Preparation method of fluralana intermediate

Abstract

The invention relates to the field of medicine synthesis, in particular to a synthesis technology of a medicine fluralana, and more particularly relates to a preparation method of a fluralana intermediate, which is characterized in that the existing synthesis thought is skipped through a Grignard reaction under carbonyl protection, so that participation of carbon monoxide under a high-pressure preparation condition is not needed, and the synthesis process is simplified. According to the method, the fluralana intermediate can be obtained in a high-yield and high-purity mode without the need for preparing the raw materials or expensive catalysts such as palladium carbon, and the method is low in production cost, high in production safety degree, suitable for industrial application and popularization and high in industrial value.

Description

Technical Field

[0001] The present invention relates to the field of drug synthesis, particularly to the synthesis technology of the drug fluralaner, and more specifically to a preparation method of a fluralaner intermediate. Background Art

[0002] Fluralaner is an isoxazoline insecticide and acaricide. By antagonizing the γ-aminobutyric acid receptor and the glutamate receptor-gated chloride channel, it prevents chloride ions from penetrating into the postsynaptic membrane, interfering with the transmembrane signal transmission of the nervous system, leading to disorders in the insect nervous system and subsequent death.

[0003] There are mainly two synthesis methods for fluralaner. One is the intermolecular cyclization method of [CC + CNO], and the other is the intramolecular cyclization method of [CCC + NO]. The synthesis route of the [CCC + NO] intramolecular cyclization method is as follows:

[0004]

[0005] It can be seen that 4-acetyl-2-methylbenzoic acid is an important intermediate compound for the synthesis of fluralaner. Currently, there are mainly the following two methods for synthesizing this intermediate compound:

[0006] The first method is the one disclosed in the patent document WO2009001942. In this method, 4-acetyl-2-methylaniline is prepared from 4-acetyl-2-methylbenzamide under the action of sulfuric acid. 4-Acetyl-2-methylaniline is diazotized and then hydrolyzed to obtain 4-bromo-3-methylacetophenone. 4-Bromo-3-methylacetophenone is catalytically reacted with carbon monoxide under pressure in the presence of palladium-carbon to obtain 4-bromo-2-methyl-benzoic acid.

[0007] The second method is the one disclosed in the patent document CN109553528A. In this method, 2-fluorotoluene is used as the raw material, and through acylation reaction, cyanation reaction, and hydrolysis reaction, 2-methyl-4-acetylbenzoic acid is obtained. Its synthesis route is as follows:

[0008]

[0009] The process of the first preparation method is very cumbersome, and it is necessary to catalytically react 4-bromo-3-methylacetophenone with carbon monoxide under pressure in the presence of palladium-carbon. This not only involves expensive raw materials and catalysts, but also the reaction conditions such as pressure further increase the synthesis cost.

[0010] The synthesis steps of the second method are long, and dangerous compounds such as cyanide are required in the reaction, which have high requirements for reaction equipment and production conditions. At the same time, in Patent CN116478057A, it is pointed out that when professional experimental personnel in the field repeated the above process, the reaction temperature of the second-step cyanidation reaction was increased to 170 °C and the reaction was extended to 24 h, but no chemical reaction occurred. It is further pointed out that in "Optimization of Organic Synthesis Processes" written by Chen Rongye (Beijing: Chemical Industry Press), it is proposed that fluoroarenes are difficult to undergo cyanidation reactions. This shows that it is difficult to achieve the chemical reaction route disclosed by the second synthesis method.

[0011] Therefore, providing a new preparation method for the fluralaner intermediate 4-acetyl-2-methylbenzoic acid has become a key and difficult problem for those skilled in the art to research and develop. Summary of the Invention

[0012] In view of the problems existing in the existing synthesis technology, such as high synthesis cost and low synthesis safety, the present invention provides a preparation method for a fluralaner intermediate. The synthesis route of this preparation method is as follows:

[0013]

[0014] Specifically, it includes the following steps:

[0015] (1) Compound 1 reacts with a ketal reagent to obtain compound 2 with a carbonyl protecting group M;

[0016] (2) Compound 2 reacts with a carbonyl reagent to obtain compound 3;

[0017] Wherein M is independently and arbitrarily selected from:

[0018]

[0019] any one of;

[0020] X is independently and arbitrarily selected from one of F, Cl, or Br.

[0021] Preferably, the ketal reagent is any one of ethylene glycol, ethanedithiol, methanol, ethanol, isopropanol, benzyl alcohol, propylene glycol, propanedithiol, and methanethiol.

[0022] Preferably, the molar ratio of compound 1 to the ketal reagent is 1:1 to 3.

[0023] Preferably, the carbonyl reagent is any one of carbon dioxide, Boc anhydride, dimethyl carbonate, diethyl carbonate, and chloroformate.

[0024] Preferably, the molar ratio of compound 2 to the carbonyl reagent is 1:1 to 1.2.

[0025] In a preferred technical solution, the compound 1 is prepared from (a) o-halotoluene and an acetylating reagent under the action of a Lewis acid, and its synthetic route is as follows:

[0026]

[0027] Among them, X is independently and arbitrarily selected from one of F, Cl or Br.

