TW201632491A - Use of antroqiononol for treating obesity, and process for preparation of antroquinonol - Google Patents

Abstract

The present invention relates to the use of antroquinonol for manufacturing a composition or medicament for treating obesity. In addition, the prevent invention relates to a new process for the total synthesis of antroquinonol. Also provided the new compounds produced during the process for preparing of antroquinonol.

Description

Use of Android Quinol in the treatment of obesity and method for preparing Android quinol

The present invention relates to the use of Android Quinon in the manufacture of a medicament for the treatment of obesity, and also to a novel method of preparing an Android quinol.

In recent years, obesity has become a public health problem that cannot be ignored in modern society. Because of the imbalance between food intake and energy expenditure, obesity is thought to be an excess of energy that is converted into fat and then accumulates in adipose tissue causing progressive weight gain. Adipogenesis, which occurs during the differentiation of adipocytes, is a complex process involving various changes, including gene expression, hormone sensitivity, and cell morphology (Farmer, Cell Metabolism, 2006, 4:263-273; Rosen et al., Nature Reviews Molecular Cell Biology, 2006, 7: 885-896). The conversion of fat to fatty acids and glycerol relies on the enzymatic digestion of pancreatic lipase, which is secreted by the pancreas into the duodenum and then absorbed into the body by diffusion. The liver and bile salts are first released and adhere to the surface of the fat droplets, making them more susceptible to decomposition by lipase. Lipase (lipase, EC 3.1.1.3), is a triglyceride hydrolase (triterpene glyceride hydrolase), which is a family of α/β hydrolases in enzymes, whose enzyme activity is mainly directed to triglycerides. (triterpene glyceride) digestion reaction. Most of the lipase is produced by the pancreas, and other parts of the body, including the stomach, liver and salivary glands, are also produced.

Orlistat (Xenical) is a saturated derivative of lipstatin, a naturally potent pancreatic lipase inhibitor from Streptomyces toxytricini . Isolated and used for oral treatment of obesity (Drent et al., Internatinal Journal of Obesity, 1993, 12:241-244; Barbier et al., Helvetica Chimica Acta, 1987, 70: 196-202). Orlistat is the only legal anti-obesity drug that reduces intestinal lipid absorption in the diet by inhibiting lipase. Orlistat is very hydrophobic: (logP value 7.6-8.1) and covalently binds to the active site of pancreatic lipase serine (Hadvary et al., The Journal of Biological Chemistry, 1991, 12: 2021-2027 ). The main side effects of orlistat are gastrointestinal-related and include steatorrhea (oily, loose feces with excessive venting due to unabsorbed fat reaching the large intestine), fecal incontinence and frequent or urgent bowel movements. The use of orlistat also inhibits the absorption of fat-soluble vitamins and other fat-soluble nutrients. Considering the cost of drug development and adverse side effects, current research for the treatment of obesity is moving towards exploring anti-obesity studies in which natural compounds inhibit lipase activity, thereby achieving its lipid-lowering effect and reducing the market for drugs such as orlistat and chronic diseases. The side effects caused.

It is still necessary to develop new drugs for the treatment of obesity.

Surprisingly, it has been found in the present invention that synthetic Android quinol is effective in treating obesity.

In one aspect, the invention provides a method of treating obesity in a subject comprising administering to the individual a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of formula (I): Wherein X, Y and Z are the same or different, independently hydrogen, oxygen, sulfur, selenium, or NH, and each of R ¹ , R ² , R ³ and R ⁴ is the same or different, independently hydrogen, Alkyl, aryl, or alkoxy.

In one embodiment of the invention, the compound of formula (I) is Android quinol, in particular, (+) or (-) Android quinol.

In other embodiments of the invention, (+) or (-) Android quinol is effective to inhibit lipase activity.

In another aspect, the invention provides a pharmaceutical composition for treating obesity comprising a therapeutically effective amount of a compound of formula (I), and a pharmaceutically acceptable carrier. An example of a compound of formula (I) is Android quinol, in particular, (+) or (-) Android quinol.

In another aspect, the invention provides the use of a compound of formula (I) for the preparation of a composition or medicament for the treatment of obesity. An example of a compound of formula (I) is Android quinol, in particular, (+) or (-) Android quinol.

In still another aspect, the present invention provides a novel process for preparing (+) or (-) Android quinol comprising Suzuki-Miyaura cross coupling, Barton-McCombie reaction, and selenization/oxidation step.

In addition, the present invention further provides a method of preparing (±) Android Quinol D comprising chelation and non-stereoselective cyclohexenone reduction reaction undergoing quality control and lactonization reaction on cyclohexadienone Dimethyl malonate Michael addition reaction, dihydroxylation, Wittig olefination reaction, and sesquiterpene side chain via coupling of geranyl phenyl sulfide and Bouveault-Blanc reduction reaction.

In another aspect, the invention provides novel compounds made during the preparation of the Android Quinon process in accordance with the present invention.

The above summary of the invention, as well as the following detailed description of the invention The preferred embodiments are disclosed in the drawings for the purpose of illustrating the invention. However, it should be understood that the invention is not limited to the precise arrangements and arrangements shown.

In the picture:

Figure 1 shows the potential inhibitory activity of Andrew Quinol on lipase activity compared to the commercially available drugs orlistat and simvastatin, including (A) lipase activity, (B) serum lipase, and And (C) fecal triglyceride; wherein * indicates P < 0.05, a significant difference compared to the control group.

Unless defined otherwise, all technical and scientific terms used herein have the same meaning meaning meaning In the event of a conflict, this document, including definitions, will be controlled.

As used herein, the singular forms "", " Thus, for example, reference to "a sample" includes a plurality of such samples and equivalents known to those of ordinary skill in the art.

As used herein, the term "individual" refers to a human or mammal, such as a patient, a companion animal (eg, a dog, a cat, etc.), a farm animal (eg, cow, sheep, pig, horse, etc.) or an experimental animal (eg, , rat, mouse, rabbit, etc.).

Unexpectedly, the present invention demonstrates that Android quinol is effective for the treatment of obesity, which is similar to or superior to traditional drugs for the treatment of obesity, such as orlistat and simvastatin. Accordingly, the present invention provides a novel method/pharmaceutical composition for treating obesity that inhibits lipase activity and increases fecal triglyceride in mice that are induced to induce fat.

In the present invention, a method for treating obesity in a subject comprises administering to the individual a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of formula (I): Wherein X, Y and Z are the same or different, independently hydrogen, oxygen, sulfur, selenium, or NH, and each of R ¹ , R ² , R ³ and R ⁴ is the same or different, independently hydrogen, Alkyl, aryl, or alkoxy.

An example of such a compound is Andrew Quinol, which has the general formula (II) as follows:

安卓奎诺尔is a conventional compound, which is only found in A.camphorate (Kuo et al., Novelcompounds from antrodia camphorata, US20100130584A1) fermentation product. In the conventional method, the cost of purifying the Android quinol from the ferment is high, and the recovery rate is low. Andrew Quinault includes (+) and (-)-Android Quinon. (+)-Android Quinol has the general formula (III):

On the other hand, (-)-Android quinol has the general formula (IV), which is first synthesized in the present invention:

Further, the present invention provides a novel process for preparing (+) or (-)-Android quinol comprising a Suzuki-Miyaura cross-coupling reaction, a Barton-McCombie reaction, and a selenization/oxidation step. Specifically, the method comprises the following steps: (1) Compound 1 Addition to lithium trimethyl decyl acetylide and treatment with potassium carbonate (K ₂ CO ₃ ) / methanol (MeOH) to give compound 2 (2) tert-butyldimethylsilyl chloride Silane (TBSCI) in dichloromethane (DCM, CH ₂ Cl ₂₎ and triethylamine treating compound 2 to produce compound 3 (3) Conversion of Compound 3 to Compound 4 by excess deuterated thiochloroformate and pyridine in DCM via Barton-McCombie deoxygenation reaction Then, compound 4 is treated with tributyltin hydride (Bu ₃ SnH) and azobisisobutyronitrile (AIBN) in cyclopentyl methyl ether via a deoxy radical cyclization reaction to produce compound 5 , (4) in MeOH, pyridine p-toluenesulfonate (pyridinium p -toluenesulfonate; PPTS) treating the compound 5 to give compound 6 Followed by iodination reaction, as well as methoxymethyl (MOM) ether treatment to obtain Compound 7, (5) program to Marshall (Marshall protocol) Compound 7 And compound 8 Performing Suzuki-Miyaura cross-coupling reaction to obtain compound 9 , followed by deprotection of tert-butyldimethylmethylalkyl (TBS) ether with tetrabutylammonium fluoride (TBAF), and oxidation of the resulting alcohol with Dess-Martin periodinane to obtain a compound 10 (6) treating compound 10 with Raney nickel, followed by treatment with cerium (III) chloride (CeCl ₃ ) and oxalic acid in acetonitrile followed by Purdie reagent (Ag ₂ O, MeI) Dimethylation to obtain compound 11 (7) treating compound 11 with bis-trimethyldecylamino lithium (LiHMDS) in tetrahydrofuran, followed by oxidation elimination reaction with hydrogen peroxide (H ₂ O ₂ ) to obtain compound 12 Then in DCM, dry zinc bromide (ZnBr ₂₎ and ethanethiol obtained by treating compound 12 (+) or (-) -安卓奎诺尔.

For example, the method of preparing (+)-Android quinol includes the steps as shown in Flowchart I below:

In another example, the method comprises the steps of: (1) treating compound 14 with trimethyldecyl acetylene and n-butyllithium And get compound 15 Then DCM and pyridine, ethyl chloroformate to obtain Compound 15 Compound 16 (2) treating compound 16 with phenyl chlorochloroformate and pyridine in DCM to obtain compound 17 , Then deoxygenated via radical cyclization reaction, cyclopentyl methyl ether, Bu ₃ SnH and AIBN in a process to produce Compound 17 Compound 18 And compound 19 Compound 18 is treated with hydrochloric acid (HCl) in methanol to obtain compound 20 (3) treating compound 20 with toluenesulfonyl chloride and N,N -diisopropylethylamine in DCM, followed by refluxing with sodium iodide in acetone for iodination and treatment with MOM ether to obtain compound 21 (4) heating the solution containing activated zinc in a THF solution at 50 ° C to conjugate the compound 21 with the compound 8 , and then in THF, bis(di-tert-butyl(4-dimethylaminophenyl)phosphine) dichloride Palladium (II) (PdCl ₂ (Amphos) ₂ ) and tetramethylethylenediamine (TMEDA) are treated to obtain compound 22 , In MeOH followed by K ₂ CO ₃ treatment to obtain compound 23 (5) treating compound 23 with a Dess-Martin oxidant followed by treatment with Raney nickel to obtain compound 24 Then, compound 24 is treated with LiHMDS in THF, followed by oxidation elimination reaction with H ₂ O ₂ to obtain compound 12 , and then compound 12 is treated with ZnBr ₂ and ethanethiol in DCM to obtain (+) or (- ) - Andrew Quinnor.

For example, the method of preparing (+)-Android quinol includes the steps as shown in Flowchart II below:

The present invention also provides a novel process for preparing (±) Android Quinol D comprising chelation and non-stereoselective cyclohexenone reduction reaction undergoing quality control and lactonization reaction on cyclohexadienone Dimethyl malonate Michael addition reaction, dihydroxylation, Wittig olefination reaction, and sesquiterpene side chain via coupling of geranyl phenyl sulfide and Bouveault-Blanc reduction reaction. Specifically, the method comprises the steps of: (1) making 4-methoxyphenol Reacting with methanol to prepare compound 25 Adding Compound 25 to dimethyl malonate to obtain Compound 26 Then, compound 26 is placed under Luche condition, followed by lactonization to obtain compound 27 (2) Next, compound 27 is subjected to Krapcho decarboxylation reaction with 1,4-diazabicyclo[2.2.2]octane (DABCO) in toluene and water to obtain compound 28 And treating compound 28 with HCl to obtain compound 29 (3) treating compound 29 with borohydride (NaBH ₄ ) and CeCl ₃ in MeOH to obtain compound 30 Then, compound 30 is treated with MOM ether and subjected to a dihydroxylation reaction, followed by treatment with osmium tetroxide (OsO ₄ ) and N-methylmorpholine oxide (NMO) in acetone-water to obtain compound 31. (4) treating compound 31 with Purdie's reagent (methyl iodide, silver oxide) to obtain compound 32 Then, compound 32 is reduced to hemiacetal with diisobutylaluminum hydride (DIBAL-H), and then in benzene, triphenylphosphonium ylide (Ph ₃ PC (Me) CO ₂ Et) is subjected to a condensation reaction, and then treated with TBS ether to obtain a compound 33 (5) Compound 34 is obtained by treating compound 33 by bromination reaction under Appel reaction condition (CBr ₄ /PPh ₃ , DCM, 0 ° C) And compound 34 with lithioation compound 35 in the presence of TMEDA Coupling to obtain compound 36 Compound 36 is then treated with TBAF in THF followed by oxidation of the Dess-Martin oxidant to obtain the compound 37. , (6) in of THF, to lithium diisopropylamide (LDA) at or LiHMDS in compound 37 to give compound 38 Or compound 39 , then treated with TFA in DCM to obtain (±)- Android Quinol D (Compound 40 ) .

