A method for preparing endo-bicyclo[2.2.2]oct-5-ene-2,3-dicarboxylic anhydride

Abstract

The present invention discloses a preparation method of endo-bicyclo[2.2.2]oct-5-ene-2,3-dicarboxylic anhydride. Using 3-halocyclohexene and maleic anhydride as raw materials, under the action of an organic base, endo-bicyclo[2.2.2]oct-5-ene-2,3-dicarboxylic anhydride is prepared by a one-pot and one-step reaction in an organic solvent. The preparation method provided by the present invention prepares endo-bicyclo[2.2.2]oct-5-ene-2,3-dicarboxylic anhydride in a high yield through a one-pot and one-step reaction.

Description

Technical Field

[0001] The present invention belongs to the technical field of pharmaceuticals, and particularly relates to a method for preparing endo-bicyclo[2.2.2]oct-5-ene-2,3-dicarboxylic anhydride. Background Art

[0002] Endo-bicyclo[2.2.2]oct-5-ene-2,3-dicarboxylic anhydride is a key intermediate of the novel influenza A virus inhibitor pimodivir. Pimodivir is a first-in-class RNA polymerase complex PB2 subunit inhibitor drug that inhibits influenza virus replication by competitively binding to the 5-methyl cap binding site on the PB2 subunit of influenza virus. Phase II clinical trials have shown that the combination of pimodivir and oseltamivir can reduce the viral load of patients to a lower level, with broad market prospects.

[0003] Currently, the main route for the preparation of endo-bicyclo[2.2.2]oct-5-ene-2,3-dicarboxylic anhydride uses cyclohexadiene and maleic anhydride as raw materials. For example, Patent WO2018127096A1 discloses a method for preparing endo-bicyclo[2.2.2]oct-5-ene-2,3-dicarboxylic anhydride. Maleic anhydride and chloroform are successively added to a reaction flask, 1,3-cyclohexadiene is added dropwise at 0 °C, the reaction is carried out overnight at room temperature, the solvent is evaporated under reduced pressure, then methanol is added to the obtained residue, the mixture is heated to 50 °C and stirred, then cooled to 0 °C and stirred, and the target product is obtained by filtration and drying, with a yield of 81%. However, in this route, 1,3-cyclohexadiene is expensive and unstable, and prone to polymerization, resulting in difficult control of product costs.

[0004]

[0005] Journal of Medicinal Chemistry 2014 57(15),6668-6678 discloses a method for preparing endo-bicyclo[2.2.2]oct-5-ene-2,3-dicarboxylic anhydride. Cyclohexene is used as a raw material to prepare 1,3-cyclohexadiene, and the subsequent steps are still the Diels-Alder reaction with maleic anhydride. The specific route is as follows: Cyclohexene is brominated to obtain 3-bromocyclohexene, which is then subjected to an elimination reaction to obtain 1,3-cyclohexadiene, and then the target product is obtained by the Diels-Alder reaction with maleic anhydride. Although this route uses cyclohexene as a raw material and avoids the problem of directly using cyclohexadiene to a certain extent, the reaction temperature for preparing cyclohexadiene from 3-bromocyclohexene is relatively high, resulting in an increase in energy consumption costs, and the yield of this step is relatively low. It is also not a reasonable industrialization route.

[0006]

[0007] Patent US20130324688A1 discloses a method for preparing endo-bicyclo[2.2.2]oct-5-ene-2,3-dicarboxylic anhydride, which uses 1,4-cyclohexadiene as a raw material and reacts with maleic anhydride to prepare the target product. However, similar to the previous description, 1,4-cyclohexadiene is also expensive, unstable, prone to polymerization, and cannot be industrially produced.

