Cyclohexenone spirolactone derivative and preparation method thereof

Abstract

The preparation method comprises the following steps: firstly, removing air and moisture in a reaction container, and then carrying out nitrogen replacement on the reaction container; adding a certain amount of an o-bromophenyl acetylenic ketone compound, an indanone compound and an alkali accelerant into the reaction container treated in the step 1 in a nitrogen atmosphere, and then adding a reaction solvent; sealing the reaction container, and stirring and reacting for 2-3 hours under the heating condition of the reaction container; after the reaction is finished, adding acid into the reaction container and stirring at room temperature; adding a certain amount of an oxidant and a catalyst into the reaction container, placing the reaction container at room temperature, and carrying out a stirring reaction for a certain time; and after the reaction is completed, adding water for quenching, and carrying out column separation to obtain the target product cyclohexenone spirolactone derivative. The one-pot two-step preparation method is simple and convenient, the raw materials are simple and easy to obtain, and the prepared ketene spirolactone derivative can be used as an organic synthesis intermediate.

Description

Technical Field

[0001] The present invention belongs to the technical field of cyclohexenone spiro lactone derivatives, and particularly relates to a cyclohexenone spiro lactone derivative and a preparation method thereof. Background Art

[0002] Cyclohexenone is a very important organic intermediate. Since its structure contains C=O and C=C, it can undergo chemical reactions such as addition, oxidation, reduction, polymerization, and condensation. The cyclohexenone fragment is widely present in fragrance and flavor, medicine, pesticide, surfactant, and polymer material molecules. Highly functionalized cyclohexenone compounds are widely present in the molecular structures of natural products. For example, Discorhabdin A, the most cytotoxic in anti-colon tumor drugs, and Delesconol B have important uses in weakening human rejection reactions and the treatment of autoimmune diseases. Puupehenone is a natural product molecule isolated from deep-sea sponges and has pharmacological properties such as antifungal, anti-tumor, and anti-malaria ([ Figure 1 ).

[0003]

[0004] Over the years, scientists have tried many synthetic methods for cyclohexenone compounds. The synthesis of existing cyclohexenone compounds mostly reports intramolecular cyclization reactions. Although this method meets the requirements of atom economy, it still has great limitations. The main limitations are: the need to synthesize phenolic compounds with complex structures, and usually requires noble metal catalysis. Therefore, there is still a need to develop a more economical and efficient synthesis method for cyclohexenone compounds with simple and easily available substrates and simple reaction conditions. Summary of the Invention

[0005] To achieve the above object and solve the above problems existing in the prior art, the cyclohexenone spiro lactone derivative prepared by the raw materials and methods of the present invention is prepared by a one-pot two-step method with simple operation, simple and easily available raw materials, and the prepared enone spiro lactone derivative can be used as an organic synthesis intermediate.

[0006] One object of the present invention is to provide a cyclohexenone spiro lactone derivative,

[0007] whose structure is shown in formula (I):

[0008]

[0009]

[0010] Wherein, R 1 is hydrogen, chlorine, fluorine or methyl; R 2 is hydrogen, fluorine or methoxy.

[0011] As a preferred embodiment, the cyclohexenone spiro lactone derivatives are selected from:

[0012]

[0013] The second object of the present invention is to provide a preparation method of cyclohexenone spiro lactone derivatives, comprising the following steps:

[0014] In a certain amount of solvent, the raw material o-bromophenyl alkynone compounds and indanone compounds are successively reacted under the action of a base and under acid-catalyzed oxidation conditions to prepare cyclohexenone spiro lactone derivatives.

[0015] As a preferred embodiment, in the second step, the o-bromophenyl alkynone compounds are alkynones with an electron-withdrawing group or an electron-donating group attached to the benzene ring.

[0016] As a preferred embodiment, the reaction process is shown in formula (II):

[0017]

[0018] Wherein, R 1 is hydrogen, chlorine, fluorine or methyl; R 2 is hydrogen, fluorine or methoxy group.

[0019] Comprising the following steps:

[0020] Step 1: First, remove the air and moisture in the reaction vessel, and then replace the air in the reaction vessel with nitrogen;

[0021] Step 2: Under a nitrogen atmosphere, first add a certain amount of o-bromophenyl alkynone compounds, indanone compounds and a base promoter to the reaction vessel treated in Step 1, and then add a reaction solvent;

[0022] Step 3: Seal the reaction vessel in Step 2, and stir the reaction vessel under heating conditions for 2-3 h;

[0023] Step 4: After the reaction in Step 3 is completed, add acid to the reaction vessel and stir at room temperature;

[0024] Step 5: Add a certain amount of oxidant and catalyst to the reaction vessel in Step 4, and place the reaction vessel at room temperature and stir for a certain time;

[0025] Step 6: After the reaction is completed, quench with water and separate by column chromatography to obtain the target product cyclohexenone spiro lactone derivatives.

[0026] As a preferred embodiment, the o-bromophenyl alkynone compounds are selected from:

[0027]

[0028] As a preferred embodiment, in the second step, the molar ratio of the o-bromophenylpropynone compound: the indanone compound: the base promoter is 1:1-2:1-2, and the base promoter is Cs2CO3.

[0029] As a preferred embodiment, in the third step, the reaction vessel is stirred and reacted for 2-3 h under the heating condition of 80-140 °C.

[0030] As a preferred embodiment, in the fourth step, the acid is selected from one of hydrochloric acid, sulfuric acid, nitric acid or acetic acid.

[0031] As a preferred embodiment, in the fifth step, a certain amount of oxidant and catalyst are added to the reaction vessel in the fourth step, and the reaction vessel is placed at room temperature and stirred and reacted for 1-3 h.

[0032] As a preferred embodiment, in the fifth step, the oxidant is selected from one of iodobenzene acetate or iodine.

[0033] As a preferred embodiment, in the fifth step, the catalyst is one of copper chloride, cuprous iodide, cuprous bromide, ferric chloride or ferrous bromide.

[0034] In this scheme, the obtained cyclohexenone spiro lactone derivatives can exhibit potential anti-tumor activity, antibacterial and antiviral activities in medicine.

