Preparation process of fluralana intermediate

Abstract

The invention relates to the technical field of synthesis of drug intermediates, in particular to a preparation process of a fluralana intermediate, m-trichlorobenzene is used as a raw material, the fluralana intermediate is obtained through Grignard reaction and fluorination synthesis, and the synthesis route is as follows: # imgabs0 #. Compared with a traditional method, the preparation process of the fluralana intermediate is simpler in procedure, low in raw material cost and high in yield, and the preparation process is suitable for industrial production. And the process is safer and more suitable for industrial mass production.

Description

Technical Field

[0001] The invention relates to the field of pharmaceutical intermediate synthesis, and specifically relates to a preparation process of 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] CN116535298A discloses a method for synthesizing 3',5'-dichloro-2,2,2-trifluoroacetophenone, using 3,5-dichlorobenzoic acid methyl ester as a raw material and trifluoromethane as a trifluoromethylation agent to prepare the target compound 2 under the catalytic action of a base. However, this scheme requires the use of trifluoromethane, which is a Freon reagent and is highly destructive to the environment. The reaction controllability is low and it is easy to produce trifluoroacylated impurities on the benzene ring.

[0005] US9006447B2 discloses a method for preparing the intermediate, using CF3TMS as a trifluoromethyl reagent to react with 3,5-dichlorobenzoic acid methyl ester to prepare the target compound 2. However, CF3TMS is expensive and not easy to commercialize. Summary of the invention

[0006] In view of the above problems in the prior art, the present invention provides a preparation process of a flurellane intermediate.

[0007] To achieve the above object, the present invention provides the following technical solutions:

[0008] A preparation process of a flurellane intermediate: using m-trichlorobenzene as a raw material, the flurellane intermediate is obtained by Grignard reaction and fluorination synthesis. The synthesis route is as follows:

[0009]

[0010] The specific preparation steps are as follows:

[0011] (1) Using m-trichlorobenzene as a raw material and a trichloroacetic acid derivative through a Grignard reaction to insert a trichloroacetyl group to synthesize compound 1;

[0012] (2) reacting the compound 1 obtained in step (1) with a fluorinating agent to synthesize compound 2;

[0013] Wherein, in the step (1), the molar ratio of m-trichlorobenzene, magnesium powder and trichloroacetic acid derivative is 1:1-1.5:1-1.5.

[0014] Furthermore, the trichloroacetyl derivative is any one of trichloroacetyl chloride, sodium trichloroacetate, ethyl trichloroacetate, methyl trichloroacetate, and trifluoroacetyl dimethylamide.

[0015] Wherein, the molar ratio of the compound 1 to the fluorination agent is 1:1-3.

[0016] Furthermore, the fluorination agent is any one of potassium fluoride, sodium fluoride and hydrogen fluoride.

[0017] Furthermore, the step (2) is carried out in the absence of a solvent.

[0018] Compared with the prior art, the beneficial effects of the process for preparing the fluororana intermediate of the present invention include at least:

[0019] (1) The preparation process of the present invention uses m-trichlorobenzene as a raw material, and prepares the target compound through Grignard reaction and fluorination synthesis, avoiding the use of trifluoromethylation reagents that are highly destructive to the environment and reducing the risk of material use.

[0020] (2) Compared with the traditional method, the preparation process of the present invention has lower raw material cost, simpler process and easier operation, and is more suitable for large-scale industrial production. DETAILED DESCRIPTION

[0021] 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.

[0022] Example 1

[0023]

[0024] Magnesium powder (3.12 g, 0.13 mol), dry tetrahydrofuran (60 mL) and iodine particles (0.25 g, 0.001 mol) were added to the dry reactor, the air was replaced by nitrogen three times, and a tetrahydrofuran solution (60 mL) of m-trichlorobenzene (18.14 g, 0.1 mol) was added dropwise. After the addition was completed, the system was temperature controlled at 25-30 ° C and stirred for 4 hours. Trichloroacetyl chloride (21.82 g, 0.12 mol) was added dropwise to the system, the temperature was controlled at 15-20 ° C, and the reaction was stirred for 3 hours.

