-effect". In another example, difluoromethylene is an isopolar and isosteric: of ether oxygen, which can replace oxygen atoms in many cases and exhibit important physiological properties. One famous example is the phosphate ester. The oxygen atom is replaced by a difluoromethylene group, and the modified molecule not only maintains the biological activity of the original phosphate ester, but also greatly enhances its stability, thereby exerting a more effective effect.

3. The electronegativity of fluorine atoms is the most embarrassing of all atoms (C: 2.6, H: 2.2, F: 4.0). Microscopically, the electron cloud distribution will shift after the introduction of fluorine atoms into the molecule, which will affect the electronic properties, dipole moment and acidity and alkalinity of the molecule, and the reactivity of the ortho group will also change. This macroscopically shows that many fluorine-containing organic compounds tend to have great changes in both chemical and physical properties compared with corresponding non-fluorine compounds. From a physiological point of view, it is in the process of metabolism that the fluorine-containing substrate binds to the receptor in a different way than the non-fluorinated parent, resulting in different biochemical reactions, triggering different metabolic processes and making the receptor irreversibly inactivated. This is the basis for many fluoropharmaceutical designs.

4, many drugs due to metabolic degradation rate is too fast, not only reduces the efficacy, but also increases the burden of liver and kidney, limiting its clinical application. Some drugs produce substances that are toxic or can induce mutations in the organism during metabolism, and cannot be applied to the clinic at all. The carbon-fluorine bond has a high bond energy (CF: 115.7 kcal/mol; CH: 98.0 kcal/mol), and the fluorine atom is difficult to leave as a positive ion or a free radical, so it cannot be broken by a carbon-hydrogen bond. Way to break the carbon-fluorine bond. Therefore, the introduction of a fluorine atom in a specific part of the substrate can selectively block some metabolic pathways that we do not want.

5. The introduction of a fluorine atom into an organic molecule often increases the lipophilicity of the molecule, which enhances the penetration of the fluorine-containing compound into the membrane and the tissue, thereby increasing the absorption and transport speed of the fluorine-containing compound in the living body.

6. Recent studies have shown that the fluorine atoms in carbon-fluorine bonds can attract weak interactions with electron-deficient centers (such as acidic protons, carbon groups, cyano groups, etc.) in the molecule to generate hydrogen bonds, thereby affecting the molecular Conformation, binding to receptors, and reactivity.

It is precisely because of the above-mentioned characteristics of fluorine atoms that the application of fluorine-containing organic compounds is more and more extensive, and the demand for the variety and quantity of fluorine-containing organic compounds is also increasing, and the degree of attention of fluorine-containing drugs is increasing. .

However, in nature, natural fluoroorganic compounds are very rare and are only isolated in small amounts of tropical and subtropical plants, as well as in two actinomycetes. In fact, so far, in nature Only 12 kinds of fluorine-containing organic compounds were found. Therefore, the selective introduction of fluorine atoms or fluorine-containing groups into organic molecules to synthesize fluorine-containing organic substances has been a research field that chemists have been eagerly awaiting.

(+)-Patulolide C was isolated from Professor Yamada's Pemcillmmurticae S11R59. It is a dodecalide compound and has very good antibacterial and anti-inflammatory activity. Due to the unique structural features of (+)-Patulolide C and the biological activity it exhibits, chemists have shown great interest in it. As early as 1992, a number of research groups represented by Professor Me used the Yamaguchi lactonization reaction to realize the construction of the twelve-ring. Subsequently, several groups used the Mitsunobu lactonization reaction, the Shiina lactonization reaction and the The ring metathesis reaction completes the synthesis of Patulolide C. In 2012, Professor Steven used the hydrogenation carbonylation-macrolide internalization reaction of olefins to synthesize Patulolide C. Although Patulolide C has more synthetic reports, few studies have examined its structure-activity relationship.

