Preparation method of 3-chlorobicyclo[3.2.1]-3-octen-2-ol

Abstract

The present invention is a divisional application with application number 202310074577.6. The present invention discloses a method for preparing 3-chlorobicyclo[3.2.1]-3-octen-2-ol, which belongs to the field of pharmaceutical technology. The method for preparing 3-chlorobicyclo[3.2.1]-3-octen-2-ol can be obtained by any of the following reaction routes: Reaction route 1: 3,4-dichlorobicyclo[3.2.1]-2-octenes are esterified under the action of carboxylates and hydrolyzed in strong bases to obtain 3-chlorobicyclo[3.2.1]-3-octen-2-ol; Reaction route 2: 3,4-dichlorobicyclo[3.2.1]-2-octenes are reacted in a solvent under the action of inorganic strong base weak acid salts to obtain 3-chlorobicyclo[3.2.1]-3-octen-2-ol. The present invention can reduce the generation of polymers and impurities, make the stratification more obvious, and improve the purification efficiency.

Description

[0001] The present invention is a divisional application of a Chinese application filed on January 19, 2023, with application number 202310074577.6 and invention name “Method for preparing 3-chlorobicyclo[3.2.1]-3-octen-2-ol”. Technical Field

[0002] The invention relates to the technical field of medicines, and in particular to a method for preparing 3-chlorobicyclo[3.2.1]-3-octen-2-ol. Background Art

[0003] 3-Chlorobicyclo[3.2.1]-3-octen-2-ol (Formula I) is a commonly used intermediate in the synthesis of pesticide herbicides. Compounds synthesized from it, such as flupyralidone: 4-hydroxy-3-{2-[(2-methoxyethoxy)methyl]-6-(trifluoromethyl)-3-pyridylcarbonyl}bicyclo[3.2.1]oct-3-ene-2-one, and bicyclosulfone: 3-(2-chloro-4-methylsulfonylbenzoyl)-2-phenylthiobicyclo[3,2,1]oct-2-ene-4-one, have certain herbicidal activity. Flupyralidone and bicyclosulfone are both 4-hydroxyphenylpyruvate dioxygenase (HPPD) inhibitor herbicides.

[0004] Flupyralid was developed by Syngenta and has good activity against broadleaf weeds and perennial and annual weeds. It can be used in corn, wheat, barley, sugarcane and other crop fields, both before and after emergence. It has excellent control effects on resistant weeds and other stubborn broadleaf weeds, especially those weeds that have developed resistance to ALS inhibitors, auxin herbicides and glyphosate.

[0005] Bicyclopyralid was developed by Styx Bioscience Co., Ltd. It can be absorbed by the roots and stems of weeds and then transmitted to the whole plant. It mainly acts on the biochemical synthesis of carotenoids in photosynthetic pigments, resulting in a decrease in their content, causing weed leaves to turn white and kill weeds. Bicyclopyralid is highly selective between rice and weeds, safe for rice, highly compatible with the environment, and low in toxicity to fish and mammals; it has a broad spectrum of weed control and a long lasting effect.

[0006] The current methods for synthesizing the compound of formula I are:

[0007]

[0008] 1) Literature Kaenel, Hans Ruedi; Ganter, Camille, The novel adamantine isomertricyclo [4.4.0.0 3,9]decane(2-homotwistbrendane)[J]Helvetica Chimica Acta(1985),68(5),1226-34 has a similar structure and is hydrolyzed using potassium hydroxide solution.

[0009] Route A-1:

[0010]

[0011] This route uses potassium hydroxide solution for hydrolysis, and the yield is only 82%.

[0012] 2) 3,4-dichlorobicyclo[3.2.1]-2-octene is used as the raw material, and 3-chlorobicyclo[3.2.1]-3-octen-2-ol is obtained after hydrolysis. Three articles describe it as follows: Patent (CN1440376A), Patent (CN105693569A), and Literature (Ge, Fa-xiang, Synthesis of post-emergence paddy herbicide benzob[J] Anhui Huagong (2013), 39(6), 41-43), as shown in Route A-1.

[0013] Route A-2:

[0014]

[0015] The yield of route A-2 is about 94%. It uses 3,4-dichlorobicyclo[3.2.1]-2-octene as raw material and performs hydrolysis reaction at high temperature. The disadvantage is that a large amount of alkali is used. The patent examples and the experimental part of the literature all use 4 equivalent sodium hydroxide solution for reaction, and the wastewater treatment is difficult. However, under this reaction condition, route A-2 is prone to produce flocculent impurities. The flocculent impurities are insoluble in the water phase and the oil phase, and it is difficult to separate them during extraction, which increases the difficulty of purification. It is also easy to produce by-products 4,4'-oxybis(3-chlorobicyclo[3.2.1]-2-octene (referred to as ether impurities), resulting in a decrease in yield. The ether impurities will also be in the organic phase of the extraction, resulting in low material purity, which is generally not higher than 90%. In actual production, the purity needs to reach 94% or above to be suitable for subsequent production. Since the boiling point of the ether impurities is higher than that of the target product, further purification requires complex processes such as distillation, which not only increases the three wastes, but also increases production costs. Summary of the invention

[0016] Purpose of the Invention

[0017] In order to overcome the above disadvantages, the object of the present invention is to provide a method for preparing 3-chlorobicyclo[3.2.1]-3-octen-2-ol. The present invention can reduce the generation of polymers and impurities, make the extraction stratification more obvious, and improve the purification efficiency.

[0018] Solution

[0019] To achieve the purpose of the present invention, the technical solution adopted by the present invention is as follows:

[0020] In a first aspect, the present invention provides a substituted bicyclic alcohol ester compound, the structural formula of which is shown in Formula IV:

[0021]

[0022] Among them, R 1 It is a hydrogen group, a C1-C8 alkyl group, a phenyl group, a C1-C8 halogen-substituted alkyl group or a halogen-substituted phenyl group.

[0023] Furthermore, R 1 is a hydrogen group, a C1-C5 alkyl group, a phenyl group, a C1-C5 chloro-substituted alkyl group (which may be a monochloro-substituted alkyl group, a dichloro-substituted alkyl group or a trichloro-substituted alkyl group) or a chloro-substituted phenyl group (which may be a monochloro-substituted phenyl group, a dichloro-substituted phenyl group or a trichloro-substituted phenyl group). Preferably, R 1 It is hydrogen, methyl, ethyl, 4-chlorophenyl or phenyl.

[0024] In a second aspect, a method for preparing the substituted bicyclic alcohol ester compound is provided, comprising the following steps: subjecting 3,4-dichlorobicyclo[3.2.1]-2-octene to an esterification reaction in a solvent under the action of a carboxylate to obtain a compound of formula IV.

[0025] In a third aspect, a method for preparing 3-chlorobicyclo[3.2.1]-3-octen-2-ol is provided, which is obtained by any of the following reaction routes:

[0026] Reaction route 1: 3,4-dichlorobicyclo[3.2.1]-2-octene is esterified under the action of carboxylate and hydrolyzed in a strong base to obtain 3-chlorobicyclo[3.2.1]-3-octen-2-ol;

[0027] Reaction route 2: 3,4-dichlorobicyclo[3.2.1]-2-octene is reacted in a solvent under the action of an inorganic strong base and a weak acid salt to obtain 3-chlorobicyclo[3.2.1]-3-octen-2-ol.

[0028] In the preparation method of the second aspect or the third aspect, in the esterification reaction of reaction route one, the carboxylate is selected from alkali metal carboxylates or alkaline earth metal carboxylates, and the carboxylate is selected from one or more of alkali metal formates, alkali metal acetates, alkali metal propionates, alkali metal 4-chlorobenzoates, alkali metal benzoates, alkaline earth metal formates, alkaline earth metal acetates, alkaline earth metal propionates, alkaline earth metal 4-chlorobenzoates, and alkaline earth metal benzoates; or the carboxylate is selected from one or more of sodium formate, sodium acetate, potassium acetate, calcium acetate, magnesium acetate, sodium propionate, potassium propionate, sodium 4-chlorobenzoate, potassium 4-chlorobenzoate, sodium benzoate, and potassium benzoate.

[0029] In the preparation method of the second aspect or the third aspect, in the esterification reaction of reaction route 1, the molar ratio of 3,4-dichlorobicyclo[3.2.1]-2-octene to carboxylate is 1:1-4, or 1:1.2-4, or 1:1.5-3;

[0030] In the preparation method of the second aspect or the third aspect, in the esterification reaction of reaction route 1, the reaction temperature is 0°C to the reflux temperature of each solvent, or 50°C to the reflux temperature of each solvent, or 70°C to the reflux temperature of each solvent, or 80°C to the reflux temperature of each solvent, or 90°C to the reflux temperature of each solvent, or the reflux temperature of each solvent;

[0031] In the preparation method of the second aspect or the third aspect, in each reaction (including the preparation method of the second aspect and the different reactions of the two routes of the third aspect, a catalyst may be added or not added according to the situation), 0-10% catalyst is also added, and the catalyst in each reaction is independently or independently selected from one or more of polyethylene glycol, tetrabutylammonium bromide, tetrabutylammonium chloride, benzyltrimethylammonium chloride, benzyltriethylammonium chloride, diisopropylethylamine, triethylamine, triethylenediamine, and crown ether. In each reaction, the type of catalyst may be the same or different.

[0032] In the preparation method of the second aspect or the third aspect, the esterification reaction of reaction route 1 is carried out in a solvent, and the mass ratio of 3,4-dichlorobicyclo[3.2.1]-2-octene to the solvent is 1:1-20, or 1:1-12.