[0028] Preferably, the acetylating reagent is acetic anhydride or acetyl chloride.

[0029] Preferably, the Lewis acid is independently and arbitrarily selected from any one of aluminum chloride, zinc chloride, and magnesium chloride.

[0030] Preferably, the molar ratio of the o-halotoluene, the acetylating reagent, and the Lewis acid is 1:1-2:1-1.2.

[0031] In the preparation method of the fluralaner intermediate disclosed in the present invention, the participation of carbon monoxide is not required, and thus high-pressure preparation conditions are not required. At the same time, the participation of expensive catalysts such as palladium-carbon is not required in the present invention, which can greatly reduce the synthesis production cost; in addition, the preparation method disclosed in the present invention has a high synthesis yield, high product purity, and low production cost; it is a new synthesis preparation method suitable for industrial promotion and application and has high industrial value. Description of the Drawings

[0032] Figure 1 For the compound 3 obtained in Example 3 1 1H-NMR spectrum. Detailed Embodiments

[0033] To better understand the present invention, the present invention will be further described below in conjunction with specific examples. Unless otherwise specified, the reagents used in the embodiments of the present invention are all commercially available reagents, and the equipment and instruments used are all commercially available equipment and instruments. Unless otherwise specified, all operations are carried out according to conventional methods and conditions or with reference to the product specifications.

[0034] The synthetic route of the present invention:

[0035]

[0036] Specifically includes the following steps:

[0037] (a) o-Halotoluene and an acetylating reagent react under the action of a Lewis acid to obtain compound 1;

[0038] (1) Compound 1 reacts with a ketal reagent to obtain compound 2 with a carbonyl protecting group M;

[0039] (2) Compound 2 reacts with a carbonyl reagent to obtain Compound 3;

[0040] Among them, M is independently and arbitrarily selected from:

[0041]

[0042] any one of;

[0043] X is independently and arbitrarily selected from one of F, Cl or Br.

[0044] Example 1

[0045]

[0046] o-Chlorotoluene (12.66 g, 0.1 mol), acetyl chloride (11.78 g, 0.15 mol), aluminum chloride (14.67 g, 0.11 mol), and dichloromethane (100 ml) are added to a reactor, stirred, and reacted at 25 - 30 °C for 8 h.

[0047] After the reaction is completed, water (100 ml) is added to the system, stirred, separated, the organic layer is taken, washed twice with water, and the dichloromethane is concentrated under reduced pressure to dryness to obtain Compound 1 (15.88 g, 0.0942 mol), with a yield of 94.2%.

[0048] Example 2

[0049]

[0050] Compound 1 (16.86 g, 0.1 mol), toluene (150 ml) and ethylene glycol (7.93 g, 0.12 mol) are added to a dry reactor, then p-toluenesulfonic acid (8.6 g, 0.05 mol) is added, and the temperature is raised to 90 - 100 °C and reacted for 2 h.

[0051] After the reaction is completed, it is cooled to room temperature, water (100 ml) is added to the system, stirred, separated, the organic layer is washed twice with water, and the toluene is concentrated under reduced pressure to dryness to obtain Compound 2 (18.67 g, 0.0878 mol), with a yield of 87.8%.

[0052] Example 3

[0053]

[0054] Magnesium powder (2.43 g, 0.1 mol), dry tetrahydrofuran (60 ml) and iodine grains (0.25 g, 0.001 mol) are added to a dry reactor, the air is displaced with nitrogen three times, and a tetrahydrofuran solution (60 ml) of Compound 2 (21.27 g, 0.1 mol) is added dropwise.

[0055] After the dropping is completed, the temperature of the system is controlled at 25 - 30 °C, and the reaction is stirred for 4 h. Dry carbon dioxide gas (5.28 g, 0.12 mol) is introduced into the system, the temperature is controlled at -15 - -20 °C, and the reaction is stirred for 3 h.

[0056] After the reaction is completed, the pH of the system is adjusted to less than 3 (4N hydrochloric acid solution can be used), THF is recovered under reduced pressure, toluene (100 ml) is added to the remaining aqueous layer for extraction twice, the toluene extraction liquids are combined, and concentrated to dryness under reduced pressure to obtain compound 3 (14.72 g, 0.0826 mol), with a yield of 82.6%.

[0057] Example 4

[0058]

[0059] o-Chlorotoluene (12.66 g, 0.1 mol), acetic anhydride (15.31 g, 0.15 mol) are added to the reactor, then aluminum chloride (14.67 g, 0.11 mol), dichloromethane (100 ml) are added, stirred and mixed, and the reaction temperature is maintained at 25 - 30 °C for 8 h.

[0060] After the reaction is completed, water (100 ml) is added to the system, stirred, separated, the organic layer is washed with water twice, and dichloromethane is concentrated to dryness under reduced pressure to obtain compound 1 (15.61 g, 0.0926 mol), with a yield of 92.6%.

