Preparation method of 3-ethyl bicyclo [3.2. 0] hept-3-ene-6-ketone

Abstract

The invention belongs to the technical field of organic compounds, and particularly relates to a preparation method of 3-ethyl bicyclo [3.2. 0] hept-3-ene-6-ketone. According to the preparation method of the 3-ethyl bicyclo [3.2. 0] hept-3-ene-6-ketone, provided by the invention, a 4-pentene compound is taken as an initial raw material, the preparation process is simple and easy to operate, the reaction conditions are mild, and the preparation method is suitable for industrial production; the reaction raw materials selected by the preparation method are cheap and easy to obtain, and the production cost is reduced; the 3-ethyl bicyclo [3.2. 0] hept-3-ene-6-ketone prepared by the method provided by the invention has relatively high yield and purity, the purity of the 3-ethyl bicyclo [3.2. 0] hept-3-ene-6-ketone is more than 99%, and the yield of the 3-ethyl bicyclo [3.2. 0] hept-3-ene-6-ketone is more than 81%.

Description

Technical Field

[0001] The invention belongs to the technical field of organic compounds, and specifically relates to a method for preparing 3-ethylbicyclo[3.2.0]hept-3-en-6-one. Background Art

[0002] Mirogabalin besilate is a GABA drug that acts on the α2-δ1 subunit of the voltage-sensitive calcium channel complex, thereby treating chronic neuropathic pain. The structural formula of Mirogabalin besilate is as follows:

[0003]

[0004] There are many reports on the synthesis route of melogabalin benzenesulfonate, most of which use 3-ethylbicyclo[3.2.0]hept-3-en-6-one or its single chiral substance as an intermediate or starting material to prepare melogabalin benzenesulfonate. However, the preparation steps of 3-ethylbicyclo[3.2.0]hept-3-en-6-one are relatively complicated, and strict reaction conditions are required to make it have a low yield, thereby affecting the yield of melogabalin benzenesulfonate. Summary of the invention

[0005] In view of this, the present invention provides a method for preparing 3-ethylbicyclo[3.2.0]hept-3-en-6-one. The preparation method provided by the present invention is simple and easy to operate. The 3-ethylbicyclo[3.2.0]hept-3-en-6-one prepared according to the method provided by the present invention has a high yield and purity.

[0006] In order to solve the above technical problems, the present invention provides a method for preparing 3-ethylbicyclo[3.2.0]hept-3-en-6-one, comprising the following steps:

[0007] A 4-pentene compound, an ethyl halide, a first alkaline compound and a first organic solvent are first mixed and then subjected to an ethylation reaction to obtain a compound 2; the 4-pentene compound has a structure shown in Formula 1; and the compound 2 has a structure shown in Formula 2;

[0008] When R 1 When R is a carboxyl group or an ester group, compound 5 is prepared according to method a; when R 1 When it is cyano, compound 5 is prepared according to method b;

[0009] The method a comprises the following steps:

[0010] The compound 2, the acyl chloride reagent and the second organic solvent are mixed for a second time and then subjected to an acyl chloride reaction to obtain a compound 3; the compound 3 has a structure shown in Formula 3;

[0011] The compound 3, the 1,3-dicarbonyl ester compound, the second alkaline compound and the third organic solvent are mixed and subjected to a condensation reaction, and then an acidic compound is added to carry out a hydrolysis and decarboxylation reaction to obtain a compound 5; the compound 5 has a structure shown in Formula 5;

[0012] The method b comprises the following steps:

[0013] The compound 2, the halogenated ester compound, the catalyst and the fourth organic solvent are mixed and then subjected to a Bryce reaction to obtain a compound 4; the compound 4 has a structure shown in Formula 4;

[0014] The compound 4, the third basic compound, water and the fifth organic solvent are mixed and then subjected to a hydrolysis reaction to obtain a compound 5;

[0015] The compound 5, the reducing agent and the sixth organic solvent are mixed and then subjected to a reduction reaction to obtain a compound 6; the compound 6 has a structure shown in Formula 6;

[0016] The compound 6, a cyclization reagent and a seventh organic solvent are mixed and then subjected to a ring-closing reaction to obtain the 3-ethylbicyclo[3.2.0]hept-3-en-6-one; the cyclization reagent is a mixture of acetic anhydride and potassium acetate;

[0017]

[0018] Among them, R 1 is a carboxyl group, an ester group or a cyano group; R 2 It is methyl or ethyl.

[0019] Preferably, the 4-pentene compound includes 4-pentenenitrile, 4-pentenoic acid, 4-pentenoic acid methyl ester, 4-pentenoic acid ethyl ester, 4-pentenoic acid n-propyl ester, 4-pentenoic acid isopropyl ester or 4-pentenoic acid n-butyl ester;

[0020] The ethyl halide includes ethyl chloride, ethyl bromide or ethyl iodide;

[0021] The molar ratio of the 4-pentene compound to the ethyl halide is 1:1 to 1:5;

[0022] The first alkaline compound includes one or more of sodium hydride, sodium hydroxide, potassium hydroxide, n-butyl lithium, lithium diisopropylamide and 1,8-diazabicycloundec-7-ene;

[0023] The molar ratio of the 4-pentene compound to the first basic compound is 1:1 to 1:5.

[0024] Preferably, the ethylation reaction is carried out at a temperature of 50 to 100° C. and for a time of 4 to 6 hours.

[0025] Preferably, the acyl chloride reagent comprises thionyl chloride, oxalyl chloride, phosphorus trichloride, bis(trichloromethyl) carbonate or carbon tetrachloride;

[0026] The molar ratio of the compound 2 to the acyl chloride reagent is 1:1 to 1:10;

[0027] The temperature of the acyl chlorination reaction is 50-100° C. and the time is 1.5-2.5 hours.

[0028] Preferably, the 1,3-dicarbonyl ester compound includes dimethyl malonate, diethyl malonate, dipropyl malonate or dibutyl malonate;

[0029] The molar ratio of the compound 3 to the 1,3-dicarbonyl ester compound is 1:1 to 1:5;

[0030] The second alkaline compound includes one or more of sodium methoxide, sodium hydride, sodium hydroxide, 1,8-diazabicycloundec-7-ene, butyl lithium, triethylamine, pyridine, morpholine and piperidine;

[0031] The molar ratio of the compound 3 to the second basic compound is 1:1 to 1:5;

[0032] The condensation reaction temperature is 0-50°C and the reaction time is 4-6 hours.