[0035] The reaction mechanism of the present invention is as follows: The present invention uses o-bromophenylpropynone compounds and indanone compounds as raw materials, and undergoes an intramolecular nucleophilic addition reaction under the action of a base to generate intermediate I. Intermediate I undergoes a 1,3-H migration to generate intermediate II. Intermediate II undergoes an intramolecular nucleophilic attack to generate a spiro intermediate III. Intermediate III undergoes isomerization again under alkaline conditions to generate an allenone intermediate V. The intermediate is hydrolyzed into intermediate VI under acidification. Intermediate VI generates a radical intermediate VII in the presence of an oxidant and a catalyst. Finally, an intramolecular radical attack gives the product 1-3a. The reaction mechanism process is as follows:

[0036]

[0037] The present invention has the following beneficial effects:

[0038] First, the present invention prepares cyclohexenone spiro lactone derivatives from o-bromophenylpropynone compounds and indanone compounds, which can be used as organic synthesis intermediates, have good biological activity, and have potential pharmaceutical activity and medicinal value.

[0039] Second, by optimizing the preparation method of cyclohexenone spiro lactone derivatives, the one-pot two-step method is adopted in this solution, which can effectively reduce raw material loss. The raw materials used are simple and easily available, and the preparation process is green and economical, and the method is easy to operate; the method has good universality. By strictly controlling the process indexes, the substrates with electron-donating or electron-withdrawing groups can all obtain the target product cyclohexenone spiro lactone derivatives in good yields through the preparation process of this solution. BRIEF DESCRIPTION OF THE DRAWINGS

[0040] Figure 1 Structural formulas of some highly functionalized cyclohexenone derivatives in the prior art;

[0041] Figure 2 General structural formula of cyclohexenone spiro lactone derivatives in the present invention;

[0042] Figure 3 General structural formula of the starting material o-bromophenyl propargyl ketone compounds in the present invention;

[0043] Figure 4 Reaction general formula of cyclohexenone spiro lactone derivatives in the present invention;

[0044] Figure 5 Reaction mechanism diagram of the present invention;

[0045] Figure 6 Reaction formula of Example 1;

[0046] Figure 7 1H NMR spectrum (400 MHz, CDCl3) of the product 1-3a obtained in Example 1;

[0047] Figure 8 13C NMR spectrum (100 MHz, CDCl3) of the product 1-3a obtained in Example 1;

[0048] Figure 9 Reaction formula of Example 2;

[0049] Figure 10 1H NMR spectrum (400 MHz, CDCl3) of the product 1-3b obtained in Example 2;

[0050] Figure 11 13C NMR spectrum (100 MHz, CDCl3) of the product 1-3b obtained in Example 2;

[0051] Figure 12 Single crystal structure diagram of the product 1-3b obtained in Example 2;

[0052] Figure 13 Reaction formula of Example 3;

[0053] Figure 141H NMR spectrum (400 MHz, CDCl3) of the product 1-3c obtained in Example 3;

[0054] Figure 15 13C NMR spectrum (100 MHz, CDCl3) of the product 1-3c obtained in Example 3;

[0055] Figure 16 Reaction scheme of Example 4;

[0056] Figure 17 1H NMR spectrum (400 MHz, CDCl3) of the product 1-3d obtained in Example 4;

[0057] Figure 18 13C NMR spectrum (100 MHz, CDCl3) of the product 1-3d obtained in Example 4;

[0058] Figure 19 Reaction scheme of Example 5;

[0059] Figure 20 1H NMR spectrum (400 MHz, CDCl3) of the product 1-3e obtained in Example 5;

[0060] Figure 21 13C NMR spectrum (100 MHz, CDCl3) of the product 1-3e obtained in Example 5;

[0061] Figure 22 Reaction scheme of Example 6;

[0062] Figure 23 1H NMR spectrum (400 MHz, CDCl3) of the product 1-3f obtained in Example 6;

[0063] Figure 24 1H NMR spectrum (400 MHz, CDCl3) of the product 1-3f obtained in Example 6;

[0064] Figure 25 Reaction scheme of Example 7;

[0065] Figure 26 1H NMR spectrum (400 MHz, CDCl3) of the product 1-3g obtained in Example 7;

[0066] Figure 27 13C NMR spectrum (100 MHz, CDCl3) of the product 1-3g obtained in Example 7;

[0067] Figure 28 Reaction scheme of Application Example 1;

[0068] Figure 29 Crystal structure diagram of the target product of Application Example 1;

[0069] Figure 30 Reaction formula for Application Example 2;

[0070] Figure 31 Crystal structure diagram of the target product in Application Example 2; Detailed implementation manners

[0071] To make the technical means, creative features, achieved purposes and beneficial effects of the present invention easy to understand, the present invention will be further described below in conjunction with specific implementation manners.

[0072] In addition, to better illustrate the present invention, numerous specific details are given in the following detailed implementation manners. Those skilled in the art should understand that the present invention can also be implemented without some specific details. In other embodiments, methods, means, equipment and steps well-known to those skilled in the art are not described in detail in order to highlight the gist of the present invention.

[0073] The present invention provides a cyclohexenone spiro lactone derivative, the structure of which is shown in formula (I):

[0074]

[0075] wherein, R 1 is hydrogen, chlorine, fluorine or methyl; R 2 is hydrogen, fluorine or methoxy group.

[0076] The present invention also provides a preparation method for the above cyclohexenone spiro lactone derivative, comprising the following steps:

[0077] In a certain amount of solvent, the raw material o-bromophenyl propynone compound and indanone compound are successively under the action of a base promoter and under the condition of acid-catalyzed oxidation to synthesize a cyclohexenone spiro lactone derivative;

[0078] The reaction process is shown in formula (II):

[0079]

[0080] wherein, R 1 is hydrogen, chlorine, fluorine or methyl; R 2 is hydrogen, fluorine or methoxy group.

[0081] The specific preparation method of the above cyclohexenone spiro lactone derivative is as follows:

[0082] Step 1: First, remove the air and moisture in the reaction vessel, and then replace the air in the reaction vessel with nitrogen;

[0083] In this step, a Schlenk tube is used as the reaction device. First, under vacuum conditions, a heat gun is used to remove the air and moisture in the reaction tube, and then the reaction tube is replaced with nitrogen;

[0084] Step 2: Under a nitrogen atmosphere, first add a certain amount of o-bromophenyl propargyl ketone compounds, indanone compounds and a base promoter to the reaction vessel treated in Step 1, and then add a reaction solvent.