For example, the method of preparing (±)-Android Quinol D includes the steps as shown in Flowchart III below:

According to the present invention, some new compounds are found in the above process for preparing Android quinol. The novel compound obtained in Scheme I comprises any one selected from the group consisting of:

The novel compound obtained in Scheme II is selected from any of the group consisting of: ,as well as

The novel compound obtained in Scheme III comprises any one selected from the group consisting of: ,as well as

Furthermore, the present invention provides a novel use of a compound of formula (I) for the preparation of a composition or medicament for the treatment of obesity.

The invention also provides a pharmaceutical composition for treating obesity comprising a therapeutically effective amount of a compound of formula (I), and a pharmaceutically acceptable carrier.

In one example of a pharmaceutical composition according to the invention, the compound of formula (I) is Android quinol, in particular, (+) or (-)-Android quinol.

The term "therapeutically effective amount" as used herein means an amount of a reagent sufficient to achieve a predetermined therapeutic purpose. The therapeutically effective amount of a given agent will vary depending on factors such as the nature of the agent, the route of administration, the size and species of the animal receiving the agent, and the purpose of administration. In each individual, a therapeutically effective amount can be determined empirically by those of ordinary skill in the art in light of the present invention and the methods established in the prior art.

The term "alkyl" as used herein denotes a branched or straight chain alkyl group having from 1 to a specified number of carbon atoms. Typically, C ₁ -C ₆ alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl and many more.

"Aromatic group" as used herein means a mono- or bicyclic carbocyclic ring system which is optionally substituted and has one or two aromatic rings, including, but not limited to, phenyl, benzyl, naphthyl, tetrahydronaphthyl , 茚满基, 茚基, and so on.

The term "alkoxy" as used herein denotes a branched or straight chain alkyl group having from 1 to a specific number of oxygen-containing carbon atoms. In general, C ₁ -C ₆ alkoxy includes, but is not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy , tert-butoxy, pentyloxy, hexyloxy and the like.

The pharmaceutical compositions of this invention may be administered by any suitable route including, but not limited to, parenteral or oral administration. Pharmaceutical compositions for parenteral administration include solutions, suspensions, emulsions, and solid injectable compositions which are dissolved or suspended in a solvent before use. The injection can be prepared by dissolving, suspending or emulsifying one or more active ingredients in a diluent. Examples of such diluents are distilled water for injection, physiological saline, vegetable oil, alcohol, and combinations thereof. Further, the injection may contain a stabilizer, a solubilizer, a suspending agent, an emulsifier, a soothing agent, a buffering agent, a preservative, and the like. The injection is sterilized in a final formulation step or as a sterile process.

According to the invention, the composition can be administered by the oral route, wherein the composition can be in solid or liquid form. Solid compositions include tablets, nine doses, capsules, dispersible powders, granules and the like. Oral compositions also include gargles and sublingual tablets that are adhered to the oral cavity. Capsules include hard and soft capsules. In such a solid composition for oral use, one or more active compounds may be mixed alone or with a diluent, a binder, a disintegrant, a lubricant, a stabilizer, a solubilizing agent, and then in a conventional manner. The preparation is made by the method. These preparations may be coated with a coating agent as necessary, or they may be coated with two or more coatings. In another aspect, the liquid compositions for oral administration include pharmaceutically acceptable aqueous solutions, suspensions, emulsions, syrups, elixirs, and the like. In such compositions, the one or more active compounds can be dissolved, suspended or emulsified in a diluent (eg, pure water, ethanol or mixtures thereof, etc.) which are conventionally employed. In addition to such diluents, the compositions may contain wetting agents, suspending agents, emulsifying agents, sweetening agents, flavoring agents, perfumes, preservatives, buffers, and the like.

The following specific examples are to be construed as illustrative only and not in any way limiting. Without further elaboration, those skilled in the art will be able

Instance Example 1: Preparation of Android Quinol from Hemiacetal I

1.1 Flowchart for (+)-Android Quinon

The (+)-Android quinol synthesis is performed according to the following flow chart I:

The synthesis of Android quinol is initiated by the addition of lithium trimethyl decyl acetylide to the hemiacetal compound ( 1 ), which can be synthesized from D-mannose in a single step (Gelas, and Horton, Carbohydr. Res. 1978) , 67 , 371-387), using a slightly modified method developed by Lopez (Lopes et al., Eur. J. Org. Chem. 2004, 1830-1840). n- BuLi (131.43 mmol, 65.71 mL of 2.0 M cyclohexane solution) was added to a solution of trimethyl decylacetylene (19.70 mL, 138.36 mmol) and 150 mL of anhydrous THF at -78 ° C and stirred for 5 min. A solution of Compound 1 (9 g, 34.59 mmol) was added dropwise to 30 mL of anhydrous THF, and the reaction mixture was stirred at -78 ° C for 1 hour, then allowed to reach room temperature, and then stirring was continued for further 12 hours. Then, the reaction mixture was concentrated, and the obtained residue was dissolved in 50 mL MeOH. K ₂ CO ₃ (4.7 g, 34.6 mmol) was added and stirred at room temperature for 1 hour. The methanol was removed and the residue was diluted with 200 mL of Et ₂ O and then washed with water. The organic layer was separated, dried and concentrated and purified by flash chromatography (hexanes / EtOAc, 4: 1) to obtain the residue was purified diol compound (2), which is inseparable diastereomers (7.5g , 76%).

TBSCl (2.10 g, 13.97 mmol) and Et ₃ N (2.11 g, 20.92 mmol) were added to a solution of compound 2 (4.0 g, 13.97 mmol) in 50 mL of CH ₂ Cl ₂ and stirred at room temperature for 3 hours. . The reaction mixture was washed twice with 50 mL brine and dried over MgSO ₄ . To remove CH ₂ Cl _2, and to flash column chromatography (hexane / EtOAc, 4: 1) to obtain the residue was purified mono OTBS compound (3) (4.46g, 78% ).

In CH ₂ Cl ₂ in 50mL of pyridine (2.01mL, 25.03mmol) and chloromethyl phenyl thio ester (5.18mL, 37.52mmol) was added Compound 3 (5.0g, 12.50mmol) in. The mixture was stirred at room temperature for 3 hours. The solution was washed with brine, and dried over anhydrous MgSO _4. After concentration, flash chromatography (hexane / EtOAc, 4/1) to obtain a thiocarbonate compound (4) (5.23g, 78% ) The residue was purified on silica gel.

Compound 4 (5.0 g, 9.33 mmol) defoaming solution in 250 mL CPME was added to tri-n-butyltin hydride in 15 mL of CPME (3.76 mL, 13.99 mmol) in argon at 90 °C over 3 hours. And AIBN (153 mg, 0.93 mmol) in solution. The reaction mixture was stirred for 6 h and concentrated under reduced pressure. The deoxy-free radical cyclization reaction can obtain the exo-methylenecyclohexane compound ( 5 ) and purify by flash chromatography (hexane/EtOAc, 19/1) to obtain the main non-separable cis-fusion. Mirror image isomer (2.25 g, 63%), minor non-image isomer (1.0 g, 28%).

A solution of compound 5 (2.25 g, 5.86 mmol) in 20 mL of MeOH was taken from pyridine p-toluenesulfonate (PPTS) ( </RTI><RTIgt; The mixture was concentrated and diluted with 30 mL EtOAc then brine and brine. Remove EtOAc, and purified by flash chromatography (hexanes / EtOAc, 3: 2) to obtain the residue was purified diol compound (6) (1.63g, 81% ).

At 0 ℃, the TsCl (0.91g, 4.79mmol) was added dissolved in 20mL CH ₂ Cl ₂ containing pyridine and (0.71mL, 8.70mmol) compound 6 (1.50g, 4.35mmol) solution. The reaction mixture was stirred at room temperature for 10 hours. Wash with 1 M HCl and a saturated aqueous solution of sodium bicarbonate. CH ₂ Cl _{2 was} removed and the residue was dissolved in 20 mL EtOAc. NaI (1.17 g, 7.80 mmol) was added to the solution and refluxed for 15 h. Acetone was removed and the residue was diluted with ether, then washed with water and dried with MgSO ₄ and then concentrated to give residue, which can be used in a further step. The crude residue was dissolved in 20 mL of EtOAc (EtOAc) (EtOAc) After stirring at 70 ° C for 5 hours, the solution was separated with dichloromethane and 0.5 M aqueous hydrochloric acid. The organic layer was washed with brine, and dried MgSO _4. The solvent was evaporated, and to flash column chromatography (hexane / EtOAc, 9: 1) The resulting residue was purified to give compound (7) (1.65g, 76% ).

Zirconium dichloride (6.63 g, 22.69 mmol) dissolved in 20 mL of CH ₂ Cl ₂ was added dropwise to a solution of heptane in trimethylaluminum (2 M in heptane, 12.48 mL). , 24.96mmol). After 15 minutes, the solution was cooled to 0 °C. A solution of ( E )-6,10-dimethyl-5,9-undecene-1-yne (2.00 g, 11.34 mmol) dissolved in 10 mL of CH ₂ Cl ₂ was added to the above solution. The reaction mixture was stirred at 0 °C for 6 hours and then cooled to -30 °C. Iodine (1.80 g, 14.18 mmol) in 15 mL THF was added. The resulting brown slurry was warmed to 0 ° C and poured into ice saturated aqueous NaHCO ₃ with stirring. The aqueous layer was extracted with 100 mL of ether (3x). Washed with saturated aqueous NaHCO ₃ organic layers were combined and dried in MgSO _4. Concentration, followed by flash chromatography with 2:1 hexane/ether as a solvent to give the desired product, iodoethylene compound ( 8 ), which is a colorless oil (2.89 g, 80%) ).

9-MeO-9-BBN (4.81 mL, 1.0 M solution in hexane) was added to a solution of compound 7 (0.60 g, 1.20 mmol) containing 10 mL of Et ₂ O and the mixture was cooled to -78 °C. Lithium t-butylate was quickly added to the solution (2.48 mL, 1.7 M solution in pentane). The mixture was stirred for 5 minutes, then 5.0 mL of THF was added and the mixture was warmed to 25 ° C for one hour. In a separate flask, 5 mL of DMF, Pd(dppf)Cl ₂ (44 mg, 0.6 mmol), AsPh ₃ (55 mg, 0.18 mmol), CsCO ₃ (1.56 g, 4.81 mmol) and water (0.52 mL, 28.8) were added. Methyl) solution of compound 8 (0.38 g, 1.20 mmol). The lighter alkyl borate mixture was added dropwise to the DMF solution and stirred overnight. The reaction mixture was diluted with water, and extracted with Et ₂ O to. The organic extracts were washed with brine, as usual manner to column chromatography (hexane / EtOAc, 19: 1) was purified on silica gel, to give compound (9) (1.01g, 90% ).

A solution of compound 9 (0.60 g, 1.07 mmol) containing 10 mL of THF was taken in TBAF (2.13 mL, 1M in THF, 21.4 mmol). The reaction mixture was stirred at room temperature for 3 hours and then the THF was removed. The residue was diluted with 20mL ether, and washed with water, brine, and then dried over anhydrous MgSO _4. Then, the residue was filtered and concentrated to give a crude product which was subsequently subjected to an oxidation reaction. Dess-Martin periodinane (0.67 g, 1.60 mmol) was added to a solution of the above crude product containing 10 mL of CH ₂ Cl ₂ and the mixture was stirred at room temperature for 2 hours. After the reaction mixture was diluted with CH ₂ Cl ₂ to, and is quenched with saturated aqueous sodium bicarbonate to the reaction to brine. The ketone compound ( 10 ) (0.41 g, yield 87% after two steps) was obtained by flash column chromatography (hexane/EtOAc, 9:1).

A suspension of 0.5 mL of 50% Raney nickel in water was added to a solution of Compound 10 (0.3 g, 0.67 mmol) containing 10 mL of THF at 0 °C with vigorous stirring. The mixture was stirred at 0 ° C for 30 minutes. 20 mL of ether was added and the residue was washed with brine, dried with MgSO ₄ and evaporated. Oxalic acid (4 mg, 0.05 mmol) and CeCl _{3 were added} at room temperature. 7H ₂ O (0.75 g, 2.02 mmol) was added to the above crude product solution containing 5 mL of acetonitrile. The mixture was stirred at room temperature for 3 hours and cooled to 0 °C. A sodium bicarbonate solid was added to neutralize the pH of the reaction mixture and then concentrated under vacuum. The residue was taken up in 10 mL EtOAc and filtered over EtOAc. The filtrate was concentrated to obtain a diol compound. The diol compound was dissolved in 5 mL of iodomethane, and Ag ₂ O (0.47 g, 2.02 mmol) was added and stirred under reflux for 12 hours. The reaction mixture was _diluted with 10mL CH ₂ Cl, diatomaceous earth and is filtered. The filtrate was concentrated, and the resulting product was subjected to flash chromatography (hexane / EtOAc, 4: 1) to obtain a ketone compound (11) (196mg, 67% ).