It is well known that the strong electron absorptivity of trifluoromethyl groups enhances the metabolic stability and lipophilicity of organic compounds containing trifluoromethyl groups. In recent years, trifluoromethyl groups have also appeared more and more in drug molecules. Therefore, the introduction of trifluoromethyl into Patulolide C is undoubtedly attractive. Based on the research interest in fluorine-containing bioactive substances, we designed to introduce trifluoromethylthio group into Patulolide C C (11M stand, using the stereo electron effect of trifluoromethyl group, hoping to improve its antibacterial and anti-inflammatory activities (see attached) Figure 2). Summary of the invention

As can be seen from Fig. 3, compound 8 was obtained by reacting 1,8-octanediol as a starting material through 8 Torr. Thus, we reacted 1,8-octanediol with 1.0 equivalent of benzoyl chloride to selectively protect the compound 1 with a hydroxyl group at one end. Compound 1 was reacted with IBX in dimethyl sulfoxide to give aldehyde 2 in a yield of 82%. The aldehyde 2 was directly used in the next reaction without purification, and reacted with CF3TMS under the catalysis of TBAF to obtain the compound 3 in a moderate yield. Compound 3 was reacted with BnBr under the action of NaH, and Compound 4 was obtained in a higher isolated yield. Compound 4 was smoothly removed from Bz in a 1% OH methanol solution to give compound 5. Compound 5 is oxidized by Dess-Martin to obtain intermediate aldehyde 6, which is rapidly separated by column chromatography and reacted with a vinyl format reagent to obtain compound 7 in a two-step 50% yield. The key intermediate 8 can be prepared by protecting the hydroxyl group of compound 7 with Bz. However, Intermediate 8 does not work under the influence of BC1 ₃ The benzyl group was removed and the starting material did not react. When Me ₃ SiI was used for debenzylation, Compound 8 did not react. The inventors of the present invention were unable to effectively remove the benzyl group after a large number of conditions (reaction charge ratio, temperature, and reaction time;). Subsequently, we redesigned the following route (see Figure 4). That is, 1,8-octanediol is reacted with 1.0 equivalent of TBSC1 to selectively protect the compound 9 with a hydroxyl group at one end. The aldehyde obtained by the oxidation of compound 9 by IBX was directly reacted with CF ₃ TMS under the catalysis of TBAF without further purification, and finally TBS was completely removed by adding 2.0 eq of TBAF to obtain compound 10. With Et ₃ N as the base, the primary hydroxyl group of Compound 10 can be smoothly reacted with TBSC1 to obtain Compound 11 in a single manner. This is because the steric hindrance of the trifluoromethyl group is relatively large, preventing the secondary hydroxyl group of the compound 10 from reacting with the TBSC1. Compound 11 was reacted with acryloyl chloride in dichloromethane to give compound 12 in a yield of 63%. Under the combined action of TBAF and acetic acid, compound 12 was smoothly removed from the TBS protecting group, and compound 13 was obtained in a yield of 64%. Compound 13 is oxidized by Dess-Martin to give the intermediate aldehyde. After flash column chromatography, it is reacted with a vinyl format reagent to obtain compound 14 in 24% yield. The low yields of these two oximes are due to the fact that the ester groups on the intermediate aldehydes can also react with the vinyl format reagents. Finally, under the catalysis of the Grubbs second generation catalyst, compound 14 successfully synthesized 11-trifluoromethyl-Patulolide C using the RCM ring-closing reaction. BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 is a graph showing the share of fluorine-containing drugs marketed in 1957-2006 and their occupation of listed drugs;

Figure 2 is a schematic diagram of trifluoromethyl-modified (+)-Patulolide C prepared from (+)-Patulolide C;

Figure 3 is a schematic illustration of a process flow in the synthesis of trifluoromethyl-modified (+)-Patulolide C;

4 is a process flow diagram of (+)-Patulolide C capable of smoothly obtaining a trifluoromethyl group according to the present invention. detailed description The trifluoromethyl-modified (+)-Patulolide of the present invention will be specifically described below in conjunction with the examples.

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2°g. After the dropwise addition, the reaction was carried out at 0 to 5 ° C for 1 hour. The solid was filtered off, and the solvent was evaporated under reduced pressure. The residue was dissolved in methylene chloride, and washed with 1N hydrochloric acid and brine, and the organic phase was separated and dried over anhydrous sodium sulfate. 25.3 g of Compound 1 was obtained (yield: 56%).

