A method for preparing a benzo[6,6]spiroketal compound

Abstract

The present invention relates to a method for preparing a benzo[6,6]-spiroketal compound, belonging to the technical field of organic synthesis. The method for preparing the benzo[6,6]-spiroketal compound of the present invention comprises the following steps: reacting a phenyl hydroxy ketone compound, an acid, and a solvent at 20-35 °C for 30-120 min to obtain the benzo[6,6]-spiroketal compound. The method for preparing the benzo[6,6]-spiroketal compound of the present invention only needs to use an acid as a catalyst to efficiently synthesize the benzo[6,6]-spiroketal compound in one step under room temperature and normal pressure. The reaction conditions of the present invention are simple and mild, the reaction time is short, the reaction efficiency is high, and the yield can reach 91%. Using conventional ethyl acetate as a solvent conforms to atom economy. Compared with using precious metals as catalysts, using p-toluenesulfonic acid as a catalyst has a lower cost and is simple to obtain.

Description

Technical Field

[0001] The present invention relates to the technical field of organic synthesis, and particularly relates to a method for preparing a benzo[6,6]-spiroketal compound. Background Art

[0002] Compounds with a benzo[6,6]-spiroketal skeleton are widely present in natural products and chiral spirocyclic ligands. Generally, for the benzo[6,6]-spiroketal skeleton, most cases use dihydroxy ketones or dihydroxy alkynes as substrates to directly undergo spiroketalization. There are a few synthesis cases that use intramolecular oxa-Michael addition, [4+2] cycloaddition reaction, oxidative radical cyclization, and metal catalysis. The above preparation methods are complex, use noble metals as catalysts with high costs, have relatively harsh reaction conditions (such as high reaction temperature), and cannot directly synthesize benzo[6,6]-spiroketal compounds in one step, having certain limitations. Summary of the Invention

[0003] The purpose of the present invention is to overcome the deficiencies of the prior art and provide a method for preparing a benzo[6,6]-spiroketal compound capable of directly synthesizing a benzo[6,6]-spiroketal skeleton in one step reaction.

[0004] To achieve the above purpose, the technical solution adopted by the present invention is as follows:

[0005] The present invention provides a method for preparing a benzo[6,6]-spiroketal compound, including the following steps: reacting a phenylhydroxy ketone compound, an acid, and a solvent at 20-35°C for 30-120 min to obtain the benzo[6,6]-spiroketal compound; the structural formula of the phenylhydroxy ketone compound is as shown in Formula 1, and the structure of the benzo[6,6]-spiroketal compound is as shown in Formula 2:

[0006] ;

[0007] The solvent is ethyl acetate; the acid is p-toluenesulfonic acid; the phenylhydroxy ketone compound is prepared from a ketene compound as a raw material; the structural formula of the ketene compound is as shown in Formula 3:

[0008]

[0009] By selecting a phenylhydroxy ketone compound as the reaction substrate, the present invention directly synthesizes a compound containing a benzo[6,6]-spiroketal skeleton through one-step reaction under acid catalysis, with mild, simple, and efficient reaction conditions and atom economy.

[0010] An acid is a substance that can accept electron pairs. p-Toluenesulfonic acid belongs to one of the acids and has an acid-catalyzing effect. The TBS group on the phenylhydroxy ketone compound forms a hydroxyl group under the catalysis of an acid, and the hydroxyl group at the benzylic position undergoes a hemi-ketalization reaction with the ketone group, and then undergoes a ketalization reaction with another hydroxyl group to form a benzo[6,6]-spiroketal skeleton. During the experiment, the inventor found that p-toluenesulfonic acid in the acid gave the highest yield (91%) of benzo[6,6]-spiroketal compounds as a catalyst.

[0011] As a preferred embodiment of the preparation method described in the present invention, the molar ratio of the phenylhydroxy ketone compound to the acid is phenylhydroxy ketone compound: acid = 1:(1 - 2.5). Within the preferred ratio range, the phenylhydroxy ketone compound can efficiently complete the spirocyclization reaction to synthesize benzo[6,6]-spiroketal compounds under the catalysis of an excessive amount of acid, and the yield of benzo[6,6]-spiroketal compounds is above 88%.