LiHMDS (1 M solution in THF, 0.43 mL) was added dropwise to a cold (-78 ° C) solution of compound 11 (0.19 g, 0.43 mmol) containing 5 mL of THF. After stirring for 20 minutes, phenyl selenium bromide (0.10 g, 0.43 mmol) containing 1 mL of THF was added. The mixture was stirred at -78 ° C for 40 minutes and then quenched with saturated ammonium chloride solution. The aqueous layer was extracted with Et ₂ O. In combined organic phases were washed with brine, MgSO ₄ to evaporate the solvent to be dried. This crude product was used in the next step. The above crude product was dissolved in 10 mL of THF. In treating the mixture was 3mL NaHCO _3, and slowly added 1mL of hydrogen peroxide (30wt.% Aqueous solution). The reaction mixture was kept warm and then stirred at room temperature for 2 hours. Quenching was carried out with a Na ₂ S ₂ O ₃ solution, and the aqueous layer was extracted with Et ₂ O. In combined organic phases were washed with brine, MgSO ₄ to evaporate the solvent to be dried. To flash chromatography (hexane / EtOAc, 19: 1) was purified on silica gel to obtain an unsaturated ketone compound (12) (0.11g, 55% ).

Dry ZnBr ₂ (57 mg, 0.25 mmol) and EtSH (36 μL, 0.50 mmol) were added to a stirred solution of compound 12 (0.1 g, 0.23 mmol) containing 5 mL of anhydrous CH ₂ Cl ₂ . After stirring at room temperature for 1 hour, the resulting mixture was diluted with 10 mL of CH ₂ Cl ₂ . 5 mL of NaHCO ₃ was slowly added at 0 ° C, and the mixture was filtered with diatomaceous earth. The aqueous layer was separated and further extracted with 10 mL of CH ₂ Cl ₂ . The aqueous layer was separated and further extracted with 10 mL of CH ₂ Cl ₂ . In 3mL organic layers were washed with brine, it was dried in MgSO ₄ and concentrated under reduced pressure. To flash column chromatography (hexane / EtOAc, 4/1) to obtain the mixture was purified安卓奎诺尔(13) (72mg, 80% ) on silica gel.

1.2 Identification of synthetic compounds

In the preparation of the Android Quinol method, the following new compounds were found: The spectral data is as follows: R _f (hexane / EtOAc, ₃ : ₂ ) 0.3. IR (film): 3306, 2118, 1634, 1372, 1222 cm ^-1 . ¹ H-NMR (400 MHz, CDCl ₃ ): δ 7.34 (m, 5H), 5.11 (s, 1H), 4.70 (d, J = 11.72 Hz, 1H), 4.52 (d, J = 11.72 Hz, 1H), 4.22 (d, J = 5.64 Hz, 1H), 4.16 (m, 1H), 4.12 (m, 1H), 3.84 (m, 1H), 3.76 (m, 2H), 3.63 (m, 1H), 1.55 (s, 3H), 1.52 (s, 3H), 1.43 ( s,3H), 1.34(s,3H). ¹³ C-NMR (100.6MHz, CDCl ₃ ): δ 109.70,108.95,99.07,98.53,82.56,80.98,79.93,78.38,75.04,74.34,74.09,73.86,72.05 , 71.51, 64.46, 64.32, 62.31, 62.11, 61.00, 60.81, 60.38, 28.28, 28.21, 26.19, 26.18, 25.68, 25.38, 20.82, 19.00, 13.88.C HRMS-EI (m/z) of ₁₄ H ₂₂ O ₆ [M] ⁺ calculated value: 286.1416, measured value: 286.1421; The spectral data is as follows: R _f (hexane / EtOAc, 19: ¹ ) 0.5. IR (film): 2930, 2119, 1781, 1591, 1490, 1248 cm ^-1 . ¹ H-NMR (400 MHz, CDCl ₃ ): δ 7.30 (m, 5H), 5.56 (m, 1H), 4.75 (m, 1H), 4.29 (m, 3H), 3.93 (m, 2H), 3.68 (m, 1H), 2.61 (m, 1H), 1.55 (s, 3H), 1.52 (s, 3H), 1.42 (m, 6H), 0.92 (m, 9H), 0.26 (s, 3H), 0.23 (s, 3H). ¹³ C-NMR (100.6 MHz, CDCl ₃ ): δ 194.4, 153.3, 129.5, 126.4, 121.7, 110.4, 99.7, 83.3, 79.4, 76.3 75.5, 75.2, 68.5, 61.9, 61.4, 26.1, 26.1, 25.9, 25.7, 22.1, 18.1, -3.2, - 4.3.C ₂₇ H40O ₇ SSi in HRMS-EI (m / z) [m] + calcd: 536.2264, Found: 536.2265; The spectral data is as follows: main R _f (hexane / EtOAc, 15:1) 0.7. [α] _D ²⁵ = +160.0 ° (c = 1.3 in CHCl ₃ ). ¹ H-NMR (400 MHz, CDCl ₃ ) : δ 5.46 (s, 1H), 5.10 (s, 1H), 5.05 (m, 1H), 4.41 (dd, J = 7.66 Hz, J = 2.78 Hz, 1H), 4.26 (dd, J = 7.42 Hz, J = 2.32 Hz, 1H), 4.13 (dd, J = 11.62 Hz, J = 3.58 Hz, 1H), 4.08 (t, J = 3.04 Hz, 1H), 3.89 (dd, J = 11.67 Hz, J = 2.32 Hz, 1H), 2.51 (m, 1H), 1.43 (s, 3H), 1.39 (s, 3H), 1.33 (s, 3H), 1.32 (s, 3H), 0.95 (s, 9H), 0.16 (s, 3H) ), 0.13 (s, 3H). ¹³ C-NMR (100.6 MHz, CDCl ₃ ): δ 144.96, 110.65, 109.11, 98.64, 75.83, 70.57, 67.66, 65.86, 35.04, 29.16, 26.21, 26.08, 23.98, 18.96, _{18.73, -4.54, -5.19.C 20 H 36} O 5 Si in HRMS-EI (m / z) [m] + calcd: 384.2332, Found: 384.2338; Secondary R _f (hexane / EtOAc, 15: 1) 0.8. [α] _D ²⁵ = +68.0° (c = 1.05 in CHCl ₃ ). ¹ H-NMR (400MHz, CDCl ₃ ): δ 5.46 (m, 1H), 5.33 (m, 1H), 4.49 (m, 1H), 4.12 (m, 2H), 4.02 (m, 2H), 3.89 (dd, J = 7.48 Hz, J = 5.45 Hz, 1H), 2.18, (m, 1H), 1.51 (s, 3H) ), 1.46 (s, 3H), 1.36 (s, 3H), 1.33 (s, 3H), 0.94 (s, 9H), 0.12 (s, 3H), 0.05 (s, 3H). ¹³ C-NMR (100.6 MHz, CDCl ₃ ): δ 143.11, 110.80, 108.04, 99.02, 82.34, 77.42, 75.96 HRMS-EI(m/z)[M] ⁺ calculated value: 384.2332, ???: 69.27,60.77,36.41,29.45,28.41,26.24,25.92,18.73,18.32,-4.51,-4.79.C ₂₀ H ₃₆ O ₅ Si Found: 384.2330; The spectral data is as follows: main R _f (hexane / EtOAc, 9:1) 0.80. [α] _D ²⁵ = +65.6 ° (c = 1.4 in CHCl ₃ ). IR (film): 2904, 1755, 1658 , 1446, 1259, 787cm ^-1 . ¹ H-NMR (400MHz, CDCl ₃ ): δ 5.46 (s, 1H), 5.11 (s, 1H), 4.80 (m, 3H), 4.52 (dd, J = 7.67 Hz , J = 3.54 Hz, 1H), 4.38 (dd, J = 7.32 Hz, J = 3.20 Hz, 1H), 4.02 (t, J = 3.40 Hz, 1H), 3.59 (dd, J = 10.04 Hz, J = 5.60 Hz, 1H), 3.51 (t, J = 10.73 Hz, 1H), 3.37 (s, 3H), 3.05 (m, 1H), 1.40 (s, 3H), 1.31 (s, 3H), 0.92 (s, 9H) ), 0.12 (s, 3H), 0.09 (s, 3H). ¹³ C-NMR (100.6 MHz, CDCl ₃ ): δ 143.82, 112.71, 109.54, 98.36, 77.06, 75.48, 74.89, 69.84, 55.72, 42.15, 32.92 _{, 26.33,24.23,18.55,7.00, -4.68, -5.10.C 12 H} 35 IO 5 Si in HRMS-EI (m / z) [m] + calcd: 598.1298, Found: 598.1292; Secondary R _f ( hexane ^{_{/EtOAc,9:1)0.80 [α] D 25 = +}} 61.73 ° (c = 1.1 in CHCl ₃ in) IR (film):.. 2928,1654,1576,1450,1170,1079cm ^{-1 1} H-NMR (400MHz, CDCl ₃ ): δ 5.34 (s, 1H), 4.88 (s, 1H), 4.73 (m, 2H), 4.25 (m, 2H), 4.10 (d, J = 6.34 Hz, 1H) , 3.95 (t, J = 5.96 Hz, 1H), 3.47 (m, 2H), 3.44 (s, 3H), 2.71 (m, 1H), 1.52 (s, 3H), 1.38 (s, 3H), 0.93 ( s, 9H), 0.13 (s, 3H), 0.07 (s, 3H). ¹³ C-NMR (100.6MHz, CDCl ₃ ): δ 144.69, 110.44, 109.12, 97.27, 82.74, 76.78, 75.83, 75.66, 55.97, 45.09, 28.43, 26.43, 25.89, 18.23, 4.10, -4.60, -4.76.C ₁₉ H ₃₅ IO ₅ Si in HRMS-EI (m / z) [m] + calcd: 598.1298, Found: 598.1294; The spectral data is as follows: main R _f (hexane / EtOAc, 15:1) 0.60. [α] _D ²⁵ = +25.83 ° (c = 1.2 in CHCl ₃ ). IR (film): 2929, 1645, 1464 , 1090, 1035cm ^-1 . ¹ H-NMR (400MHz, CDCl ₃ ): δ 5.35 (s, 1H), 5.10 (m, 4H), 4.68 (m, 2H), 4.37 (d, J = 2.80, 1H) , 3.71 (m, 1H), 3.37 (s, 3H), 2.72 (m, 1H), 2.32 (m, 1H), 2.19 (m, 1H), 1.95-2.05 (m, 8H), 1.68 (s, 3H) ), 1.60 (s, 6H), 1.57 (s, 3H), 1.46 (s, 3H), 1.33 (s, 3H), 0.94 (s, 9H), 0.14 (s, 3H), 0.11 (s, 3H) ¹³ C-NMR (100.6 MHz, CDCl ₃ ): δ 146.03, 136.41, 135.10, 131.25, 124.40, 124.12, 122.34, 110.85, 109.39, 97.24, 81.25, 77.62, 77.48, 76.11, 69.75, 55.55, 41.48, 39.76, 39.68,29.69,27.62,27.02,26.74,26.65,25.98,25.69,24.86,18.58,17.67,16.27,15.99,-4.57,-5.03.C HRMS-EI(m/z) of ₃₃ H ₅₈ O ₅ Si[M ] ⁺ calculated: 562.4054, Found: 562.4059; Secondary R _f (hexane ^{_{/EtOAc,15:1)0.30 [α] D 25 = +}} 25.14 ° (c = 0.7 in CHCl ₃ in) IR (film ): 2930, 1640, 1610, 1584, 1471, 1154, 837 cm ^-1 . ¹ H-NMR (400 MHz, CDCl ₃ ): δ 5.32 (s, 1H), 5.18 (m, 1H), 5.10 (m, 2H) , 4.89 (s, 1H), 4.69 (d, J = 6.68 Hz, 1H), 4.61 (d, J = 6.68 Hz, 1H), 4.25 (dd, J = 5.25 Hz, J = 2.78 Hz, 1 H), 4.10 (dt, J = 6.94 Hz, J = 1.94 Hz, 1H), 3.99 (t, J = 2.60 Hz, 1H), 3.94 (dd, J = 6.52 Hz, J = 5.40 Hz, 1H), 3.36 (s, 3H), 2.39 (m, 2H), 2.28 (m, 1H), 1.97-2.09 (m, 8H), 1.68 (s, 3H), 1.64 (s, 3H), 1.60 (s, 6H), 1.53 (s, 3H), 1.38 (s, 3H), 0.93 (s, 9H), 0.13 (s, 3H), 0.06 (s, 3H). ¹³ C-NMR (100.6 MHz, CDCl ₃ ): δ 146.25, 136.41,135.07,131.22,124.39,124.08,122.37,112.17108.87,97.22,83.21,76.88,76.41,76.38,55.75,41.49,39.75,39.68,28.46,26.73,26.60,26.45,25.91,25.80,25.68,18.27, _{17.67,16.32,15.98, -4.50, -4.84.C 33 H 58} O 5 Si in HRMS-EI (m / z) [m] + calcd: 562.4054, Found: 562.4057; The spectral data is as follows: R _f (hexane / EtOAc, 4: ¹ ) 0.40. [α] _D ²⁵ = IR (film): 2928, 1736, 1455, 1375, 1259, 1095, 919 cm ^-1 . ¹ H- NMR (400MHz, CDCl ₃ ): δ 6.62 (s, 1H), 5.45 (s, 1H), 5.16 (m, 1H), 5.09 (m, 2H), 4.69 (d, J = 6.68 Hz, 1H), 4.67 (dd, J = 7.45 Hz, J = 4.16 Hz, 1H), 4.63 (d, J = 6.68 Hz, 1H), 4.46 (d, J = 7.68 Hz, 1H), 3.86 (dd, J = 3.72 Hz, J =1.98 Hz, 1H), 3.34 (s, 3H), 2.99 (m, 1H), 2.35 (m, 2H), 1.97-2.08 (m, 8H), 1.68 (s, 3H), 1.61 (s, 3H) , 1.60 (s, 6H), 1.49 (s, 3H), 1.38 (s, 3H). ¹³ C-NMR (100.6 MHz, CDCl ₃ ): δ 143.57, 137.66, 135.23, 131.27, 124.31, 123.89, 121.42, 110.95 , 96.97,77.02,76.70,76.26,55.80,40.01,39.70,39.67,29.67,27.09,26.71,26.51,26.48,25.68,17.66,16.26,16.00.C HRMS-EI(m/z) of ₂₇ H ₄₂ O ₅ [M] ⁺ calculated value: 446.3230, measured value: 446.3038; The spectral data is as follows: R _f (hexane / EtOAc, 7: ₃ ) 0.50. [α] _D ²⁵ = -67.7 ° (c = 1.3 in CHCl ₃ ). IR (film): 2927, 1726, 1655, 1457, 1119, 1031, 919cm ^-1 . ¹ H-NMR (400MHz, CDCl ₃ ): δ 5.09 (m, 3H), 4.74 (d, J = 6.76Hz, 1H), 4.69 (d, J = 6.76Hz, 1H), 4.25 (d, J = 2.84 Hz, 1H), 4.10 (t, J = 3.72 Hz, 1H), 3.87 (t, J = 3.28 Hz, 1H), 3.48 (s, 3H), 3.44 (s, 3H), 3.41 (s, 3H), 2.46 (m, 1H), 2.19 (m, 2H), 1.96-2.09 (m, 8H), 1.91 (m, 1H), 1.36 (s, 3H), 1.33 (s) , 3H), 1.32 (s, 6H), 1.07 (d, J = 6.52 Hz, 3H); ¹³ C-NMR (100.6 MHz, CDCl ₃ ): δ 207.86, 136.84, 135.23, 131.28, 124.29, 123.96, 122.09, 98.30, 83.97, 83.04, 76.27, 59.00, 58.53, 56.09, 44.47, 44.03, 39.75, 39.71, 27.26, 26.74, 26.58, 25.66, 17.65, 16.21, 15.98, 11.09; HRMS-EI of C ₂₆ H ₄₄ O ₅ /z)[M] ⁺ Calculated value: 436.3189 Found: 436.3181.