[0085] In this step, under a nitrogen atmosphere, first add o-bromophenyl propargyl ketone and indanone compounds, and then add a base promoter. The base promoter can be selected from one of K2CO3, Cs2CO3 or t-BuOK. Preferably, Cs2CO3 is selected. Then add a dry reaction solvent. The reaction solvent is one of N,N-dimethylformamide, N,N-dimethylacetamide or dimethyl sulfoxide.

[0086] Preferably, N,N-dimethylacetamide is selected. The dosage of the reaction solvent is preferably 1 mL of the reaction solvent added per 0.1 mmol of o-bromophenyl propargyl ketone compounds. The molar ratio of o-bromophenyl propargyl ketone compounds: indanone compounds: base promoter is 1:1 - 2:1 - 2.

[0087] Step 3: Seal the reaction vessel in Step 2 and stir the reaction in the reaction vessel under heating conditions for 2 - 3 h.

[0088] In this Step 3, after the feeding is completed, seal the reaction tube, place the reaction tube in an oil bath and heat it, and stir the reaction at 80 - 140 °C for 2 - 3 h. Preferably, react at 100 °C for 3 h.

[0089] Step 4: After the reaction in Step 3 is completed, add an acid to the reaction vessel and stir at room temperature.

[0090] In this step, after the reaction in Step 3 is completed, add any one of hydrochloric acid, nitric acid, sulfuric acid or acetic acid. Preferably, hydrochloric acid is selected, and stir at room temperature for more than 2 min.

[0091] Step 5: Add a certain amount of an oxidant and a catalyst to the reaction vessel in Step 4, and place the reaction vessel under room temperature conditions and stir the reaction for 1 - 3 h; preferably, stir the reaction at room temperature for 2 h; the molar ratio of o-bromophenyl propargyl ketone compounds: oxidant: catalyst is 1:1 - 3:0.05 - 0.1. Preferably, the molar ratio of o-bromophenyl propargyl ketone compounds: oxidant: catalyst is 1:2:0.1. The oxidant is selected from iodine or iodobenzene acetate, and the catalyst is one of copper chloride, copper iodide, copper bromide, iron chloride or iron bromide.

[0092] Step 6: After the reaction is completed, quench with water and perform column chromatography separation to obtain a pure target product cyclohexenone spiro lactone derivatives.

[0093] In this Step 6, the reaction was quenched by adding water, and extracted with ethyl acetate for more than three times. The organic phases were combined, dried over anhydrous sodium sulfate, rotary evaporated, and purified by column chromatography to obtain the pure product cyclohexenone spiro lactone derivatives.

[0094] The obtained product cyclohexenone spiro lactone derivatives may exhibit potential anti-tumor activity, antibacterial and antiviral activities in medicine.

[0095] Example 1

[0096] Synthesis of 1-3a: Synthesis of 2'-phenyl-4'H-spiro[isochromene-1,1'-naphthalene]-3,4-dione.

[0097]

[0098] Using a Schlenk tube as the reaction device, first, the reaction tube was purged with nitrogen, and then 0.3 mmol of 1-(2-bromophenyl)-3-phenylprop-2-yn-1-one and 0.6 mmol of 1,3-dihydro-2H-inden-2-one were added under a nitrogen atmosphere. Then 0.3 mmol of the catalyst Cs2CO3 was added, and then 3 ml of the dry reaction solvent N,N-dimethylacetamide was added. After the addition was completed, the reaction tube was sealed and reacted at 100 °C in an oil bath for 3 h. Then 0.6 mmol of hydrochloric acid (1 M HCl, 0.6 mL) was added and stirred at room temperature for 2 min. Then 0.6 mmol of iodobenzene diacetate and 0.03 mmol of iron(III) chloride were added, and then stirred at room temperature for 2 h. After the reaction was completed, the reaction was quenched by adding water, extracted with 10 ml (10 ml each time) of ethyl acetate for three times, the organic phases were combined, dried over anhydrous sodium sulfate, rotary evaporated, and purified by column chromatography with petroleum ether:ethyl acetate = 3:1 to obtain the target product of formula (1-3a), a light yellow solid, 76.0 mg, with a separation yield of 72%.

[0099] NMR data: 1 H NMR(400MHz,CDCl3)δ2.44(d,J=10.8Hz,1H),3.55(d,J=10.8Hz,1H),6.32(S,1H),6.77-6.83(m,3H),6.94-6.97(m,1H),7.15-7.19(m,1H),7.22-7.29(m,4H),7.34-7.39(m,1H),7.51-7.61(m,2H),8.22-8.26(m,1H); 1313C NMR (100 MHz, CDCl3) δ 183.8, 167.6, 158.4, 143.9, 135.4, 133.9, 132.0, 130.3, 129.6, 129.1, 129.0, 128.8, 122.8, 128.3, 1278, 127.7, 127.5, 126.7, 126.0, 84.8, 32.5.

[0100] Example 2

[0101] Synthesis of 1-3b: Synthesis of 2'-(p-tolyl)-4'H-spiro[isochromene-1,1'-naphthalene]-3,4-dione.

[0102]

[0103] Using a Schlenk tube as the reaction device, first replace the reaction tube with nitrogen, and then add 0.3 mmol of 1-(2-bromophenyl)-3-(p-tolyl)prop-2-yn-1-one and 0.6 mmol of 1,3-dihydro-2H-indene-2-one under a nitrogen atmosphere. Then add 0.3 mmol of the catalyst Cs2CO3, and then add 3 ml of the dry reaction solvent N,N-dimethylacetamide. After the addition is completed, seal the reaction tube and react at 100 °C in an oil bath for 3 h. Then add 0.6 mmol of hydrochloric acid (1 M HCl, 0.6 mL) and stir at room temperature for 2 min. Then add 0.6 mmol of iodobenzene diacetate and 0.03 mmol of iron(III) chloride, and then stir and react at room temperature for 2 h. After the reaction is completed, quench the reaction with water, extract three times with 10 ml (10 ml each time) of ethyl acetate, combine the organic phases, dry over anhydrous sodium sulfate, rotary evaporate, and column chromatograph with petroleum ether:ethyl acetate = 3:1 to obtain the target product of formula (1-3b), a light yellow solid, 73.9 mg, with a separation yield of 67%.