[0012] As a preferred embodiment of the preparation method described in the present invention, the molar ratio of the phenylhydroxy ketone compound to the acid is phenylhydroxy ketone compound: acid = 1:(1 - 1.5). Within the preferred ratio range, the phenylhydroxy ketone compound can efficiently complete the spirocyclization reaction to synthesize benzo[6,6]-spiroketal compounds under the catalysis of an excessive amount of acid, and the yield of benzo[6,6]-spiroketal compounds is above 90%.

[0013] As a preferred embodiment of the preparation method described in the present invention, the molar ratio of the phenylhydroxy ketone compound to the acid is phenylhydroxy ketone compound: acid = 1:1. Within the preferred ratio range, the phenylhydroxy ketone compound can efficiently complete the spirocyclization reaction to synthesize benzo[6,6]-spiroketal compounds under the catalysis of an acid, and the yield of benzo[6,6]-spiroketal compounds is 91%.

[0014] As a preferred embodiment of the preparation method described in the present invention, the reaction time is 30 - 60 min. Under the preferred parameter conditions, the phenylhydroxy ketone compound can efficiently synthesize benzo[6,6]-spiroketal compounds under the catalysis of an acid, and the yield of benzo[6,6]-spiroketal compounds is above 90%.

[0015] As a preferred embodiment of the preparation method described in the present invention, the reaction time is 30 min. Under the preferred parameter conditions, the phenylhydroxy ketone compound can efficiently synthesize benzo[6,6]-spiroketal compounds under the catalysis of an acid, and the highest yield of benzo[6,6]-spiroketal compounds is 91%.

[0016] As a preferred embodiment of the preparation method described in the present invention, the preparation method of the phenylhydroxy ketone compound comprises the following steps:

[0017] (1)Perform a metathesis reaction on the enone compound, (1,3-bis-(2,4,6-trimethylphenyl)-2-imidazolidinylidene)dichloro(o-isopropoxybenzylidene)ruthenium, [(1-penten-4-yloxy)methyl]benzene, and dichloromethane to obtain compound A4;

[0018] (2)Perform a reduction reaction on the compound A4 obtained in step (1), diisobutylaluminum hydride, and dichloromethane to obtain compound A5;

[0019] (3)Perform a reduction reaction on the compound A5 obtained in step (2), palladium / carbon, sodium carbonate, and tetrahydrofuran to obtain compound A6;

[0020] (4)Perform a nucleophilic substitution reaction on the compound A6 obtained in step (3), tert-butyldimethylsilyl chloride, and triethylamine to obtain compound A7;

[0021] (5)Perform an oxidation reaction on the compound A7 obtained in step (4), phthalic ester, and dichloromethane to obtain compound A8;

[0022] (6)Perform a reduction reaction on the compound A8 obtained in step (5), palladium / carbon, and tetrahydrofuran to obtain a phenylhydroxyketone compound;

[0023] The structural formula of compound A4 in step (1) is as shown in formula 4, the structural formula of compound A5 in step (2) is as shown in formula 5, the structural formula of compound A6 in step (3) is as shown in formula 6, the structural formula of compound A7 in step (4) is as shown in formula 7, and the structural formula of compound A8 in step (5) is as shown in formula 8:

[0024]

[0025] The enone compound extends the carbon chain of the acryloyl group and connects a benzyloxy group under the action of [(1-penten-4-yloxy)methyl]benzene and the catalyst (1,3-bis-(2,4,6-trimethylphenyl)-2-imidazolidinylidene)dichloro(o-isopropoxybenzylidene)ruthenium to obtain compound A4; the formate group on the benzene ring of compound A4 is reduced to a hydroxyl group under the action of the reducing agent diisobutylaluminum hydride (DIBAL) to obtain compound A5; the carbon-carbon double bond on the carbon chain of compound A5 is broken under the action of the catalyst palladium / carbon and sodium carbonate to obtain compound A6; the hydrogen of the hydroxyl group on the benzene ring of compound A6 is replaced by TBS under the action of triethylamine and tert-butyldimethylsilyl chloride (TBSCl) to obtain compound A7; the hydroxyl group on the carbon chain of compound A7 is oxidized to a ketone group under the action of phthalic diester (DMP) to obtain compound A8; using palladium / carbon as a catalyst, the benzyl group in compound A8 is removed and reduced to a hydroxyl group to obtain a phenylhydroxyketone compound with a phenylhydroxy group and a ketone group.