[0008]

[0009] Faulkner, James disclosed a method for preparing endo-bicyclo[2.2.2]oct-5-ene-2,3-dicarboxylic anhydride in Metal Catalysed Cyclisations in Organic Synthesis, 2007, University of Manchester. This method uses 2-cyclohexen-1-one as a raw material, reacts with maleic anhydride after obtaining 3-(trichloroacetoxy)cyclohexene to get the product. However, the raw materials of this route are not easily available, the reaction route is complex, and the yield is not high. The total yield of the three steps is only 57.6%.

[0010]

[0011] It can be seen that the current synthesis methods of endo-bicyclo[2.2.2]oct-5-ene-2,3-dicarboxylic anhydride have problems such as difficult cost control, harsh reaction conditions, complex routes, and low yields. Therefore, there is an urgent need for a simple, high-yield, and low-cost synthesis process. Summary of the Invention

[0012] The purpose of the present invention is to provide a method for preparing endo-bicyclo[2.2.2]oct-5-ene-2,3-dicarboxylic anhydride, which prepares endo-bicyclo[2.2.2]oct-5-ene-2,3-dicarboxylic anhydride in high yield through a one-pot method and a one-step reaction.

[0013] The present invention provides the following technical solutions:

[0014] A method for preparing endo-bicyclo[2.2.2]oct-5-ene-2,3-dicarboxylic anhydride, using 3-halocyclohexene and maleic anhydride as raw materials, under the action of an organic base, in an organic solvent, through a one-pot method and a one-step reaction to prepare endo-bicyclo[2.2.2]oct-5-ene-2,3-dicarboxylic anhydride.

[0015] The method provided by the present invention is a preparation method for an intermediate for preparing an influenza virus replication inhibitor drug. Specifically, the compound prepared by the present invention can be used as an intermediate for an inhibitor of influenza virus RNA polymerase.

[0016] The preparation method provided by the present invention avoids the disadvantages of high reaction temperature, instability, easy polymerization, low yield, etc. required for synthesizing 1,3-cyclohexadiene intermediates; the preparation method provided by the present invention has the advantages of few steps, strong operability, mild reaction conditions, high economic benefits, high product yield, etc., and is suitable for industrial production.

[0017] The reaction formula is as follows:

[0018]

[0019] Furthermore, the preparation method comprises:

[0020] (1) mixing 3-halocyclohexene, maleic anhydride and a reaction solvent, heating and adding an organic base to react;

[0021] (2) After the reaction is complete, water is added and the mixture is allowed to stand for separation. The organic layer is concentrated under reduced pressure, cooled and crystallized, and filtered to obtain endo-bicyclo(2.2.2)oct-5-ene-2,3-dicarboxylic anhydride.

[0022] The 3-halogenated cyclohexene is selected from 3-chlorocyclohexene or 3-bromocyclohexene. The reactivity of 3-bromocyclohexene is higher than that of 3-chlorocyclohexene, and the yield of the product prepared by using 3-bromocyclohexene as a raw material is higher. Further, 3-bromocyclohexene is preferred.

[0023] The organic base is selected from one or a combination of at least two of triethylamine, tetramethylguanidine, 1,8-diazabicycloundec-7-ene, pyridine, piperidine, quinoline, 4-dimethylaminopyridine or N-methylmorpholine.

[0024] The organic base can be added all at once or slowly added dropwise, preferably slowly added dropwise.

[0025] The molar ratio of the 3-halocyclohexene, maleic anhydride and organic base is 1:0.5-1.5:0.5-2.

[0026] The reaction temperature in step (1) is 50-120°C. When the reaction temperature is too low, the reaction rate is slow; when the reaction temperature is too high, side reactions such as polymerization may occur because the reaction system uses an organic base and the raw materials and other compounds used all contain unsaturated carbon chains. Preferably, the reaction temperature in step (1) is 60-110°C.

[0027] The reaction solvent in step (1) is selected from aprotic organic solvents, preferably aromatic hydrocarbons such as toluene, xylene, chlorobenzene, p-xylene, benzene, etc.

[0028] The crystallization temperature in step (2) is 0-40° C. Preferably, the crystallization temperature in step (2) is 5-25° C., which is conducive to improving the yield of the product.