[0104] NMR data: 1 1H NMR (400 MHz, CDCl3) δ 2.34 (s, 3H), 2.50 (d, J = 10.8 Hz, 1H), 3.56 (d, J = 10.8 Hz, 1H), 6.31 (s, 1H), 6.69 - 6.72 (m, 2H), 6.76 - 6.79 (m, 1H), 7.14 - 7.19 (m, 1H), 7.24 - 7.29 (m, 2H), 7.51 - 7.61 (m, 2H), 8.22 - 8.25 (m, 1H); 1313C NMR (100 MHz, CDCl3) δ 184.4, 168.2, 159.0, 144.2, 139.4, 134.0, 132.7, 132.4, 130.5, 129.8, 129.3, 129.3, 129.2, 129.2, 129.0, 128.8, 128.0, 127.9, 127.7, 126.8, 126.2, 84.9, 32.4, 21.0.

[0105] Example 3

[0106] Synthesis of 1-3c: Synthesis of 2'-(4-fluorophenyl)-4'H-spiro[isochromene-1,1'-naphthalene]-3,4-dione.

[0107]

[0108] Using a Schlenk tube as the reaction device, first replace the reaction tube with nitrogen, and then add 0.3 mmol of 1-(2-bromophenyl)-3-(4-fluorophenyl)prop-2-yn-1-one and 0.6 mmol of 1,3-dihydro-2H-inden-2-one under a nitrogen atmosphere. Then add 0.3 mmol of the catalyst Cs2CO3, and then add 3 ml of the dry reaction solvent N,N-dimethylacetamide. After the addition is completed, seal the reaction tube and react at 100 °C in an oil bath for 3 h. Then add 0.6 mmol of hydrochloric acid (1 M HCl, 0.6 mL) and stir at room temperature for 2 min. Then add 0.6 mmol of iodobenzene diacetate and 0.03 mmol of iron(III) chloride, and then stir the reaction at room temperature for 2 h. After the reaction is completed, quench the reaction with water, extract three times with 10 ml (10 ml each time) of ethyl acetate, combine the organic phases, dry over anhydrous sodium sulfate, rotary evaporate, and column chromatograph with petroleum ether:ethyl acetate = 3:1 to obtain the target product of formula (1-3c), a light yellow solid, 70.1 mg, with a separation yield of 63%.

[0109] NMR data: 1 1H NMR (400 MHz, CDCl3) δ 2.62 (d, J = 10.8 Hz, 1H), 3.64 (d, J = 10.8 Hz, 1H), 6.32 (s, 1H), 6.78 - 6.83 (m, 2H), 6.93 - 7.01 (m, 3H), 7.15 - 7.20 (m, 1H), 7.23 - 7.26 (m, 1H), 7.27 - 7.30 (m, 1H), 7.51 - 7.61 (m, 3H), 8.22 - 8.25 (m, 1H); 1313C NMR (100 MHz, CDCl3) δ 183.7, 167.3, 157.4, 143.8, 137.5, 134.0, 131.7, 130.8, 130.7, 130.0, 129.4, 129.2, 128.7, 128.2, 128.0, 127.7, 126.6, 126.1, 115.6, 115.4, 84.9, 32.4, 29.7.

[0110] Example 4

[0111] Synthesis of 1-3d: Synthesis of 2'-(3-chlorophenyl)-4'H-spiro[isochromene-1,1'-naphthalene]-3,4-dione.

[0112]

[0113] Using a Schlenk tube as the reaction apparatus, first replace the reaction tube with nitrogen, then add 0.3 mmol of 1-(2-bromophenyl)-3-(3-chlorophenyl)prop-2-yn-1-one and 0.6 mmol of 1,3-dihydro-2H-inden-2-one under a nitrogen atmosphere, then add 0.3 mmol of the catalyst Cs2CO3, and then add 3 ml of the dry reaction solvent N,N-dimethylacetamide. After the addition is complete, seal the reaction tube and react at 100 °C in an oil bath for 3 h. Then add 0.6 mmol of hydrochloric acid (1 M HCl, 0.6 mL) and stir at room temperature for 2 min. Then add 0.6 mmol of iodobenzene diacetate and 0.03 mmol of iron(III) chloride, and then stir the reaction at room temperature for 2 h. After the reaction is completed, quench the reaction with water, extract three times with 10 ml (10 ml each time) of ethyl acetate, combine the organic phases, dry over anhydrous sodium sulfate, rotary evaporate, and column chromatograph with petroleum ether:ethyl acetate = 3:1 to obtain the target product of formula (1-3d), a light yellow solid, 79.7 mg, with a separation yield of 69%.

[0114] NMR data: 1 1H NMR (400 MHz, CDCl3) δ 2.69 (d, J = 10.8 Hz, 1H), 3.66 (d, J = 10.8 Hz, 1H), 6.34 (s, 1H), 6.69 - 6.71 (m, 1H), 6.79 - 6.84 (m, 2H), 7.01 - 7.04 (m, 1H), 7.19 - 7.26 (m, 2H), 7.30 - 7.36 (m, 2H), 7.52 - 7.62 (m, 3H), 8.22 - 8.25 (m, 1H); 1313C NMR (100 MHz, CDCl3) δ 183.5, 167.2, 156.7, 143.8, 137.1, 134.3, 134.0, 131.5, 130.0, 129.7, 129.4, 129.2, 128.8, 128.7, 128.1, 127.7, 127.0, 126.6, 126.1, 84.7, 32.4.

[0115] Example 5

[0116] Synthesis of 1-3e: Synthesis of 2'-(4-chlorophenyl)-4'H-spiro[isochromene-1,1'-naphthalene]-3,4-dione.