[0033] Preferably, the acidic compound includes formic acid, acetic acid, hydrochloric acid or sulfuric acid;

[0034] The molar ratio of the compound 3 to the acidic compound is 1:1 to 1:10;

[0035] The temperature of the hydrolysis decarboxylation reaction is 50-100° C. and the time is 7-9 hours.

[0036] Preferably, the halogenated ester compound includes methyl bromoacetate, ethyl bromoacetate, methyl chloroacetate or ethyl chloroacetate;

[0037] The molar ratio of the compound 2 to the halogenated ester compound is 1:1 to 1:5;

[0038] The catalyst includes zinc powder;

[0039] The temperature of the Bryce reaction is 0-60° C. and the time is 4-6 hours.

[0040] Preferably, the third alkaline compound includes one or more of sodium methoxide, sodium tert-butoxide, sodium hydroxide and potassium hydroxide;

[0041] The molar ratio of the compound 4 to the third basic compound is 1:1 to 1:5;

[0042] The temperature of the hydrolysis reaction is 60-100° C. and the time is 7-9 hours.

[0043] Preferably, the reducing agent includes one or more of sodium borohydride, sodium triacetoxyborohydride, palladium on carbon, lithium aluminum hydride and diisobutylaluminum hydride;

[0044] The molar ratio of the compound 5 to the reducing agent is 1:1 to 1:5;

[0045] The temperature of the reduction reaction is 0-50° C. and the time is 1.5-2.5 hours.

[0046] Preferably, the molar ratio of acetic anhydride to potassium acetate in the cyclization reagent is 1.2 to 2:1;

[0047] The molar ratio of the compound 6 to acetic anhydride is 1:2-4;

[0048] The temperature of the ring-closure reaction is 100-130° C., and the time is 3-5 hours.

[0049] The present invention provides a method for preparing 3-ethylbicyclo[3.2.0]hept-3-en-6-one, comprising the following steps: first mixing a 4-pentene compound, an ethyl halide, a first alkaline compound and a first organic solvent, and then performing an ethylation reaction to obtain a compound 2; the 4-pentene compound has a structure shown in formula 1; the compound 2 has a structure shown in formula 2; when R 1 When R is a carboxyl group or an ester group, compound 5 is prepared according to method a; when R 1 When the compound 2 is cyano, the compound 5 is prepared according to method b; the method a comprises the following steps: the compound 2, the chlorination agent and the second organic solvent are mixed for the second time, and then the chlorination reaction is carried out to obtain the compound 3; the compound 3 has the structure shown in formula 3; the compound 3, the 1,3-dicarbonyl ester compound, the second alkaline compound and the third organic solvent are mixed for the third time, and then the condensation reaction is carried out, and then the acidic compound is added to carry out the hydrolysis decarboxylation reaction to obtain the compound 5; the compound 5 has the structure shown in formula 5; the method b comprises the following steps: the compound 2, the halogenated ester compound, the catalyst and the fourth organic solvent are mixed for the third time, and then the condensation reaction is carried out, and then the acidic compound is added to carry out the hydrolysis decarboxylation reaction to obtain the compound 5; the compound 5 has the structure shown in formula 5. The fourth mixing is followed by a Bryce reaction to obtain compound 4; the compound 4 has a structure shown in formula 4; the compound 4, the third basic compound, water and the fifth organic solvent are mixed fifthly and then subjected to a hydrolysis reaction to obtain compound 5; the compound 5, the reducing agent and the sixth organic solvent are mixed sixthly and then subjected to a reduction reaction to obtain compound 6; the compound 6 has a structure shown in formula 6; the compound 6, the cyclization agent and the seventh organic solvent are mixed seventhly and then subjected to a ring-closing reaction to obtain the 3-ethylbicyclo[3.2.0]hept-3-en-6-one; the cyclization agent is a mixture of acetic anhydride and potassium acetate; Among them, R 1 is a carboxyl group, an ester group or a cyano group; R 2 Methyl or ethyl. The present invention uses 4-pentene compounds as starting materials, the preparation process is simple and easy to operate, the reaction conditions are mild, and it is suitable for industrial production; the preparation method of the present invention uses cheap and readily available reaction materials, which is conducive to reducing production costs; the 3-ethylbicyclo[3.2.0]hept-3-ene-6-one prepared according to the method provided by the present invention has a high yield and purity, the purity is more than 99%, and the yield is more than 81%. DETAILED DESCRIPTION

[0050] The present invention provides a method for preparing 3-ethylbicyclo[3.2.0]hept-3-en-6-one, comprising the following steps:

[0051] A 4-pentene compound, an ethyl halide, a first alkaline compound and a first organic solvent are first mixed and then subjected to an ethylation reaction to obtain a compound 2; the 4-pentene compound has a structure shown in Formula 1; and the compound 2 has a structure shown in Formula 2;

[0052] When R 1 When R is a carboxyl group or an ester group, compound 5 is prepared according to method a; when R 1 When it is cyano, compound 5 is prepared according to method b;

[0053] The method a comprises the following steps:

[0054] The compound 2, the acyl chloride reagent and the second organic solvent are mixed for a second time and then subjected to an acyl chloride reaction to obtain a compound 3; the compound 3 has a structure shown in Formula 3;

[0055] The compound 3, the 1,3-dicarbonyl ester compound, the second alkaline compound and the third organic solvent are mixed and subjected to a condensation reaction, and then an acidic compound is added to carry out a hydrolysis and decarboxylation reaction to obtain a compound 5; the compound 5 has a structure shown in Formula 5;

[0056] The method b comprises the following steps:

[0057] The compound 2, the halogenated ester compound, the catalyst and the fourth organic solvent are mixed and then subjected to a Bryce reaction to obtain a compound 4; the compound 4 has a structure shown in Formula 4;

[0058] The compound 4, the third basic compound, water and the fifth organic solvent are mixed and then subjected to a hydrolysis reaction to obtain a compound 5; the compound 5 has a structure shown in Formula 5;

[0059] The compound 5, the reducing agent and the sixth organic solvent are mixed and then subjected to a reduction reaction to obtain a compound 6; the compound 6 has a structure shown in Formula 6;

[0060] The compound 6, a cyclization reagent and a seventh organic solvent are mixed and then subjected to a ring-closing reaction to obtain the 3-ethylbicyclo[3.2.0]hept-3-en-6-one; the cyclization reagent is acetic anhydride and potassium acetate;

[0061]

[0062] Among them, R 1 is a carboxyl group, an ester group or a cyano group, R 2 It is methyl or ethyl.