[0029] More preferably, in step (1), the organic base is selected from triethylamine, pyridine or quinoline, the 3-halocyclohexene is selected from 3-bromocyclohexene, and the molar ratio of 3-bromocyclohexene, maleic anhydride and the organic base is 1:1:1, and the reaction temperature is 70-110 °C; in step (2), the crystallization temperature is 10-25 °C; the yield of the endo-bicyclo[2.2.2]oct-5-ene-2,3-dicarboxylic anhydride prepared is at least 87%.

[0030] More preferably, in step (1), the organic base is selected from pyridine or quinoline, the 3-halocyclohexene is selected from 3-bromocyclohexene, and the molar ratio of 3-bromocyclohexene, maleic anhydride and the organic base is 1:1:1, and the reaction temperature is 90-110 °C; in step (2), the crystallization temperature is 10-15 °C; the yield of the endo-bicyclo[2.2.2]oct-5-ene-2,3-dicarboxylic anhydride prepared is at least 88.5%.

[0031] Compared with the prior art, the beneficial effects of the present invention are as follows:

[0032] 1. The preparation method provided by the present invention prepares endo-bicyclo[2.2.2]oct-5-ene-2,3-dicarboxylic anhydride in a high yield through a one-pot method and a one-step reaction, and the yield is at least 78%;

[0033] 2. The preparation method provided by the present invention does not use and prepare cyclohexadiene, reducing the cost and avoiding the high energy consumption and high risk caused by high temperature in the process of preparing cyclohexadiene;

[0034] 3. The preparation method provided by the present invention avoids the deterioration of raw materials and the reduction of yield caused by the easy polymerization of cyclohexadiene;

[0035] 4. The halogen in the preparation method provided by the present invention can be recycled and reused, which is environmentally friendly and has a high atom utilization rate;

[0036] 5. The preparation method provided by the present invention has short steps, strong operability and high economic benefits. BRIEF DESCRIPTION OF THE DRAWINGS

[0037] Figure 1 1H NMR spectrum of the endo-bicyclo[2.2.2]oct-5-ene-2,3-dicarboxylic anhydride prepared in Example 1 of the present invention;

[0038] Figure 2 13C NMR spectrum of the endo-bicyclo[2.2.2]oct-5-ene-2,3-dicarboxylic anhydride prepared in Example 1 of the present invention. DETAILED DESCRIPTION OF THE INVENTION

[0039] To make the purpose, technical solution and advantages of the present invention more clearly understood, the present invention is further described in detail below in conjunction with the accompanying drawings and embodiments. It should be understood that the specific implementation methods described herein are only used to explain the present invention and do not limit the scope of protection of the present invention.

[0040] The 3-halocyclohexene (3-chlorocyclohexene and 3-bromocyclohexene) in the following examples were purchased from Shanghai MacLean Biochemical Technology Co., Ltd., and other raw materials were purchased from Shanghai Aladdin Biochemical Technology Co., Ltd.

[0041] Example 1

[0042] In a 250mL reaction bottle, maleic anhydride (19.6g, 0.2mol), 150ml toluene and 3-bromocyclohexene (32.2g, 0.2mol) were added in sequence, the temperature was raised to 70°C, triethylamine (20.2g, 0.2mol) was added at once, and after the addition was complete, the reaction was tracked by HPLC. After the reaction was complete, the temperature was lowered, 50ml of water was added, the mixture was allowed to stand and the layers were separated. The organic layer was concentrated under reduced pressure, cooled to 20°C, filtered, and the filter cake was dried in vacuo to obtain 31.1g of endo-bicyclo (2.2.2) oct-5-ene-2,3-dicarboxylic anhydride with a yield of 87%.