[0025] After the reaction was completed, the pH of the system was adjusted to less than 3 with 4N hydrochloric acid, THF was recovered under reduced pressure, toluene (100 mL) was added to the remaining aqueous layer and extracted twice, the toluene extracts were combined and concentrated to dryness under reduced pressure to obtain compound 1 (24.06 g, 0.0823 mol) with a yield of 82.3%.

[0026] Example 2

[0027]

[0028] Compound 1 (29.24 g, 0.1 mol), 18-crown-6 (1.85 g, 0.007 mol) and potassium fluoride (9.3 g, 0.16 mol) were added to a dry reactor. The air in the container was replaced with nitrogen three times. The temperature was raised to 150-160° C. and the reaction was stirred for 5 h.

[0029] After the reaction was completed, the temperature was maintained at 150-160° C. and the pressure was reduced to -0.085-0.095 MPa to obtain compound 2 (19.73 g, 0.0812 mol) with a yield of 81.2%.

[0030] Embodiments 3 to 6

[0031] Other conditions were the same as those in Example 1, except that the molar ratio of m-trichlorobenzene, magnesium powder and trichloroacetic acid derivative and the type of trichloroacetyl derivative were changed. The yields of Example 1 and Examples 3 to 6 are shown in Table 1.

[0032] Table 1 Different conditions and results of Example 1 and Examples 3-6

[0033] Example m-Trichlorobenzene: magnesium powder: trichloroacetic acid derivative Trichloroacetyl derivatives Yield / % 1 1：1.3：1.2 Trichloroacetyl chloride 82.3 3 1：1：1 Trichloroacetyl chloride 80.5 4 1：1.5：1.5 Trichloroacetyl chloride 81.8 5 1：1.3：1.2 Sodium trichloroacetate 80.2 6 1：1.3：1.2 Ethyl trichloroacetate 78.9

[0034] Embodiments 7 to 9

[0035] Other conditions were the same as those in Example 2, except that the molar ratio of compound 1 to the fluorinating agent and the type of fluorinating agent were changed. The yields of Example 2 and Examples 7 to 9 are shown in Table 2.

[0036] Table 2 Different conditions and results of Example 2, Example 7-9

[0037] Example Compound 1: Fluorination reagent Fluorination reagents Yield / % 2 1：1.6 Potassium fluoride 81.2 7 1：1 Potassium fluoride 77.6 8 1：3 Potassium fluoride 81.5 9 1：1.6 Sodium fluoride 79.8

[0038] 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 process for preparing a fluororana intermediate, characterized in that: The following steps are involved: (1) Using m-trichlorobenzene as a raw material and a trichloroacetic acid derivative through a Grignard reaction to insert a trichloroacetyl group to synthesize compound 1; (2) reacting the compound 1 obtained in step (1) with a fluorinating agent to synthesize compound 2; 2. The process for preparing the fluororana intermediate according to claim 1, characterized in that: In the step (1), the molar ratio of m-trichlorobenzene, magnesium powder and trichloroacetic acid derivative is 1:1-1.5:1-1.

5.

3. The process for preparing the fluororana intermediate according to claim 2, characterized in that: The trichloroacetyl derivative is any one of trichloroacetyl chloride, sodium trichloroacetate, ethyl trichloroacetate, methyl trichloroacetate, and trifluoroacetyl dimethylamide.

4. The process for preparing the fluororana intermediate according to claim 1, characterized in that: In the step (2), the molar ratio of compound 1 to the fluorination agent is 1:1-3.

5. The process for preparing the fluororana intermediate according to claim 4, characterized in that: In the step (2), the fluorination agent is any one of potassium fluoride, sodium fluoride and hydrogen fluoride.

6. The process for preparing the fluororana intermediate according to claim 1, characterized in that: The step (2) is carried out in the absence of a solvent.

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