[0117]

[0118] Using a Schlenk tube as the reaction device, first replace the reaction tube with nitrogen, then add 0.3 mmol of 1-(2-bromophenyl)-3-(4-chlorophenyl)prop-2-yn-1-one and 0.6 mmol of 1,3-dihydro-2H-inden-2-one under a nitrogen atmosphere, then add 0.3 mmol of the catalyst Cs2CO3, and then add 3 ml of the dry reaction solvent N,N-dimethylacetamide. After the addition is complete, seal the reaction tube and react at 100 °C in an oil bath for 3 h. Then add 0.6 mmol of hydrochloric acid (1 M HCl, 0.6 mL) and stir at room temperature for 2 min. Then add 0.6 mmol of iodobenzene diacetate and 0.03 mmol of iron(III) chloride, and then stir the reaction at room temperature for 2 h. After the reaction is completed, quench the reaction with water, extract three times with 10 ml (10 ml each time) of ethyl acetate, combine the organic phases, dry over anhydrous sodium sulfate, rotary evaporate, and column chromatograph with petroleum ether:ethyl acetate = 3:1 to obtain the target product of formula (1-3e), a light yellow solid, 75.0 mg, with a separation yield of 65%.

[0119] NMR data: 1 1H NMR (400 MHz, CDCl3) δ 2.68 (d, J = 8.6 Hz, 1H), 3.66 (d, J = 8.6 Hz, 1H), 6.32 (s, 1H), 6.76 - 6.80 (m, 3H), 7.00 - 7.02 (m, 1H), 7.16 - 7.20 (m, 1H), 7.22 - 7.30 (m, 4H), 7.52 - 7.61 (m, 2H), 8.22 - 8.24 (m, 1H); 1313C NMR(100MHz,CDCl3)δ183.6,167.2,157.1,143.8,135.5,134.0,133.9,131.6,130.1,129.9,129.3,129.2,128.6,128.1,128.0,127.8,126.6,126.1,84.8,32.5.

[0120] Example 6

[0121] Synthesis of 1-3f: Synthesis of 6',7'-dimethoxy-2'-phenyl-4'H-spiro[isochromene-1,1'-naphthalene]-3,4'-dione.

[0122]

[0123] Using a Schlenk tube as the reaction device, first displace the reaction tube with nitrogen, then add 0.3 mmol of 1-(2-bromo-4,5-dimethoxyphenyl)-3-phenylprop-2-yn-1-one and 0.6 mmol of 1,3-dihydro-2H-inden-2-one under a nitrogen atmosphere. Then add 0.3 mmol of the catalyst Cs2CO3, and then add 3 ml of the dry reaction solvent N,N-dimethylacetamide. After the addition is completed, seal the reaction tube and react at 100 °C in an oil bath for 3 h. Then add 0.6 mmol of hydrochloric acid (1 M HCl, 0.6 mL) and stir at room temperature for 2 min. Then add 0.6 mmol of iodobenzene diacetate and 0.03 mmol of iron(III) chloride, and then stir the reaction at room temperature for 2 h. After the reaction is completed, quench the reaction with water, extract three times with 10 ml (10 ml each time) of ethyl acetate, combine the organic phases, dry over anhydrous sodium sulfate, rotary evaporate, and column chromatograph with petroleum ether:ethyl acetate = 3:1 to obtain the target product of formula (1-3f), a light yellow solid, 68.9 mg, with a separation yield of 56%.

[0124] NMR data: 1 1H NMR(400MHz,CDCl3)δ2.27(d,J=10.8Hz,1H),3.49(d,J=10.8Hz,1H),3.78(s,3H),4.02(s,3H),6.24(s,1H),6.58(s,1H),6.77-6.82(m,3H),6.92-6.95(m,1H),7.16-7.21(m,1H),7.22-7.26(m,2H),7.27-7.30(m,1H),7.34-7.39(m,1H),7.68(s,1H); 1313C NMR (100 MHz, CDCl3) δ 183.0, 168.1, 158.1, 153.9, 150.0, 138.1, 135.3, 132.2, 130.5, 129.2, 128.9, 128.2, 127.9, 127.5, 127.4, 126.5, 123.8, 110.0, 106.9, 84.9, 56.3, 56.2, 32.7.

[0125] Example 7

[0126] Synthesis of 1-3f: Synthesis of 6',7'-dimethoxy-2'-phenyl-4'H-spiro[isochromene-1,1'-naphthalene]-3,4'-dione.

[0127]

[0128] Using a Schlenk tube as the reaction device, first replace the reaction tube with nitrogen, then add 0.3 mmol of 1-(2-bromo-5-fluorophenyl)-3-phenylprop-2-yn-1-one and 0.6 mmol of 1,3-dihydro-2H-inden-2-one under a nitrogen atmosphere, then add 0.3 mmol of the catalyst Cs2CO3, and then add 3 ml of the dry reaction solvent N,N-dimethylacetamide. After the addition is complete, seal the reaction tube and react at 100 °C in an oil bath for 3 h. Then add 0.6 mmol of hydrochloric acid (1 M HCl, 0.6 mL) and stir at room temperature for 2 min. Then add 0.6 mmol of iodobenzene diacetate and 0.03 mmol of iron(III) chloride, and then stir the reaction at room temperature for 2 h. After the reaction is completed, quench the reaction with water, extract three times with 10 ml (10 ml each time) of ethyl acetate, combine the organic phases, dry over anhydrous sodium sulfate, rotary evaporate, and column chromatograph with petroleum ether:ethyl acetate = 3:1 to obtain the target product of formula (1-3g), a light yellow solid, 74.1 mg, with a separation yield of 67%.

[0129] NMR data: 1 1H NMR (400 MHz, CDCl3) δ 2.38 (d, J = 10.8 Hz, 1H), 3.52 (d, J = 10.8 Hz, 1H), 6.33 (s, 1H), 6.75 - 6.81 (m, 3H), 6.94 - 6.97 (m, 1H), 7.17 - 7.30 (m, 6H), 7.35 - 7.40 (m, 1H), 7.87 - 7.90 (m, 1H); 1313C NMR (100 MHz, CDCl3) δ 182.7, 167.5, 162.8 (d, J = 11.5 Hz), 158.9, 139.8, 135.1, 131.7, 131.6, 131.5, 131.4, 130.4, 129.3, 129.1, 128.7, 128.3, 127.9, 127.6, 127.4, 126.6, 121.4 (d, J = 11.5 Hz), 112.0 (d, J = 11.5 Hz), 84.5, 32.5.

[0130] Example 8

[0131] Synthesis of 1-3a: Synthesis of 2'-phenyl-4'H-spiro[isochromene-1,1'-naphthalene]-3,4-dione.