[0026] As a preferred embodiment of the preparation method of the present invention, at least one of the following (I) to (VI):

[0027] (I) The condition for the metathesis reaction in step (1) is to react at normal temperature and pressure for 8 h;

[0028] (II) The condition for the reduction reaction in step (2) is to react at -78 °C and normal pressure for 60 min;

[0029] (III) The condition for the reduction reaction in step (3) is to react under the bubbling of a hydrogen balloon at normal temperature for 20 min;

[0030] (IV) The condition for the nucleophilic substitution reaction in step (4) is to react at normal temperature and pressure for 120 min;

[0031] (V) The condition for the oxidation reaction in step (5) is to react at normal temperature and pressure for 10 min;

[0032] (VI) The condition for the reduction reaction in step (6) is to react under hydrogen at room temperature and normal pressure for 30 min.

[0033] As a preferred embodiment of the preparation method of the present invention, the enone compound is prepared through the following steps:

[0034] (1) Perform a nucleophilic substitution reaction on methyl 2,4-dihydroxy-3,6-dimethylbenzoate, triethylamine, tert-butyldimethyltrifluorosilane, and dichloromethane to obtain compound A2; the condition for the nucleophilic substitution reaction is to react at normal temperature and pressure for 8 h;

[0035] (2) Perform an acylation reaction on compound A2 obtained in step (1), 2,2,6,6-tetramethylpiperidine, n-butyllithium, zinc chloride, tetrakis(triphenylphosphine)palladium, acryloyl chloride, and a solvent to obtain an enone compound;

[0036] The structural formula of compound A2 is as shown in formula 9:

[0037] ;

[0038] Among them, the acylation reaction in step (2) is specifically:

[0039] (a) React 2,2,6,6-tetramethylpiperidine, n-butyllithium, and a solvent at normal temperature and pressure for 30 min to obtain a mixed liquid system 1;

[0040] (b) Add compound A2 and a solvent to the mixed liquid system 1 obtained in step (a) at -78 °C and react at -78 °C for 90 min to obtain a mixed system 2;

[0041] (c) Mix the mixed system 2 obtained in step (b) with zinc chloride, react at -78 °C for 20 min, and stir at room temperature for 25 min to obtain a mixed system 3;

[0042] (d) Mix the mixed system 3 obtained in step (c), tetrakis(triphenylphosphine)palladium, acryloyl chloride and a solvent, and react at normal temperature and pressure for 10 h to obtain a ketene compound.

[0043] The hydrogen atoms on the hydroxyl groups at the 2nd and 4th carbon positions on the benzene ring of methyl 2,4-dihydroxy-3,6-dimethylbenzoate are replaced by TBS groups under the action of tert-butyldimethylsilyl trifluoromethanesulfonate (TBSOTf) and triethylamine to obtain compound A1; the methyl group at the 6th carbon position of compound A1 is connected with an acryloyl group under the action of 2,2,6,6-tetramethylpiperidine (HTMP), n-butyllithium, zinc chloride, tetrakis(triphenylphosphine)palladium and acryloyl chloride to obtain compound a1.

[0044] Compared with the prior art, the beneficial effects of the present invention are as follows:

[0045] The preparation method of the benz[6,6]-spiroketal compound of the present invention only needs to use an acid as a catalyst to efficiently synthesize the benz[6,6]-spiroketal compound in one step at room temperature and normal pressure. Compared with the method of using metal or boron reagents to catalyze the cyclization of dihydroxyalkynes in the prior art, the reaction conditions of the present invention are simple and mild, the reaction time is short, the reaction efficiency is high, the yield of the benz[6,6]-spiroketal compound can reach 91%, and conventional ethyl acetate, tetrahydrofuran, and dichloromethane are used as solvents, which conforms to atom economy. Compared with using precious metals as catalysts, using p-toluenesulfonic acid as a catalyst has a lower cost and is simple and easy to obtain. Brief Description of the Drawings