3⁄4 NMR (400 MHz, CDC1 ₃ ) δ 7.98 (d, J = 7.6 Hz, 2H), 7.48 (t, J = 7.6 Hz, 1H), 7.37 (t, J = 7.6 Hz, 2H), 4.25 (t, J = 6.8 Hz, 2H), 3.56 (t, J = 6.8 Hz, 2H), 2.83 (br, 1H), 1.73-1.66 (m, 2H), 1.52-1.47 (m, 2H), 1.39-1.29 (m , 8H).

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25.3 g of Compound 1 was dissolved in 250 mL of DMSO, 42.4 g of hydrazine was added in portions, and the reaction was stirred for 4 hours at rt. The above reaction system was poured into 150 mL of ice water, and the solid was stirred and dispersed. The celite was filtered, and the filter cake was washed repeatedly with dichloromethane, and the organic layer was combined, dried over anhydrous sodium sulfate, and the solvent was evaporated. The fraction was isolated to give 20.6 g of Compound 2C yield: 82%.

3⁄4 NMR (400 MHz, CDC1 ₃ ) δ 9.72 (t, J = 1.2 Hz, 1H), 8.00 (d, J = 9.6 Hz: 2H), 7.52 (t, J = 9.6 Hz, 1H), 7.40 (t, J = 9.6 Hz, 2H), 4.28 (t, J = 6.8 Hz, 2H), 2.39 (td, J = 7.2 Hz, 1.6 Hz, 2H), 1.76-1.70 (m, 2H), 1.64-1.57 (m, 2H), 1.44-1.31 (m, 6H).

20.6 g of compound 2 was dissolved in 200 mL of anhydrous tetrahydrofuran, and the temperature was lowered to -5 to 0 ° C. 17.9 g of CF ₃ TMS was added, and 6.6 mL of TBAF (1.0 M tetrahydrofuran solution) was slowly added dropwise under controlled temperature, and the temperature was raised to 20 React at ~25 ° C overnight. After quenching with 60 mL of 1N hydrochloric acid, the solvent was evaporated, evaporated, mjjjjjjjjjjjjjjjjjjjjjjjjjjjj Yield: 53%).

3⁄4 NM (400 MHz, CDC1 ₃ ) δ 8.02 (d, J = 7.6 Hz, 2H), 7.54 (t, J = 7.6 Hz: 1H), 7.42 (t, J = 7.6 Hz, 2H), 4.30 (t, J = 6.8 Hz, 2H), 3.91-3.87 (m, 1H), 1.77-1.55 (m, 5H), 1.43-1.33 (m, 7H); ¹³ C NMR (100 MHz, CDC1 ₃ ) δ 166.8, 132.8, 130.4, 129.5, 128.3, 125.2 (q, J = 280.5 Hz), 70.4 (q, J = 30.6 Hz), 65.0, 29.5 (q, J = 1.5 Hz), 29.0, 28.9, 28.6, 25.8, 24.8; ¹⁹ F NMR (376 MHz, CDC1 ₃ ) δ -80.1 (d, J = 6.8 Hz, 3F).

1.6 g of 60% sodium hydride, 100 mL of anhydrous tetrahydrofuran and 0.8 g of Bu4NI were sequentially added to the reaction flask, and the temperature was lowered to -5 to 0 ° C, and a mixed solution of the compound 3 and 40 mL of anhydrous tetrahydrofuran was added dropwise under controlled temperature. The reaction was stirred for 1 hour. 9 g of BnBr was added dropwise under temperature control, and the reaction was carried out for 3 hours. The reaction was quenched by the addition of saturated aqueous sodium chloride. The solvent was evaporated, evaporated, evaporated, evaporated, evaporated, evaporated. Compound 4 (Yield: 88%)