[0132]

[0133] Using a Schlenk tube as the reaction device, first replace the reaction tube with nitrogen, then add 0.3 mmol of 1-(2-bromophenyl)-3-phenylprop-2-yn-1-one and 0.6 mmol of 1,3-dihydro-2H-inden-2-one under a nitrogen atmosphere. Then add 0.6 mmol of the catalyst Cs2CO3, and then add 3 ml of the dry reaction solvent N,N-dimethylacetamide. After the addition is complete, seal the reaction tube and react at 100 °C in an oil bath for 3 h. Then add 0.6 mmol of hydrochloric acid (1 M HCl, 0.6 mL) and stir at room temperature for 2 min. Then add 0.6 mmol of iodobenzene diacetate and 0.03 mmol of iron(III) chloride, and then stir the reaction at room temperature for 2 h. After the reaction is completed, quench the reaction with water, extract three times with 10 ml (10 ml each time) of ethyl acetate, combine the organic phases, dry over anhydrous sodium sulfate, rotary evaporate, and column chromatograph with petroleum ether:ethyl acetate = 3:1 to obtain the target product of formula (1-3a), a light yellow solid, 68.5 mg, with a separation yield of 65%.

[0134] Example 9

[0135] Synthesis of 1-3a: Synthesis of 2'-phenyl-4'H-spiro[isochromene-1,1'-naphthalene]-3,4-dione.

[0136]

[0137] Using a Schlenk tube as the reaction device, first, the reaction tube was purged with nitrogen, and then 0.3 mmol of 1-(2-bromophenyl)-3-phenylprop-2-yn-1-one and 0.6 mmol of 1,3-dihydro-2H-inden-2-one were added under a nitrogen atmosphere. Then, 0.3 mmol of the catalyst Cs2CO3 was added, and then 3 ml of the dry reaction solvent N,N-dimethylformamide was added. After the addition was completed, the reaction tube was sealed and reacted at 100 °C in an oil bath for 3 h. Then, 0.6 mmol of hydrochloric acid (1 M HCl, 0.6 mL) was added, and the mixture was stirred at room temperature for 2 min. Then, 0.6 mmol of iodobenzene diacetate and 0.03 mmol of iron(III) chloride were added, and then the reaction was stirred at room temperature for 2 h. After the reaction was completed, the reaction was quenched with water, extracted three times with 10 ml (10 ml each time) of ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, rotary evaporated, and column chromatographed with petroleum ether:ethyl acetate = 3:1 to obtain the target product of formula (1-3a), a light yellow solid, 56.2 mg, with a separation yield of 53%.

[0138] Example 10

[0139] Synthesis of 1-3a: Synthesis of 2'-phenyl-4'H-spiro[isochromene-1,1'-naphthalene]-3,4-dione.

[0140]

[0141] Using a Schlenk tube as the reaction device, first, the reaction tube was purged with nitrogen, and then 0.3 mmol of 1-(2-bromophenyl)-3-phenylprop-2-yn-1-one and 0.6 mmol of 1,3-dihydro-2H-inden-2-one were added under a nitrogen atmosphere. Then, 0.3 mmol of the catalyst Cs2CO3 was added, and then 3 ml of the dry reaction solvent dimethyl sulfoxide was added. After the addition was completed, the reaction tube was sealed and reacted at 100 °C in an oil bath for 3 h. Then, 0.6 mmol of hydrochloric acid (1 M HCl, 0.6 mL) was added, and the mixture was stirred at room temperature for 2 min. Then, 0.6 mmol of iodobenzene diacetate and 0.03 mmol of iron(III) chloride were added, and then the reaction was stirred at room temperature for 2 h. After the reaction was completed, the reaction was quenched with water, extracted three times with 10 ml (10 ml each time) of ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, rotary evaporated, and column chromatographed with petroleum ether:ethyl acetate = 3:1 to obtain the target product of formula (1-3a), a light yellow solid, 49.8 mg, with a separation yield of 47%.

[0142] Example 11

[0143] Synthesis of 1-3a: Synthesis of 2'-phenyl-4'H-spiro[isochromene-1,1'-naphthalene]-3,4-dione.

[0144]

[0145] Using a Schlenk tube as the reaction apparatus, first, the reaction tube was purged with nitrogen, and then 0.3 mmol of 1-(2-bromophenyl)-3-phenylprop-2-yn-1-one and 0.6 mmol of 1,3-dihydro-2H-inden-2-one were added under a nitrogen atmosphere. Then, 0.3 mmol of the catalyst Cs2CO3 was added, and then 3 mL of the dry reaction solvent N,N-dimethylacetamide was added. After the addition was completed, the reaction tube was sealed and reacted at 100 °C in an oil bath for 2 h. Then, 0.6 mmol of hydrochloric acid (1 M HCl, 0.6 mL) was added, and the mixture was stirred at room temperature for 2 min. Then, 0.6 mmol of iodobenzene diacetate and 0.03 mmol of iron(III) chloride were added, and then the reaction was stirred at room temperature for 2 h. After the reaction was completed, the reaction was quenched with water, extracted three times with 10 mL (10 mL each time) of ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, rotary evaporated, and column chromatographed with petroleum ether:ethyl acetate = 3:1 to obtain the target product of formula (1-3a), a light yellow solid, 70.6 mg, with a separation yield of 67%.

[0146] Example 12

[0147] Synthesis of 1-3a: Synthesis of 2'-phenyl-4'H-spiro[isochromene-1,1'-naphthalene]-3,4-dione.

[0148]

[0149] Using a Schlenk tube as the reaction apparatus, first, the reaction tube was purged with nitrogen, and then 0.3 mmol of 1-(2-bromophenyl)-3-phenylprop-2-yn-1-one and 0.3 mmol of 1,3-dihydro-2H-inden-2-one were added under a nitrogen atmosphere. Then, 0.3 mmol of the catalyst Cs2CO3 was added, and then 3 mL of the dry reaction solvent N,N-dimethylacetamide was added. After the addition was completed, the reaction tube was sealed and reacted at 100 °C in an oil bath for 3 h. Then, 0.6 mmol of hydrochloric acid (1 M HCl, 0.6 mL) was added, and the mixture was stirred at room temperature for 2 min. Then, 0.6 mmol of iodobenzene diacetate and 0.03 mmol of iron(III) chloride were added, and then the reaction was stirred at room temperature for 2 h. After the reaction was completed, the reaction was quenched with water, extracted three times with 10 mL (10 mL each time) of ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, rotary evaporated, and column chromatographed with petroleum ether:ethyl acetate = 3:1 to obtain the target product of formula (1-3a), a light yellow solid, 59.3 mg, with a separation yield of 56%.