[0046] Figure 1 It is the total synthesis reaction process of the benz[6,6]-spiroketal compound of the present invention;

[0047] Figure 2 It is the nuclear magnetic resonance hydrogen spectrum of the benz[6,6]-spiroketal compound in Example 1 of the present invention;

[0048] Figure 3 It is the nuclear magnetic resonance carbon spectrum of the benz[6,6]-spiroketal compound in Example 1 of the present invention;

[0049] Figure 4 It is the nuclear magnetic resonance hydrogen spectrum of compound A4 of the present invention;

[0050] Figure 5 It is the nuclear magnetic resonance carbon spectrum of compound A4 of the present invention;

[0051] Figure 6 It is the nuclear magnetic resonance hydrogen spectrum of compound A5 of the present invention;

[0052] Figure 7 13C NMR spectrum of compound A5 of the present invention;

[0053] Figure 8 1H NMR spectrum of compound A6 of the present invention;

[0054] Figure 9 13C NMR spectrum of compound A6 of the present invention;

[0055] Figure 10 1H NMR spectrum of compound A7 of the present invention;

[0056] Figure 11 13C NMR spectrum of compound A7 of the present invention;

[0057] Figure 12 1H NMR spectrum of compound A8 of the present invention;

[0058] Figure 13 13C NMR spectrum of compound A8 of the present invention. Detailed Description of the Invention

[0059] To better illustrate the purpose, technical solution and advantages of the present invention, the present invention will be further described below in conjunction with specific embodiments.

[0060] The materials, reagents, etc. used in the following examples and comparative examples can be obtained from commercial sources unless otherwise specified.

[0061] Example 1

[0062] An embodiment of the preparation method of the benz[6,6]-spiroketal compound of the present invention. The preparation method of the benz[6,6]-spiroketal compound described in this embodiment is as Figure 1 shown and includes the following steps:

[0063] (1) After mixing 1M methyl 2,4-dihydroxy-3,6-dimethylbenzoate (compound A1), 3.5M triethylamine, and 0.2M dichloromethane, 2.2M tert-butyldimethylsilyl trifluoromethanesulfonate (TBSOTf) was added under a nitrogen environment at 0 °C, and the reaction was carried out at normal temperature and pressure for 8 h. The reaction was quenched with saturated ammonium chloride aqueous solution, extracted, washed, dried, concentrated, and purified to obtain compound A2;

[0064] (2) 1.5 M of n-butyllithium was added dropwise to 1.5 M of 2,2,6,6-tetramethylpiperidine and 0.5 M of tetrahydrofuran at -78 °C, and the reaction was carried out at normal temperature and pressure for 30 min to obtain a mixed system 1; 1 M of compound A2 obtained in step (1) and 0.5 M of tetrahydrofuran were added to the mixed system 1 at -78 °C, and the reaction was carried out at -78 °C for 90 min to obtain a mixed system 2; the mixed system 2 was mixed with 1.5 M of zinc chloride, and the reaction was carried out at -78 °C for 20 min, and then stirred at room temperature for 25 min to obtain a mixed system 3; the mixed system 3, 0.05 M of tetrakis(triphenylphosphine)palladium, 2 M of acryloyl chloride and 0.5 M of tetrahydrofuran were mixed, and the reaction was carried out at normal temperature and pressure for 10 h to obtain compound A3;

[0065] (3) 1 M of compound A3 obtained in step (2), 1 M of [(1-penten-4-yloxy)methyl]benzene, 0.1 M of dichloromethane and 0.02 M of (1,3-bis-(2,4,6-trimethylphenyl)-2-imidazolidinylidene)dichloride(o-isopropoxybenzylidene)ruthenium were reacted at room temperature for 8 h, concentrated, and purified to obtain compound A4;

[0066] (4) 1 M of compound A4 obtained in step (3), 3.2 M of diisobutylaluminum hydride and 0.1 M of dichloromethane were reacted at -78 °C and normal pressure for 60 min, quenched with dilute hydrochloric acid, extracted with ethyl acetate, washed, dried, concentrated, and purified to obtain compound A5;

