Preparation method of fluralana intermediate

Abstract

The invention relates to the technical field of synthesis of drug intermediates, in particular to a preparation method of a fluralana intermediate, which comprises the following steps: by taking o-methylphenol as a raw material, carrying out acetylation and sulfonation docking, and finally reacting with carbon dioxide under the action of a nickel catalyst to synthesize the fluralana intermediate. Compared with the traditional method, the preparation method of the fluralan intermediate disclosed by the invention has the advantages that the process is simpler, the raw material cost is low, and the industrial production is convenient.

Description

Technical Field

[0001] The invention relates to the technical field of pharmaceutical intermediate synthesis, and specifically relates to a method for preparing a flurellan intermediate. Background Art

[0002] Flurellan is an isoxazoline insecticide and acaricide that antagonizes the γ-aminobutyric acid receptor and glutamate receptor gated chloride ion channels, preventing chloride ions from penetrating into the postsynaptic membrane, interfering with transmembrane signaling in the nervous system, leading to nervous system disorders in insects and death. The structural formula of an important intermediate in its preparation process is as follows:

[0003]

[0004] CN116987042A and CN117186022A both disclose the preparation method of the intermediate, using 4-bromo-2-methyl-benzoic acid and n-butyl vinyl ether as raw materials, and a substitution reaction occurs under the catalysis of a composite catalyst of palladium acetate and DPPP to obtain the target compound. The raw material cost used in this scheme is relatively high, the reaction temperature reaches 80-100°C, there are many by-products, and the use of catalysts such as palladium acetate further increases the material cost, and the process production value is very low.

[0005] CN116478057A discloses a method for preparing a fluororana intermediate, using o-aminotoluene as a raw material, and obtaining the target compound through steps such as acylation to protect the amino group, Friedel-Crafts reaction acetylation, deprotection, cyanation, and hydrolysis. The scheme has complicated steps, low reaction efficiency in the cyanation and hydrolysis steps, high reaction temperature, long reaction time, and low production efficiency.

[0006] Therefore, there is an urgent need in the art to develop a method for preparing a fluororana intermediate with lower cost and higher efficiency. Summary of the invention

[0007] In view of the above problems in the prior art, the present invention provides a method for preparing a flurellane intermediate.

[0008] To achieve the above object, the present invention provides the following technical solutions:

[0009] A method for preparing a flurellane intermediate: using o-methylphenol as a raw material, acetylation, sulfonation docking, and finally reacting with carbon dioxide under the action of a nickel catalyst to synthesize the flurellane intermediate. The synthesis route is as follows:

[0010]

[0011] The specific preparation steps are as follows:

[0012] (1) Compound 1 was synthesized by using o-methylphenol as a raw material to insert an acetyl group;

[0013] (2) reacting the compound 1 obtained in step (1) with a sulfonyl reagent to synthesize compound 2;

[0014] (3) reacting the compound 2 obtained in step (2) with carbon dioxide in the presence of a nickel catalyst to synthesize compound 3;

[0015] Here, M is any one of methanesulfonyl, p-toluenesulfonyl, nitrobenzenemethylsulfonyl and trifluoromethanesulfonyl.

[0016] Wherein, in the step (1), o-methylphenol and acetyl reagent are used to synthesize compound 1 under the action of Lewis acid; the molar ratio of o-methylphenol, acetyl reagent and Lewis acid is 1:1-2:1-1.2.

[0017] Furthermore, the acetyl reagent is acetic anhydride or acetyl chloride, and the Lewis acid is any one of aluminum chloride, zinc chloride, and magnesium chloride.

[0018] Wherein, in the step (2), the molar ratio of compound 1 to the sulfonyl reagent is 1:1-2.

[0019] Furthermore, the sulfonyl reagent is any one of methanesulfonyl chloride, p-toluenesulfonyl chloride, nitrobenzene methanesulfonyl chloride and trifluoromethanesulfonyl chloride.

[0020] Wherein, in the step (3), compound 2 reacts with carbon dioxide in the presence of a nickel catalyst to synthesize compound 3; the molar ratio of compound 2 to carbon dioxide is 1:1 to 3.