[0043] like Figure 1 and Figure 2 As shown, they are the hydrogen NMR spectrum and carbon NMR spectrum of the prepared endo-bicyclo (2.2.2) oct-5-ene-2,3-dicarboxylic anhydride:

[0044] 1 HNMR (500MHz, CDCl3) δ6.31 (dd, J=4.6, 3.1Hz, 2H), 3.19-3.22 (m, 2H), 3.17-3.13 (m, 2H), 1.66-1.58 (m, 2H), 1.44-1.36 (m, 2H).

[0045] 13 CNMR (126MHz, CDCl3) δ173.06, 133.06, 44.75, 31.64, 29.67, 22.92.

[0046] Example 2

[0047] In a 250 mL reaction flask, maleic anhydride (19.6 g, 0.2 mol), 110 mL of toluene and 3-chlorocyclohexene (23.32 g, 0.2 mol) were successively added. The temperature was raised to 90 °C, and triethylamine (20.2 g, 0.2 mol) was added dropwise. After the addition was complete, the reaction was monitored by HPLC. After the reaction was complete, the temperature was lowered, 60 mL of water was added, and the mixture was allowed to stand and separate into layers. The organic layer was concentrated under reduced pressure, cooled to 25 °C, filtered, and the filter cake was dried in vacuo to obtain 28.1 g of endo-bicyclo[2.2.2]oct-5-ene-2,3-dicarboxylic anhydride, with a yield of 78.9%.

[0048] Example 3

[0049] In a 250 mL reaction flask, maleic anhydride (19.6 g, 0.2 mol), 140 mL of toluene and 3-bromocyclohexene (32.2 g, 0.2 mol) were successively added. The temperature was raised to 110 °C, and pyridine (15.82 g, 0.2 mol) was added dropwise. After the addition was complete, the reaction was monitored by HPLC. After the reaction was complete, the temperature was lowered, 80 mL of water was added, and the mixture was allowed to stand and separate into layers. The organic layer was concentrated under reduced pressure, cooled to 15 °C, filtered, and the filter cake was dried in vacuo to obtain 32.1 g of endo-bicyclo[2.2.2]oct-5-ene-2,3-dicarboxylic anhydride, with a yield of 90.17%.

[0050] Example 4

[0051] In a 250 mL reaction flask, maleic anhydride (9.8 g, 0.1 mol), 80 mL of chlorobenzene and 3-chlorocyclohexene (11.66 g, 0.1 mol) were successively added. The temperature was raised to 100 °C, and pyridine (7.9 g, 0.1 mol) was added dropwise. After the addition was complete, the reaction was monitored by HPLC. After the reaction was complete, the temperature was lowered, 40 mL of water was added, and the mixture was allowed to stand and separate into layers. The organic layer was concentrated under reduced pressure, cooled to 10 °C. Filtered, the filter cake was dried in vacuo to obtain 14.5 g of endo-bicyclo[2.2.2]oct-5-ene-2,3-dicarboxylic anhydride, with a yield of 81.5%.

[0052] Example 5

[0053] In a 250 mL reaction flask, maleic anhydride (39.2 g, 0.4 mol), 300 mL of xylene and 3-bromocyclohexene (64.5 g, 0.4 mol) were successively added. The temperature was raised to 90 °C, and quinoline (51.7 g, 0.4 mol) was added all at once. After the addition was complete, the reaction was monitored by HPLC. After the reaction was complete, the temperature was lowered, 120 mL of water was added, and the mixture was allowed to stand and separate into layers. The organic layer was concentrated under reduced pressure, cooled to 10 °C, filtered, and the filter cake was dried in vacuo to obtain 63 g of endo-bicyclo[2.2.2]oct-5-ene-2,3-dicarboxylic anhydride, with a yield of 88.5%.

[0054] Example 6

[0055] In a 250 mL reaction flask, maleic anhydride (48, 0.5 mol), 600 mL of p-xylene, and 3-chlorocyclohexene (58.5 g, 0.5 mol) were successively added. The temperature was raised to 110 °C, and quinoline (65 g, 0.51 mol) was added dropwise. After the addition was complete, the reaction was monitored by HPLC. After the reaction was complete, the temperature was lowered, 200 mL of water was added, and the mixture was allowed to stand and separate into layers. The organic layer was concentrated under reduced pressure, cooled to 5 °C, filtered, and the filter cake was dried in vacuo to obtain 73.9 g of endo-bicyclo(2.2.2)oct-5-ene-2,3-dicarboxylic anhydride, with a yield of 83%.