[0033] In the preparation method of the second aspect or the third aspect, in the esterification reaction of reaction route 1, the solvent is water or an organic solvent; the organic solvent is selected from one or more of dimethylformamide, dimethylacetamide, ethylene glycol monomethyl ether, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, N-methylpyrrolidone, dimethyl sulfoxide, and sulfolane. Preferably, one or more of dimethylformamide and dimethylacetamide are selected; when the esterification reaction is carried out in an organic solvent, the organic solvent is completely or partially evaporated or not evaporated after the esterification reaction, and water and a strong base are added after the esterification reaction to carry out a hydrolysis reaction.

[0034] Further, in the reaction route 1, after the esterification reaction of the reaction route 1 is complete, a strong base is added to carry out a hydrolysis reaction, or a carboxylate and a strong base are added to the reaction system at the same time to carry out an esterification and hydrolysis reaction. Preferably, adding a strong base after the esterification reaction is complete can make the purity of the product higher. When the carboxylate and the strong base are added at the same time, the molar ratio of the compound of formula II to the sodium hydroxide is ≤1:1.

[0035] In the preparation method of the third aspect, in the hydrolysis reaction of reaction route one, the strong base is an alkali metal hydroxide and / or an alkaline earth metal hydroxide; or, in the hydrolysis reaction of reaction route one, the strong base is one or more of sodium hydroxide, potassium hydroxide, calcium hydroxide, and magnesium hydroxide.

[0036] In the preparation method of the third aspect, in the hydrolysis reaction of reaction route 1, the molar ratio of 3,4-dichlorobicyclo[3.2.1]-2-octene to the strong base is 1:0.5-2, or 1:1-2, or 1:1-1.5.

[0037] In the preparation method of the third aspect, in the reaction route 2, the inorganic strong base weak acid salt is selected from one or more of carbonates, phosphates, and hydrogen phosphates; or, the inorganic strong base weak acid salt is one or more of alkali metal carbonates, alkali metal phosphates, and alkali metal hydrogen phosphates; or, the inorganic strong base weak acid salt is one or more of sodium carbonate, potassium carbonate, tripotassium phosphate, and dipotassium hydrogen phosphate. Preferably, sodium carbonate and / or potassium carbonate.

[0038] In the preparation method of the third aspect, in reaction route 2, the molar ratio of the 3,4-dichlorobicyclo[3.2.1]-2-octene to the inorganic strong base weak acid salt is 1:1-4, or 1:1-3, or 1:1.5-3.

[0039] In the preparation method of the third aspect, in reaction route 2, the reaction solvent is water, and the mass ratio of the 3,4-dichlorobicyclo[3.2.1]-2-octene to water is 1:1-20, or 1:1-15, or 1:3-15.

[0040] In the preparation method of the third aspect, in reaction route 2, the reaction temperature is 0°C to the reflux temperature of the solvent, or 50°C to the reflux temperature of the solvent, or 70°C to the reflux temperature of the solvent, or 90°C to the reflux temperature of the solvent, or the reflux temperature of the solvent.

[0041] The above reaction route 1 includes two reaction routes: one is reaction route B-2 in which the esterification reaction is carried out in water, and the other is reaction route B-3 in which the esterification reaction is carried out in anhydrous conditions (organic solvent). Reaction route 2 includes a reaction route named reaction route B-4.

[0042] The characteristics of the three reaction routes B-2, B-3, and B-4 are as follows:

[0043] The esterification reaction of reaction route B-2 is carried out in water:

[0044]

[0045] In route B-2, R 1 is hydrogen, C1-C8 alkyl, phenyl, C1-C8 halogen-substituted alkyl (preferably chlorine-substituted alkyl, which may be monochlorine-substituted alkyl, dichlorine-substituted alkyl or trichlorine-substituted alkyl) or halogen-substituted phenyl (preferably chlorine-substituted phenyl, which may be monochlorine-substituted phenyl, dichlorine-substituted phenyl or trichlorine-substituted phenyl); optionally, R 1 It is a hydrogen group, a C1-C5 alkyl group, a phenyl group, a C1-C5 chloro-substituted alkyl group (which may be a monochloro-substituted alkyl group, a dichloro-substituted alkyl group or a trichloro-substituted alkyl group) or a chloro-substituted phenyl group (which may be a monochloro-substituted phenyl group, a dichloro-substituted phenyl group or a trichloro-substituted phenyl group); it may optionally be a hydrogen group, a methyl group, an ethyl group, a 4-chlorophenyl group or a phenyl group.

[0046] In the B-2 route, M 1 It is a metal, optionally an alkali metal or an alkaline earth metal, preferably one or more of potassium, sodium, calcium and / or magnesium.

[0047] In this route B-2, a strong base and a weak acid salt (carboxylate, preferably an alkali metal or alkaline earth metal carboxylate) are used in water to first react to form formula I and formula IV, and then the temperature is lowered and an alkali metal hydroxide or an alkaline earth metal hydroxide is added to hydrolyze formula IV to formula I, which can effectively reduce the generation of polymers and ether impurities (compounds represented by formula III). Carboxylates and alkali metal hydroxides or alkaline earth metal hydroxides can also be mixed and added to react, but the yield will be reduced (see Examples 2 to 13).

[0048] Reaction route B-3, the first step of this route is carried out in an organic solvent under anhydrous conditions, and the second step is hydrolysis:

[0049]

[0050] The route B-3, R 1 It is a hydrogen group, a C1-C8 alkyl group, a phenyl group, a C1-C8 halogen-substituted alkyl group (preferably a chlorine-substituted alkyl group, which may be a monochlorine-substituted alkyl group, a dichlorine-substituted alkyl group or a trichlorine-substituted alkyl group) or a substituted phenyl group (preferably a chlorine-substituted phenyl group, which may be a monochlorine-substituted phenyl group, a dichlorine-substituted phenyl group or a trichlorine-substituted phenyl group), and may optionally be a hydrogen group, a methyl group, an ethyl group, a 4-chlorophenyl group or a phenyl group.

[0051] In the route B-3, M 1 It is a metal, optionally an alkali metal or an alkaline earth metal, preferably one or more of potassium, sodium, calcium and magnesium.

[0052] In route B-3, the first step is to carry out esterification under anhydrous conditions, so that no ether impurity, the compound of formula III, is produced. After filtering and removing salts, the solvent is evaporated and then an alkali metal hydroxide or alkaline earth metal hydroxide aqueous solution is added. Hydrolysis can be carried out at room temperature. The hydrolysis reaction can be carried out in an alkali metal hydroxide or alkaline earth metal hydroxide aqueous solution without going through a high temperature process. This method is basically free of the impurity of formula III, which can improve selectivity and yield (see Examples 14 to 22).

[0053] Reaction route B-4, adding an inorganic strong base and a weak acid salt for hydrolysis, can directly react to form Formula I without esterification, and can also reduce the generation of the impurity Formula III:

[0054]

[0055] The route B-4, M 2 is a metal, optionally an alkali metal, preferably potassium and / or sodium;

[0056] R 2 It is an inorganic weak acid radical, optionally carbonate, phosphate or hydrogen phosphate.

[0057] In this route B-4, the generation of impurity formula III can be reduced, the reaction rate is reduced, and basically no floccules are generated during extraction and stratification. However, a trace amount of impurity formula III is still generated, and the yield is slightly lower than that of route B-3 (see Examples 23-32). The product after distillation can also be directly used for subsequent reactions.

[0058] Beneficial Effects

[0059] (1) The present invention can select three methods B-2, B-3, and B-4 to synthesize 3-chlorobicyclo[3.2.1]-3-octen-2-ol according to the raw materials or solvents. Routes B-2 and B-4 can reduce alkali waste and wastewater treatment difficulty by changing the type of alkali and reducing the alkali equivalent; reduce the alkalinity of the reaction solution, reduce the generation of polymers and impurities, make stratification more obvious, and improve purification efficiency; the purity of the product after distillation can reach 94%, which can be directly used in subsequent reactions. The esterification reaction of B-3 can effectively avoid the generation of impurities under anhydrous conditions, and low-temperature hydrolysis can avoid the generation of polymers. The reaction conditions of the inventive method are simple and mild, the yield is high, and it is suitable for industrial production; the purity of the product after distillation can reach 94%, which can be directly used in subsequent reactions. BRIEF DESCRIPTION OF THE DRAWINGS

[0060] One or more embodiments are exemplarily described by the pictures in the accompanying drawings, and these exemplary descriptions do not constitute limitations on the embodiments. The special word "exemplary" here means "used as an example, embodiment or illustrative". Any embodiment described as "exemplary" here is not necessarily interpreted as being superior or better than other embodiments.

[0061] Figure 1 It is the mass spectrum of the analysis sample (4,4'-oxybis(3-chlorobicyclo[3.2.1]oct-2-ene) of Example 1 of the present invention.

[0062] Figure 2 It is the hydrogen spectrum of the analytical sample (3-chlorobicyclo[3.2.1]-3-octen-2-ol) of Example 1 of the present invention.

[0063] Figure 3 This is the carbon spectrum of the analytical sample (3-chlorobicyclo[3.2.1]-3-octen-2-ol) of Example 1 of the present invention.

[0064] Figure 4 This is the mass spectrum of the analytical sample (3-chlorobicyclo[3.2.1]-3-octen-2-ol) of Example 1 of the present invention.

[0065] Figure 5 This is the hydrogen spectrum of the intermediate (3-chlorobicyclo[3.2.1]-3-octene-2-acetate) of Example 1 of the present invention.

[0066] Figure 6 This is the carbon spectrum of the intermediate (3-chlorobicyclo[3.2.1]-3-octene-2-acetate) of Example 1 of the present invention.

[0067] Figure 7 This is the mass spectrum of the intermediate (3-chlorobicyclo[3.2.1]-3-octene-2-acetate) of Example 1 of the present invention.