3⁄4 NMR (400 MHz, CDC1 ₃ ) δ 8.05-8.03 (m, 2Η), 7.57-7.53 (m, 1H), 7.43 (t, J = 8.0 Hz, 2H), 7.35-7.30 (m, 5H), 4.70 (dd, J = 110.0 Hz, 11.2 Hz, 2H), 4.30 (t, J = 6.8 Hz, 2H), 3.68-3.66 (m, 1H), 1.78-1.71 (m, 2H), 1.66-1.60 (m, 2H), 1.43-1.23 (m, 8H); ¹⁹ F NMR (376 MHz, CDC1 ₃ ) δ -76.4 (d, J = 6.8 Hz,

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15.8 g of Compound 4 was dissolved in 150 mL of methanol, and 24 g of a 10% aqueous potassium hydroxide solution was added thereto, and the mixture was heated under reflux for 3 hours. The solvent was concentrated under reduced pressure. EtOAcjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj

3⁄4 MR (400 MHz, CDC1 ₃ ) δ 7.36-7.30 (m, 5H), 4.69 (dd, J = 109.6 Hz, 11.2 Hz, 2H), 3.69-3.60 (m, 3H), 1.65-1.47 (m, 5H ), 1.35-1.25 (m, 8H); ¹⁹ F NMR (376 MHz, CDC1 ₃ ) δ -76.4 (d, J = 6.8 Hz, 3F).

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7.4 g of compound 5 was dissolved in 150 mL of dichloromethane, and the temperature was controlled at 20 to 25 ° C in a water bath, and 30.9 g of Dess-Martin Reagent was added in portions, and the temperature was reacted for 4 hours. The reaction system was poured into 200 mL of ice water, and the precipitated solid was stirred and filtered, and filtered over Celite. The filter cake was washed thoroughly with dichloromethane, and the organic phase was dried over anhydrous sodium sulfate.

3⁄4 MR (400 MHz, CDC1 ₃ ) δ 9.75 (d, J = 1.6 Hz), 7.38-7.25 (m, 5H), 4.70 (dd, J = 113.2 Hz, 11.2 Hz, 2H), 3.69-3.64 (m, 1H), 2.42-2.31 (m, 2H), 1.65-1.49 (m, 5H), 1.27-1.24 (m, 5H); ¹⁹ F NMR (376 MHz, CDC1 ₃ ) δ -76.4 (d, J = 6.8 Hz , 3F). f ³ , ■ 伦 THF return to people „~~

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5 feriw. : s eps The compound 6 obtained from the upper oxime was dissolved in anhydrous tetrahydrofuran, cooled to -50 - 40 ° C, and 24 mL of a 1.0 M solution of vinylmagnesium bromide in tetrahydrofuran was added dropwise under controlled temperature, and the reaction was kept for 1 hour. The reaction mixture was quenched with EtOAc (EtOAc) (EtOAc). : 50% for two steps ). Ή MR (400 MHz, CDC1 ₃ ) δ 7.39-7.30 (m, 5H), 5.90-5.82 (m, 1H), 5.22 (dt, J = 17.2 Hz, 1.6 Hz, 1H), 5.10 (dd, J = 11.6 Hz, 0.8 Hz, 1H), 4.33 (dd, J = 110.0 Hz, 11.2 Hz, 1H), 4.08 (q, J = 6.8 Hz, 1H), 3.70-3.65 (m, 1H), 1.67-1.26 (m, 12H); ¹⁹ F NMR (376 MHz, CDC1 ₃ ) δ -76.4 (dd, J = 6.8 Hz, 4.1 Hz, 3F).

4.0 g of the compound 7 was dissolved in 40 mL of tetrahydrofuran, 1.5 g of triethylamine was added, and the temperature was lowered to 0 to 5 ° C, BzCl was added dropwise, and the reaction was kept for 1 hour. The solid was removed by filtration, and the filtrate was evaporated, evaporated, evaporated, evaporated, evaporated, evaporated

3⁄4 NMR (400 MHz, CDC1 ₃ ) δ 8.06 (d, J = 7.6 Hz, 2H), 7.56 (t, J = 7.6 Hz, 1H), 7.44 (t, J = 7.6 Hz, 2H), 7.35-7.30 ( m, 5H), 5.93-5.84 (m, 1H), 5.48 (q, J = 6.4 Hz, 1H), 5.32 (dt, J = 17.2 Hz, 1.2 Hz, 1H), 5.20 (dt, J = 10.4 Hz, 1.2 Hz, 1H), 4.70 (dt, J = 110.4 Hz, 11.2 Hz, 1H), 3.68-3.63 (m, 1H), 1.79-1.60 (m, 4H), 1.39-1.24 (m, 8H); ¹⁹ F NMR (376 MHz, CDC1 ₃ ) δ -76.4 (d, J = 6.8 Hz, 3F).