[0063] In the present invention, if there is no special limitation, all materials are conventional commercially available products.

[0064] In the present invention, a 4-pentene compound, an ethyl halide, a first alkaline compound and a first organic solvent are first mixed and then subjected to an ethylation reaction to obtain compound 2. As a specific embodiment of the present invention, the first mixing may include the following steps:

[0065] dissolving the ethyl halide in a portion of the first organic solvent to obtain an ethyl halide solution;

[0066] dissolving the 4-pentene compound in the remaining first organic solvent to obtain a 4-pentene compound solution;

[0067] The first basic compound and the ethyl halide solution are added to the 4-pentene compound solution.

[0068] As a specific embodiment of the present invention, the ethyl halide may include ethyl chloride, ethyl bromide or ethyl iodide; the first organic solvent may include one or more of cyclohexane, acetonitrile, acetone, tetrahydrofuran, toluene and methyl tert-butyl ether, and may specifically be cyclohexane, acetonitrile, acetone, tetrahydrofuran, toluene or methyl tert-butyl ether.

[0069] As a specific embodiment of the present invention, the 4-pentene compound may include 4-pentenenitrile, 4-pentenoic acid, 4-pentenoic acid methyl ester, 4-pentenoic acid ethyl ester, 4-pentenoic acid n-propyl ester, 4-pentenoic acid isopropyl ester or 4-pentenoic acid n-butyl ester; the molar ratio of the 4-pentene compound to the ethyl halide may be 1:1 to 1:5, or may be 1:1.5 to 1:3.

[0070] As a specific embodiment of the present invention, the first alkaline compound may include one or more of sodium hydride, sodium hydroxide, potassium hydroxide, n-butyl lithium, lithium diisopropylamide and 1,8-diazabicycloundec-7-ene (DBU), and may specifically be sodium hydride, sodium hydroxide, potassium hydroxide, n-butyl lithium, lithium diisopropylamide or DBU; the molar ratio of the 4-pentene compound to the first alkaline compound may be 1:1 to 1:5, or may be 1:2 to 1:3.

[0071] As a specific embodiment of the present invention, the temperature of the ethylation reaction can be 50-100° C., or 70-80° C.; the time of the ethylation reaction can be 4-6 hours, or 5-5.5 hours.

[0072] In the present invention, the equation of the ethylation reaction is as follows:

[0073]

[0074] Among them, R 1 is a carboxyl group, an ester group or a cyano group, and X is -Br, -Cl or I.

[0075] As a specific embodiment of the present invention, the ethylation reaction can also be followed by post-treatment. 1 When it is a carboxyl group or an ester group, the post-treatment comprises the following steps:

[0076] The ethylation reaction system is cooled, water is added to quench the reaction, and rotary evaporation is performed to obtain an oily product;

[0077] The oily product is mixed with water and ethyl acetate, and the aqueous phase is taken after separation;

[0078] The aqueous phase and the hydrochloric acid solution are mixed to adjust the pH value to 1-2, and then mixed with ethyl acetate and water, and the organic phase is collected after separation;

[0079] The organic phase is washed and then the solvent is removed to obtain the compound 2.

[0080] As a specific embodiment of the present invention, the temperature after cooling can be 0-20°C, or 5-10°C; the present invention has no special requirements for the cooling method, as long as the required temperature can be reached. The present invention has no special limitation on the rotary evaporation, and the conventional method in the art can be used.

[0081] As a specific embodiment of the present invention, the mass concentration of the hydrochloric acid solution can be 1-4 mol / L, or 2-3 mol / L. In the present invention, the product generated by the ethylation reaction will combine with the alkaline compound in the reaction system to form a salt that dissolves in the aqueous phase, and the product after acid adjustment and alkali removal can be soluble in the organic phase.

[0082] As a specific embodiment of the present invention, the washing detergent may include a saturated sodium chloride aqueous solution; the solvent removal method includes dehydration and reduced pressure distillation in sequence; the dehydration may be adding anhydrous magnesium sulfate to the washed system and then standing, filtering to remove the magnesium sulfate after absorbing water. The present invention has no special limitation on the reduced pressure distillation, and the conventional method in the art can be used.

[0083] When R 1 When it is cyano, the post-treatment comprises the following steps:

[0084] After cooling the system after the ethylation reaction, water is added to quench the reaction and perform extraction, and an organic phase is taken;

[0085] The organic phase was dehydrated and then distilled under reduced pressure to obtain the compound 2.

[0086] As a specific implementation of the present invention, the temperature after cooling can be 0-20°C, or 5-10°C; the present invention has no special requirements on the cooling method, as long as the required temperature can be reached.

[0087] As a specific embodiment of the present invention, the extraction liquid is toluene.

[0088] As a specific embodiment of the present invention, the dehydration can be performed by adding anhydrous magnesium sulfate to the organic phase, leaving it to stand, and filtering to remove the magnesium sulfate after absorbing water. The present invention has no special limitation on the reduced pressure distillation, and conventional methods in the art can be used.

[0089] In the present invention, when R 1 When R is a carboxyl group or an ester group, compound 5 is prepared according to method a; when R 1

[0090] When it is cyano, compound 5 is prepared according to method b;

[0091] The method a comprises the following steps:

[0092] The compound 2, the acyl chlorination agent and the second organic solvent are mixed for a second time, and then subjected to an acyl chlorination reaction to obtain a compound 3;

[0093] The compound 3, the 1,3-dicarbonyl ester compound, the second alkaline compound and the third organic solvent are mixed and subjected to a condensation reaction, and then an acidic compound is added to carry out a hydrolysis and decarboxylation reaction to obtain the compound 5.

[0094] The present invention performs an acyl chlorination reaction after mixing the compound 2, the acyl chlorination agent and the second organic solvent for the second time to obtain compound 3. As a specific embodiment of the present invention, the acyl chlorination agent may include thionyl chloride, oxalyl chloride, phosphorus trichloride, bis(trichloromethyl) carbonate (triphosgene) or carbon tetrachloride; the molar ratio of the compound 2 to the acyl chlorination agent may be 1:1 to 1:10, or 1:2 to 1:8, or further 1:3 to 1:6. As a specific embodiment of the present invention, the second organic solvent may include one or more of cyclohexane, acetonitrile, acetone, tetrahydrofuran, toluene and methyl tert-butyl ether, and may specifically be cyclohexane, acetonitrile, acetone, tetrahydrofuran, toluene or methyl tert-butyl ether. As a specific embodiment of the present invention, the temperature of the acyl chlorination reaction may be 50 to 100°C, or 60 to 80°C; the time of the acyl chlorination reaction may be 1.5 to 2.5h, or 2h.