[0067] (5) 1 M of palladium / carbon, 0.2 M of sodium carbonate and 0.1 M of tetrahydrofuran were added to 1 M of compound A5 obtained in step (4), and the reaction was carried out at room temperature with hydrogen balloon bubbling for 20 min, filtered, and concentrated to obtain compound A6;

[0068] (6) 0.1 M of compound A6 obtained in step (5), 1.5 M of triethylamine, 1.5 M of tert-butyldimethylchlorosilane (TBSCl) and 0.1 M of dichloromethane were reacted at normal temperature and pressure for 120 min, the reaction was stopped by adding water, extracted, washed, dried, concentrated, and purified to obtain compound A7;

[0069] (7) 1.5 M of phthalic acid ester, 1 M of compound A7 obtained in step (6) and 0.1 of dichloromethane were reacted at normal temperature and pressure for 10 min, the reaction was stopped with saturated aqueous sodium bicarbonate solution and aqueous sodium thiosulfate solution, extracted, washed with water, dried, concentrated, and purified to obtain compound A8;

[0070] (8) 1 M of palladium / carbon, 1 M of compound A8 obtained in step (7) and 0.1 M of tetrahydrofuran were reacted under hydrogen at room temperature for 30 min to obtain phenylhydroxy ketone compound (compound 1);

[0071] (9) React 1 M of phenylhydroxy ketone compound, 1 M of p-toluenesulfonic acid, and 0.2 M of ethyl acetate at room temperature for 30 min, quench with water, extract with ethyl acetate three times, combine the organic phases extracted three times, wash, dry, filter, concentrate under reduced pressure, and purify by column chromatography to obtain benz[6,6]-spiroketal compound (Compound 2);

[0072] In the above steps, unless otherwise specified, dichloromethane is used for extraction, saturated brine is used for washing, concentrated by rotary evaporator, and purified by silica gel column chromatography;

[0073] In the above steps, the structural formulas of Compounds A1 to A8, Compound 1, and Compound 2 are as follows:

[0074]

[0075] Example 2

[0076] An embodiment of the preparation method of the benz[6,6]-spiroketal compound of the present invention. The preparation method of the benz[6,6]-spiroketal compound in this embodiment is similar to that in Example 1, except that the reaction time in step (9) is 60 min, and the other parameter conditions remain unchanged.

[0077] Example 3

[0078] An embodiment of the preparation method of the benz[6,6]-spiroketal compound of the present invention. The preparation method of the benz[6,6]-spiroketal compound in this embodiment is similar to that in Example 1, except that the reaction time in step (9) is 120 min, and the other parameter conditions remain unchanged.

[0079] Example 4

[0080] An embodiment of the preparation method of the benz[6,6]-spiroketal compound of the present invention. The preparation method of the benz[6,6]-spiroketal compound in this embodiment is similar to that in Example 1, except that the concentration of p-toluenesulfonic acid in step (9) is 2.5 M, and the other parameter conditions remain unchanged.

[0081] Example 5

[0082] An embodiment of the preparation method of the benz[6,6]-spiroketal compound of the present invention. The preparation method of the benz[6,6]-spiroketal compound in this embodiment is similar to that in Example 1, except that the concentration of p-toluenesulfonic acid in step (9) is 1.5 M, and the other parameter conditions remain unchanged.

[0083] Comparative Example 1

[0084] A comparative example of the preparation method of the benz[6,6]-spiroketal compound of the present invention. The preparation method of the benz[6,6]-spiroketal compound in this comparative example is similar to that in Example 1, except that compound 1 is replaced by compound 3, and the remaining parameter conditions remain unchanged.

[0085] The preparation method of compound a1 is similar to that of compound 1, except that TBSOTf in step (1) is replaced by tert-butyldiphenylchlorosilane (TBDPSCl), and TBSCl in step (6) is replaced by TBDPSCl, and the remaining steps and parameter conditions remain unchanged.

[0086] Comparative Example 2

[0087] A comparative example of the preparation method of the benz[6,6]-spiroketal compound of the present invention. The preparation method of the benz[6,6]-spiroketal compound in this comparative example is similar to that in Example 1, except that the reaction time in step (9) is 20 min, and the remaining parameter conditions remain unchanged.