[0068] Figure 8 The figures are of the reaction solutions of Examples 2, 23 and Comparative Example 1 of the present invention after extraction with dichloroethane; wherein, a is the extraction figure of Comparative Example 1, in which both the aqueous phase and the organic phase are orange-brown; b is the extraction figure of Example 2, in which the aqueous phase is clear and colorless, and the oil phase is yellow; c is the extraction figure of Example 23, in which the aqueous phase is clear and colorless, and the oil phase is yellow.

[0069] Fig. 9 is a gas chromatogram of the product after distillation of the organic phase of Example 1 of the present invention; wherein 10.19′ is the compound of formula I, 12.20′ is the compound of formula IV-1, and 15.89′ and 16.08′ are impurity compounds III;

[0070] Fig.10 is a gas chromatogram of the product after distillation of the organic phase of Example 2 of the present invention; wherein 10.62′ is the compound of formula I, and 15.53′ and 15.80′ are impurity compounds III;

[0071] Fig.11 is a gas chromatogram of the product after distillation of the organic phase of Example 14 of the present invention; wherein 10.20′ is a compound of formula I; Fig.12is a gas chromatogram of the product after distillation of the organic phase of Example 23 of the present invention; wherein 10.61′ is the compound of formula I, and 15.53′ and 15.80′ are impurity compounds III;

[0072] Fig.13 It is a gas chromatogram of the product after distillation of the organic phase of Comparative Example 1 of the present invention; wherein, 10.17′ is the compound of formula I, and 15.89′ and 16.07′ are impurity compounds III. DETAILED DESCRIPTION

[0073] In order to make the purpose, technical solution and advantages of the embodiments of the present invention clearer, the technical solution in the embodiments of the present invention will be described clearly and completely below. Obviously, the described embodiments are part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0074] In addition, in order to better illustrate the present invention, numerous specific details are provided in the specific embodiments below. It should be understood by those skilled in the art that the present invention can be implemented without certain specific details. In some embodiments, raw materials, schemes, methods, means, etc. well known to those skilled in the art are not described in detail, so as to highlight the main purpose of the present invention.

[0075] Unless explicitly stated otherwise, throughout the specification and claims, the term “comprise” or variations such as “include” or “comprising”, etc., will be understood to include the stated elements or components but not to exclude other elements or components.

[0076] When the inventors repeated the methods reported in the prior art (patent CN1440376A, patent CN105693569A, document Ge, Fa-xiang, Synthesis of post-emergence paddy herbicide benzob, Anhui Huagong (2013), 39 (6), 41-43), floccules were found at the interface between the water phase and the oil phase during extraction, which resulted in difficulty in stratification (e.g. Figure 8 -a), and an obvious ether impurity was found in the organic phase. GC-MS detection showed a molecular weight of 298. According to the properties of Formula I and Formula II, the mass spectrometry molecular weight GC-MS (EI): 298.1 (mass spectrum see Figure 1 ), the structure of M298 was inferred to be 4,4'-oxybis(3-chlorobicyclo[3.2.1]oct-2-ene) as shown in Formula III.

[0077] Formula III

[0078]

[0079] The boiling point of the impurity compound shown in formula III is higher than that of the target product (compound of formula I), and further purification requires complex operations such as distillation, which greatly affects production efficiency. The purity of formula I must be greater than 94% to ensure that the subsequent reaction proceeds normally. If the content of ether impurity (III) in the target product is high and no purification is performed, it will affect the subsequent reaction. In the prior art route, after the solvent is evaporated by extraction, the product will contain about 5% of ether impurity (III), which requires further complex purification such as distillation, which greatly affects production efficiency.

[0080] In order to ensure the yield while reducing the generation of impurity compounds (such as ether impurity (III)), the inventors have made various attempts, including:

[0081] Route B-1:

[0082]

[0083] After the compound shown in Formula II and water were stirred at room temperature, the aqueous phase was acidic, and trace amounts of the compound of Formula I were identified. Further research found that the conversion rate could be increased to 54% and the yield was 35% after increasing the reaction temperature, but the selectivity was relatively low, as shown in Table 1:

[0084] Table 1 Reaction of direct hydrolysis of the compound represented by formula II in water

[0085]

[0086] It can be seen from Table 1 that the direct yield in water is poor, and in route B-1, an impurity compound of formula III is still produced.

[0087] The inventors have found through continuous research that after adding sodium acetate in route B-1, 3-chlorobicyclo[3.2.1]-3-octene-2-acetate will be produced in the system, and the structure is as follows (see NMR data for details): Figure 5 , 6 ).

[0088]

[0089] The inventors have found that after the formation of 3-chlorobicyclo[3.2.1]-3-octene-2-acetate, the generation of impurities, namely compounds of formula III, can be reduced. However, further hydrolysis is required to convert the compounds of formula IV into compounds of formula I.

[0090] The inventors also tried different carboxylates - sodium formate, potassium acetate, sodium propionate, potassium propionate, sodium 4-chlorobenzoate, potassium 4-chlorobenzoate, sodium benzoate, potassium benzoate, etc., which can also generate ester compounds. The structure of the ester compound is shown in Formula IV:

[0091]

[0092] In the compound of formula IV, R 1 It may be a hydrogen group, an alkyl group, a phenyl group, a substituted alkyl group (preferably a chlorine-substituted alkyl group) or a substituted phenyl group (preferably a chlorine-substituted phenyl group), and may alternatively be a hydrogen group, a methyl group, an ethyl group, a 4-chlorophenyl group or a phenyl group.

[0093] Thus, the inventors obtained reaction route B-2, which is carried out in solvent water:

[0094]

[0095] In route B-2, R 1 It is hydrogen, alkyl, phenyl, substituted alkyl (preferably chlorine-substituted alkyl) or substituted phenyl (preferably chlorine-substituted phenyl), and can be optionally hydrogen, methyl, ethyl, 4-chlorophenyl or phenyl.

[0096] In the B-2 route, M 1 It is a metal, optionally an alkali metal or an alkaline earth metal, preferably one or more of potassium, sodium, calcium and magnesium.

[0097] In this route B-2, a strong base weak acid salt (carboxylate, preferably alkali metal or alkaline earth metal carboxylate) is used in water to first react to form formula I and formula IV, and then the temperature is lowered and an alkali metal hydroxide or alkaline earth metal hydroxide is added to hydrolyze formula IV to formula I, which can effectively reduce the generation of polymers and impurities (such as compounds represented by formula III). A strong base weak acid salt and an alkali metal hydroxide or an alkaline earth metal hydroxide can also be mixed and added to react, but the yield and purity will be reduced (see Examples 2 to 13).

[0098] In this route B-2, in the first step of the esterification reaction, an alkali metal carboxylate or an alkaline earth metal carboxylate is used; optionally, the carboxylate is selected from one or more of alkali metal formates, alkali metal acetates, alkali metal propionates, alkali metal 4-chlorobenzoates, alkali metal benzoates, alkaline earth metal formates, alkaline earth metal acetates, alkaline earth metal propionates, alkaline earth metal 4-chlorobenzoates, and alkaline earth metal benzoates; or the carboxylate is selected from one or more of sodium formate, sodium acetate, potassium acetate, calcium acetate, magnesium acetate, sodium propionate, potassium propionate, sodium 4-chlorobenzoate, potassium 4-chlorobenzoate, sodium benzoate, and potassium benzoate; preferably one or more of sodium acetate, potassium acetate, and potassium propionate. The reaction temperature of this step is 0°C to the reflux temperature of each solvent, preferably: 50°C to the reflux temperature of each solvent, and more preferably: 90°C to the reflux temperature of each solvent.

[0099] In route B-2, the inorganic strong base in the second step hydrolysis reaction is one or more of alkali metal hydroxides or alkaline earth metal hydroxides; optionally, the alkali metal hydroxide includes one or more of sodium hydroxide, potassium hydroxide, and lithium hydroxide; optionally, the alkaline earth metal hydroxide includes one or more of calcium hydroxide and magnesium hydroxide; optionally, the inorganic strong base is selected from one or more of sodium hydroxide and potassium hydroxide.

[0100] In the preparation method of route B-2, in the reaction, a catalyst can also be used in the two-step reaction, and the catalyst is polyethylene glycol, tetrabutylammonium bromide, tetrabutylammonium chloride, benzyltrimethylammonium chloride, diisopropylethylamine, triethylamine, triethylenediamine, crown ether, and optionally, the catalyst is tetrabutylammonium bromide, benzyltrimethylammonium chloride, tetrabutylammonium chloride, polyethylene glycol.

[0101] The inventors further discovered that in route B-2, the first step of esterification is carried out under anhydrous conditions, so that no impurity, the compound of formula III, is produced. After filtering and removing salt, the solvent is evaporated and then an alkali metal hydroxide or alkaline earth metal hydroxide aqueous solution is added, and hydrolysis can be carried out at room temperature. The hydrolysis reaction can be carried out in an alkali metal hydroxide or alkaline earth metal hydroxide aqueous solution without going through a high temperature process. This method is basically free of impurities of formula III, and can improve selectivity and yield (see Examples 14 to 22). That is route B-3, the first step of this route is carried out in an organic solvent under anhydrous conditions, and the second step is hydrolysis:

[0102]

[0103] The route B-3, R 1 It is hydrogen, alkyl, phenyl, substituted alkyl (preferably chlorine-substituted alkyl) or substituted phenyl (preferably chlorine-substituted phenyl), and can be optionally hydrogen, methyl, ethyl, 4-chlorophenyl or phenyl.

[0104] In the B-3 route, M 1 It is a metal, optionally an alkali metal or an alkaline earth metal, preferably one or more of potassium, sodium, calcium and magnesium.