[0095] In the present invention, the equation of the acyl chloride reaction is as follows:

[0096]

[0097] As a specific embodiment of the present invention, the acyl chloride reaction may further include: cooling the system after the acyl chloride reaction to room temperature and then performing reduced pressure distillation, and directly using the system after reduced pressure distillation for subsequent reactions. As a specific embodiment of the present invention, the room temperature may be 20 to 35°C, or 25 to 30°C; the present invention has no special requirements for the cooling method, as long as the required temperature can be reached. The present invention can remove unreacted acyl chloride reagent and acidic gas (gas generated by the acyl chloride reagent, such as HCl) in the system through reduced pressure distillation; the present invention has no special limitation on the reduced pressure distillation, and the conventional method in the art can be used.

[0098] After obtaining compound 3, the present invention performs a third mixing of compound 3, 1,3-dicarbonyl ester compound, second alkaline compound and third organic solvent, performs a condensation reaction, and then adds an acidic compound to perform a hydrolysis decarboxylation reaction to obtain compound 5. As a specific embodiment of the present invention, the third mixing may include the following steps:

[0099] Dissolving the 1,3-dicarbonyl ester compound in a portion of the third organic solvent and then adding the second alkaline compound in batches to obtain a mixed solution;

[0100] The compound 3 is dissolved in the remaining third organic solvent and then added into the mixed solution.

[0101] As a specific embodiment of the present invention, the 1,3-dicarbonyl ester compound may include dimethyl malonate, diethyl malonate, dipropyl malonate or dibutyl malonate; the third organic solvent may include one or more of cyclohexane, acetonitrile, acetone, tetrahydrofuran, toluene and methyl tert-butyl ether, and may specifically be cyclohexane, acetonitrile, acetone, tetrahydrofuran, toluene or methyl tert-butyl ether; the molar ratio of the compound 3 to the 1,3-dicarbonyl ester compound may be 1:1 to 1:5, and may also be 1:1.1 to 1:3.

[0102] As a specific embodiment of the present invention, the second alkaline compound may include one or more of sodium methoxide, sodium hydride, sodium hydroxide, 1,8-diazabicycloundec-7-ene (DBU), butyl lithium, triethylamine, pyridine, morpholine and piperidine, and may specifically be sodium methoxide, sodium hydride, sodium hydroxide, DBU, butyl lithium, triethylamine, pyridine, morpholine or piperidine; the molar ratio of the compound 3 to the second alkaline compound may be 1:1 to 1:5, and may also be 1:1.2 to 1:3.

[0103] In a specific embodiment of the present invention, the temperature of the condensation reaction can be 0-50°C, or 20-30°C; the time of the condensation reaction can be 4-6h, or 5h; and the condensation reaction can be accompanied by stirring.

[0104] As a specific embodiment of the present invention, after the condensation reaction, the method further comprises: mixing the system after the condensation reaction with water and ethyl acetate for extraction to obtain an organic phase;

[0105] The organic phase was concentrated and mixed with an acidic mixture for subsequent reaction.

[0106] As a specific embodiment of the present invention, the acidic compound may include formic acid, acetic acid, hydrochloric acid or sulfuric acid; the molar ratio of the compound 3 to the acidic compound may be 1:1 to 1:10, or 1:2 to 1:5. As a specific embodiment of the present invention, the solvent for the hydrolysis decarboxylation reaction may be a mixture of water and an organic solvent; the organic solvent may be the same as the third organic solvent.

[0107] As a specific embodiment of the present invention, the temperature of the hydrolysis decarboxylation reaction can be 50-100° C., or 80-90° C.; the time of the hydrolysis decarboxylation reaction can be 7-9 hours, or 8-8.5 hours.

[0108] In the present invention, the equations of the condensation reaction and the hydrolysis decarboxylation reaction are as follows:

[0109]

[0110] Among them, R3 methyl, ethyl, propyl or butyl.

[0111] As a specific embodiment of the present invention, the hydrolysis decarboxylation reaction further comprises: cooling the system after the hydrolysis decarboxylation reaction to room temperature and then removing the solvent by reduced pressure distillation; mixing the product after reduced pressure distillation, water and ethyl acetate, adjusting the pH value to 8-9 with sodium hydroxide aqueous solution, and extracting to obtain an aqueous phase; adjusting the pH value of the aqueous phase to 2-3 with hydrochloric acid solution, extracting with ethyl acetate to obtain an organic phase; washing the organic phase with saturated sodium chloride aqueous solution to obtain the compound 5.

[0112] In the present invention, the method b comprises the following steps:

[0113] The compound 2, the halogenated ester compound, the catalyst and the fourth organic solvent are mixed for the fourth time and then subjected to a Bryce reaction to obtain compound 4. As a specific embodiment of the present invention, the fourth mixing may include the following steps: dissolving the compound 2 in part of the fourth organic solvent to obtain a solution of compound 2; dissolving the halogenated ester compound in the remaining fourth organic solvent and then adding the catalyst and the solution of compound 2. As a specific embodiment of the present invention, the catalyst may include zinc powder; the halogenated ester compound may include methyl bromoacetate, ethyl bromoacetate, methyl chloroacetate or ethyl chloroacetate; the molar ratio of the compound 2 to the halogenated ester compound may be 1:1 to 1:5, and may also be 1:1.5 to 1:3. As a specific embodiment of the present invention, the fourth organic solvent may include one or more of hexane, acetonitrile, acetone, tetrahydrofuran, toluene and methyl tert-butyl ether, and may specifically be hexane, acetonitrile, acetone, tetrahydrofuran, toluene or methyl tert-butyl ether.

[0114] As a specific embodiment of the present invention, the temperature of the Bryce reaction can be 0-60°C, or 0-10°C; the time of the Bryce reaction can be 4-6h, or 5h.

[0115] In the present invention, the equation of the Bryce reaction is as follows:

[0116]

[0117] Among them, R 2 is methyl or ethyl; X is -Br or -Cl.