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1) 100 mg of the compound 8 was dissolved in anhydrous tetrahydrofuran, and the temperature was lowered to 5 to 10 ° C, 88 mg of boron trichloride ether complex was added dropwise, and the temperature was raised to RT overnight, and TLC showed no reaction.

2) 100 mg of the compound 8 was dissolved in anhydrous tetrahydrofuran, the temperature was lowered to 5 to 10 ° C, 92 mg of trimethylsilyl iodide was added, and the temperature was raised to RT overnight, and TLC showed no reaction.

20 g of 1,8-octanediol was dissolved in 300 mL of dichloromethane, 27.6 g of triethylamine was added, and the temperature was lowered to 5 to 10 ° C, and a mixed solution of 21 g of TBSC1 and 50 mL of dichloromethane was added dropwise thereto. 1 hour. The reaction was quenched by the addition of EtOAc (EtOAc) (EtOAc)

3⁄4 NMR (400 MHz, CDC1 ₃ ) δ 3.61-3.54 (m, 4H), 1.54-1.45 (m, 5H), 1.33-1.27 (m, 8H), 0.85 (s, 9H), 0.01 (s, 6H) .

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3⁄4 TBAF Dissolve 15.3g of compound 9 in 150mL of DMSO, control the temperature at 20~25 °C, add 24.7g IBX in batches, add the reaction, and keep the reaction for 4 hours. The reaction system was poured into 300 mL of ice water, and the precipitated solid was dispersed by stirring. The celite was filtered, and the filter cake was washed thoroughly with dichloromethane, and the organic layer was combined, dried over anhydrous sodium sulfate, and evaporated. The solution was dissolved in 150 mL of anhydrous tetrahydrofuran, cooled to -5 to 0 ° C, and 12.5 g of CF ₃ TMS was added thereto, and 4.7 mL of TBAF (1.0 M TBAF tetrahydrofuran solution) was added dropwise thereto under temperature control, and the reaction was allowed to proceed overnight at room temperature. The reaction was quenched by the addition of 50 mL of EtOAc.

Compound 10 was dissolved in 150 mL of dichloromethane, 7.1 _{g of} triethylamine was added, and the mixture was cooled to 5-10 ^D C, and a mixed solution of 9.7 _{g of} TBSCl and 30 mL of dichloromethane was added dropwise thereto at a temperature, and the mixture was reacted at room temperature for 3 hours. The reaction was quenched by the addition of EtOAc EtOAc (EtOAc)EtOAc.

1H NMR (400 MHz, CDC1 ₃ ) δ 3.87-3.86 (m, 1H), 3.57 (t, J = 6.8 Hz, 2H), 2.12 (br, 1H), 1.67-1.29 (m, 12H), 0.86 (s , 9H), 0.02 (s, 6H); ¹⁹ F NMR (376 MHz, CDCI3) δ -80.1 (d, J = 6.8 Hz, 3F).

In the reaction flask, llg of compound 11, 100 mL of dichloromethane and 4.1 g of triethylamine were successively added, and the temperature was lowered to 0 to 5 ° C, 3.3 g of acryloyl chloride was added dropwise, and the reaction was kept for 1 hour. The reaction was quenched by the addition of water (30 mL), and then evaporated.