[0105] In route B-3, the first step of esterification reaction is carried out in an organic solvent, and the solvent is one or more of dimethylformamide, dimethylacetamide, ethylene glycol monomethyl ether, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, N-methylpyrrolidone, dimethyl sulfoxide, and cyclopentane sulfone; optionally, the solvent is selected from one or more of dimethylformamide and dimethylacetamide.

[0106] In route B-3, in the first step of the esterification reaction, the catalyst is polyethylene glycol, tetrabutylammonium bromide, tetrabutylammonium chloride, diisopropylethylamine, triethylamine, triethylenediamine, crown ether, and optionally, the catalyst is tetrabutylammonium bromide, tetrabutylammonium chloride, polyethylene glycol.

[0107] In route B-3, in the second step of the hydrolysis reaction, the organic solvent is completely or partially evaporated after the esterification reaction, and water and an inorganic strong base are added. The inorganic strong base is one or more of an alkali metal hydroxide or an alkaline earth metal hydroxide; optionally, the alkali metal hydroxide includes one or more of sodium hydroxide, potassium hydroxide, and lithium hydroxide; optionally, the alkaline earth metal hydroxide includes one or more of calcium hydroxide and magnesium hydroxide; optionally, the inorganic strong base is selected from one or more of sodium hydroxide and potassium hydroxide.

[0108] In route B-3, in the second step of the hydrolysis reaction, the catalyst is polyethylene glycol, tetrabutylammonium bromide, tetrabutylammonium chloride, benzyltrimethylammonium chloride, diisopropylethylamine, triethylamine, triethylenediamine, crown ether, and optionally, the catalyst is tetrabutylammonium bromide, benzyltrimethylammonium chloride, tetrabutylammonium chloride, polyethylene glycol.

[0109] In addition, the inventors have also tried to add an inorganic strong base and a weak acid salt to route B-1 for hydrolysis, which can directly react to form formula I without esterification, and can also reduce the generation of impurity formula III. The designed route B-4 is as follows, and the reaction is carried out in water:

[0110]

[0111] The route B-4, M 2 is a metal, optionally an alkali metal, preferably potassium and / or sodium;

[0112] R 2 It is an inorganic weak acid radical, optionally carbonate, phosphate or hydrogen phosphate.

[0113] In this route B-4, the generation of impurity formula III can be reduced, the reaction rate is reduced, and basically no floccules are generated during extraction and stratification. However, a trace amount of impurity formula III is still generated, and the yield is slightly lower than that of route B-3 (see Examples 23 to 32). The product after distillation can be directly used in subsequent reactions.

[0114] In the reaction of route B-4, the strong base weak acid salt is selected from one or more of sodium carbonate, potassium carbonate, tripotassium phosphate, and dipotassium hydrogen phosphate; optionally, the strong base weak acid salt includes one or more of sodium carbonate and potassium carbonate.

[0115] In the reaction of route B-4, the catalyst is polyethylene glycol, tetrabutylammonium bromide, tetrabutylammonium chloride, benzyltrimethylammonium chloride, benzyltriethylammonium chloride, diisopropylethylamine, triethylamine, triethylenediamine. Optionally, the catalyst is tetrabutylammonium bromide, benzyltrimethylammonium chloride, benzyltriethylammonium chloride, tetrabutylammonium chloride, polyethylene glycol.

[0116] The present invention can select three methods B-2, B-3, and B-4 for synthesis according to the raw materials or solvents. Routes B-2 and B-4 can reduce alkali waste and the difficulty of wastewater treatment by changing the type of alkali and reducing the alkali equivalent; reduce the alkalinity of the reaction solution, reduce the generation of polymers and impurities, make stratification more obvious, and improve purification efficiency; the purity of the product after distillation can reach 94%, which can be directly used for subsequent reactions. The esterification reaction of B-3 can effectively avoid the generation of impurities under anhydrous conditions, and low-temperature hydrolysis can avoid the production of polymers. The reaction conditions of the inventive method are simple and mild, the yield is high, and it is suitable for industrial production; the purity of the product after distillation can reach 94%, which can be directly used for subsequent reactions.

[0117] The product contents in the following examples were confirmed by liquid or gas chromatography, the reaction process was tracked by area normalization, and the product purity was determined by external standard method after the reaction was completed to calculate the yield.

[0118] LCMS: Liquid chromatography mass spectrometry, liquid quality.

[0119] GCMS: Gas chromatography mass spectrometry, temperament.

[0120] HPLC: High Performance Liquid Chromatography, high pressure liquid chromatography.

[0121] GC: Gas chromatography.

[0122] NMR: Nuclear magnetic resonance spectrometry.

[0123] The 3,4-dichlorobicyclo[3.2.1]-2-octene in the following examples can be obtained commercially or homemade; if not otherwise specified, the reaction process and results are detected by high pressure liquid chromatography or gas chromatography.

[0124] Example 1

[0125]

[0126] A mixture of 3,4-dichlorobicyclo[3.2.1]-2-octene (88.5 g, 0.5 mol), water (200 ml), sodium acetate (82.0 g, 1.0 mol) and tetrabutylammonium bromide (0.1 g) was heated and refluxed for about 7 hours. The reaction was controlled in the gas phase until 3,4-dichlorobicyclo[3.2.1]-2-octene was less than 1% and then the reaction was stopped. After cooling, the mixture was extracted with dichloroethane, and the organic phase was dried with sodium sulfate and distilled to obtain 83.5 g of yellow oil. After quantitative analysis, 57.9 g of 3-chlorobicyclo[3.2.1]-3-octen-2-ol (Ⅰ) and 21.1 g of 3-chlorobicyclo[3.2.1]-3-octen-2-acetate (compound of formula Ⅳ-1, which can react to formula Ⅰ after hydrolysis) were obtained. The gas phase spectrum is shown in FIG. Fig. 9 As shown, the ether impurities represented by formula III (15.89' and 16.08') are 1.2% (area normalization method), formula I (10.19') is 80.4% (area normalization method), formula IV-1 (12.20') is 17.4% (area normalization method), and the combined yield of the compound of formula IV-1 and the compound of formula I is 94%.

[0127] The H NMR, C NMR and GC-MS analysis of the intermediate 3-chlorobicyclo[3.2.1]-3-octen-2-ol (Ⅰ) Figure 2 , Figure 3 , Figure 4 ) is analyzed as follows:

[0128] 1 H NMR(400MHz,Chloroform-d)δ6.10(d,J=7.1Hz,1H),3.72(dd,J=4.9,2.9Hz,1H), 2.54–2.48(m,1H),2.46(d,J=4.8Hz,1H),1.88(ddt,J=13.7,9.6,5.2Hz,1H),1.78

[0129] (d,J=11.4Hz,1H),1.68–1.56(m,2H),1.35–1.21(m,2H).

[0130] 13 C NMR (101MHz, Chloroform-d) δ134.36,132.03,77.40,77.09,76.77,76.43,40.58,36.44,30.90,30.67,24.55.

[0131] GC-MS(EI):158.0.

[0132] The intermediate 3-chlorobicyclo[3.2.1]-3-octen-2-acetate was analyzed by H NMR, C NMR and GC-MS ( Figure 5 , Figure 6 , Figure 7 ) is analyzed as follows:

[0133] 1 H NMR(500MHz,Chloroform-d)δ6.24(dd,J=7.2,1.0Hz,1H),4.94(d,J=3.0Hz,1H) ,2.67–2.62(m,1H),2.52(t,J=8.1Hz,1H),2.09(s,3H),1.97–1.87(m,1H),1.78

[0134] (d,J=9.7Hz,1H),1.70–1.62(m,2H),1.45–1.36(m,1H),1.30(m,1H).

[0135] 13 C NMR (126MHz, Chloroform-d) δ169.81,136.49,127.94,76.41,38.73,36.24,31.09,30.82,24.23,20.92.

[0136] GC-MS(EI):200.1.

[0137] Route B-2 Synthesis of 3-chlorobicyclo[3.2.1]-3-octen-2-ol.

[0138]

[0139] Example 2

[0140] A mixture of 3,4-dichlorobicyclo[3.2.1]-2-octene (88.5 g, 0.5 mol), water (200 ml), sodium acetate (82.0 g, 1.0 mol) and tetrabutylammonium bromide (0.1 g) was heated to reflux temperature and kept warm for 6 hours. The reaction was controlled in the gas phase until the concentration of 3,4-dichlorobicyclo[3.2.1]-2-octene was less than 1% and then the reaction was stopped. The temperature was lowered to 50°C and sodium hydroxide (20.0 g, 0.5 mol) was added. The reaction was kept warm for 1 hour. After cooling, the mixture was extracted with dichloroethane. No flocs were produced when the layers were separated ( Figure 8 -b), the organic phase was dried with sodium sulfate and then distilled to obtain 78.4 g of a yellow oil, the gas phase spectrum of which is shown in Fig.10 As shown, the ether impurities of formula III (15.53' and 15.80') are 1.3% (area normalization method), and the compound of formula I (10.625') is 96.2% (area normalization method). The purity of the target product (compound of formula I) is 95.3% (external standard method); the yield is 94.2%.

[0141] Example 3

[0142] A mixture of 3,4-dichlorobicyclo[3.2.1]-2-octene (88.5 g, 0.5 mol), water (200 ml), sodium acetate (82.0 g, 1.0 mol) and tetrabutylammonium bromide (0.1 g) was heated to 90°C and kept warm for 8 hours. The mixture was cooled to 50°C and sodium hydroxide (20.0 g, 0.5 mol) was added and kept warm for 1 hour. After cooling, the mixture was extracted with dichloroethane. No floccules were produced during stratification. The organic phase was dried with sodium sulfate and then distilled to obtain 78.3 g of a yellow oil. The gas phase spectrum showed that only a trace amount of the impurity compound shown in formula III was produced. The purity of the target product (compound of formula I) was 94.9% (external standard method); the yield was 93.7%.