[0118] As a specific embodiment of the present invention, after the Bryce reaction, the process further comprises: cooling the system after the Bryce reaction, adding water to quench it, filtering, and subjecting the filtrate obtained by the filtration to reduced pressure distillation to obtain compound 4. As a specific embodiment of the present invention, the temperature after the cooling can be 0 to 20° C., or 5 to 10° C. The present invention has no special requirements for the filtration and reduced pressure distillation, and the conventional methods in the art can be used.

[0119] After obtaining compound 4, the present invention mixes the compound 4, the third basic compound, water and the fifth organic solvent and then performs a hydrolysis reaction to obtain compound 5. As a specific embodiment of the present invention, the third basic compound can include one or more of sodium methoxide, sodium tert-butoxide, sodium hydroxide and potassium hydroxide, and can be specifically sodium methoxide, sodium tert-butoxide, sodium hydroxide or potassium hydroxide; the molar ratio of the compound 4 to the third basic compound can be 1:1 to 1:5, and can also be 1.5 to 1:3.

[0120] As a specific embodiment of the present invention, the fifth organic solvent may include one or more of methanol, ethanol, acetonitrile, tetrahydrofuran and toluene, and may be specifically methanol, ethanol, acetonitrile, tetrahydrofuran or toluene; the volume ratio of water to the fifth organic solvent may be 0.8 to 1.2:1, and may be specifically 1:1.

[0121] As a specific embodiment of the present invention, the temperature of the hydrolysis reaction can be 60-100° C., or 70-80° C.; the time of the hydrolysis reaction can be 7-9 hours, or 8-8.5 hours.

[0122] In the present invention, the equation of the hydrolysis reaction is as follows:

[0123]

[0124] As a specific embodiment of the present invention, after the hydrolysis reaction, the method further includes: cooling the system after the hydrolysis reaction to room temperature and then removing the solvent by reduced pressure distillation; extracting the product after reduced pressure distillation, water and ethyl acetate to obtain an aqueous phase; adjusting the pH value of the aqueous phase to 2-3 with a hydrochloric acid solution, extracting with ethyl acetate to obtain an organic phase; washing the organic phase with a saturated sodium chloride aqueous solution, drying the washed organic phase over anhydrous magnesium sulfate and then distilling under reduced pressure to obtain the compound 5.

[0125] After obtaining compound 5, the present invention performs a reduction reaction after mixing the compound 5, the reducing agent and the sixth organic solvent for the sixth time to obtain compound 6. As a specific embodiment of the present invention, the sixth mixing may include the following steps: dissolving the compound 5 in the sixth organic solvent and then adding the reducing agent in batches under a protective atmosphere. As a specific embodiment of the present invention, the sixth organic solvent may include one or more of methanol, ethanol, acetone, acetonitrile, tetrahydrofuran and toluene, and may specifically be methanol, ethanol, acetone, acetonitrile, tetrahydrofuran or toluene.

[0126] As a specific embodiment of the present invention, the protective atmosphere can be nitrogen; the reducing agent includes one or more of sodium borohydride, sodium triacetoxyborohydride, palladium carbon, lithium aluminum hydride and diisobutylaluminum hydride, and can be specifically sodium borohydride, sodium triacetoxyborohydride, palladium carbon, lithium aluminum hydride or diisobutylaluminum hydride; the molar ratio of the compound 5 to the reducing agent can be 1:1 to 1:5, and can be specifically 1:1.5 to 1:3; the reducing agent can be added at 0 to 3°C; the reducing agent can be stirred after being added; the stirring time can be 1.5 to 2.5h, and can be specifically 2h.

[0127] As a specific embodiment of the present invention, the temperature of the reduction reaction can be 0-50° C., and can also be 20-30° C.; the time of the reduction reaction can be 1.5-2.5 hours, and can be specifically 2 hours.

[0128] In the present invention, the equation of the reduction reaction is as follows:

[0129]

[0130] As a specific embodiment of the present invention, the reduction reaction may also include: cooling the system after the reduction reaction to 0-10°C, adding hydrochloric acid solution to adjust the pH value to 2-3, extracting the aqueous layer with toluene, and taking the organic layer; washing the organic layer with sodium hydroxide aqueous solution to obtain a water layer; adjusting the pH value of the aqueous layer to 2-3 with hydrochloric acid aqueous solution, and then extracting with toluene to obtain an organic layer; washing the organic layer with saturated sodium chloride aqueous solution, drying over anhydrous magnesium sulfate, and distilling under reduced pressure to obtain compound 6.

[0131] After obtaining compound 6, the present invention mixes the compound 6, a cyclization reagent and a seventh organic solvent and then performs a ring-closing reaction to obtain the 3-ethylbicyclo[3.2.0]hept-3-en-6-one. As a specific embodiment of the present invention, the cyclization reagent is a mixture of acetic anhydride and potassium acetate, and the molar ratio of the acetic anhydride to potassium acetate can be 1.2 to 2:1, and can also be 1.2 to 1.5:1; the molar ratio of the compound 6 to acetic anhydride is 1:2 to 4, and can also be 1:3.

[0132] As a specific embodiment of the present invention, the temperature of the ring-closing reaction can be 100-130°C, or 110-120°C; the time of the ring-closing reaction can be 3-5h, or 3.5-4h. In the present invention, the 3-ethylbicyclo[3.2.0]hept-3-en-6-one has a structure shown in Formula 7:

[0133] In the present invention, the equation of the ring-closure reaction is as follows:

[0134]

[0135] As a specific embodiment of the present invention, the ring-closing reaction may further include: adding water and ethyl acetate to the system after the ring-closing reaction for extraction, taking an organic phase; washing the organic phase with sodium hydroxide aqueous solution and water in sequence, and then mixing with anhydrous sodium sulfate for drying, filtering, and rotary evaporating the filtrate obtained by the filtration to obtain a crude product of 3-ethylbicyclo[3.2.0]hept-3-ene-6-one; and vacuum distilling the crude product of 3-ethylbicyclo[3.2.0]hept-3-ene-6-one to obtain a pure product of 3-ethylbicyclo[3.2.0]hept-3-ene-6-one. As a specific embodiment of the present invention, the molar concentration of the sodium hydroxide aqueous solution is 0.8 to 1.2 mol / L, and can be specifically 1 mol / L.

[0136] In order to further illustrate the present invention, the technical solutions provided by the present invention are described in detail below in conjunction with embodiments, but they should not be construed as limiting the protection scope of the present invention.