Example 2: Preparation of Andrew Quinol from Hemiacetal II

2.1 Flowchart II for (+)-Android Quinol

The (+)-Android quinol synthesis is performed according to the following flow chart II:

To a solution of benzyl acetal (6.0 g, 17.75 mmol) in MeOH (50 mL) was added triethylamine (0.5 mL), Pd / C (10%, 0.5 g) and stirred at room temperature under hydrogen. hour. The catalyst was filtered off, the solvent was evaporated under reduced pressure, and the obtained anomeric quantitative yield of the alcohol (14).

Add n- BuLi (61.22 mmol, 30.61 mL of a 2.0 M solution in cyclohexane) to a solution containing 100 mL of anhydrous THF trimethyl decyl acetylene (9.17 mL, 64.45 mmol) at -78 ° C and stir. minute. A solution of hemiacetal 14 (4 g, 16.11 mmol) containing 30 mL of anhydrous THF was added dropwise to the reaction mixture, and the mixture was stirred at -78 ° C for 1 hour, and then allowed to reach room temperature under stirring for 12 hours. The reaction mixture was concentrated and the residue dissolved in 50 mL MeOH. K ₂ CO ₃ (4.7 g, 34.6 mmol) was added to the mixture, and stirred at room temperature for 1 hour. The methanol was removed, the residue was diluted with 100mL Et ₂ O, then washed with water. The organic layer was separated, dried over MgSO ₄ and concentrated. To flash chromatography (hexane / EtOAc, 4: 1) to obtain residue was purified diol compound (15), which is inseparable diastereomers (3.57g, 81%).

Under argon at -20 ℃, pyridine (2.05mL, 25.52mmol) and ethyl chloroformate (1.33mL, 14.04mmol) was added 50mL of anhydrous CH containing compound _{15 (3.5g, 12.76mmol) 2 Cl} 2 is In solution. The solution was stirred at -20 ° C for 1 hour, and the temperature was raised to 0 ° C and stirred for 1 hour. The mixture was diluted with CH ₂ Cl ₂ and the mixture was washed with 10% HCl, aqueous sodium hydrogen carbonate, water and brine. In the organic layer was dried over MgSO ₄ and concentrated, the resulting residue was purified by flash chromatography (hexane / EtOAc, 4: 1) for purification to obtain the carbonate compound (16) (3.71g, 84% ), which A mixture of two non-mirromeric isomers at the C-1 position.

Pyridine (1.63mL, 20.21mmol) and thio phenyl chloroformate (2.79mL, 20.21mmol) was added compound containing 40mL CH ₂ Cl ₂ of 16 (3.50g, 10.10mmol) solution. The mixture was stirred at room temperature for 3 hours. The solution was washed with brine and dried over anhydrous MgSO _4. After concentration, the residue was purified by flash chromatography (hexane / EtOAc, 4: 1) was purified on silica gel to obtain thiocarbonate compound (17) (3.94g, 81% ).

Compound 17 (3.5 g, 6.53 mmol) defoaming solution containing CPME (150 mL) was added to tri-n-butyltinhydride (2.63 mL, 13.99 mmol) containing 15 mL of CPME and AIBN at 90 ° C under argon. In a solution of 107 mg, 0.65 mmol), and stirred for at least 3 hours. After stirring for 12 hours, the reaction mixture was concentrated under reduced pressure. To flash chromatography (hexane / EtOAc, 19/1) the residue obtained was purified, and the obtained cis fused separable diastereomers main compound (18) (1.46g, 61% ) and transferrin-containing fusion A secondary non-image isomer of the product (0.53 g).

A solution of compound 18 (1.20 g, 2.49 mmol) containing 15 mL of MeOH was treated with 2 mL 1M HCl and the solution was stirred for 3 hr. The mixture was concentrated and diluted with EtOAc (30 mL)EtOAc. Removed under reduced pressure with EtOAc, flash chromatography (hexane / EtOAc, 1: 1) The resulting residue was purified to obtain the diol compound (20) (0.97g, 92% ).

TsCl (0.69 g, 3.60 mmol) was added to a solution of compound 20 (0.95 g, 3.28 mmol) and N,N -diisopropylethylamine (0.86 mL, 4.91 mmol) containing 10 mL of CH ₂ Cl ₂ at 0 ° C in. The reaction mixture was stirred at room temperature for 12 hours. Wash with 1 M HCl and a saturated aqueous solution of sodium bicarbonate. CH ₂ Cl _{2 was} removed and the residue was dissolved in 15 mL of acetone. NaI (1.23 g, 8.18 mmol) was added and the solution was refluxed for 15 h. The acetone was removed, and the residue was diluted with ether, washed with water and then dried after MgSO _4, then concentrated to obtain the crude product was then purified by column chromatography to obtain ethyl to - (3 R, 4 R, 5 S , 6 S )-4-Hydroxy-3-(iodomethyl)-5,6-dimethoxy-2-methylenecyclohexyl carbonate (1.12 g, 86%). The above compound (1.1 g, 2.75 mmol) was dissolved in 20 mL of EDC and diisopropylethylamine (0.958 mL, 5.50 mmol) and bromomethyl methyl ether (0.27 mL, 3.30 mmol). After stirring at 70 ° C for 5 hours, the solution was separated with dichloromethane and 0.5 M aqueous hydrochloric acid. The organic layer was washed with brine, and dried MgSO _4. The solvent was evaporated, and to flash column chromatography (hexane / EtOAc, 4: 1) to obtain the resulting residue was purified compound (21) (1.13g, 93% ).

Activated zinc (44 mg, 0.68 mmol) was added to a solution of compound 21 (0.2 g, 0.45 mmol) containing 2 mL of THF and stirred at 50 ° C for 8 hours. The vinyl iodide compound ( 8 ) (0.286 g, 0.90 mmol) and TMEDA (0.074 mL, 0.49 mmol) were added to a solution of PdCl ₂ (phenylpropylamine) ₂ (6 mg) containing 2 mL of THF. Then, the zinc iodide solution prepared above was dropped into the resulting solution, and stirred at room temperature for 24 hours. The saturated reaction mixture was quenched with NH ₄ Cl solution and the product was extracted with EtOAc Cuiqu. The organic layer was washed with brine, and dried MgSO _4. The solvent was evaporated to flash column chromatography (hexane / EtOAc, 9: 1) The resulting residue was purified to give compound (22) (0.118g, 52% ).

A solution of compound 22 (0.23 g, 0.42 mmol) containing 10 mL of THF was treated with TBAF (0.6 mL, 1 M in THF, 0.60 mmol) at 50 ° C for 5 hours. After completion of the deprotection group effect removal of THF, to the resulting residue was diluted with 20mL ether, washed with brine, and dried over anhydrous MgSO _4, and then the obtained crude product was filtered and concentrated and by column chromatography ( Purification with hexane / EtOAc, 4:1) gave the compound ( 23 ) (0.167 g, 92%).

Dess-Martin oxidizing agent (0.19 g, 0.45 mmol) was added to a solution of compound 23 (0.15 g, 0.34 mmol) containing 10 mL of CH ₂ Cl, and the mixture was stirred at room temperature for 2 hours. After the reaction mixture was diluted with CH ₂ Cl ₂ to, and is quenched with saturated aqueous sodium bicarbonate and the reaction mixture was stirred at room temperature for 2 hours. The organic layer was separated, washed with brine and dried with MgSO ₄ The residue was purified by EtOAc EtOAcqqqqqq A suspension of 0.3 mL of 50% Raney nickel in water was added to a cold (0 ° C) solution of the above ketone compound (0.12 g, 0.28 mmol) in 5 mL THF with vigorous stirring. The mixture was stirred at 0 ° C for 30 minutes. 20mL ether was added, and washed with brine, dried MgSO ₄ to obtain a crude product was concentrated, and to flash column chromatography (hexane / EtOAc, 9: 1) to obtain a purified cyclohexanone compound (24) Heavy oil (84 mg, 70%).

LiHMDS (1 M solution in THF, 0.20 mL, 0.20 mmol) was added dropwise to a cold (-78 ° C) solution of compound 24 (80 mg, 0.18 mmol) containing 5 mL of THF. After stirring for 20 minutes, phenyl selenium bromide (43 mg, 0.18 mmol) containing 1 mL of THF was added. The mixture was stirred at -78 ° C for 1 hour and then quenched with saturated ammonium chloride solution. The aqueous layer was extracted with Et ₂ O. In combined organic phases were washed with brine, MgSO ₄ to evaporate the solvent to be dried. This crude product was used in the next step. The above crude product was dissolved in 5 mL of THF. In treating the mixture was 3mL NaHCO _3, and slowly added 1mL of hydrogen peroxide (30wt.% Aqueous solution). The reaction mixture was kept warm and then stirred at room temperature for 2 hours. To Na ₂ S ₂ O ₃ solution was quenched in Et ₂ O and the aqueous layer was Cuiqu, washed with brine and the combined organic phase, MgSO ₄ dried and the solvent evaporated. To flash column chromatography (hexane / EtOAc, 19: 1) was purified on silica gel to obtain an unsaturated ketone compound (12) (37mg, 47% ).