[0143] Example 4

[0144] A mixture of 3,4-dichlorobicyclo[3.2.1]-2-octene (88.5 g, 0.5 mol), water (200 ml), sodium acetate (82.0 g, 1.0 mol) and tetrabutylammonium bromide (0.1 g) was heated to 103°C and refluxed for 5 h. The mixture was cooled to 20°C and sodium hydroxide (20.0 g, 0.5 mol) was added and kept warm for 3 h. After cooling, the mixture was extracted with dichloroethane. No floccules were produced during stratification. The organic phase was dried with sodium sulfate and then distilled to obtain 78.9 g of a yellow oil. The gas phase spectrum showed that only a trace amount of the impurity compound shown in formula III was produced. The purity of the target product (compound of formula I) was 95.5% (external standard method); the yield was 95.0%.

[0145] Example 5A

[0146] A mixture of 3,4-dichlorobicyclo[3.2.1]-2-octene (88.5 g, 0.5 mol), water (200 ml), sodium acetate (82.0 g, 1.0 mol) and tetrabutylammonium bromide (0.1 g) was heated to 103°C and refluxed for 5 h. The reaction was controlled in the gas phase until 3,4-dichlorobicyclo[3.2.1]-2-octene was less than 1% and then the reaction was stopped. The temperature was lowered to 50°C, sodium hydroxide (20.0 g, 0.5 mol) was added and the reaction was kept warm for 1 h. After cooling, the mixture was extracted with dichloroethane. No floccules were produced during stratification. The organic phase was dried with sodium sulfate and then distilled to obtain 78.6 g of a yellow oil. The gas phase spectrum showed that only a trace amount of the impurity compound shown in formula III was produced. The purity of the target product (compound of formula I) was 95.4% (external standard method); the yield was 94.5%.

[0147] Example 5B

[0148] A mixture of 3,4-dichlorobicyclo[3.2.1]-2-octene (88.5 g, 0.5 mol), water (200 ml) and sodium acetate (82.0 g, 1.0 mol) was heated to 103°C and refluxed for 9 h. The reaction was stopped after the gas phase reaction was controlled until the concentration of 3,4-dichlorobicyclo[3.2.1]-2-octene was less than 1%. The mixture was cooled to 50°C and sodium hydroxide (20.0 g, 0.5 mol) was added and kept warm for 3 h. After cooling, the mixture was extracted with dichloroethane. No floccules were produced during stratification. The organic phase was dried with sodium sulfate and then distilled to obtain 78.1 g of a yellow oil. The gas phase spectrum showed that only a trace amount of the impurity compound shown in formula III was produced. The purity of the target product (compound of formula I) was 94.6% (external standard method); the yield was 93.2%.

[0149] Example 5C

[0150] A mixture of 3,4-dichlorobicyclo[3.2.1]-2-octene (88.5 g, 0.5 mol), water (200 ml), sodium acetate (82.0 g, 1.0 mol) and tetrabutylammonium bromide (5.0 g) was heated to 103°C and refluxed for 4 h. The reaction was controlled in the gas phase until 3,4-dichlorobicyclo[3.2.1]-2-octene was less than 1% and then the reaction was stopped. The temperature was lowered to 50°C, sodium hydroxide (20.0 g, 0.5 mol) was added and the reaction was kept warm for 1 h. After cooling, the mixture was extracted with dichloroethane. No floccules were produced during stratification. The organic phase was dried with sodium sulfate and then distilled to obtain 78.9 g of a yellow oil. The gas phase spectrum showed that only a trace amount of the impurity compound shown in formula III was produced. The purity of the target product (compound of formula I) was 95.5% (external standard method); the yield was 95.0%.

[0151] Example 6

[0152] A mixture of 3,4-dichlorobicyclo[3.2.1]-2-octene (88.5 g, 0.5 mol), water (200 ml), sodium acetate (82.0 g, 1.0 mol) and tetrabutylammonium bromide (0.1 g) was heated to 103°C and refluxed for 5 h. The reaction was controlled in the gas phase until 3,4-dichlorobicyclo[3.2.1]-2-octene was less than 1% and then the reaction was stopped. The temperature was lowered to 40°C, sodium hydroxide (20.0 g, 0.5 mol) was added and the mixture was kept warm for 2 h. After cooling, the mixture was extracted with dichloroethane. No floccules were produced during stratification. The organic phase was dried with sodium sulfate and then distilled to obtain 78.6 g of a yellow oil. The gas phase spectrum showed that only a trace amount of the impurity compound shown in formula III was produced. The purity of the target product (compound of formula I) was 95.2% (external standard method) and the yield was 94.4%.

[0153] Example 7

[0154] A mixture of 3,4-dichlorobicyclo[3.2.1]-2-octene (88.5 g, 0.5 mol), water (200 ml), sodium acetate (69.7 g, 0.85 mol) and tetrabutylammonium bromide (0.1 g) was heated to 103°C and refluxed for 5 h. The reaction was controlled in the gas phase until 3,4-dichlorobicyclo[3.2.1]-2-octene was less than 1% and then the reaction was stopped. The mixture was cooled to 50°C and sodium hydroxide (40.0 g, 1.0 mol) was added and kept warm for 1 h. After cooling, the mixture was extracted with dichloroethane. No floccules were produced during stratification. The organic phase was dried with sodium sulfate and then distilled to obtain 78.1 g of a yellow oil. The gas phase spectrum showed that only a trace amount of the impurity compound shown in formula III was produced. The purity of the target product (compound of formula I) was 95.1% (external standard method) and the yield was 93.7%.

[0155] Example 8

[0156] A mixture of 3,4-dichlorobicyclo[3.2.1]-2-octene (88.5 g, 0.5 mol), water (150 ml), sodium acetate (61.5 g, 0.75 mol) and tetrabutylammonium bromide (0.1 g) was heated to 103°C and refluxed for 5 h. The mixture was cooled to 50°C and sodium hydroxide (20.0 g, 0.5 mol) was added and kept warm for 1 h. After cooling, the mixture was extracted with dichloroethane. No floccules were produced during stratification. The organic phase was dried with sodium sulfate and then distilled to obtain 76.2 g of a yellow oil. The gas phase spectrum showed that only a trace amount of the impurity compound shown in formula III was produced. The target product (compound of formula I) had an external standard purity of 95.0% (external standard method) and a yield of 91.3%.

[0157] Example 9A

[0158] A mixture of 3,4-dichlorobicyclo[3.2.1]-2-octene (88.5 g, 0.5 mol), water (290 ml), sodium acetate (123.0 g, 1.5 mol) and tetrabutylammonium bromide (0.1 g) was heated to 103°C and refluxed for 5 h. The reaction was controlled in the gas phase until 3,4-dichlorobicyclo[3.2.1]-2-octene was less than 1% and then the reaction was stopped. The temperature was lowered to 50°C, sodium hydroxide (20.0 g, 0.5 mol) was added and the reaction was kept warm for 1 h. After cooling, the mixture was extracted with dichloroethane. No floccules were produced during stratification. The organic phase was dried with sodium sulfate and then distilled to obtain 79.1 g of a yellow oil. The gas phase spectrum showed that only a trace amount of the impurity compound shown in formula III was produced. The target product (compound of formula I) had an external standard purity of 95.2% (external standard method) and a yield of 95.0%.

[0159] Example 9B

[0160] A mixture of 3,4-dichlorobicyclo[3.2.1]-2-octene (88.5 g, 0.5 mol), water (900 ml), sodium acetate (123.0 g, 1.5 mol) and tetrabutylammonium bromide (0.1 g) was heated to 103°C and refluxed for 6 h. The reaction was controlled in the gas phase until 3,4-dichlorobicyclo[3.2.1]-2-octene was less than 1% and then the reaction was stopped. The mixture was cooled to 50°C and sodium hydroxide (20.0 g, 0.5 mol) was added and kept warm for 2 h. After cooling, the mixture was extracted with dichloroethane. No floccules were produced during stratification. The organic phase was dried with sodium sulfate and then distilled to obtain 78.8 g of a yellow oil. The gas phase spectrum showed that only a trace amount of the impurity compound shown in formula III was produced. The target product (compound of formula I) had an external standard purity of 95.4% (external standard method) and a yield of 94.8%.

[0161] Example 10

[0162] A mixture of 3,4-dichlorobicyclo[3.2.1]-2-octene (88.5 g, 0.5 mol), water (470 ml), sodium acetate (82.0 g, 1.0 mol) and tetrabutylammonium bromide (0.1 g) was heated to 103°C and refluxed for 5 h. The reaction was controlled in the gas phase until 3,4-dichlorobicyclo[3.2.1]-2-octene was less than 1% and then the reaction was stopped. The temperature was lowered to 50°C, sodium hydroxide (20.0 g, 0.5 mol) was added and the reaction was kept warm for 2 h. After cooling, the mixture was extracted with dichloroethane. No floccules were produced during stratification. The organic phase was dried with sodium sulfate and then distilled to obtain 78.2 g of a yellow oil. The gas phase spectrum showed that only a trace amount of the impurity compound shown in formula III was produced. The target product (compound of formula I) had an external standard purity of 95.4% (external standard method) and a yield of 94.0%.