[0150] Example 13

[0151] Synthesis of 1-3a: Synthesis of 2'-phenyl-4'H-spiro[isochromene-1,1'-naphthalene]-3,4-dione.

[0152]

[0153] Using a Schlenk tube as the reaction device, first displace the reaction tube with nitrogen, and then under a nitrogen atmosphere, first add 0.3 mmol of 1-(2-bromophenyl)-3-phenylprop-2-yn-1-one and 0.6 mmol of 1,3-dihydro-2H-inden-2-one. Then add 0.3 mmol of the catalyst Cs2CO3, and then add 3 mL of the dry reaction solvent N,N-dimethylacetamide. After the addition is completed, seal the reaction tube and place it in an oil bath at 100 °C for 3 h. Then add 0.6 mmol of hydrochloric acid (1 M HCl, 0.6 mL) and stir at room temperature for 2 min. Then add 0.6 mmol of iodine and 0.03 mmol of iron(III) chloride, and then stir at room temperature for 2 h. After the reaction is completed, quench the reaction with water, extract three times with 10 mL (10 mL each time) of ethyl acetate, combine the organic phases, dry over anhydrous sodium sulfate, rotary evaporate, and column chromatograph with petroleum ether:ethyl acetate = 3:1 to obtain the target product of formula (1-3a), a light yellow solid, 66.7 mg, with a separation yield of 63%.

[0154] Example 14

[0155] Synthesis of 1-3a: Synthesis of 2'-phenyl-4'H-spiro[isochromene-1,1'-naphthalene]-3,4-dione.

[0156]

[0157] Using a Schlenk tube as the reaction device, first displace the reaction tube with nitrogen, and then under a nitrogen atmosphere, first add 0.3 mmol of 1-(2-bromophenyl)-3-phenylprop-2-yn-1-one and 0.6 mmol of 1,3-dihydro-2H-inden-2-one. Then add 0.3 mmol of the catalyst Cs2CO3, and then add 3 mL of the dry reaction solvent N,N-dimethylacetamide. After the addition is completed, seal the reaction tube and place it in an oil bath at 100 °C for 3 h. Then add 0.6 mmol of hydrochloric acid (1 M HCl, 0.6 mL) and stir at room temperature for 2 min. Then add 0.6 mmol of iodobenzene diacetate and 0.03 mmol of copper(I) chloride, and then stir at room temperature for 2 h. After the reaction is completed, quench the reaction with water, extract three times with 10 mL (10 mL each time) of ethyl acetate, combine the organic phases, dry over anhydrous sodium sulfate, rotary evaporate, and column chromatograph with petroleum ether:ethyl acetate = 3:1 to obtain the target product of formula (1-3a), a light yellow solid, 54.7 mg, with a separation yield of 52%.

[0158] Comparative Example 1

[0159] Synthesis of 1-3a: Synthesis of 2'-phenyl-4'H-spiro[isochromene-1,1'-naphthalene]-3,4-dione.

[0160]

[0161] Using a Schlenk tube as the reaction device, first, the reaction tube was purged with nitrogen, and then under a nitrogen atmosphere, 0.3 mmol of 1-(2-bromophenyl)-3-phenylprop-2-yn-1-one and 0.6 mmol of 1,3-dihydro-2H-inden-2-one were added first. Then, 0.3 mmol of the catalyst Cs2CO3 was added, and then 3 ml of the dry reaction solvent N,N-dimethylacetamide was added. After the addition was completed, the reaction tube was sealed and placed in an oil bath at 100 °C for reaction for 3 h. Then, 0.6 mmol of hydrochloric acid (1 M HCl, 0.6 mL) was added, and the mixture was stirred at room temperature for 2 min. Then, 0.6 mmol of hydrogen peroxide and 0.03 mmol of iron(III) chloride were added, and then the mixture was stirred at room temperature for 2 h. After the reaction was completed, the reaction was quenched with water, and the reaction was detected, but 1-3a was not obtained.

[0162] Comparative Example 2

[0163] Synthesis of 1-3a: Synthesis of 2'-phenyl-4'H-spiro[isochromene-1,1'-naphthalene]-3,4-dione.

[0164]

[0165] Using a Schlenk tube as the reaction device, first, the reaction tube was purged with nitrogen, and then under a nitrogen atmosphere, 0.3 mmol of 1-(2-bromophenyl)-3-phenylprop-2-yn-1-one and 0.6 mmol of 1,3-dihydro-2H-inden-2-one were added first. Then, 0.3 mmol of the catalyst Cs2CO3 was added, and then 3 ml of the dry reaction solvent N,N-dimethylacetamide was added. After the addition was completed, the reaction tube was sealed and placed in an oil bath at 100 °C for reaction for 3 h. Then, 0.6 mmol of hydrochloric acid (1 M HCl, 0.6 mL) was added, and the mixture was stirred at room temperature for 2 min. Then, 0.6 mmol of potassium persulfate and 0.03 mmol of iron(III) chloride were added, and then the mixture was stirred at room temperature for 2 h. After the reaction was completed, the reaction was quenched with water, and the reaction was detected, but 1-3a was not obtained.

[0166] Comparative Example 3

[0167] Synthesis of 1-3a: Synthesis of 2'-phenyl-4'H-spiro[isochromene-1,1'-naphthalene]-3,4-dione.

[0168]

[0169] Using a Schlenk tube as the reaction device, first displace the reaction tube with nitrogen, and then under a nitrogen atmosphere, add 0.3 mmol of 1-(2-bromophenyl)-3-phenylprop-2-yn-1-one and 0.6 mmol of 1,3-dihydro-2H-inden-2-one. Then add 0.3 mmol of the catalyst Cs2CO3, and then add 3 ml of the dry reaction solvent N,N-dimethylacetamide. After the addition is completed, seal the reaction tube and react at 100 °C in an oil bath for 3 h. Then add 0.6 mmol of iodobenzene acetate and 0.03 mmol of iron(III) chloride, and then stir the reaction at room temperature for 2 h. After the reaction is completed, quench the reaction with water, extract three times with 10 ml of ethyl acetate, combine the organic phases, dry over anhydrous sodium sulfate, rotary evaporate, and column chromatograph with petroleum ether:ethyl acetate = 3:1 to obtain the target product of formula (1-3a), a light yellow solid, 10.3 mg, with a separation yield of 10%.