[0088] Comparative Example 3

[0089] A comparative example of the preparation method of the benz[6,6]-spiroketal compound of the present invention. The preparation method of the benz[6,6]-spiroketal compound in this comparative example is similar to that in Example 1, except that p-toluenesulfonic acid in step (9) is replaced by hydrochloric acid, and the remaining parameter conditions remain unchanged.

[0090] Comparative Example 4

[0091] A comparative example of the preparation method of the benz[6,6]-spiroketal compound of the present invention. The preparation method of the benz[6,6]-spiroketal compound in this comparative example is similar to that in Example 1, except that the concentration of p-toluenesulfonic acid in step (9) is 3.5 M, and the remaining parameter conditions remain unchanged.

[0092] Effect Example 1 Characterize the compound

[0093] The compounds 2, A4 - A8 were characterized by nuclear magnetic resonance (NMR), and the results are shown in Figures 2 to 13 .

[0094] As Figure 2 , 3 shown, compound 2 has 48 hydrogen atoms in the 1H NMR spectrum and 27 carbon atoms in the 13C NMR spectrum, which is in line with expectations, and it is determined that compound 2 was successfully prepared.

[0095] As Figure 4 , 5As shown, compound A4 has 54 hydrogen atoms in its 1H NMR spectrum and 35 carbon atoms in its 13C NMR spectrum, which is in line with expectations, indicating that compound A4 has been successfully prepared.

[0096] As Figure 6 , 7 shown, compound A5 has 56 hydrogen atoms in its 1H NMR spectrum and 34 carbon atoms in its 13C NMR spectrum, which is in line with expectations, indicating that compound A5 has been successfully prepared.

[0097] As Figure 8 , 9 shown, compound A6 has 58 hydrogen atoms in its 1H NMR spectrum and 34 carbon atoms in its 13C NMR spectrum, which is in line with expectations, indicating that compound A6 has been successfully prepared.

[0098] As Figure 10 , 11 shown, compound A7 has 72 hydrogen atoms in its 1H NMR spectrum and 40 carbon atoms in its 13C NMR spectrum, which is in line with expectations, indicating that compound A7 has been successfully prepared.

[0099] As Figure 12 , 13 shown, compound A8 has 70 hydrogen atoms in its 1H NMR spectrum and 40 carbon atoms in its 13C NMR spectrum, which is in line with expectations, indicating that compound A8 has been successfully prepared.

[0100] Effect Example 2: Determination of the Yield of Compounds

[0101] According to the yield calculation formula, the yields of compounds A2 - A8 and compound 1 in Example 1 were calculated, and the results are shown in Table 1; the yields of compound 2 in Examples 1 - 5 and Comparative Examples 1 - 4 were calculated, and the results are shown in Table 2. The calculation formula is yield (%) = (theoretical yield / actual yield) × 100%.

[0102] Table 1 Yields of Compounds A2 - A8 and Compound 1

[0103]

[0104] Table 2 Yields of Compound 2 in Examples 1 - 5 and Comparative Examples 1 - 4

[0105]