3⁄4 MR (400 MHz, CDC1 ₃ ) δ 6.49 (dd, J = 17.6 Hz, 1.2 Hz, 1H), 6.15 (dd, J = 17.6 Hz, 10.8 Hz, 1H), 5.93 (dd, J = 10.8 Hz, 1.2 Hz, 1H), 5.37-5.32 (m, 1H), 3.57 (t, J = 10.8 Hz, 1H), 1.79-1.73 (m, 2H), 1.49-1.46 (m, 2H), 1.32-1.24 (m, 8H), 0.87 (s, 9H), 0.02 (s, 6H); ¹³ C NMR (100 MHz, CDC1 ₃ ) δ 164.5, 132.7, 127.1, 123.8 (q, J = 279.4 Hz), 69.7 (q, J = 31.9 Hz), 63.2, 32.7, 29.0, 27.8 (q, J = 1.5 Hz), 25.9, 25.6, 24.4, 18.3, -4.9, -5.3; ¹⁹ F NMR (376 MHz, CDC1 ₃ ) δ -77.2 (d, J = 6.8 Hz, 3F). Η

8.1 g of compound 12 was dissolved in 80 mL of anhydrous tetrahydrofuran, and the temperature was lowered to 0 to 5 ° C. 4.5 g of glacial acetic acid was added dropwise, and the mixture was stirred for 15 minutes, and 64 mL of TBAF (1.0 M TBAF tetrahydrofuran solution) was added dropwise. The temperature was naturally raised to RT overnight. The reaction system was poured into 300 mL of ice water, and the organic layer was combined, dried over anhydrous sodium sulfate and evaporated.

3⁄4 MR (400 MHz, CDC1 ₃ ) δ 6.48 (dd, J = 17.2 Hz, 0.8 Hz, 1H), 6.15 (dd, J = 17.6 Hz, 10.8 Hz, 1H), 5.92 (dd, J = 10.4 Hz, 1.2 Hz, 1H), 5.37-5.29 (m, 1H), 3.59 (t, J = 6.8 Hz, 1H), 1.80-1.72 (m, 2H), 1.65 (br, 1H), 1.53-1.48 (m, 2H) , 1.30-1.23 (m, 8H); ¹³ C NMR (100 MHz, CDC1 ₃ ) δ 164.6, 132.8, 125.2, 123.8 (q, J = 280.0 Hz), 69.6 (q, J = 31.9 Hz), 62.8, 32.6 , 29.0, 28.9, 27.7 (q, J = 1.5 Hz), 25.5, 24.4; ^iy F NMR (376 MHz, CDC1 ₃ ) δ -77.2 (d, J = 6.8 Hz, 3F).

3.6 g of Compound 13 was dissolved in 40 mL of DMSO, temperature controlled at 20 25 ° C, 5.6 g of IBX was added in portions, and the reaction was incubated for 4 hours. The reaction system was poured into 100 mL of ice water to precipitate a solid, and the solid was dispersed by stirring. The diatomaceous earth was filtered, the filter cake was thoroughly washed with dichloromethane, and the aqueous phase was extracted with dichloromethane, and the organic phase was combined. The mixture was dried over sodium sulfate and concentrated under reduced pressure. The residue was dissolved in 50 mL of anhydrous tetrahydrofuran. The mixture was cooled to -50 to 40 ° C, and 13 mL of 1.0 M solution of vinylmagnesium bromide in tetrahydrofuran was added dropwise at controlled temperature. hour. The reaction was quenched with 10 mL of EtOAc EtOAc (EtOAc m. Two yields: 24%).

3⁄4 NMR (400 MHz, CDC1 ₃ ) δ 6.48 (dd, J = 17.6 Hz, 1.2 Hz, IH), 6.18-6.11 (m, IH), 5.95-5.92 (m, IH), 5.87-5.79 (m, IH ), 5.37-5.31 (m, IH), 5.18 (d, J = 17.2 Hz, IH ), 5.07 (d, J = 10.4 Hz, IH), 4.05 (q, J = 6.4 Hz, IH), 1.77-1.74 (m, 2H), 1.49-1.47 (m, 2H), 1.30-1.23 (m, 8H); ¹³ C NMR (100 MHz, CDC1 ₃ ) δ 164.6, 132.8, 127.0, 123.8 (q, J = 279.2 Hz) , 69.7 (q, J = 31.9 Hz), 62.8, 32.6, 29.0, 28.9, 27.8, 25.5, 24.4; ¹⁹ F NMR (376 MHz, CDC1 ₃ ) δ -77.2 (d,

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II, nitrogen was replaced three times, and the reaction was refluxed for 48 hours, cooled to room temperature, and concentrated under reduced pressure to give a crude material.