[0056] Example 7

[0057] In a 250 mL reaction flask, maleic anhydride (19.6 g, 0.2 mol), 120 mL of chlorobenzene, 3-bromocyclohexene (32.2 g, 0.2 mol), and quinoline (25.83 g, 0.2 mol) were successively added. The temperature was raised to 65 °C, and the reaction was monitored by HPLC. After the reaction was complete, the temperature was lowered, 50 mL of water was added, and the mixture was allowed to stand and separate into layers. The organic layer was concentrated under reduced pressure, cooled to 20 °C, filtered, and the filter cake was dried in vacuo to obtain 29.6 g of endo-bicyclo(2.2.2)oct-5-ene-2,3-dicarboxylic anhydride, with a yield of 83.15%.

[0058] The above examples are only used to explain the inventive concept of the present invention, rather than limiting the protection scope of the rights of the present invention. Any simple modification, equivalent change, and modification made to the above examples based on the essence of the technology and method of the present invention still fall within the scope of the technical and method solutions of the present invention.

Claims

1. A method for preparing endo-bicyclo[2.2.2]oct-5-ene-2,3-dicarboxylic anhydride, characterized in that, Using 3-halocyclohexene and maleic anhydride as raw materials, under the action of an organic base, endo-bicyclo(2.2.2)oct-5-ene-2,3-dicarboxylic anhydride is prepared by a one-pot and one-step reaction in an organic solvent; The organic base is selected from one or a combination of at least two of triethylamine, tetramethylguanidine, 1,8-diazabicycloundec-7-ene, pyridine, piperidine, quinoline, 4-dimethylaminopyridine or N-methylmorpholine. The 3-halocyclohexene is selected from 3-chlorocyclohexene or 3-bromocyclohexene, and the reaction temperature is 50-120 °C.

2. The preparation method of endo-bicyclo(2.2.2)oct-5-ene-2,3-dicarboxylic anhydride according to claim 1, characterized in that, The preparation method includes: (1) After mixing 3-halocyclohexene, maleic anhydride and a reaction solvent, the temperature is raised and then an organic base is added for reaction; (2) After the reaction is complete, water is added and the mixture is allowed to stand and separate layers. The organic layer is concentrated under reduced pressure, cooled for crystallization, and filtered to obtain endo-bicyclo(2.2.2)oct-5-ene-2,3-dicarboxylic anhydride.

3. The preparation method of endo-bicyclo(2.2.2)oct-5-ene-2,3-dicarboxylic anhydride according to claim 1 or 2, characterized in that, The molar ratio of the 3-halocyclohexene, maleic anhydride and organic base is 1:0.5-1.5:0.5-2.

4. The preparation method of endo-bicyclo(2.2.2)oct-5-ene-2,3-dicarboxylic anhydride according to claim 2, characterized in that, The reaction solvent in the step (1) is selected from aprotic organic solvents.

5. The preparation method of endo-bicyclo(2.2.2)oct-5-ene-2,3-dicarboxylic anhydride according to claim 2, characterized in that, The temperature for crystallization in the step (2) is 0-40 °C.

6. The preparation method of endo-bicyclo[2.2.2]oct-5-ene-2,3-dicarboxylic anhydride according to claim 2, characterized in that, In the step (1), the organic base is selected from pyridine or quinoline, the 3-halocyclohexene is selected from 3-bromocyclohexene, the molar ratio of 3-bromocyclohexene, maleic anhydride and organic base is 1:1:1, and the reaction temperature is 90-110 °C; in the step (2), the temperature for crystallization is 10-15 °C.

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