[0137] Example 1

[0138] Preparation of the compound of formula 7 using 4-pentenoic acid as the starting material

[0139]

[0140] Under nitrogen protection, 70 mL of anhydrous tetrahydrofuran and 160 mmol of diisopropylamine were added to a round-bottom flask, cooled to -10°C, and then 160 mmol of n-butyl lithium was added dropwise and stirred for 0.5 h to obtain lithium diisopropylamide (LDA);

[0141] 120 mmol of ethyl bromide was dissolved in 10 mL of anhydrous tetrahydrofuran at 0°C to obtain an ethyl bromide solution; 80 mmol of 4-pentenoic acid was dissolved in 10 mL of anhydrous tetrahydrofuran at -10°C, and then 160 mmol of lithium diisopropylamide was added, stirred at 20°C for 0.5 h, and then the ethyl bromide solution was added; the ethylation reaction was carried out at 80°C for 5 h; the reaction was monitored to be complete by TLC, cooled to 0°C, 50 mL of water was added to quench the reaction, and the solvent was removed by rotary evaporation; water and ethyl acetate were added to the oily product after rotary evaporation, and the aqueous phase was separated and retained; aqueous hydrochloric acid was added to the aqueous phase to adjust the pH value to 1, extracted with ethyl acetate and water, and the organic phase was taken, washed with saturated sodium chloride aqueous solution, dried with anhydrous magnesium sulfate, and distilled under reduced pressure to obtain 8.8 g of oily compound 2 with a yield of 86% and a purity of 99%.

[0142] 1 H NMR (400MHz, CDCl3) δ11.42(s,1H),5.88-5.66(m,1H),5.16-4.95(m,2H),2.43-2.32(m ,2H),2.31-2.19(m,1H),1.73-1.50(m,2H),0.94(t,J=7.5Hz,3H).HRMS(ESI)m / z:[M+H] + Calcd for C7H 13 O2129.0910; Found:129.0912.

[0143]

[0144] Compound 2 (50 mmol), thionyl chloride (100 mmol), and N,N-dimethylformamide (1 mmol) were added to the reaction bottle in sequence under nitrogen protection, and the temperature was raised to 80°C, and refluxed for chlorination reaction for 2 h. The reaction was completed when detected by TLC, and the reaction was stopped. The mixture was cooled to room temperature (25°C), and the excess thionyl chloride and acid gas (HCl) were removed by distillation under reduced pressure to obtain compound 3;

[0145]

[0146] Add dimethyl malonate (50 mmol) and 80 mL of acetonitrile to the reaction flask, add sodium hydride (100 mmol) in batches under ice bath, and stir at room temperature (25°C) for 0.5 h; dissolve compound 3 (2-ethylpentyl-4-enoyl chloride) in 20 mL of acetonitrile, add dropwise to the reaction flask, and stir at 30°C for 5 h to carry out condensation reaction; TLC detection shows that the reaction is complete, extract with water and ethyl acetate to obtain an organic layer, and concentrate to obtain an oil;

[0147] The oil, acetic acid (150 mmol), 20 mL of water and 100 mL of acetonitrile were added to a new reaction bottle in sequence, the temperature was raised to 90°C, and the reaction was refluxed for hydrolysis and decarboxylation for 8 h; TLC detected that the reaction was complete, the reaction was stopped, the mixture was cooled to room temperature (25°C), and the solvent was removed by distillation under reduced pressure; water and ethyl acetate were added, the pH value was adjusted to 8-9 with aqueous sodium hydroxide solution, and an aqueous phase was extracted; the pH value of the aqueous phase was adjusted to 2-3 with hydrochloric acid, and the organic phase was extracted with ethyl acetate to obtain an organic phase, which was washed with saturated brine and concentrated to obtain an oily compound 5 with a two-step yield of 90% and a purity of 99%;

[0148] 1 H NMR(400MHz, CDCl3)δ11.32(s,1H),5.88-5.66(m,1H),5.14-4.93(m,2H),3.47(s,2H),2.46-2 .31(m,2H),2.30-2.18(m,1H),1.72-1.50(m,2H),0.94(t,J=7.4Hz,3H).HRMS(ESI)m / z:[M+H] + Calcd for C7H 15 O3171.1016;Found:171.1016.

[0149]

[0150] Compound 5 (50 mmol) was dissolved in 100 mL of methanol; sodium borohydride (100 mmol) was added to the solution in batches at 0°C under nitrogen protection, and the solution was stirred at the same temperature for reduction reaction for 2 h; TLC monitored the reaction to be complete, 1 mol / L hydrochloric acid was added to adjust the pH value to 2-3, the aqueous layer was extracted with toluene, and the organic layers were combined; the combined organic layers were washed with an aqueous sodium hydroxide solution to obtain an aqueous layer, the pH value of the aqueous layer was adjusted to 2-3 with hydrochloric acid, and then extracted with toluene to obtain an organic layer; the organic layer was washed with a saturated aqueous sodium chloride solution, and then dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain 6.95 g of compound 6 as a yellow oil with a yield of 80.7% and a purity of 99%;

[0151] 1 H NMR (400MHz, CDCl3): δ5.74-5.86(1H,m),5.03-5.10(2H,m),4.05-4.15(2H,m),2.52-2. 55(2H,m),2.01-2.28(2H,m),1.39-1.52(3H,m),0.91-0.96(3H,m).HRMS(ESI)m / z:[M+H] + Calcd for C7H 17O3173.1172; Found:173.1170.

[0152]

[0153] Compound 6 (20 mmol) was dissolved in toluene (20 mL); acetic anhydride (60 mmol) and potassium acetate (46 mmol) were added to the solution, and the mixture was stirred at room temperature (20° C.) for 1 h, and the mixture was heated to 120° C. and stirred for 4 h for ring-closure reaction. The reaction was completed by GC monitoring; H2O (200 mL) was added, and ethyl acetate (EA) was used for extraction (200 mL×3). The organic phase obtained by extraction was washed with a 1 mol / L NaOH solution (100 mL), then washed with water (200 mL), dried over anhydrous Na2SO4, filtered, and rotary evaporated to obtain a crude product of 3-ethylbicyclo[3.2.0]hept-3-en-6-one. 2.21 g of pure 3-ethylbicyclo[3.2.0]hept-3-en-6-one was obtained by reduced pressure distillation under a vacuum degree of 25 mmHg, which was a colorless to light yellow oily liquid with a yield of 81.1% and a purity of 99%. 1 HNMR (400MH, CDCl3) δ5.22-5.19 (m, 1H), 4.21-4.14 (m, 1H), 3.30-3.07 (m, 1H), 2.89-2.65 (m, 3H), 2.40-2.23 (m, 1H), 2.18-2.03 (m, 2H), 1.06 (t, J = 7.5Hz, 3H). HRMS (ESI) m / z: [M+H] + Calcd for C9H 13 O 137.0961;Found:137.0961.