3⁄4 MR (400 MHz, CDC13) δ 6.48 (dd, J = 17.2 Hz, 1.2 Hz, 1H), 6.14 (dd, J = 17.2 Hz, 10.4 Hz, 1H), 5.93 (dd, J = 10.0 Hz, 0.8 Hz , 1H), 5.36-5.31 (m, 1H), 2.42-2.35 (m, 4H), 1.78-1.72 (m, 2H), 1.60-1.49 (m, 2H), 1.35-1.23 (m, 7H), 1.02 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDC13) δ 211.7, 164.6, 132.8, 127.0, 123.8 (q, J = 279.3 Hz), 69.6 (q, J = 31.3 Hz), 42.2, 35.9, 28.85, 28.82, 27.7 (q, J = 1.5 Hz), 24.3, 23.6, 7.8 19F NMR (376 MHz, CDC13) δ -77.2 (d, J = 6.8 Hz, 3F). The above is only the invention The preferred embodiments of the present invention are not intended to limit the scope of the present invention; the modifications and equivalents of the present invention are intended to be included within the scope of the appended claims.

Industrial applicability

The present invention provides a trifluoromethyl-modified (+)-Patulolide C which, due to the inclusion of a trifluoromethyl group, is expected to have higher antibacterial and anti-inflammatory activities than the conventional (+)-Patulolide C. . The present invention also provides a process for preparing the trifluoromethyl-modified (+)-Patulolide C, which is capable of rapidly and efficiently preparing the trifluoromethyl-modified (+)-Patulolide

C, therefore has a good application prospects.

Claims

A trifluoromethyl-modified (+)-Patulolide C characterized by the structural formula (15),

■ r

G丫,

0

Chemical formula (15).

The trifluoromethyl-modified (+)-Patulolide C according to claim 1, which is based on 1,8-octanediol.

A method for producing the trifluoromethyl-modified (+)-Patulolide C according to claim 1 or 2, which comprises the following steps - Step 1: Reacting 1,8-octanediol with TBSC1 Obtained compound (9)

Compound (9);

Step 2: The compound 9 is oxidized by IBX to obtain an aldehyde, and the aldehyde is reacted with CF ₃ TMS, and then TBAF is added to completely remove TBS to obtain a compound (10).

H

One, ^", Z, ~,

Ά · Compound (10);

Step 3: Compound Compound (11)

Compound (11);

Step 4: reacting compound (11) with acryloyl chloride to obtain compound (12)

Compound (12);

Step 5: Compound (12) removes the TBS protecting group to obtain the compound (13)

Compound (13);

Step 6: Compound (13) is oxidized by Dess-Martm to obtain intermediate aldehyde, which is then reacted with Grignard reagent by flash column chromatography (14)

Compound (14)

Step 7: Compound (14) synthesizes the target product compound by RCM ring closure reaction (15)

^:F 3C:, factory o

Compound (15).

The method according to claim 3, wherein in the first step, in order to obtain the compound (9), a hydroxyl group at one end of 1,8-octanediol is selectively protected in the reaction.

5. Method according to claim 3, characterized in that the reaction in step two is carried out under the catalysis of TBAF.

6. The method according to claim 3, characterized in that, in the three-step reaction ho is Et ₃ N as base occurs.

7. The method according to claim 3, wherein the reaction in the fourth step is carried out in methylene chloride.

8. The method according to claim 3, wherein the reaction in the step 5 is carried out under the action of TB AF and acetic acid.

9. The method according to claim 3, wherein the Grignard reagent in the sixth step is a vinyl Grignard reagent.

10. The method according to claim 3, wherein the reaction in the step (7) is carried out under the catalysis of a Gmbbs second generation catalyst.