The dried ZnBr ₂ (16mg, 0.07mmol) and EtSH (36μL, 0.50mmol) was added with stirring containing anhydrous CH ₂ Cl ₂ (3mL) of MOM ether 12 (30mg, 0.07mmol) solution. After stirring at room temperature for 1 hour, the resulting mixture was diluted with CH ₂ Cl ₂ (10 mL). NaHCO ₃ salt (5 mL) was slowly added at 0 ° C, and the mixture was filtered over Celite. The aqueous layer was separated, and further Cuiqu in CH ₂ Cl ₂ (10mL). The aqueous layer was separated and further extracted with 10 mL of CH ₂ Cl ₂ . With brine (3mL) The combined organic layer was washed, in order MgSO ₄ dried and concentrated under reduced pressure. Rapid analysis column chromatography (hexane / EtOAc, 4/1) to obtain安卓奎诺尔(13) (72mg, 80% ) The crude product was purified on silica gel.

2.2 Identification of synthetic compounds

In the preparation of the Android Quinol method, the following new compounds were found: The spectral data is as follows: R _f (hexane / ethyl acetate 3:2) 0.35. [α] _D ²⁵ = +8.1 ° (c = 1.15 in CHCl ₃ ). IR (film): 3437, 2115, 1704 , 1610, 1510, 1034, 811cm ^-1 . ¹ H-NMR (400MHz, CDCl ₃ ): δ 4.56 (m, 1H), 3.85 (m, 3H), 3.61 (m, 8H), 3.30 (d, J = 8.16 Hz, 1H), 2.53 (m, 2H), 1.77 (brs, 1H), 1.46 (s, 3H), 1.38 (s, 3H). ¹³ C-NMR (100.6 MHz, CDCl ₃ ): δ 99.10, 83.11 , 82.89,82.27 81.57,81.21,80.49,74.55,73.74,72.61,64.65,64.18,63.74,62.20,62.06,61.00,60.94,60.40,60.34,59.55,28.27,28.13,19.42,19.28.C ₁₃ H ₂₂ O ₆ HRMS-EI(m/z) [M+Na] ⁺ calc.: 297.1314, found: 297.1323; The spectral data is as follows: R _f (hexane / ethyl acetate 4:1) 0.7. [α] _D ²⁵ = -11.1 ° (c = 1.5 in CHCl ₃ ). IR (film): 3289, 2987, 2125 , 1754, 1748, 1590, 1259, 1095cm ^-1 . ¹ H-NMR (400MHz, CDCl ₃ ): δ 7.38 (m, 2H), 7.27 (m, 1H), 7.05 (m, 2H), 5.58 (m, 1H), 5.41 (m, 1H), 4.17 (m, 1H), 3.88 (m, 1H), 3.60 (m, 7H), 2.61 (m, 1H), 1.49 (s, 3H), 1.48 (s, 3H) ), 1.39 (m, 3H). ¹³ C-NMR (100.6 MHz, CDCl ₃ ): δ 193.84, 193.76, 154.04, 153.88, 153.11, 153.09, 129.41, 126.52, 121.62, 121.56, 100.20, 100.15, 81.93, 81.44, 79.62,79.27,77.94, 77.44,76.86,76.14,75.91,69.53,69.15,67.71,67.50,64.47,61.32,61.12,61.06,61.01,60.74,26.07,25.90,21.24,20.79,14.04,14.00.C ₂₃ H ₃₀ O ₉ S in HRMS-EI (m / z) [m] + calcd: 482.1611, Found: 482.1627; The spectral data is as follows: R _f (hexane / ethyl acetate 4:1) 0.35. [α] _D ²⁵ = +42.4 ° (c = 1.5 in CHCl ₃ ). IR (film): 2924, 1750, 1604 , 1459, 1372, 1259cm ^-1 . ¹ H-NMR (400MHz, CDCl ₃ ): δ 5.66 (m, 1H), 5.28 (s, 1H), 5.12 (s, 1H), 4.22 (q, J = 7.02 Hz , 2H), 4.19 (t, J = 4.72 Hz, 1H), 4.05 (dd, J = 11.84 Hz, J = 4.96 Hz, 1H), 3.87 (dd, J = 11.84 Hz, J = 4.40 Hz, 1H), 3.48 (s, 3H), 3.44 (s, 3H), 3.38 (t, J = 4.08Hz, 1H), 3.32 (dd, J = 7.82Hz, J = 4.00Hz, 1H), 2.60 (m, 1H), 1.44 (s, 3H), 1.40 (s, 3H), 1.32 (t, J = 7.25 Hz, 3H). ¹³ C-NMR (100.6 MHz, CDCl ₃ ): δ 154.56, 141.39, 112.84, 99.00, 83.19, 82.88 _{, HRMS-EI 78.38,69.43,64.10,62.76,58.51,58.04,36.34,28.17,20.37,14.22.C 16 H 26} O 7 a (m / z) [m] + calcd: 330.1679, Found: 330.1686; The spectral data is as follows: R _f (hexane / ethyl acetate 4:1) 0.50. [α] _D ²⁵ = +20.3 ° (c = 1.25 in CHCl ₃ ). IR (film): 2933, 1752, 1655 , 1374, 1153, 1034, 917 cm ^-1 . ¹ H-NMR (400 MHz, CDCl ₃ ): δ 5.21 (s, 1H), 5.13 (d, J = 9.36 Hz, 1H), 5.04 (s, 1H), 4.74 (d, J = 6.76 Hz, 1H), 4.69 (d, J = 6.76 Hz, 1H), 4.24 (m, 2H), 3.67 (dd, J = 9.80 Hz, J = 3.80 Hz, 1H), 3.56 (dd , J = 9.20Hz, J = 5.60Hz, 1H), 3.56(s, 3H), 3.54(s, 3H), 3.40(s, 3H), 3.34(t, J = 9.80Hz, 1H), 3.05(m , 3H), 1.32 (t, J = 7.12 Hz, 3H). ¹³ C-NMR (100.6MHz, CDCl ₃ ): δ 154.29, 138.98, 114.15, 96.78, 84.85, 82.56, 78.16, 75.85, 64.28, 60.73, 60.69 _{, HRMS-EI 55.73,49.70,14.18,3.11.C 15 H 25} IO 7 is (m / z) [m] + calcd: 444.0645, Found: 444.0641; The spectral data is as follows: R _f (hexane / ethyl acetate 7:1) 0.6. [α] _D ²⁵ = +3.75 ° (c = 0.8 in CHCl ₃ ). IR (film): 2897, 2856, 1742 ^{, 1635,1471,1253,1154,1036,837cm -1 1 H-NMR (} 400MHz, CDCl 3):. δ 5.22 (d, J = 10.36Hz, 1H), 5.08 (m, 4H), 4.90 (s, 1H), 4.74 (d, J = 6.56 Hz, 1H), 4.71 (d, J = 6.56 Hz, 1H), 4.24 (m, 2H), 3.61 (s, 3H), 3.57 (s, 3H), 3.53 ( Dd, J = 8.82 Hz, J = 4.60 Hz, 1H), 3.44 (m, 1H), 3.41 (s, 3H), 3.04 (t, J = 9.21 Hz, 1H), 2.61 (m, 1H), 2.49 ( m, 1H), 2.03 (m, 8H), 1.67 (s, 3H), 1.61 (s, 3H), 1.59 (s, 3H), 1.58 (s, 3H), 1.33 (t, J = 7.08, 3H) ¹³ C-NMR (100.6 MHz, CDCl ₃ ): δ 154.48, 140.72, 136.60, 134.84, 131.21, 124.36, 124.19, 121.46, 111.30, 96.28, 85.41, 83.49, 78.70, 76.76, 64.15, 60.95, 60.86, 55.54, _{HRMS-EI 47.12,39.77,39.70,26.77,26.66,25.65,24.91,17.64,16.17,15.92,14.23C 29 H 48 O} 7 a (m / z) [m] + calcd: 508.3400, Found: 508.3410; The spectral data is as follows: R _f (hexane / ethyl acetate 4:1) 0.45. [α] _D ²⁵ = +4.5 ° (c = 1.0 in CHCl ₃ ). IR (film): 2925, 1734, 1456 , 1377, 1260, 1041, 919, 803. ¹ H-NMR (400MHz, CDCl ₃ ): δ 5.10 (m, 3H), 4.70 (d, J = 6.78 Hz, 1H), 4.60 (d, J = 6.78 Hz, 1H ), 3.87 (d, J = 5.78 Hz, 1H), 3.82 (dd, J = 3.87 Hz, J = 2.00 Hz, 1H), 3.50 (d, J = 5.70 Hz, J = 3.87 Hz, 1H), 3.49 ( s, 3H), 3.48 (s, 3H), 3.36 (s, 3H), 2.41 (m, 1H), 2.49 (m, 1H), 2.21 (m, 1H), 2.03 (m, 10H), 1.68 (s) , 3H), 1.60 (s, 9H), 1.19 (d, J = 7.38 Hz, 3H). ¹³ C-NMR (100.6 MHz, CDCl ₃ ): δ 210.77, 137.50, 135.19, 131.30, 124.35, 124.00, 121.80, 96.59,84.78,84.69,75.30,58.88,58.45,55.79,44.98,43.15,39.82,39.73,27.59,26.77,26.65,25.69,17.68,16.42,16.21,15.99.C ₂₆ H ₄₄ O ₅ HRMS-EI (m /z)[M] ⁺ Calculated value: 436.3189, found: 436.3181.

Example 3: Preparation of (±)-Android Quinol D from 4-methoxyphenol

3.1 Flowchart for (±)-Android Quinol D

The full synthesis of (±)-Android quinol was carried out according to the following Scheme III:

Diethyl Acetyl group iodobenzene (25.95g, 80.55mmol) was dissolved in 150mL CH ₂ Cl _2, cooled to 0 ℃. 4-Methoxyphenol (10.00 g, 80.55 mmol) containing 80 mL of MeOH was slowly added and allowed to reach room temperature, then stirred for 2 hr. After the reaction was completed, 50 mL of a saturated aqueous solution of sodium hydrogencarbonate was added and the mixture was extracted with CH ₂ Cl ₂ . The combined organic phases were dried over anhydrous sodium sulfate, filtered under reduced pressure and concentrated, and distilled under high vacuum to remove iodobenzene. The obtained crude product ( 25 ) was dissolved in THF (yield: EtOAc), EtOAc (EtOAc) The reaction mixture was concentrated and purified by column chromatography (hexane / EtOAc, 9: 1) The residue was purified on silica gel to give compound 26 (dimethyl-2- (2,2-dimethoxy-5 -Oxocyclohex-3-ene)malonate) (18.90 g, 66.52 mmol), yield of 82.6% in 2 steps.

At 0 ℃, the NaBH ₄ (0.09g, 2.38mmol) was added in 20mL MeOH was dissolved with stirring compound 26 (0.67g, 2.35mmol) and CeCl _3. 7H ₂ O (0.88 g, 2.35 mmol). After the reaction was completed, 5 mL of a saturated aqueous NaHCO ₃ solution was added. The methanol was removed, the residue was diluted with water, and then extracted with _{10mL CH 2 Cl 2 (2 ×} ). The combined organic phases were dried over anhydrous sodium sulfate then filtered and concentrated. The obtained crude product was dissolved in 5 mL of DMF, NaH (0.40 g, 8. After completion of the reaction, it was cooled, quenched with a saturated aqueous solution of NH ₄ Cl, and extracted with 10 mL of CH ₂ Cl ₂ (2×). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. product. The resulting residue was purified by column chromatography (hexane / EtOAc, 7: 3) was purified on silica gel to give compound (27) (methyl 6,6-dimethoxy-3-oxo-2- Hetero-bicyclo[3.3.1]non-7-en-4-carboxylate) (0.60 g, 2.34 mmol), yield 98.9% in 2 steps.

DABCO (3.10 g, 27.60 mmol) and H ₂ O (0.10 mL) were added to Compound 27 (1.76 g, 6.90 mmol) containing 50 mL of toluene, and then heated to reflux for 24 hours. The reaction mixture ( 28 ) was cooled and acidified with 1N HCl and stirred for 30 min. The reaction mixture was diluted with water, and the organic layer was evaporated. By column chromatography (hexane / EtOAc, 4: 1) The residue was purified on silica gel to give compound 29 (2-oxa - [3.3.1] non-7-ene-3,6-bicyclo Ketone) (0.68 g, 4.44 mmol), yield 64.3%.