[0154] Example 2

[0155] 3-Ethylbicyclo[3.2.0]hept-3-en-6-one was prepared according to the method of Example 1, except that 4-pentenyl ester was used as the starting material. The yield of 3-ethylbicyclo[3.2.0]hept-3-en-6-one prepared was 83.5% and the purity was 99%.

[0156] Example 3

[0157] Preparation of 3-ethylbicyclo[3.2.0]hept-3-en-6-one using 4-pentenenitrile as starting material:

[0158]

[0159] Under nitrogen protection, 100 mL of toluene and 80 mmol of 4-pentenenitrile were added to the reaction vessel, and 120 mmol of potassium hydroxide was slowly added at 0°C. After stirring for 0.5 h, 10 mL of toluene and 120 mmol of ethyl iodide were added, and the temperature was raised to 80°C for ethylation reaction for 5 h. The reaction was monitored to be complete by TLC, and the mixture was cooled to 0°C, 50 mL of water was added to quench the reaction, and water and toluene were added for extraction, and the organic phase was separated and retained. The organic phase was dried over anhydrous magnesium sulfate, filtered, and then distilled under reduced pressure to obtain an oily product. The oily product was distilled under reduced pressure to obtain 8.0 g of anhydrous transparent liquid compound 2 with a yield of 92% and a purity of 98%.

[0160] 1 H NMR (400MHz, CDCl3) δ5.68-5.88(m,1H),5.10-5.19(m,2H),2.43-2.54(m,1H),2.31(m,2H),1.61(m,2H),1.05(t,3H,J=7.2Hz).HRMS(ESI)m / z:[M+H] + Calcd for C7H 12 N110.0964; Found:110.0966.

[0161]

[0162] Under nitrogen protection, methyl bromoacetate (50 mmol), 50 mL of tetrahydrofuran, and zinc powder (75 mmol) were added to the reaction bottle in sequence at 0°C, and stirred for 1 h; at 0°C, 50 mmol of compound 2 (2-ethylpent-4-enenitrile) was dissolved in 50 mL of tetrahydrofuran and then dropped into the reaction bottle, and the Bryce reaction was carried out at room temperature (20°C) for 5 h; TLC detected that the reaction was complete, the reaction was stopped, cooled to 0°C, 5 mL of water was added to quench, the insoluble matter was filtered, and the solvent was removed by distillation under reduced pressure to obtain an oily compound 4;

[0163]

[0164] Compound 4, 100 mmol potassium hydroxide, 100 mL water and 100 mL ethanol were added to a new reaction bottle in sequence, and the temperature was raised to 60°C and stirred for hydrolysis reaction for 8 h; TLC monitored the reaction to be complete, and the solvent was distilled off under reduced pressure; water and ethyl acetate were added for extraction, and the aqueous phase was retained; hydrochloric acid was added to the aqueous phase to adjust the pH value of the aqueous layer to 2-3, and then the organic phase was extracted with ethyl acetate to retain the organic phase; the organic phase was washed with saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate, and distilled under reduced pressure to obtain compound 5 as an oil, with a two-step yield of 90% and a purity of 99%;

[0165] 1H NMR(400MHz, CDCl3)δ11.32(s,1H),5.88-5.66(m,1H),5.14-4.93(m,2H),3.47(s,2H),2.46-2 .31(m,2H),2.30-2.18(m,1H),1.72-1.50(m,2H),0.94(t,J=7.4Hz,3H).HRMS(ESI)m / z:[M+H] + Calcd for C7H 15 O3171.1016;Found:171.1016.

[0166]

[0167] Compound 5 (50 mmol) was dissolved in 100 mL of ethanol; sodium borohydride (100 mmol) was added to the solution in batches at 0°C under nitrogen protection, and the solution was stirred at this temperature for reduction reaction for 2 h; TLC monitored the reaction to be complete, 1 mol / L hydrochloric acid was added to adjust the pH value to 2-3, the aqueous layer was extracted with toluene, and the organic layers were combined; the combined organic layers were washed with sodium hydroxide aqueous solution to obtain a water layer, the pH value of the aqueous layer was adjusted to 2-3 with hydrochloric acid, and then extracted with toluene to obtain an organic layer; the organic layer was washed with saturated sodium chloride aqueous solution, and then dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain 6.91 g of compound 6 as a light yellow oil with a yield of 80.2% and a purity of 99%;

[0168] 1 H NMR (400MHz, CDCl3): δ5.74-5.86(1H,m),5.03-5.10(2H,m),4.05-4.15(2H,m),2.52-2. 55(2H,m),2.01-2.28(2H,m),1.39-1.52(3H,m),0.91-0.96(3H,m).HRMS(ESI)m / z:[M+H] + Calcd for C7H 17 O3173.1172; Found:173.1170.

[0169]

[0170] Compound 6 (20 mmol) was dissolved in toluene (20 mL); acetic anhydride (60 mmol) and potassium acetate (46 mmol) were added to the solution, and the mixture was stirred at room temperature (20° C.) for 1 h, and the mixture was heated to 120° C. and stirred for 4 h for ring-closure reaction. The reaction was monitored by GC to be complete; H2O (200 mL) was added, and ethyl acetate (EA) was used for extraction (200 mL×3). The organic phase obtained by the extraction was washed with a 1 mol / L NaOH solution (100 mL), then washed with water (200 mL), dried over anhydrous Na2SO4, filtered, and rotary evaporated to obtain a crude product of 3-ethylbicyclo[3.2.0]hept-3-en-6-one. 2.23 g of pure 3-ethylbicyclo[3.2.0]hept-3-en-6-one was obtained by reduced pressure distillation under a vacuum degree of 25 mmHg, and the appearance was a colorless to light yellow oily liquid. The yield was 81.9% and the purity was 99%.