[0163] Embodiment 11

[0164] A mixture of 3,4-dichlorobicyclo[3.2.1]-2-octene (88.5 g, 0.5 mol), water (200 ml), sodium acetate (82.0 g, 1.0 mol), sodium hydroxide (20.0 g, 0.5 mol) and tetrabutylammonium bromide (0.1 g) was heated to 103°C and refluxed for 6 h. The reaction was controlled in the gas phase until 3,4-dichlorobicyclo[3.2.1]-2-octene was less than 1% and then the reaction was stopped. After cooling, the mixture was extracted with dichloroethane. A trace amount of floccules was produced during stratification. The organic phase was dried with sodium sulfate and then distilled to obtain 78.0 g of a yellow oil. The gas phase spectrum showed that the impurity compound shown in formula III was 2.2% (area normalization method), and the purity of the target product (compound of formula I) was 94.1% (external standard method), and the yield was 92.5%.

[0165] In this embodiment, by adding sodium acetate and sodium hydroxide at the same time, sodium acetate will react with formula II to form an ester, and the amount of sodium hydroxide used will also be reduced, which can reduce the probability of ether. Although trace impurities III will be generated, they are less than those in the prior art. However, because they are added at the same time, trace floccules and impurity III compounds will also be generated, which will lead to a decrease in the yield and purity of the product.

[0166] Example 12

[0167] A mixture of 3,4-dichlorobicyclo[3.2.1]-2-octene (88.5 g, 0.5 mol), water (200 ml), sodium acetate (82.0 g, 1.0 mol), potassium hydroxide (28.1 g, 0.5 mol) and tetrabutylammonium bromide (0.1 g) was heated to 103°C and refluxed for 6 h. The reaction was controlled in the gas phase until 3,4-dichlorobicyclo[3.2.1]-2-octene was less than 1% and then the reaction was stopped. After cooling, the mixture was extracted with dichloroethane. A trace amount of floccules was produced during stratification. The organic phase was dried with sodium sulfate and then distilled to obtain 78.0 g of a yellow oil. The gas phase spectrum showed that the impurity compound shown in formula III was 2.3% (area normalization method), and the purity of the target product (compound of formula I) was 94.3% (external standard method), and the yield was 92.7%.

[0168] By adding sodium acetate and potassium hydroxide at the same time, sodium acetate will react with formula II to form an ester, reducing the probability of forming an ether. Although a trace amount of impurity III will be produced, it is less than that of the prior art.

[0169] Embodiment 13

[0170] A mixture of 3,4-dichlorobicyclo[3.2.1]-2-octene (88.5 g, 0.5 mol), water (200 ml), sodium acetate (82.0 g, 1.0 mol), sodium hydroxide (20.0 g, 0.5 mol) and benzyltrimethylammonium chloride (0.1 g) was heated to 103°C and refluxed for 6 h. The reaction was controlled in the gas phase until 3,4-dichlorobicyclo[3.2.1]-2-octene was less than 1% and then the reaction was stopped. After cooling, the mixture was extracted with dichloroethane. A trace amount of floccules was produced during stratification. The organic phase was dried with sodium sulfate and then distilled to obtain 78.6 g of a yellow oil. The gas phase spectrum showed that the impurity compound shown in formula III was 2.1% (area normalization method), and the purity of the target product (compound of formula I) was 94.2% (external standard method); the yield was 93.3%.

[0171] By adding sodium acetate and sodium hydroxide at the same time, sodium acetate will react with formula II to form an ester, reducing the probability of forming an ether. Although a trace amount of impurity III will be produced, it is less than that of the prior art.

[0172] Route B-3 Synthesis of 3-chlorobicyclo[3.2.1]-3-octen-2-ol.

[0173]

[0174] In the B-3 route, the yield under anhydrous conditions will be improved, but almost no impurity compound represented by formula III is produced. Although the purity in the following examples is about 95%, it is because a small amount of solvent remains after the distillation process. However, the presence of the solvent does not affect the subsequent reaction, so distillation is not continued. If distillation is continued, the purity can be higher.

[0175] Embodiment 14

[0176] A mixture of 3,4-dichlorobicyclo[3.2.1]-2-octene (88.5g, 0.5mol), dimethylformamide (450ml), anhydrous sodium acetate (82.0g, 1.0mol) and tetrabutylammonium bromide (0.1g) was refluxed and kept warm for 4h. The reaction was controlled in the gas phase until the concentration of 3,4-dichlorobicyclo[3.2.1]-2-octene was less than 1% and then the reaction was stopped. The mixture was cooled, filtered, and the solvent was distilled. Sodium hydroxide (30g, 0.75mol), water (270ml) and tetrabutylammonium bromide (0.1g) were added and stirred at 30℃ for 2h. The reaction was controlled in the gas phase until the concentration of 3-chlorobicyclo[3.2.1]-3-octene-2-acetate was less than 0.5% and then the reaction was stopped. The reaction solution was extracted with dichloroethane. No flocs were produced during the separation. The organic phase was dried with sodium sulfate and then distilled to obtain 79.7g of a yellow oil. The gas phase spectrum is as follows: Fig.11 As shown, there is no impurity compound represented by formula III, the compound of formula I (10.20′) is 98.5% (area normalization method), and the purity of the target product (compound of formula I) is 95.3% (external standard method); the yield is 95.8%.

[0177] Embodiment 15

[0178] A mixture of 3,4-dichlorobicyclo[3.2.1]-2-octene (88.5 g, 0.5 mol), dimethylacetamide (450 ml), anhydrous sodium acetate (82.0 g, 1.0 mol) and tetrabutylammonium bromide (0.1 g) was refluxed and kept warm for 4 h, and the reaction was controlled in the gas phase until 3,4-dichlorobicyclo[3.2.1]-2-octene was less than 1% and then the reaction was stopped. The mixture was cooled, filtered, and the solvent was distilled, and then sodium hydroxide (30 g, 0.75 mol), water (270 ml) and tetrabutylammonium bromide (0.1 g) were added, stirred at 30°C for 2 h, and the reaction was controlled in the gas phase until 3-chlorobicyclo[3.2.1]-3-octene-2-acetate was less than 0.5% and then the reaction was stopped. The reaction solution was extracted with dichloroethane. No floccules were produced during layer separation. The organic phase was dried over sodium sulfate and then distilled to obtain 79.8 g of a yellow oil. The gas phase spectrum showed that no impurity compound represented by formula III was produced. The purity of the target product (compound of formula I) was 95.2% (external standard method); the yield was 95.8%.

[0179] Example 16

[0180] A mixture of 3,4-dichlorobicyclo[3.2.1]-2-octene (88.5 g, 0.5 mol), ethylene glycol monomethyl ether (450 ml), anhydrous sodium acetate (82.0 g, 1.0 mol) and tetrabutylammonium bromide (0.1 g) was refluxed and kept warm for 6 h, and the reaction was stopped after the gas phase was controlled until the 3,4-dichlorobicyclo[3.2.1]-2-octene was less than 1%. The mixture was cooled, filtered, and the solvent was distilled, and then sodium hydroxide (30 g, 0.75 mol), water (270 ml) and tetrabutylammonium bromide (0.1 g) were added, stirred at 30°C for 2 h, and the reaction was stopped after the gas phase was controlled until the 3-chlorobicyclo[3.2.1]-3-octene-2-acetate was less than 0.5%. The reaction solution was extracted with dichloroethane. No floccules were produced during layer separation. The organic phase was dried over sodium sulfate and then distilled to obtain 77.8 g of a yellow oil. The gas phase spectrum showed that no impurity compound represented by formula III was produced. The purity of the target product (compound of formula I) was 95.0% (external standard method); the yield was 93.2%.

[0181] Embodiment 17

[0182] A mixture of 3,4-dichlorobicyclo[3.2.1]-2-octene (88.5 g, 0.5 mol), dimethylformamide (450 ml), anhydrous potassium acetate (98.1 g, 1.0 mol) and tetrabutylammonium bromide (0.1 g) was refluxed and kept warm for 4 h, and the reaction was controlled in the gas phase until 3,4-dichlorobicyclo[3.2.1]-2-octene was less than 1% and then the reaction was stopped. The mixture was cooled, filtered, and the solvent was distilled, and then sodium hydroxide (30 g, 0.75 mol), water (270 ml) and tetrabutylammonium bromide (0.1 g) were added, stirred at 30°C for 2 h, and the reaction was controlled in the gas phase until 3-chlorobicyclo[3.2.1]-3-octene-2-acetate was less than 0.5% and then the reaction was stopped. The reaction solution was extracted with dichloroethane. No floccules were produced during layer separation. The organic phase was dried over sodium sulfate and then distilled to obtain 78.8 g of a yellow oil. The gas phase spectrum showed that no impurity compound represented by formula III was produced. The purity of the target product (compound of formula I) was 95.5% (external standard method); the yield was 94.9%.

[0183] Example 18A

[0184] A mixture of 3,4-dichlorobicyclo[3.2.1]-2-octene (88.5 g, 0.5 mol), dimethylformamide (450 ml), anhydrous sodium acetate (123 g, 1.5 mol) and polyethylene glycol (0.1 g) was refluxed and kept warm for 4 h, and the reaction was stopped after the gas phase control until the 3,4-dichlorobicyclo[3.2.1]-2-octene was less than 1%. The mixture was cooled, filtered, and the solvent was distilled, and then sodium hydroxide (30 g, 0.75 mol), water (270 ml) and benzyltrimethylammonium chloride (0.1 g) were added, stirred at 30°C for 2 h, and the reaction was stopped after the gas phase control until the 3-chlorobicyclo[3.2.1]-3-octene-2-acetate was less than 0.5%. The reaction solution was extracted with dichloroethane. No floccules were produced during layer separation. The organic phase was dried over sodium sulfate and then distilled to obtain 79.7 g of a yellow oil. The gas phase spectrum showed that no impurity compound represented by formula III was produced. The purity of the target product (compound of formula I) was 95.1% (external standard method); the yield was 95.6%.