At -20 ℃, the NaBH ₄ (5.80mg, 0.15mmol) in 5mL MeOH was added containing compound 29 (0.023g, 0.15mmol) and CeCl _3. 7H ₂ O (0.06 g, 0.15 mmol) was stirred for 10 minutes. NH ₄ Cl saturated aqueous reaction mixture was quenched, and to 5mL EtOAc (2 ×) for Cuiqu. The organic phase was dried over anhydrous magnesium sulfate, filtered and concentrated, purified by column chromatography (hexane / EtOAc, 4: 1) the crude product was purified on silica to obtain the alcohol type compound (30) (6-hydroxy - 2-oxa-bicyclo[3.3.1]non-7-en-3-one) (0.022 g, 0.14 mmol), yield 93.7%.

DIPEA (2 mL, 11.48 mmol) and MOMBr (1.07 g, 8.61 mmol) were added to a solution of compound 30 (0.884 g, 5.74 mmol) containing 10 mL of EDC and heated to 70 ° C for 2 hours. The reaction mixture was cooled to 10mL CH ₂ Cl ₂ was diluted with 1N HCl and is washed after, then washed with saturated aqueous NaHCO _3. The organic phase was dried over anhydrous MgSO.sub.sub.sub.sub.sub.sub.sub.sub. 2-oxa-bicyclo[3.3.1]non-7-en-3-one (0.99 g, 5.00 mmol), yield 86.6%.

A solution of OsO ₄ (0.12g, 0.49mmol) and NMO (0.58g, 5.00mmol) was added containing acetone _{/ H 2 O (33mL, 10} : 1) 6- (methoxymethoxy) -2- A solution of oxa-bicyclo[3.3.1]non-7-en-3-one (0.99 g, 4.98 mmol) was stirred for 24 hours. With 10% Na ₂ S ₂ O ₃ . 5H ₂ O The reaction was quenched mixture was stirred for 30 minutes and then Cuiqu to 10mL EtOAc (3 ×). The organic phase was dried over anhydrous magnesium sulfate, filtered and concentrated. The crude product was purified on silica gel by column chromatography (methanol /EtOAc, 1:9) to afford diol compound 31 (7,8-dihydroxy-6-(methoxymethoxy)-2-ox Hetero-bicyclo[3.3.1]nonan-3-one) (1.09 g, 4.72 mmol, dr > 15:1), yield 94.8%.

In a sealed tube, Ag ₂ O (1.5 g, 6.45 mmol) was added to a solution containing 5 mL of MeI Compound 31 (0.5 g, 2.15 mmol). The reaction mixture was stirred at <RTI ID=0.0></RTI><RTIgt;</RTI><RTIgt; By column chromatography (hexane / EtOAc, 7: 3) The crude product was purified on silica gel to give compound 32 (7,8-dimethoxy-6- (methoxymethoxy) -2- Oxa-bicyclo[3.3.1]nonan-3-one) (437 mg, 1.68 mmol), yield 77.8%.

Compound 32 (0.35g, 1.35mmol) was dissolved in 5mL CH ₂ Cl _2, and then cooled to -78 deg.] C under argon. DIBAL-H (1.1 M solution in cyclohexane) (1.35 mL, 1.48 mmol) was added and stirred at -78 °C for one hour. The reaction was quenched with MeOH then warmed to rt. 5 mL of 1 M sodium potassium tartrate solution was added and stirred for 2 hours. The extract was extracted with 10 mL of CH ₂ Cl ₂ (3×). The obtained crude product was dissolved in 10 mL of benzene, and ylide Ph ₃ PCH(CH ₃ )COOEt was added at 80 ° C, followed by heating and stirring in a turbulent manner for 6 hours. After the reaction, the solvent was concentrated under reduced pressure, and the crude product was purified on silica gel eluting with EtOAc (hexane/EtOAc, 4:1) to afford ( E )-4-(5-hydroxy-3,4-di Ethyl methoxy-2-(methoxymethoxy)cyclohexyl)-2-methyl-2-butenoate (400 mg, 1.16 mmol), yield 86%.

DTBSCl (0.225 g, 1.50 mmol), imidazole (0.157 g, 2.31 mmol) and DMAP (1.7 mg, 0.01 mmol) were added to ( E )-4-(5-(tert-butyldimethylhydrazine) containing 5 mL of DMF. A solution of ethyl 3-,4-dimethoxy-2-(methoxymethoxy)cyclohexyl)-2-methyl-2-butenoate (0.40 g, 1.16 mmol). The reaction mixture was stirred at room temperature for 24 hours and then a saturated NaHCO ₃ aqueous solution quenched with ether (3 ×, 10mL) was extracted, dried over anhydrous magnesium sulfate and the organic phases combined, filtered and concentrated. The crude product was purified by column chromatography (hexane/EtOAc, 9:1) to afford compound 33 (( E )-4-(5-(tert-butyldimethyloxy)-3, Ethyl 4-dimethoxy-2-(methoxymethoxy)cyclohexyl)-2-methyl-2-butenoate) (0.51 g, 1.11 mmol), yield 96%.

DIBAL-H (2.15 mL, 2.37 mmol) was added to a solution of compound 33 (436 mg, 0.95 mmol) containing 10 mL of CH ₂ Cl ₂ at -78 °C. After completion of the reaction, MeOH was added to terminate the reaction, after which 5 mL of 1.2 M sodium potassium tartrate was added and allowed to reach room temperature. In _{10mL CH 2 Cl 2 (2 ×} ) and the mixture was extracted, dried over anhydrous magnesium sulfate and the organic phases combined, concentrated and purified by column chromatography (hexane / EtOAc, 4: 1) and purified on silica gel The alcohol compound (346 mg, 0.83 mmol) was obtained in a yield of 87.3%.

PPh ₃ (0.24 g, 0.90 mmol) and CBr ₄ (0.30 g, 0.90 mmol) were added to a solution of the above-mentioned alcohol compound (346 mg, 0.83 mmol) containing 8 mL of CH ₂ Cl ₂ and stirred for 10 minutes. In quenched with saturated aqueous NaHCO ₃ and the mixture, and the organic layer thus separated. The solvent was concentrated under reduced pressure, by column chromatography (hexane / EtOAc, 9: 1) was purified on silica gel to obtain a bromo compound 34 ((E) - (5- (4- bromo-3-methyl 2-butenyl)-2,3-dimethoxy-4-(methoxymethoxy)cyclohexyloxy)(tert-butyl)dimethyl decane) (381 mg, 0.80 mmol), The rate is 96%.

At -78 deg.] C, the n -BuLi (0.06mL, 0.13mmol) was added in 5mL THF containing compound 35 (28.0mg, 0.12mmol) and stirred at the same temperature for 1 hour. Then, compound 34 (41.8 mg, 0.09 mmol) and 1 mL of THF were added and stirred for 1 hour. Saturated aqueous NH ₄ Cl and the mixture was quenched and allowed to reach room temperature. The mixture was extracted with 10 mL of EtOAc (2×). This residue was used in the next step. At -78 deg.] C to Li (0.7mg, 1mmol) was added to the solution in liquid NH ₃ so that a dark blue color. Then, the above coupling product and 2 mL of ether were added, and stirred at -60 ° C for 30 minutes. The mixture was quenched with MeOH and slowly warmed to room temperature during which aqueous ammonia evaporated. The mixture was extracted with a saturated aqueous solution of NH ₄ Cl and extracted with 10 mL of ether (2×), and the combined organic phases were dried over anhydrous magnesium sulfate, then filtered and concentrated. The residue was purified by chromatography on EtOAc (hexanes:EtOAc: 15:1) to afford compound 36 (t-butyl(2,3-dimethoxy-4-(methoxymethoxy)) 5-((2 E ,6 E )-3,7,11-trimethyl-2,6,10-dodecanetrienyl)cyclohexyloxy)dimethyl decane) (41.2 mg, 0.08 mmol ), the yield was 84.4%.

TBAF (0.15 mL, 0.15 mmol) was added to a solution of compound 36 (41.2 mg, 0.077 mmol) containing 3 mL of THF and stirred under reflux for 24 hours. After the reaction, the solvent was concentrated under reduced pressure, and then purified by chromatography on silica gel (hexane/EtOAc, 3:2) to obtain an alcohol compound.

Dess-Martin periodinane (0.045 g, 0.10 mmol) was added to a solution of the above alcohol compound containing 5 mL of CH ₂ Cl, and stirring was continued for 2 hours at room temperature. Diluted with CH ₂ Cl ₂ to the reaction mixture, saturated aqueous sodium bicarbonate and to the reaction was quenched, and washed with brine. The ketone compound ( 37 ) (2,3-dimethoxy-4-(methoxymethoxy)-5) was obtained by flash column chromatography (hexane/EtOAc, 9:1). - ((2 E, 6 E ) -3,7,11- trimethyl-2,6,10-triene-dodecyl-yl) cyclohexanone) (28mg, 0.066mmol) two step yield 87%.

LiHMDS (1 M solution in THF) (0.148 mL, 0.15 mmol) was added dropwise to a solution of Compound 37 (25 mg, 0.059 mmol) containing 1 mL of THF at -40 ° C for 30 min. The reaction mixture was cooled to -78 ° C, methyl iodide (9 μL, 0.065 mmol) was added, then the temperature was increased to 0 ° C and stirred for 1 hour. NH ₄ Cl solution to quench the mixture, and extracted with 5mL ether (2 ×), the organic phase over anhydrous magnesium sulfate and then filtered and concentrated. The crude product was purified on silica gel by column chromatography (hexane/EtOAc, 9:1) to afford compound 38 (2-methoxy-4-(methoxymethoxy)-6-hydro- 5-((2 E ,6 E )-3,7,11-trimethyl-2,6,10-dodecanetrienyl)cyclohexen-2-one) and compound 39 (2-methoxy 4--4-methoxymethoxy-6-methyl-5-((2E,6E)-3,7,11-trimethyl-2,6,10-dodecanetrienyl) Cyclohexen-2-one) (18.4 mg, 0.045 mmol) in 77% yield.

40% trifluoroacetic acid was added to compound 39 (10 mg, 0.024 mmol) containing 1 mL CH ₂ Cl ₂ at 0 °C. After stirring at room temperature for 2 hours, the reaction mixture was concentrated, and then purified and purified eluting with EtOAc (EtOAc/EtOAc, EtOAc (4-hydroxy-2-methoxy-6-methyl-5-((2 E ,6 E )-3,7,11-trimethyl-2,6,10-dodecanetrienyl) Cyclohexen-2-one) (5.7 mg, 0.016 mmol) in 64% yield.