[0171] 1 HNMR (400MH, CDCl3) δ5.22-5.19 (m, 1H), 4.21-4.14 (m, 1H), 3.30-3.07 (m, 1H), 2.89-2.65 (m, 3H), 2.40-2.23 (m, 1H), 2.18-2.03 (m, 2H), 1.06 (t, J = 7.5Hz, 3H). HRMS (ESI) m / z: [M+H] + Calcd for C9H 13 O137.0961;Found:137.0961.

[0172] It can be seen from Examples 1 to 3 that 3-ethylbicyclo[3.2.0]hept-3-en-6-one can be prepared according to the method provided by the present invention with high yield and purity.

[0173] Although the above embodiment describes the present invention in detail, it is only a part of the embodiments of the present invention, not all of the embodiments. People can also obtain other embodiments based on this embodiment without creativity, and these embodiments all fall within the protection scope of the present invention.

Claims

1. A method for preparing 3-ethylbicyclo[3.2.0]hept-3-en-6-one, comprising the following steps: A 4-pentene compound, an ethyl halide, a first alkaline compound and a first organic solvent are first mixed and then subjected to an ethylation reaction to obtain a compound 2; the 4-pentene compound has a structure shown in Formula 1; and the compound 2 has a structure shown in Formula 2; When R 1 When R is a carboxyl group or an ester group, compound 5 is prepared according to method a; when R 1 When it is cyano, compound 5 is prepared according to method b; The method a comprises the following steps: The compound 2, the acyl chlorination agent and the second organic solvent are mixed for a second time and then subjected to an acyl chlorination reaction to obtain a compound 3; the compound 3 has a structure shown in Formula 3; The compound 3, the 1,3-dicarbonyl ester compound, the second alkaline compound and the third organic solvent are mixed and subjected to a condensation reaction, and then an acidic compound is added to carry out a hydrolysis and decarboxylation reaction to obtain a compound 5; the compound 5 has a structure shown in Formula 5; The method b comprises the following steps: The compound 2, the halogenated ester compound, the catalyst and the fourth organic solvent are mixed and then subjected to a Bryce reaction to obtain a compound 4; the compound 4 has a structure shown in Formula 4; The compound 4, the third basic compound, water and the fifth organic solvent are mixed and then subjected to a hydrolysis reaction to obtain a compound 5; The compound 5, the reducing agent and the sixth organic solvent are mixed and then subjected to a reduction reaction to obtain a compound 6; the compound 6 has a structure shown in Formula 6; The compound 6, a cyclization reagent and a seventh organic solvent are mixed and then subjected to a ring-closing reaction to obtain the 3-ethylbicyclo[3.2.0]hept-3-en-6-one; the cyclization reagent is a mixture of acetic anhydride and potassium acetate; Among them, R 1 is a carboxyl group, an ester group or a cyano group; R 2 It is methyl or ethyl.

2. The preparation method according to claim 1, characterized in that: The 4-pentene compounds include 4-pentenenitrile, 4-pentenoic acid, 4-pentenoic acid methyl ester, 4-pentenoic acid ethyl ester, 4-pentenoic acid n-propyl ester, 4-pentenoic acid isopropyl ester or 4-pentenoic acid n-butyl ester; The ethyl halide includes ethyl chloride, ethyl bromide or ethyl iodide; The molar ratio of the 4-pentene compound to the ethyl halide is 1:1 to 1:5; The first alkaline compound includes one or more of sodium hydride, sodium hydroxide, potassium hydroxide, n-butyl lithium, lithium diisopropylamide and 1,8-diazabicycloundec-7-ene; The molar ratio of the 4-pentene compound to the first basic compound is 1:1 to 1:

5.

3. The preparation method according to claim 1 or 2, characterized in that: The temperature of the ethylation reaction is 50-100° C. and the time is 4-6 hours.

4. The preparation method according to claim 1, characterized in that: The acyl chloride reagent includes thionyl chloride, oxalyl chloride, phosphorus trichloride, bis(trichloromethyl) carbonate or carbon tetrachloride; The molar ratio of the compound 2 to the acyl chloride reagent is 1:1 to 1:10; The temperature of the acyl chlorination reaction is 50-100° C. and the time is 1.5-2.5 hours.

5. The preparation method according to claim 1, characterized in that: The 1,3-dicarbonyl ester compound includes dimethyl malonate, diethyl malonate, dipropyl malonate or dibutyl malonate; The molar ratio of the compound 3 to the 1,3-dicarbonyl ester compound is 1:1 to 1:5; The second alkaline compound includes one or more of sodium methoxide, sodium hydride, sodium hydroxide, 1,8-diazabicycloundec-7-ene, butyl lithium, triethylamine, pyridine, morpholine and piperidine; The molar ratio of the compound 3 to the second basic compound is 1:1 to 1:5; The condensation reaction temperature is 0-50°C and the reaction time is 4-6 hours.

6. The preparation method according to claim 1 or 5, characterized in that: The acidic compound includes formic acid, acetic acid, hydrochloric acid or sulfuric acid; The molar ratio of the compound 3 to the acidic compound is 1:1 to 1:10; The temperature of the hydrolysis decarboxylation reaction is 50-100° C. and the time is 7-9 hours.

7. The preparation method according to claim 1, characterized in that: The halogenated ester compound includes methyl bromoacetate, ethyl bromoacetate, methyl chloroacetate or ethyl chloroacetate; The molar ratio of the compound 2 to the halogenated ester compound is 1:1 to 1:5; The catalyst includes zinc powder; The temperature of the Bryce reaction is 0-60° C. and the time is 4-6 hours.

8. The preparation method according to claim 1, characterized in that: The third alkaline compound includes one or more of sodium methoxide, sodium tert-butoxide, sodium hydroxide and potassium hydroxide; The molar ratio of the compound 4 to the third basic compound is 1:1 to 1:5; The temperature of the hydrolysis reaction is 60-100° C. and the time is 7-9 hours.

9. The preparation method according to claim 1, characterized in that: The reducing agent includes one or more of sodium borohydride, sodium triacetoxyborohydride, palladium carbon, lithium aluminum hydride and diisobutylaluminum hydride; The molar ratio of the compound 5 to the reducing agent is 1:1 to 1:5; The temperature of the reduction reaction is 0-50° C. and the time is 1.5-2.5 hours.

10. The preparation method according to claim 1, characterized in that: The molar ratio of acetic anhydride to potassium acetate in the cyclization reagent is 1.2 to 2:1; The molar ratio of the compound 6 to acetic anhydride is 1:2-4; The temperature of the ring-closure reaction is 100-130° C., and the time is 3-5 hours.

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