[0106] As shown in Tables 1 and 2, the yield of the phenylhydroxyketone compound (Compound 1) obtained by the preparation method of the present invention reaches 90%. The yield of the benz[6,6]-spiroketal compound (Compound 2) synthesized by one-step reaction of the phenylhydroxyketone compound under acidic conditions is up to 91% at most, and the yield remains above 88% within the reaction time range of 30 - 120 min, indicating that the phenylhydroxyketone compound prepared by the preparation method of the present invention can efficiently synthesize the benz[6,6]-spiroketal compound under the catalysis of an acid, which conforms to the atom economy in organic chemistry. When the reaction time is 20 min, the cyclization reaction is incomplete, and the yield of the obtained benz[6,6]-spiroketal compound is only 70%, which is lower than the yields of Examples 1 - 5, indicating that the yield of the benz[6,6]-spiroketal compound obtained by the preparation method of the present invention is the highest when the reaction time is within 30 - 120 min. When the TBS group in Compound 1 is replaced by the TBDPS group, the benz[6,6]-spiroketal compound cannot be formed under acid catalysis because the TBDPS group is very stable to acids and cannot be deprotected and complete the cyclization reaction under acid catalysis, so the benz[6,6]-spiroketal compound cannot be obtained. Therefore, the TBS group that can be catalyzed by an acid is used as the protecting group to enable the phenylhydroxyketone compound to complete the cyclization reaction under acid catalysis to obtain the benz[6,6]-spiroketal compound. When p-toluenesulfonic acid is replaced by hydrochloric acid, the phenylhydroxyketone compound can complete the cyclization reaction to synthesize the benz[6,6]-spiroketal compound, but the yield of the benz[6,6]-spiroketal compound is only 50%, which does not conform to the high reaction efficiency characteristic of the present invention. When the concentration of p-toluenesulfonic acid is 3.5 M, the yield of the obtained benz[6,6]-spiroketal compound is 85%, which is better than other comparative examples but lower than that of the examples, indicating that the yield of the benz[6,6]-spiroketal compound is the highest within the range of the molar ratio of phenylhydroxyketone compound to p-toluenesulfonic acid of 1:(1 - 2.5).

[0107] Finally, it should be noted that the above examples are only used to illustrate the technical solutions of the present invention rather than to limit the protection scope of the present invention. Although the present invention has been described in detail with reference to the preferred embodiments, those of ordinary skill in the art should understand that the technical solutions of the present invention can be modified or equivalently replaced without departing from the essence and scope of the technical solutions of the present invention.

Claims

1. A method for preparing a benzo[6,6]-spiroketal compound, characterized in that, it comprises the following steps: reacting a phenylhydroxy ketone compound, an acid, and a solvent at 20-35 °C for 30-120 min to obtain the benzo[6,6]-spiroketal compound; the structural formula of the phenylhydroxy ketone compound is shown in Formula 1, and the structure of the benzo[6,6]-spiroketal compound is shown in Formula 2: the solvent is ethyl acetate; the acid is p-toluenesulfonic acid; the phenylhydroxy ketone compound is prepared from a ketene compound as a raw material; the structural formula of the ketene compound is shown in Formula 3: the molar ratio of the phenylhydroxy ketone compound to the acid is phenylhydroxy ketone compound: acid = 1:(1-2.5); the preparation method of the phenylhydroxy ketone compound comprises the following steps: (1) Performing a metathesis reaction on a ketene compound, (1,3-bis-(2,4,6-trimethylphenyl)-2-imidazolidinylidene)dichloro(o-isopropoxybenzylidene)ruthenium, [(1-penten-4-oxy)methyl]benzene, and dichloromethane to obtain compound A4; (2) Performing a reduction reaction on the compound A4 obtained in step (1), diisobutylaluminum hydride, and dichloromethane to obtain compound A5; (3) Performing a reduction reaction on the compound A5 obtained in step (2), palladium / carbon, sodium carbonate, and tetrahydrofuran to obtain compound A6; (4) Performing a nucleophilic substitution reaction on the compound A6 obtained in step (3), tert-butyldimethylchlorosilane, and triethylamine to obtain compound A7; (5) Performing an oxidation reaction on the compound A7 obtained in step (4), phthalic acid ester, and dichloromethane to obtain compound A8; (6) Performing a reduction reaction on the compound A8 obtained in step (5), palladium / carbon, and tetrahydrofuran to obtain the phenylhydroxy ketone compound; the structural formula of compound A4 in step (1) is shown in Formula 4, the structural formula of compound A5 in step (2) is shown in Formula 5, the structural formula of compound A6 in step (3) is shown in Formula 6, the structural formula of compound A7 in step (4) is shown in Formula 7, and the structural formula of compound A8 in step (5) is shown in Formula 8:

2. The preparation method according to claim 1, characterized in that, the molar ratio of the phenylhydroxy ketone compound to the acid is phenylhydroxy ketone compound: acid = 1:(1-1.5).

3. The preparation method according to claim 2, characterized in that, the molar ratio of the phenylhydroxy ketone compound to the acid is phenylhydroxy ketone compound: acid = 1:

1.

4. The preparation method according to claim 1, characterized in that, the reaction time is 30-60 min.

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