3.2 Identification of synthetic compounds

In the preparation of (±)-Android quinol, the following new compounds were found: The spectral data is as follows: IR (KBr): 3630, 2955, 2839, 1737, 1691, 1629, 1506, 1437, 1380, 1290, 1260, 1228, 1197, 1156, 1110, 1076, 1052, 965, 924, 794 cm ^-1 ; ¹ H NMR (400 MHz, CDCl ₃ ): δ 6.75-6.72 (d, J = 10.4 Hz, 1H), 6.02 - 5.99 (d, J = 10.3 Hz, 1H), 3.64 (s, 3H), 3.61-3.59 ( m, 1H), 3.57 (s, 3H), 3.25-3.24 (m, 1H), 3.20 (s, 3H), 3.19 (s, 3H), 2.68-2.63 (dd, J ₁ = 17.6 Hz, J ₂ = 4.7 Hz, 1H), 2.57-2.51 (dd, J ₁ = 17.5 Hz, J ₂ = 6.0 Hz, 1H); ¹³ C NMR (100.6 MHz, CDCl ₃ ): δ 196.57, 168.59, 168.46, 145.55, 131.81, 98.01 _{, 52.65,52.28,50.53,50.28,49.45,40.17,37.51; HRMS-EI C 13} H 18 O 7 a (m / z) [m] + calcd: 286.1053; Found: 286.1058; The spectral data is as follows: IR (KBr): 2964, 2836, 2361, 1749, 1730, 1437, 1398, 1368, 1345, 1302, 1268, 1240, 1210, 1154, 1114, 1060, 1030, 983, 952 cm ^-1 ; ¹ H NMR (400MHz, CDCl ₃ ): δ 6.11-6.08 (m, 1H), 5.87-5.85 (d, J = 10.1 Hz, 1H), 4.74 - 4.73 (t, J = 1.0 Hz, 1H), 3.72 3.71 (t, J = 1.0 Hz, 3H), 3.66-3.65 (d, J = 2.2 Hz, 1H), 3.17-3.15 (m, 6H), 2.66 (s, 1H), 2.25-2.24 (d, J = 2.4 Hz, 2H); ¹³ C NMR (100.6 MHz, CDCl ₃ ): δ 170.03, 166.89, 130.72, 129.39, 98.02, 70.20, 52.99, 49.48, 48.15, 47.50, 36.56, 25.49; HRMS of C ₁₂ H ₁₆ O ₆ - EI (m / z) [M] ⁺ calculated value: 256.0947; found: 256.0940; The spectral data is as follows: ¹ H NMR (400 MHz, CDCl ₃ ): δ 7.21-7.17 (q, J = 6.0 Hz, 1H), 6.16-6.14 (d, J = 9.8 Hz, 1H), 5.06-5.05 (t , J = 1.6 Hz, 1H), 3.02 - 2.96 (m, 2H), 2.73 - 2.69 (m, 1H), 2.41 (s, 2H); ¹³ C NMR (100.6 MHz, CDCl ₃ ): δ 199.14, 167.97, _{144.92,130.15,69.05,40.17,34.18,29..67; HRMS-EI C 8 H} 8 O 3 in (m / z) [m] + calcd: 152.0473; Found: 152.0468; The spectral data is as follows: IR (KBr): 3398, 3038, 2930, 2867, 2361, 1716, 1449, 1374, 1319, 1257, 1208, 1172, 1107, 1066, 1036, 997, 978, 959, 918, 847, 783, 741, 667, 612, 612, 519 cm ^-1 ; ¹ H NMR ( 400MHz, CDCl ₃ ): δ 5.95-5.92 (m, 1H), 5.83-5.80 (d, J = 9.9 Hz, 1H), 4.68-4.68 (d, J = 2.4 Hz, 1H), 4.42 (s, 1H) , 3.64-6.62 (d, J = 10.2 Hz, 1H), 2.94 - 2.89 (d, J = 19.5 Hz, 1H), 2.56-2.49 (dd, J ₁ = 19.5 Hz, J ₂ = 8.4 Hz, 1H), 2.45 (br, 1H), 2.16-2.13 (d, J = 14.2 Hz, 1H), 1.92-1.88 (dd, J ₁ = 14.0 Hz, J ₂ = 0.9 Hz, 1H); ¹³ C NMR (100.6 MHz, CDCl) _{3): δ 172.95,134.70,126.47,69.70,69.41,31.08,28.56,28.24; HRMS-} EI C 8 H 10 O 3 a (m / z) [m] + calculated: 154.063; Found: 154.0625; The spectral data is as follows: IR (KBr): 3901, 3747, 3675, 3615, 3421, 2940, 2904, 2829, 1724, 1649, 1541, 1517, 1455, 1419, 1378, 1339, 1251, 1212, 1095, 1035 , 919, 618 cm ^-1 ; ¹ H NMR (400 MHz, CDCl ₃ ): δ 4.71-4.67 (q, J = 7.0 Hz, 2H), 4.61 (s, 1H), 4.18 - 4.16 (d, J = 9.9 Hz, 1H ), 3.68-3.64 (dd, J ₁ = 5.6 Hz, J ₂ = 4.2 Hz, 1H), 3.57-3.55 (m, 2H), 3.37 (s, 3H), 2.92-2.87 (d, J = 18.9 Hz, 1H), 2.52-2.45 (dd, J ₁ = 19.1 Hz, J ₂ = 7.4 Hz, 1H), 2.40 (s, 1H), 2.18-2.15 (d, J = 14.2 Hz, 1H), 1.90 - 1.86 (d , J =14.4 Hz, 1H); ¹³ C NMR (100.6 MHz, CDCl3): δ 170.35, 97.18, 80.64, 76.82, 70.11, 68.30, 55.86, 30.88, 30.70, 23.54.C HRMS-EI of ₁₀ H ₁₆ O ₆ (m/z) [M] ⁺ calculated: 232.0947; found: 232.0940; The spectral data is as follows: IR (KBr): 2935, 2828, 1738, 1650, 1541, 1452, 1378, 1291, 1248, 1206, 1125, 1106, 1078, 1039, 916, 765, 692, 646, 608, cm ^-1 ; ¹ H NMR (400 MHz , CDCl ₃ ): δ 4.78-4.76 (d, J = 6.8 Hz, 1H), 4.68-4.65 (d, J = 6.7 Hz, 2H), 3.87-3.82 (m, 2H), 3.47 (s, 3H), 3.45 (s, 3H), 3.35 (s, 3H), 3.23-3.20 (dd, J ₁ = 10.1 Hz, J ₂ = 3.6 Hz, 1H), 3.02-2.97 (dd, J ₁ = 18.9 Hz, J ₂ = 1.8 Hz, 1H), 2.54-2.47 (dd, J ₁ = 19.0 Hz, J ₂ = 7.3 Hz, 1H), 2.41 (s, 1H), 2.12-2.09 (d, J = 14.3 Hz, 1H), 1.89- 1.85 (d, J = 14.4 Hz, 1H); ¹³ C NMR (100.6 MHz, CDCl ₃ ): δ 169.99, 96.93, 78.22, 77.22, 76.88, 74.77, 59.50, 58.54, 55.61, 30.94, 30.82; The spectral data are as follows: IR (KBr): 2932, 2897, 2824, 2362, 1713, 1650, 1462, 1198, 1175, 1128, 1039, 1007, 991, 935, 919, 836, 777, 747, 670 cm ^-1 ; ¹ H NMR (400 MHz, CDCl ₃ ): δ 6.77-6.74 (t, J = 7.0 Hz, 1H), 4.69-4.67 (d, J = 6.9 Hz, 1H), 4.62-4.60 (d, J = 6.9 Hz, 1H), 4.21-4.16 (q, J =7.1 Hz, 2H), 3.87-3.81 (m, 1H), 3.76-3.75 (t, J = 3.4 Hz, 1H), 3.68 (s, 1H), 3.46 (s, 3H), 3.43 (s, 3H) , 3.41 (s, 3H), 3.24 - 3.21 (dd, J ₁ = 9.1 Hz, J ₂ = 2.8 Hz, 1H), 2.28-2.23 (m, 1H), 2.19-2.11 (m, 1H), 2.01-1.95 (m, 1H), 1.83 (s, 3H), 1.65-1.58 (m, 1H), 1.48-1.39 (m, 1H), 1.30-1.27 (t, J = 7.1 Hz, 3H), 0.88 (s, 9H) ), 0.08 (s, 3H), 0.06 (s, 3H); ¹³ C NMR (100.6 MHz, CDCl ₃ ): δ 168.06, 140.31, 128.78, 97.69, 83.67, 78.57, 77.19, 70.10, 60.47, 58.92, 58.73, _{55.94,35.15,32.24,3.055,25.88,18.12,14.28,12.58, -4.49, -4.71; C 23} H 44 O 7 Si in HRMS-EI (m / z) [m] + calcd: 460.2856; Found: 460.2859; The spectral data are as follows: IR (KBr): 2931, 2823, 1700, 1650, 1541, 1521, 1393, 1253, 1208, 1152, 1129, 1100, 1039, 1007, 919, 879, 777 cm ^-1 ; ¹ H NMR (400 MHz, CDCl ₃ ): δ 5.62-5.58 (t, J = 6.8 Hz, 1H), 4.69-4.67 (d, J = 6.9 Hz, 1H), 4.63-4.61 (d, J = 7.0 Hz, 1H), 3.97 (s , 2H), 3.85-3.79 (m, 1H), 3.75 (s, 1H), 3.67 (s, 1H), 3.46 (s, 3H), 3.42, (s, 3H), 3.41 (s, 3H), 3.23 -3.20 (dd, J ₁ = 9.1 Hz, J ₂ = 2.7 Hz, 1H), 2.12-1.97 (m, 2H), 1.87-1.85 (m.1H), 1.76 (s, 3H), 1.62-1.56 (m , 1H), 1.43-1.34 (m, 1H), 0.88 (s, 9H), 0.08 (s, 3H), 0.07 (s, 3H); The spectral data are as follows: IR (KBr): 2930, 1650, 1540, 1524, 1390, 1254, 1140, 1103, 1008 cm ^-1 ; ¹ H NMR (400 MHz, CDCl ₃ ): δ 5.29-5.28 (d, J = 3.3 Hz, 1H), 5.11-5.09 (d, J = 6.5 Hz, 3H), 4.67-4.60 (dd, J ₁ = 21.8 Hz, J ₂ = 6.8 Hz, 2H), 3.83 - 3.79 (m, 1H), 3.73-3.71 (d, J = 9.7 Hz, 2H), 3.47 (s, 3H), 3.41 (s, 3H), 3.40 (s, 3H), 3.24 - 3.22 (d, J = 7.4 Hz, 1H), 2.06 -1.97 (m, 12H), 1.68 (s, 6H), 1.43-1.36 (m, 4H), 1.25 (s, 9H), 0.88 (s, 9H), 0.08 (s, 3H), 0.06 (s, 3H) ¹³ C NMR (100.6 MHz, CDCl ₃ ): δ 136.40, 135.07, 131.27, 124.37, 124.17, 122.67, 97.72, 83.90, 78.87, 70.45, 58.79, 58.63, 55.79, 40.00, 39.86, 39.74, 35.16, 34.84, 29.71,26.86,26.77,25.89,25.69,18.13,17.68,16.24,15.97,-4.49,-4.68;HRMS-EI(m/z)[M] ⁺ calculated for C ₃₁ H ₅₈ O ₅ Si: 538.4054; Value: 538.4058; The spectral data are as follows: IR (KBr): 2924, 2854, 1716, 1456, 1383, 1254, 1145, 1008 cm ^-1 ; ¹ H NMR (400 MHz, CDCl ₃ ): δ 5.11-5.07 (m, 3H), 4.79 -4.77 (d, J = 6.8 Hz, 1H), 4.73-4.71 (d, J = 6.8 Hz, 1H), 4.22-4.21 (d, J = 3.0 Hz, 1H), 4.06-4.05 (d, J = 3.6) , 1H), 3.88 (m, 1H), 3.49 (s, 3H), 3.45 (s, 3H), 3.44 (s, 3H), 2.64 (m, 1H), 2.33-1.95 (m, 12H), 1.67 ( s, 3H), 1.59 (s, 3H), 1.58 (s, 3H), 1.57 (s, 3H); ¹³ C NMR (100.6 MHz, CDCl ₃ ): δ 206.72, 138.16, 137.24, 135.19, 124.33, 123.96, 121.47,97.79,84.00,82.89,76.81,59.21,58.62,56.08,41.89,39.71,39.68,38.25,26.73,26.57,25.66,22.66,17.65,16.22,15.98,14.08;HRMS-EI of C ₂₅ H ₄₂ O ₅ (m/z) [M] ⁺ calculated: 422.3032; found: 422.3034; The spectral data is as follows: R _f (hexane / EtOAc, 4: ¹ ) 0.53. IR (film): 2921, 2851, 1682, 1640, 1456, 1365, 1148, 976 cm ^-1 ; ¹ H-NMR (400 MHz, CDCl ₃ ): δ 5.87 (d, J = 5.48 Hz, 1H), 5.10 (m, 3H), 4.72 (d, J = 6.84 Hz, 1H), 4.66 (d, J = 6.76 Hz, 1H), 4.33 ( m,1H), 3.62(s,3H), 3.36(s,3H), 2.75(m,1H),2.30-1.92(m,9H),1.67(s,3H),1.56(s,6H),1.52 (s, 3H), 1.16 (d, J = 7.20 Hz, 3H). ¹³ C-NMR (100.6MHz, CDCl ₃ ): δ 190.51, 151.35, 137.35, 135.19, 131.31, 124.33, 124.00, 121.70, 113.42, 96.38 , HRMS-EI (m / z ) 71.00,55.48,54.92,45.74,42.78,39.82,39.71,27.13,26.75,26.54,25.68,17.67,16.18,16.04,12.90.C 25 H 40 O 4 of [m] ⁺ Calculated value: 404.2927; measured value: 404.2924; The spectral data is as follows: R _f (hexane / EtOAc, 7:3) 0.4. IR (film): 2920, 2851, 1685, 1637, 1442, 1376, 1247, 1148, 1080 cm ^-1 ; ¹ H-NMR ( 400MHz, CD ₃ OD): δ 5.92 (d, J = 5.60 Hz, 1H), 5.22 (t, J = 7.30 Hz, 1H), 5.10 (m, 2H), 4.49 (dd, J ₁ = 5.24 Hz, J ₂ = 3.80 Hz, 1H), 3.61 (s, 3H), 2.68 (m, 1H), 2.27.97 (m, 9H), 1.80 (m, 1H), 1.67 (s, 3H), 1.63 (s, 3H) ), 1.61 (s, 3H), 1.60 (s, 3H), 1.16 (d, J = 7.00 Hz, 3H); ¹³ C-NMR (100.6 MHz, CDCl ₃ ): δ 198.84, 152.06, 138.11, 136.02, 132.12 , 125.44, 125.34, 123.29, 116.67, 65.07, 55.34, 47.48, 43.40, 40.93, 40.86, 28.13, 27.82, 27.40, 25.87, 17.75, 16.19, 16.14, 13.09; C ₂₃ H ₃₆ O ₃ HRMS-EI (m/ z) [M] ⁺ calculated: 360.2664; found: 360.2668.