[0021] Furthermore, the nickel catalyst is Ni(PPh3)2Cl2 or Ni(cod)2.

[0022] Compared with the prior art, the beneficial effects of the method for preparing the flurellan intermediate of the present invention at least include:

[0023] (1) The present invention avoids the use of precious metal catalysts through a completely new process design and preparation, and replaces the palladium catalyst with a nickel catalyst, which has low material cost and high product conversion rate.

[0024] (2) Compared with the traditional process, the preparation method of the present invention has mild process conditions, low energy consumption, simple operation process and is convenient for industrial production. DETAILED DESCRIPTION

[0025] The technical solutions in the embodiments of the present invention are described clearly and completely below. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of them. 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.

[0026] Example 1

[0027]

[0028] Add o-methylphenol (10.81 g, 0.1 mol), acetyl chloride (11.78 g, 0.15 mol), and aluminum chloride (14.67 g, 0.11 mol) into the reactor, add dichloromethane (100 mL), stir and mix, and keep the reaction at 25-30°C for 8 hours.

[0029] After the reaction was completed, water (100 mL) was added to the system and stirred to separate the liquids. The organic layer was washed twice with water and the dichloromethane was concentrated to dryness under reduced pressure to obtain compound 1 (14.25 g, 0.0949 mol) with a yield of 94.9%.

[0030] Example 2

[0031]

[0032] Add compound 1 (15.02 g, 0.1 mol), ethyl acetate (100 mL) and triethylamine (15.18 g, 0.15 mol) into the reactor, cool to 0-5°C, add a solution of methanesulfonyl chloride (14.89 g, 0.13 mol) in ethyl acetate (50 mL) dropwise, control the temperature not to exceed 5°C, after the addition is complete, heat to 20-30°C and react for 2 h.

[0033] After the reaction was completed, the mixture was cooled to room temperature, water (100 mL) was added to the system, stirred and separated, the organic layer was washed twice with water, and ethyl acetate was concentrated to dryness under reduced pressure to obtain compound 2 (21.55 g, 0.0944 mol) with a yield of 94.4%.

[0034] Example 3

[0035]

[0036] Ni(PPh3)2Cl2 (0.65 g, 0.001 mol), manganese powder (5.5 g, 0.1 mol), and new cuprous reagent (0.42 g, 0.002 mol) were added to a dry reactor, and the air was replaced by nitrogen three times. The mixture was stirred for 40 min, and finally, a mixed solution of dry DMF (100 mL) and compound 2 (22.83 g, 0.1 mol) was added, and the system temperature was controlled at 25-30 ° C. Dry carbon dioxide gas (8.8 g, 0.2 mol) was introduced into the system, and the temperature was controlled at 15-20 ° C. The mixture was stirred for 10 h, and the reaction was completed.

[0037] 4N hydrochloric acid solution was slowly added to the system to adjust the pH to less than 3, water (100 mL) and ethyl acetate (100 mL) were added, and the aqueous layer was extracted twice with ethyl acetate (100 mL). The organic residues were combined and the dry solvent was recovered to obtain compound 3 (14.63 g, 0.0821 mol) with a yield of 82.1%.

[0038] Embodiments 4 to 6

[0039] Other conditions were the same as those in Example 1, except that the type of acetyl reagent and the molar ratio of o-cresol, acetyl reagent and Lewis acid were changed. The yields of Example 1 and Examples 4 to 6 are shown in Table 1.

[0040] Table 1 Different conditions and yields of Example 1 and Example 4-6

[0041] Example Acetyl reagent o-Cresol: Acetyl Reagent: Lewis Acid Yield / % 1 Acetyl chloride 1:1.5:1.1 94.9 4 Acetyl chloride 1:1:1 92.3 5 Acetyl chloride 1:2:1.2 93.5 6 Acetic anhydride 1:1.5:1.1 93.3

[0042] Embodiments 7 to 9

[0043] Other conditions were the same as those in Example 2 and Example 3, except that the types of sulfonyl reagent and nickel catalyst were changed. The yields of Examples 2 and 3 and Examples 7 to 9 are shown in Table 2.