[0170] Application Example 1

[0171] To better illustrate the application of the target product obtained in the above examples as an intermediate in organic synthesis, the following examples are given for illustration.

[0172] Using a Schlenk tube as the reaction device, first add 0.2 mmol of 2'-(p-tolyl)-4'H-spiro[isochromene-1,1'-naphthalene]-3,4-dione prepared in Example 2, then add 0.4 mmol of the catalyst iodobenzene acetate and 0.4 mol of DMAP (4-dimethylaminopyridine), and then add 2 mL of DCM (dichloromethane), and stir the reaction at 60 °C for 2 h. After the reaction is completed, quench the reaction with water, extract three times with 10 ml (10 ml each time) of ethyl acetate, combine the organic phases, dry over anhydrous sodium sulfate, rotary evaporate, and column chromatograph with petroleum ether:ethyl acetate = 2:1 to obtain the target product of formula (1-4b), a light yellow solid, with a separation yield of 87%.

[0173]

[0174] Application Example 2

[0175] Using a Schlenk tube as the reaction device, first add 0.2 mmol of 2'-(p-tolyl)-4'H-spiro[isochromene-1,1'-naphthalene]-3,4-dione prepared in Example 2, then add 0.4 mmol of the catalyst liquid bromine, and then add 2 mL of DCM (dichloromethane), and stir the reaction at 60 °C for 2 h. After the reaction is completed, quench the reaction with water, extract three times with 10 ml (10 ml each time) of ethyl acetate, combine the organic phases, dry over anhydrous sodium sulfate, rotary evaporate, and column chromatograph with petroleum ether:ethyl acetate = 3:1 to obtain the target product of formula (1-5b), a light yellow solid, with a separation yield of 71%.

[0176]

[0177] As described above, it is only the preferred embodiment of the present invention and does not impose any formal restrictions on the present invention. Although the present invention has been disclosed above with the preferred embodiment, it is not intended to limit the present invention. Any person skilled in the art, without departing from the scope of the technical solution of the present invention, may make some changes or modifications to the equivalent embodiments by using the above-disclosed technical content. However, as long as it does not depart from the content of the technical solution of the present invention, any simple modification, equivalent change, and modification made to the above embodiments based on the technical essence of the present invention still fall within the scope of the technical solution of the present invention.

Claims

1. A cyclohexenone spiro lactone derivative, characterized in that: Its structure is shown in formula (I): wherein, R 1 is hydrogen, chlorine, fluorine or methyl; R 2 is hydrogen, fluorine or methoxy.

2. A cyclohexenone spiro lactone derivative according to claim 1, characterized in that: The cyclohexenone spiro lactone derivatives are selected from:

3. A method for preparing a cyclohexenone spiro lactone derivative, characterized in that: Comprising the following steps: In a certain amount of solvent, the raw material o-bromophenyl propiolone compounds and indanone compounds are successively reacted under the action of a base and under acid-catalyzed oxidation conditions to prepare the cyclohexenone spiro lactone derivatives.

4. The preparation method of a cyclohexenone spiro lactone derivative according to claim 3, characterized in that: In the second step, the o-bromophenyl propiolone compounds are propiolones with an electron-withdrawing group attached to the benzene ring or propiolones with an electron-donating group attached to the benzene ring.

5. The preparation method of a cyclohexenone spiro lactone derivative according to claim 3 or 4, characterized in that: Its reaction process is shown in formula (II): Among them, R 1 is hydrogen, chlorine, fluorine or methyl; R 2 is hydrogen, fluorine or methoxy. Comprising the following steps: Step 1: First remove the air and moisture in the reaction vessel, and then replace the air in the reaction vessel with nitrogen; Step 2: Under a nitrogen atmosphere, first add a certain amount of o-bromophenyl propiolone compounds, indanone compounds and a base promoter to the reaction vessel treated in Step 1, and then add a solvent; Step 3: Seal the reaction vessel in Step 2 and stir the reaction in the reaction vessel under heating conditions for 2-3 h; Step 4: After the reaction in Step 3 is completed, add an acid to the reaction vessel and stir at room temperature; Step 5: Add a certain amount of an oxidant and a catalyst to the reaction vessel in Step 4, and place the reaction vessel at room temperature and stir for a certain time; Step 6: After the reaction is completed, quench with water and separate by column chromatography to obtain the target product cyclohexenone spiro lactone derivative.

6. The preparation method of a cyclohexenone spiro lactone derivative according to claim 5, characterized in that: The o-bromophenyl propiolone compounds are selected from:

7. A method for preparing a cyclohexenone spiro lactone derivative according to claim 5, characterized in that: In the second step, the molar ratio of o-bromophenyl propiolone compounds: indanone compounds: base promoter is 1:1-2:1-2, and the base promoter is Cs2CO3.

8. The preparation method of a cyclohexenone spiro lactone derivative according to claim 5, characterized in that: In the third step, the reaction vessel is stirred and reacted under heating conditions at 80-140 °C for 2-3 h.

9. The preparation method of a cyclohexenone spiro lactone derivative according to claim 5, characterized in that: In the fourth step, the acid is selected from one of hydrochloric acid, sulfuric acid, nitric acid or acetic acid.

10. The preparation method of a cyclohexenone spiro lactone derivative according to claim 5, characterized in that: In the fifth step, add a certain amount of an oxidant and a catalyst to the reaction vessel in Step 4, and place the reaction vessel at room temperature and stir for 1-3 h.

11. A method for preparing a cyclohexenone spiro lactone derivative according to claim 5, characterized in that: In the fifth step, the oxidant is selected from one of iodobenzene acetate or iodine.

12. The preparation method of a cyclohexenone spiro lactone derivative according to claim 5, characterized in that: In the fifth step, the catalyst is one of copper chloride, cuprous iodide, cuprous bromide, ferric chloride or ferrous bromide.

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