[0185] Example 18B

[0186] A mixture of 3,4-dichlorobicyclo[3.2.1]-2-octene (88.5 g, 0.5 mol), dimethylformamide (900 ml), anhydrous sodium acetate (123 g, 1.5 mol) and polyethylene glycol (0.1 g) was refluxed and kept warm for 4 h, and the reaction was stopped after the gas phase control until 3,4-dichlorobicyclo[3.2.1]-2-octene was less than 1%. The mixture was cooled, filtered, and the solvent was distilled, and then sodium hydroxide (30 g, 0.75 mol), water (270 ml) and benzyltrimethylammonium chloride (0.1 g) were added, stirred at 30°C for 2 h, and the reaction was stopped after the gas phase control until 3-chlorobicyclo[3.2.1]-3-octene-2-acetate was less than 0.5%. The reaction solution was extracted with dichloroethane. No floccules were produced during layer separation. The organic phase was dried over sodium sulfate and then distilled to obtain 79.5 g of a yellow oil. The gas phase spectrum showed that no impurity compound represented by formula III was produced. The purity of the target product (compound of formula I) was 95.3% (external standard method); the yield was 95.5%.

[0187] Embodiment 19

[0188] A mixture of 3,4-dichlorobicyclo[3.2.1]-2-octene (88.5 g, 0.5 mol), dimethylformamide (450 ml), anhydrous sodium acetate (102.5 g, 1.25 mol) and polyethylene glycol (0.1 g) was refluxed for 6 h and then the reaction was stopped. The mixture was cooled, filtered, and the solvent was distilled, and then sodium hydroxide (30 g, 0.75 mol), water (270 ml) and benzyltrimethylammonium chloride (0.1 g) were added, stirred at 30°C for 2 h, and the reaction was controlled in the gas phase until 3-chlorobicyclo[3.2.1]-3-octene-2-acetate was less than 0.5% and then the reaction was stopped. The reaction solution was extracted with dichloroethane. No floccules were produced during layer separation. The organic phase was dried over sodium sulfate and then distilled to obtain 78.9 g of a yellow oil. The gas phase spectrum showed that no impurity compound represented by formula III was produced. The purity of the target product (compound of formula I) was 95.4% (external standard method); the yield was 94.9%.

[0189] Embodiment 20

[0190] A mixture of 3,4-dichlorobicyclo[3.2.1]-2-octene (88.5 g, 0.5 mol), dimethylformamide (450 ml), anhydrous sodium acetate (82.0 g, 1.0 mol) and tetrabutylammonium bromide (0.1 g) was refluxed and kept warm for 4 h, and the reaction was stopped after the gas phase was controlled until the 3,4-dichlorobicyclo[3.2.1]-2-octene was less than 1%. The mixture was cooled, filtered, and the solvent was distilled, and then sodium hydroxide (30 g, 0.75 mol), water (270 ml) and tetrabutylammonium bromide (0.1 g) were added, stirred at 50°C for 2 h, and the reaction was stopped after the gas phase was controlled until the 3-chlorobicyclo[3.2.1]-3-octene-2-acetate was less than 0.5%. The reaction solution was extracted with dichloroethane. No floccules were produced during layer separation. The organic phase was dried over sodium sulfate and then distilled to obtain 79.5 g of a yellow oil. The gas phase spectrum showed that no impurity compound represented by formula III was produced. The purity of the target product (compound of formula I) was 95.0% (external standard method); the yield was 95.2%.

[0191] Embodiment 21

[0192] A mixture of 3,4-dichlorobicyclo[3.2.1]-2-octene (88.5 g, 0.5 mol), dimethylformamide (450 ml), anhydrous sodium acetate (82.0 g, 1.0 mol) and tetrabutylammonium bromide (0.1 g) was refluxed and kept warm for 4 h, and the reaction was stopped after the gas phase was controlled until the 3,4-dichlorobicyclo[3.2.1]-2-octene was less than 1%. The mixture was cooled, filtered, and the solvent was distilled, and then sodium hydroxide (30 g, 0.75 mol), water (270 ml) and tetrabutylammonium bromide (0.1 g) were added, stirred at 60°C for 1 h, and the reaction was stopped after the gas phase was controlled until the 3-chlorobicyclo[3.2.1]-3-octene-2-acetate was less than 0.5%. The reaction solution was extracted with dichloroethane. No flocs were produced during layer separation. The organic phase was dried over sodium sulfate and then distilled to obtain 79.1 g of a yellow oil. The gas phase spectrum showed that no impurity compound represented by formula III was produced. The purity of the target product (compound of formula I) was 94.9% (external standard method); the yield was 94.7%.

[0193] Embodiment 22

[0194] A mixture of 3,4-dichlorobicyclo[3.2.1]-2-octene (88.5 g, 0.5 mol), dimethylformamide (450 ml), anhydrous sodium formate (68.0 g, 1.0 mol) and polyethylene glycol (0.1 g) was refluxed and kept warm for 6 h before the reaction was stopped. The mixture was cooled, filtered, and the solvent was distilled, and then sodium hydroxide (30 g, 0.75 mol), water (270 ml) and benzyltrimethylammonium chloride (0.1 g) were added, stirred at 30°C for 2 h, and the reaction was controlled in the gas phase until 3-chlorobicyclo[3.2.1]-3-octene-2-carboxylate was less than 0.5% and then the reaction was stopped. The reaction solution was extracted with dichloroethane, and no floccules were produced during the separation. The organic phase was dried with sodium sulfate and distilled to obtain 78.7 g of yellow oil. The purity of the target product (compound of formula I) was 95.1% (external standard method); the yield was 94.4%.

[0195] Route B-4: Synthesis of 3-chlorobicyclo[3.2.1]-3-octen-2-ol.

[0196]

[0197] Embodiment 23

[0198] A mixture of 3,4-dichlorobicyclo[3.2.1]-2-octene (88.5 g, 0.5 mol), water (450 ml), sodium carbonate (79.5 g, 0.75 mol) and tetrabutylammonium bromide (0.1 g) was heated to 103°C and refluxed for 7 h. The reaction was controlled in the gas phase until the concentration of 3,4-dichlorobicyclo[3.2.1]-2-octene was less than 1% and then the reaction was stopped. After cooling, the mixture was extracted with dichloroethane. No floccules were produced when the layers were separated. Figure 8-c, the organic phase was dried with sodium sulfate and then distilled to obtain 76.3 g of a yellow oil, the gas phase spectrum of which is shown in Fig.12 As shown, the impurity compound represented by formula III (15.53′ and 15.80′) is 1.9% (area normalization method), the compound of formula I (10.61′) is 95.3% (area normalization method), the purity of the target product (compound of formula I) is 95.1% (external standard method), and the yield is 91.5%.

[0199] Embodiment 24

[0200] A mixture of 3,4-dichlorobicyclo[3.2.1]-2-octene (88.5 g, 0.5 mol), water (450 ml), sodium carbonate (79.5 g, 0.75 mol) and tetrabutylammonium bromide (0.1 g) was heated to 90°C and kept for 7 hours before the reaction was stopped. After cooling, the mixture was extracted with dichloroethane. No floccules were produced during layering. The organic phase was dried with sodium sulfate and then distilled to obtain 76.9 g of a yellow oil. The gas phase spectrum showed that only a trace amount of the impurity compound shown in formula III was produced. The purity of the target product (compound of formula I) was 94.8% (external standard method) and the yield was 91.9%.

[0201] Embodiment 25

[0202] A mixture of 3,4-dichlorobicyclo[3.2.1]-2-octene (88.5 g, 0.5 mol), water (720 ml), sodium carbonate (79.5 g, 0.75 mol) and tetrabutylammonium bromide (0.1 g) was heated to 103°C and refluxed for 7 h. The reaction was controlled in the gas phase until 3,4-dichlorobicyclo[3.2.1]-2-octene was less than 1% and then the reaction was stopped. After cooling, the mixture was extracted with dichloroethane. No floccules were produced during stratification. The organic phase was dried with sodium sulfate and then distilled to obtain 77.1 g of a yellow oil. The gas phase spectrum showed that only a trace amount of the impurity compound shown in formula III was produced. The purity of the target product (compound of formula I) was 94.5% (external standard method) and the yield was 91.9%.

[0203] Embodiment 26

[0204] A mixture of 3,4-dichlorobicyclo[3.2.1]-2-octene (88.5 g, 0.5 mol), water (1500 ml), sodium carbonate (79.5 g, 0.75 mol) and tetrabutylammonium bromide (0.1 g) was heated to 103°C and refluxed for 8 h. The reaction was controlled in the gas phase until 3,4-dichlorobicyclo[3.2.1]-2-octene was less than 1% and then the reaction was stopped. After cooling, the mixture was extracted with dichloroethane. No floccules were produced during stratification. The organic phase was dried with sodium sulfate and then distilled to obtain 76.8 g of a yellow oil. The gas phase spectrum showed that only a trace amount of the impurity compound shown in formula III was produced. The purity of the target product (compound of formula I) was 94.1% (external standard method) and the yield was 91.1%.

[0205] Embodiment 27

[0206] A mixture of 3,4-dichlorobicyclo[3.2.1]-2-octene (88.5 g, 0.5 mol), water (300 ml), sodium carbonate (106 g, 1 mol) and tetrabutylammonium bromide (0.1 g) was heated to 103°C and refluxed for 6 h before the reaction was stopped. After cooling, the mixture was extracted with dichloroethane. No floccules were produced during layering. The organic phase was dried with sodium sulfate and then distilled to obtain 77.0 g of a yellow oil. The gas phase spectrum showed that only a trace amount of the impurity compound shown in formula III was produced. The purity of the target product (compound of formula I) was 94.9% (external standard method) and the yield was 92.1%.