[0044] Table 2 Different conditions and results of Examples 2 and 3, Examples 7-9

[0045] Example Sulfonyl reagents Nickel Catalyst Sulfonyl yield / % Carboxylation yield / % 2 and 3 Methanesulfonyl chloride <![CDATA[Ni(PPh3)2Cl2]]> 94.4 82.1 7 p-Toluenesulfonyl chloride <![CDATA[Ni(PPh3)2Cl2]]> 92.9 80.8 8 Methanesulfonyl chloride <![CDATA[Ni(cod)2]]> 94.4 80.4 9 p-Toluenesulfonyl chloride <![CDATA[Ni(cod)2]]> 92.9 79.7

[0046] Embodiments 10 to 11

[0047] Other conditions were the same as those in Example 2, except that the molar ratio of compound 1 to the sulfonyl reagent was changed. The yields of Example 2 and Examples 10 to 11 are shown in Table 3.

[0048] Table 3 Different conditions and results of Example 2, Example 10-11

[0049] Example Compound 1: Sulfonyl reagent Yield / % 2 1:1.3 94.4 10 1:1 91.2 11 1:2 93.4

[0050] Embodiments 12 to 13

[0051] Other conditions were the same as those in Example 3, except that the molar ratio of compound 2 to carbon dioxide was changed. The yields of Example 3 and Examples 12 to 13 are shown in Table 4.

[0052] Table 4 Different conditions and results of Example 3, Example 12-13

[0053] Example Compound 2: Carbon dioxide Yield / % 3 1:2 82.1 12 1:1 77.6 13 1:3 82.3

[0054] Although embodiments of the present invention have been shown and described, it will be appreciated by those skilled in the art that various changes, modifications, substitutions and variations may be made to the embodiments without departing from the principles and spirit of the present invention, and that the scope of the present invention is defined by the appended claims and their equivalents.

Claims

1. A method for preparing a fluororana intermediate, characterized in that: The following steps are involved: (1) Compound 1 was synthesized by using o-methylphenol as a raw material to insert an acetyl group; (2) reacting the compound 1 obtained in step (1) with a sulfonyl reagent to synthesize compound 2; (3) reacting the compound 2 obtained in step (2) with carbon dioxide in the presence of a nickel catalyst to synthesize compound 3; Here, M is any one of methanesulfonyl, p-toluenesulfonyl, nitrobenzenemethylsulfonyl and trifluoromethanesulfonyl.

2. The method for preparing the fluororana intermediate according to claim 1, characterized in that: In the step (1), o-methylphenol and acetyl reagent are used to synthesize compound 1 under the action of Lewis acid; wherein the molar ratio of o-methylphenol, acetyl reagent and Lewis acid is 1:1-2:1-1.

2.

3. The method for preparing the fluororana intermediate according to claim 2, characterized in that: In the step (1), the acetyl reagent is acetic anhydride or acetyl chloride, and the Lewis acid is any one of aluminum chloride, zinc chloride, and magnesium chloride.

4. The method for preparing the fluororana intermediate according to claim 1, characterized in that: In the step (2), the molar ratio of compound 1 to the sulfonyl reagent is 1:1-2.

5. The method for preparing the fluororana intermediate according to claim 4, characterized in that: In the step (2), the sulfonyl reagent is any one of methanesulfonyl chloride, p-toluenesulfonyl chloride, nitrobenzene methanesulfonyl chloride and trifluoromethanesulfonyl chloride.

6. The method for preparing the fluororana intermediate according to claim 1, characterized in that: In the step (3), compound 2 reacts with carbon dioxide in the presence of a nickel catalyst to synthesize compound 3; wherein the molar ratio of compound 2 to carbon dioxide is 1:1 to 3.

7. The method for preparing the fluororana intermediate according to claim 6, characterized in that: The nickel catalyst is Ni(PPh3)2Cl2 or Ni(cod)2.

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