[0061] Example 5

[0062]

[0063] Compound 1 (16.86 g, 0.1 mol), ethanedithiol (12.25 g, 0.13 mol) and dichloromethane (100 ml) are added to the reactor, the temperature of the reaction system is controlled at 0 - 5 °C, boron trifluoride dihydrate (10.98 g, 0.1 mol) is added dropwise thereto, and after the dropping is completed, the reaction temperature is maintained at 20 - 25 °C and the reaction is stirred for 1 h.

[0064] After the reaction is completed, it is cooled to room temperature, water (100 ml) is added to the system, stirred, separated, the organic layer is washed with water twice and then with saturated sodium bicarbonate once, and dichloromethane is concentrated to dryness under reduced pressure to obtain compound 2 (20.88 g, 0.0853 mol), with a yield of 85.3%.

[0065] Example 6

[0066]

[0067] Add magnesium powder (2.43 g, 0.1 mol), dry tetrahydrofuran (60 ml) and iodine grains (0.25 g, 0.001 mol) to a dry reactor. Replace the air with nitrogen three times, and then dropwise add a tetrahydrofuran solution (60 ml) of compound 2 (24.48 g, 0.1 mol). After the addition is complete, control the temperature of the system at 25 - 30 °C and stir for 4 h. Then introduce dry carbon dioxide gas (5.28 g, 0.12 mol) into the system, control the temperature at 15 - 20 °C, and stir for 3 h.

[0068] After the reaction is completed, adjust the pH of the system to less than 3 (4N hydrochloric acid solution can be used). Recover THF under reduced pressure. Add 30% hydrogen peroxide (10 ml) to the remaining aqueous layer, stir for 30 min, then add toluene (100 ml) and extract twice. Combine the toluene extracts and concentrate to dryness under reduced pressure to obtain compound 3 (14.31 g, 0.0803 mol), with a yield of 80.3%.

[0069] Examples 7 - 15

[0070] Under other conditions the same as in Examples 2 and 3, change the types of ketal reagents and carbonyl reagents. The yields of Examples 2, 3, and 7 - 15 are shown in Table 1.

[0071] Table 1 Different conditions and results of Examples 2, 3, and 7 - 15

[0072]

[0073] Examples 16 - 21

[0074] Under other conditions the same as in Examples 5 and 6, change the types of ketal reagents and carbonyl reagents. The yields of Examples 5, 6, and 16 - 21 are shown in Table 1.

[0075] Table 1 Different conditions and results of Examples 5, 6, and 16 - 21

[0076]

[0077] Examples 22 - 23

[0078] Under other conditions the same as in Examples 1, 2, and 3, change the types of halogens selected for X. The yields of Examples 1, 2, 3, and 22 - 23 are shown in Table 1.

[0079] Table 1 Different conditions and results of Examples 1, 2, 3, and 22 - 23

[0080]

[0081] Although embodiments of the present invention have been shown and described, it will be understood by those of ordinary skill in the art that various changes, modifications, substitutions and variations can be made to these embodiments without departing from the principles and spirit of the present invention. It should be noted that for those of ordinary skill in the art of this technology, several improvements and refinements can also be made without departing from the principles of the present invention, and these improvements and refinements are also regarded as the protection scope of the present invention.

Claims

1. A preparation method of a fluralaner intermediate, characterized in that, The synthetic route of this preparation method is as follows: Specifically, it includes the following steps: (1) Compound 1 reacts with a ketal reagent to obtain Compound 2 with a carbonyl protecting group M; (2) Compound 2 reacts with a carbonyl reagent to obtain Compound 3; wherein M is independently and arbitrarily selected from: any one of; X is independently and arbitrarily selected from one of F, Cl, or Br.

2. The preparation method of a fluralaner intermediate according to claim 1, characterized in that, The ketal reagent is any one of ethylene glycol, ethanedithiol, methanol, ethanol, isopropanol, benzyl alcohol, propylene glycol, propanedithiol, and methanethiol.

3. The preparation method of a fluralaner intermediate according to claim 1, characterized in that, The molar ratio of Compound 1 to the ketal reagent is 1:1 to 3.

4. The preparation method of a fluralaner intermediate according to claim 1, characterized in that, The carbonyl reagent is any one of carbon dioxide, Boc anhydride, dimethyl carbonate, diethyl carbonate, and chloroformate.

5. The preparation method of a fluralaner intermediate according to claim 1, characterized in that, The molar ratio of Compound 2 to the carbonyl reagent is 1:1 to 1.

2.

6. The preparation method of a fluralaner intermediate according to claim 1, characterized in that, Compound 1 is prepared from o-halotoluene and an acetyl reagent under the action of a Lewis acid, and its synthetic route is as follows: wherein, X is independently and arbitrarily selected from one of F, Cl, or Br.

7. The preparation method of a fluralaner intermediate according to claim 6, characterized in that, The acetyl reagent is acetic anhydride or acetyl chloride.

8. The preparation method of a flecainide intermediate according to claim 6, characterized in that, The Lewis acid is independently and arbitrarily selected from any one of aluminum chloride, zinc chloride, and magnesium chloride.

9. The preparation method of a fluralaner intermediate according to claim 1, characterized in that, The molar ratio of o-halotoluene, acetyl reagent, and Lewis acid is 1:1 to 2:1 to 1.2.

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