[0207] Embodiment 28

[0208] A mixture of 3,4-dichlorobicyclo[3.2.1]-2-octene (88.5 g, 0.5 mol), water (900 ml), sodium carbonate (159 g, 1.5 mol) and tetrabutylammonium bromide (0.1 g) was heated to 103°C and refluxed for 7 h. The reaction was controlled in the gas phase until 3,4-dichlorobicyclo[3.2.1]-2-octene was less than 1% and then the reaction was stopped. After cooling, the mixture was extracted with dichloroethane. No floccules were produced during stratification. The organic phase was dried with sodium sulfate and then distilled to obtain 76.8 g of a yellow oil. The gas phase spectrum showed that only a trace amount of the impurity compound shown in formula III was produced. The purity of the target product (compound of formula I) was 95.0% (external standard method) and the yield was 92.0%.

[0209] Embodiment 29

[0210] A mixture of 3,4-dichlorobicyclo[3.2.1]-2-octene (88.5 g, 0.5 mol), water (650 ml), tripotassium phosphate (159.2 g, 0.75 mol) and tetrabutylammonium bromide (0.1 g) was heated to 103°C and refluxed for 8 h. The reaction was controlled in the gas phase until 3,4-dichlorobicyclo[3.2.1]-2-octene was less than 1% and then the reaction was stopped. After cooling, the mixture was extracted with dichloroethane. No floccules were produced during stratification. The organic phase was dried with sodium sulfate and then distilled to obtain 77.6 g of a yellow oil. The gas phase spectrum showed that only a trace amount of the impurity compound shown in formula III was produced. The purity of the target product (compound of formula I) was 95.2% (external standard method) and the yield was 93.1%.

[0211] Embodiment 30

[0212] A mixture of 3,4-dichlorobicyclo[3.2.1]-2-octene (88.5 g, 0.5 mol), water (700 ml), potassium dihydrogen phosphate (174.2 g, 1.0 mol) and tetrabutylammonium bromide (0.1 g) was heated to 103°C and refluxed for 8 h. The reaction was controlled in the gas phase until 3,4-dichlorobicyclo[3.2.1]-2-octene was less than 1% and then the reaction was stopped. After cooling, the mixture was extracted with dichloroethane. No floccules were produced during stratification. The organic phase was dried with sodium sulfate and then distilled to obtain 77.4 g of a yellow oil. The gas phase spectrum showed that only a trace amount of the impurity compound shown in formula III was produced. The purity of the target product (compound of formula I) was 94.8% (external standard method) and the yield was 92.5%.

[0213] Embodiment 31

[0214] A mixture of 3,4-dichlorobicyclo[3.2.1]-2-octene (88.5 g, 0.5 mol), water (600 ml), potassium carbonate (103.7 g, 0.75 mol) and tetrabutylammonium bromide (0.1 g) was heated to 103°C and refluxed for 7 h. The reaction was controlled in the gas phase until 3,4-dichlorobicyclo[3.2.1]-2-octene was less than 1% and then the reaction was stopped. After cooling, the mixture was extracted with dichloroethane. No floccules were produced during stratification. The organic phase was dried with sodium sulfate and then distilled to obtain 77.0 g of a yellow oil. The gas phase spectrum showed that only a trace amount of the impurity compound shown in formula III was produced. The purity of the target product (compound of formula I) was 94.6% (external standard method) and the yield was 91.8%.

[0215] Embodiment 32

[0216] A mixture of 3,4-dichlorobicyclo[3.2.1]-2-octene (88.5 g, 0.5 mol), water (450 ml), sodium carbonate (79.5 g, 0.75 mol) and polyethylene glycol (0.1 g) was heated to 103° C. and refluxed for 7 h. After cooling, the mixture was extracted with dichloroethane. No floccules were produced during layering. The organic phase was dried with sodium sulfate and then distilled to obtain 76.9 g of a yellow oil. The gas phase spectrum showed that only a trace amount of the impurity compound shown in formula III was produced. The purity of the target product (compound of formula I) was 94.7% (external standard method) and the yield was 91.8%.

[0217] The purity of the product in the above embodiment can reach 94% or above after distillation, and a small amount of solvent remains in the product, which can be directly used for subsequent reactions.

[0218] Comparative Example Route A-1 hydrolysis synthesis of 3-chlorobicyclo[3.2.1]-3-octen-2-ol.

[0219]

[0220] Comparative Example 1

[0221] A mixture of 3,4-dichlorobicyclo[3.2.1]-2-octene (88.5 g, 0.5 mol), water (800 ml), sodium hydroxide (80.0 g, 2.0 mol) and benzyltrimethylammonium chloride (0.1 g) was heated to reflux temperature and kept at this temperature for 7 h. After cooling, the mixture was extracted with dichloromethane. When the layers were separated, floccules were produced, such as Figure 8 -a, the organic phase was dried with sodium sulfate and then distilled to obtain an orange-brown oil, which was repeated three times to detect the purity and calculate the yield. The data are shown in Table-2:

[0222] Table-2:

[0223]

[0224] Figure 8 -a indicates that black tar and floccules are easily produced in this comparative example 1. The inventors speculate that this may be related to the large amount of alkali used and the strong alkalinity. This reaction condition is likely to produce more black tar and floccules, resulting in a decrease in yield and purity. The product after drying and distillation of the organic phase is as follows Fig.13 As shown, the results show that the compound of formula I (10.17') is 90.3% (area normalization method), and the impurity compound of formula III (15.89' and 16.07') is 5.8% (area normalization method). The product obtained by this method requires complex operations such as distillation for subsequent production, which greatly affects the production efficiency.

[0225] Comparative Example 2

[0226] According to the operation of Comparative Example 1, 3,4-dichlorobicyclo[3.2.1]-2-octene was reacted with a mixture of water, sodium hydroxide and benzyltrimethylammonium chloride of different masses at a temperature between 85°C and reflux temperature. After cooling, the mixture was extracted with dichloromethane. When stratification, floccules were produced. The organic phase was dried with sodium sulfate and then distilled to obtain an orange-brown oil. This was repeated four times. The purity was tested and the yield was calculated. The data are shown in Table-3:

[0227] Table-3:

[0228]

[0229] In Comparative Examples 1 and 2, when synthesizing 3-chlorobicyclo[3.2.1]-3-octen-2-ol, a relatively large amount of strong base was used. After multiple adjustments of conditions, impurities such as black tar, floccules (insoluble in water and dichloromethane), and compounds of formula III were still easily produced. The content of ether impurities was greater than 5%, resulting in reduced yield and purity. The boiling point of the ether impurity (III) was higher than that of the product of formula I. The method of distilling the product of formula I by rectification was energy-intensive and cost-intensive, and the remaining ether impurities (III) would also dissolve the product, resulting in a further reduction in product yield. If purification was not performed, it would be very unfavorable for the subsequent reaction.

[0230] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention, rather than to limit it. Although the present invention has been described in detail with reference to the aforementioned embodiments, those skilled in the art should understand that they can still modify the technical solutions described in the aforementioned embodiments, or make equivalent replacements for some of the technical features therein. However, these modifications or replacements do not deviate the essence of the corresponding technical solutions from the spirit and scope of the technical solutions of the embodiments of the present invention.

Claims

1. A method for preparing 3-chlorobicyclo[3.2.1]-3-octen-2-ol, characterized in that: The following reaction route is used to obtain: 3,4-dichlorobicyclo[3.2.1]-2-octene is reacted in a solvent under the action of an inorganic strong base and a weak acid salt to obtain 3-chlorobicyclo[3.2.1]-3-octen-2-ol; the reaction solvent is water; The inorganic strong base weak acid salt is one or more of alkali metal carbonate, alkali metal phosphate and alkali metal hydrogen phosphate; The molar ratio of the 3,4-dichlorobicyclo[3.2.1]-2-octene to the inorganic strong base weak acid salt is 1:1 to 3; A catalyst is also added during the reaction. In each reaction, the catalyst is independently or non-independently selected from one or more of polyethylene glycol, tetrabutylammonium bromide, tetrabutylammonium chloride, benzyltrimethylammonium chloride, benzyltriethylammonium chloride, diisopropylethylamine, triethylamine, triethylenediamine, and crown ether.

2. The preparation method according to claim 1, characterized in that: The alkali metal in the inorganic strong base weak acid salt is potassium and / or sodium.

3. The preparation method according to claim 1, characterized in that: The inorganic strong base weak acid salt is one or more of sodium carbonate, potassium carbonate, tripotassium phosphate and dipotassium hydrogen phosphate.

4. The preparation method according to claim 1, characterized in that: The molar ratio of the 3,4-dichlorobicyclo[3.2.1]-2-octene to the inorganic strong base weak acid salt is 1:1.5-3.

5. The preparation method according to any one of claims 1 to 4, characterized in that: The mass ratio of the 3,4-dichlorobicyclo[3.2.1]-2-octene to water is 1:1-20.

6. The preparation method according to claim 5, characterized in that: The mass ratio of the 3,4-dichlorobicyclo[3.2.1]-2-octene to water is 1:1-15.

7. The preparation method according to claim 5, characterized in that: The mass ratio of the 3,4-dichlorobicyclo[3.2.1]-2-octene to water is 1:3-15.

8. The preparation method according to any one of claims 1 to 4, characterized in that: The reaction temperature is from 0°C to the reflux temperature of the solvent.

9. The preparation method according to any one of claims 1 to 4, characterized in that: The reaction temperature is from 50°C to the reflux temperature of the solvent.

10. The preparation method according to any one of claims 1 to 4, characterized in that: The reaction temperature is from 70°C to the reflux temperature of the solvent.

11. The preparation method according to any one of claims 1 to 4, characterized in that: The reaction temperature is from 90°C to the reflux temperature of the solvent.

12. The preparation method according to any one of claims 1 to 4, characterized in that: The reaction temperature is the reflux temperature of the solvent.

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