Example 4: Lipase Inhibitory Activity of Android Quinol

4.1 lipase activity test

The inhibition of lipase activity by Andrew Quinol was determined by Winkler modification, which was measured by the increase in absorbance at 410 nm, which was produced by hydrolysis of p-nitrophenyl palmitate (p-NPP). Caused by p-nitrophenol. The solution used in this test contained Solution I: 5 mg p-NPP dissolved in 3 mL isopropanol; Solution II: 88 mg Triton X-100 and 22.4 mg gum arabic dissolved in 20 mL 50 mM Tris buffer (pH 8.0) And solution III: A reaction mixture comprising solution I and solution II (1:9) was freshly prepared prior to testing. 75 μL of Android Quinol (0.1 uM, 0.5 uM, 1 uM) or 46 nM orlistat, or 0.5 mg simvastatin, 50 μL lipase solution (8 mg/mL) in Tris buffer (50 mM, pH 8.0) (Type 2 lipase from the porcine pancreas, 100-400 units/mg protein, using olive oil (cultured for 30 minutes), 30-90 units/mg protein (triacetin, Sigma, St.Louis, MO, USA) And 75 μL of Solution III as a mixture of the substance was mixed in a vial and incubated at 37 ° C for 1 hour. Orlistat as a positive control group was used to compare the inhibitory activity of the enzyme activity of Android quinol (0.1 uM, 0.5 uM, 1 uM).

4.2 Animals

C57BL/6 mice were obtained from the National Laboratory Animal Center (Taipei, Taiwan) and maintained in a controlled environment at room temperature (22 ± 2 ° C) and humidity (60 ± 10%). Maintaining 12h light throughout the study Photo and 12h dark light period (0600am-1800pm). Mice were given free access to feed and water and maintained under the standard laboratory diet (carbohydrate 60%; protein 28%; lipid 12%; vitamin 3%).

4.3 Fat-induced lipase

The drug was combined by oral gavage (po once a day) with 100 uL total saturated fatty acids and 77% total unsaturated fatty acids (Chinshan oil, Wei Lih Foods Co., Changhua, Taiwan): 50 mg/ Kg body weight of Android Quinol; 2.2 mg/kg body weight of orlistat (GlaxoSmithKline Consumer Healthcare, LP, Aiken South Carolina, USA); 12 mg/kg body weight of simvastatin (Sigma-Aldrich) for induction for 10 weeks Male C57BL/6 mice were seven days old. Test mice were divided into 5 groups (n=6), including normal control group, fat-induced, 2.2 mg/body weight of orlistat, 50 mg/kg body weight of Android quinol, and 12 mg/kg body weight of simvastatin. .

4.4 Blood biochemical detection

After 7 days of induction, blood samples of the mice were collected by penetration of the facial veins. The blood sample was centrifuged at 3000 rpm and 4 ° C for 10 minutes to obtain a serum sample. Serum was separated and analyzed for lipase and triglyceride (TG) using an automated analyzer (ARTAX Menarini Diagnostics, Florence, Italy) with enzyme colorimetric assay strips (Human, Wiesbaden, Germany).

4.5 fecal triglyceride test

0.5 g of feces per mouse was added to 10 mL of a chloroform/methanol/H2O (1:2:0.8) solution, thoroughly stirred at room temperature for 30 minutes, and centrifuged at 6000 rpm for 10 minutes. 500 μL of the supernatant was removed, and 500 μL of chloroform and water were added, respectively. After mixing, the sample was centrifuged at 6000 rpm for 10 minutes at room temperature. The supernatant was removed and 500 μL of chloroform layer was taken to a new microcentrifuge tube. Place the tube in a fume hood to allow the chloroform to evaporate. After evaporative drying, 200 μL of isopropanol/triton X-100 (9:1) solution was added. then, Triglyceride (TG) was analyzed by an automatic analyzer (ARTAX Menarini Diagnostics, Florence, Italy) with an enzyme colorimetric assay strip.

4.6 Statistical analysis

All data were presented as mean plus standard deviation (mean ± standard deviation) and analyzed by one-way ANOVA and Turkish assays. All statistical analysis procedures were performed in GraphPad Prism version 5.01 (GraphPad Software, Inc., La Jolla, CA, USA).

The results are presented in Figure 1, including (A) lipase activity, (B) serum lipase, and (C) fecal triglyceride. In view of the results shown in Figure 1, the conclusion is that Andrew Quinol has the potential to inhibit lipase activity and increase fecal triglyceride, with results similar to or better than orlistat or simvastatin. Therefore, Android Quinol can be developed into a drug for the treatment of obesity.

The present invention is intended to be used in the broadest scope of the invention, and the scope of the invention may be The scope of the invention is to be construed as being limited by the scope of the invention.

Claims (28)

A use of a compound for the preparation of a composition or medicament for the treatment of obesity, wherein the compound is of the formula (I): Wherein X, Y and Z are the same or different, independently hydrogen, oxygen, sulfur, selenium, or NH, and each of R ¹ , R ² , R ³ and R ⁴ is the same or different, independently hydrogen, Alkyl, aryl, or alkoxy. The use of Patent Range 1 wherein the compound of formula (I) is Android Quinol. The use of Patent Range 1, wherein the compound of the formula (I) is (+)-Android quinol. The use of Patent Range 1, wherein the compound of the formula (I) is (-)-Android quinol. The use of the patent scope 1, 2, 3 or 4, wherein the compound of the formula (I) is effective for inhibiting lipase activity. The use of the patent scope 1, 2, 3 or 4, wherein the compound of the formula (I) is effective for increasing fecal triglyceride. A method of treating obesity in a subject comprising administering to the subject a pharmaceutical acceptable carrier and a pharmaceutically effective amount of a compound of formula (I): Wherein X, Y and Z are the same or different, independently hydrogen, oxygen, sulfur, selenium, or NH, and each of R ¹ , R ² , R ³ and R ⁴ is the same or different, independently hydrogen, Alkyl, aryl, or alkoxy. The method of claim 7, wherein the compound of the formula (I) is an Android quinol. The method of claim 7, wherein the compound of the formula (I) is (+)-Android quinol. The method of claim 7, wherein the compound of the formula (I) is (-)-Android quinol. A method of preparing an Android quinol comprising a Suzuki-Miyaura cross-coupling reaction, a Barton-McCombie reaction, and a selenization/oxidation step. The method of claim 11, comprising the steps of: (1) treating compound 1 Addition to lithium trimethyl decyl acetylide and treatment with potassium carbonate (K ₂ CO ₃ ) / methanol (MeOH) to give compound 2 (2) treating compound 2 with tert-butyldimethylchloromethane (TBSCl) in dichloromethane (DCM, CH ₂ Cl ₂ ) and triethylamine to give compound 3 (3) Conversion of Compound 3 to Compound 4 by excess deuterated thiochloroformate and pyridine in DCM via Barton-McCombie deoxygenation reaction Then, compound 4 is treated with tributyltin hydride (Bu ₃ SnH) and azobisisobutyronitrile (AIBN) in cyclopentyl methyl ether via a deoxy radical cyclization reaction to produce compound 5 , (4) in MeOH, pyridine p-toluenesulfonate (pyridinium p -toluenesulfonate; PPTS) treating the compound 5 to give compound 6 Followed by iodination reaction, as well as methoxymethyl (MOM) ether treatment to obtain Compound 7, (5) program to Marshall (Marshall protocol) Compound 7 And compound 8 Performing Suzuki-Miyaura cross-coupling reaction to obtain compound 9 , followed by deprotection of tert-butyldimethylmethylalkyl (TBS) ether with tetrabutylammonium fluoride (TBAF), and oxidation of the resulting alcohol with Dess-Martin periodinane to obtain a compound 10 (6) treating compound 10 with Raney nickel, followed by treatment with cerium (III) chloride (CeCl ₃ ) and oxalic acid in acetonitrile followed by Purdie reagent (Ag ₂ O, MeI) Dimethylation to obtain compound 11 (7) treating compound 11 with tetras-trimethyldecylamino lithium (LiHMDS) in tetrahydrofuran (THF), followed by oxidation elimination reaction with hydrogen peroxide (H ₂ O ₂ ) to obtain compound 12 Then, compound 12 was treated with dry zinc bromide (ZnBr ₂ ) and ethanethiol in DCM to obtain (+) or (-)-Android quinol. The method of claim 12, comprising the steps as shown in flow chart I below: The method of claim 11, comprising the steps of: (1) treating compound 14 with trimethyldecyl acetylene and n-butyllithium; And get compound 15 And then treated with ethyl chloroformate in DCM and pyridine to give compound 16 (2) treating compound 16 with phenyl chlorochloroformate and pyridine in DCM to obtain compound 17 , Then deoxygenated via radical cyclization reaction, cyclopentyl methyl ether, Bu ₃ SnH and AIBN in a process to produce Compound 17 Compound 18 And compound 19 Compound 18 is treated with hydrochloric acid (HCl) in methanol to obtain compound 20 (3) treating compound 20 with toluenesulfonyl chloride and N,N -diisopropylethylamine in DCM, followed by refluxing with sodium iodide in acetone for iodination and treatment with MOM ether to obtain compound 21 (4) heating a solution containing activated zinc in a THF solution at 50 ° C to bond compound 21 with compound 8 , followed by bis(di-tert-butyl(4-dimethylaminophenyl)phosphine) dichloride in THF Palladium (II) (PdCl ₂ (Amphos) ₂ ) and tetramethylethylenediamine (TMEDA) are treated to obtain compound 22 , followed by treatment with K ₂ CO ₃ in MeOH to give compound 23 (5) treating compound 23 with a Dess-Martin oxidant followed by treatment with Raney nickel to obtain compound 24 Then, compound 24 is treated with LiHMDS in THF, followed by oxidation elimination reaction with H ₂ O ₂ to obtain compound 12 , and then compound 12 is treated with ZnBr ₂ and ethanethiol in DCM to obtain (+) or (- ) - Andrew Quinnor. The method of claim 14, comprising the steps as shown in Flowchart II below: A novel process for the preparation of Android quinol comprising chelation and non-stereoselective cyclohexenone reduction and quality control, lactonization, dimethyl malonate on cyclohexadienone The reaction, the dihydroxylation, the Wittig olefination reaction, and the sesquiterpene side chain obtained by coupling the geranyl phenyl sulfide and the Bouveault-Blanc reduction reaction. The method of claim 16, comprising the steps of: (1) making 4-methoxyphenol Reacted with methanol to produce Compound 25 Adding Compound 25 to dimethyl malonate to obtain Compound 26 Then, compound 26 is placed under Luche condition, followed by lactonization to obtain compound 27 (2) Compound 27 is subjected to Krapcho decarboxylation reaction in toluene and water with 1,4-diazabicyclo[2.2.2]octane (DABCO) to obtain compound 28 And treating compound 28 with HCl to obtain compound 29 , (3) in MeOH, sodium borohydride (NaBH ₄₎ of CeCl _3, and treating compound 29 to give compound 30 Then, compound 30 is treated with MOM ether and subjected to a dihydroxylation reaction, followed by treatment with osmium tetroxide (OsO ₄ ) and N-methylmorpholine oxide (NMO) in acetone-water to obtain compound 31. (4) treating compound 31 with Purdie's reagent (methyl iodide, silver oxide) to obtain compound 32 Then, compound 32 is reduced to hemiacetal with diisobutylaluminum hydride (DIBAL-H), and then in benzene, triphenylphosphonium ylide (Ph ₃ PC (Me) CO ₂ Et) is subjected to a condensation reaction, and then treated with TBS ether to obtain a compound 33 , (5) under the reaction conditions Appel _{(Appel reaction condition) (CBr 4} / PPh 3, DCM, 0 ℃), the bromination reaction by treatment of compound 33 to give compound 34 And compound 34 with lithioation compound 35 in the presence of TMEDA Coupling to obtain compound 36 Compound 36 is then treated with TBAF in THF followed by oxidation of the alcohol intermediate with a Dess-Martin oxidant to obtain compound 37 (6) obtaining compound 38 in THF with lithium diisopropylamide (LDA) or compound 37 at LiHMDS Or compound 39 , then treated with TFA in DCM to obtain (±)-Android Quinol D (Compound 40 ) . The method of claim 17, comprising the steps of flow chart III below: A compound selected from the group consisting of: ,as well as A pharmaceutical composition comprising a compound as claimed in claim 19. A compound selected from the group consisting of: ,as well as A pharmaceutical composition comprising a compound as claimed in claim 21. A compound selected from the group consisting of: ,as well as A pharmaceutical composition comprising a compound as claimed in claim 23. A composition or pharmaceutical composition for treating obesity comprising a therapeutically effective amount of a compound of formula (I) as described in claim 1 and a pharmaceutically acceptable carrier. A pharmaceutical composition according to claim 25, wherein the compound of the formula (I) is an Android quinol. A pharmaceutical composition according to claim 26, or a use thereof, wherein the compound of the formula (I) is (+)-Android quinol. A pharmaceutical composition according to claim 26, wherein the compound of the formula (I) is (-)-Android quinol.