A preparation method of fluopicolide intermediate

Abstract

The present invention belongs to the technical field of organic synthesis, and specifically relates to a method for preparing a fluopicolide intermediate. In the present invention, 1,3,5-trihalobenzene is selected, and a 1-(2,4,6-trihalophenyl)-propyl-2-ketone Lewis acid complex is prepared by Friedel-Crafts reaction; then, 1-(2,4,6-trihalophenyl)-propyl-2-ketone is hydrolyzed under acidic conditions. The reaction steps are few, the process flow is simple, easy to operate, and suitable for industrial production.

Description

Technical Field

[0001] The invention belongs to the technical field of organic synthesis, and particularly relates to a method for preparing a fluopicolide intermediate. Background Art

[0002] Fluopicolide is one of the most valuable products in the succinate dehydrogenase inhibitor (SDHI) class of fungicides. It has a broad fungicidal spectrum and high activity, and is particularly effective against ergot, sclerotinia, leaf spot, powdery mildew, and white rot.

[0003] Fluopicolide is synthesized from O-methyl-N-[1-methyl-2-(2,4,6-trichlorophenyl)-ethyl]-hydroxylamine and difluoropyrazole acid, and its hydroxylamine intermediate is prepared by reacting 1-(2,4,6-trichlorophenyl)-propyl-2-one with methoxyamine and then reducing it to finally prepare 1-(2,4,6-trichlorophenyl)-propyl-2-one and its analogues.

[0004] In the prior art, the method for preparing 1-(2,4,6-trichlorophenyl)-propyl-2-one has the problems of dangerous process, complicated process, high cost of raw and auxiliary materials, and the presence of dangerous goods. Therefore, it is very necessary to develop a process with simple synthesis process, easy operation, safety, and industrialization. Summary of the invention

[0005] In view of the shortcomings of the existing 1-(2,4,6-trichlorophenyl)-propyl-2-one process technology, the present invention proposes a new method for preparing a fluopicolide intermediate, the structural formula of the fluopicolide intermediate is: Wherein X is chlorine or bromine. The preparation method comprises the following steps:

[0006] The raw material 1,3,5-trihalobenzene is subjected to Friedel-Crafts reaction to obtain 1-(2,4,6-trihalophenyl)-propyl-2-keto Lewis acid complex;

[0007] The Lewis acid complex of 1-(2,4,6-trihalophenyl)-propyl-2-one is hydrolyzed by acid to obtain 1-(2,4,6-trihalophenyl)-propyl-2-one.

[0008] Optionally, the method of subjecting the raw material 1,3,5-trihalobenzene to a Friedel-Crafts reaction to obtain a 1-(2,4,6-trihalophenyl)-propyl-2-one Lewis acid complex comprises: reacting the raw material 1,3,5-trihalobenzene with 1-haloacetone under the action of a Lewis acid catalyst to obtain a 1-(2,4,6-trihalophenyl)-propyl-2-one Lewis acid complex.

[0009] Optionally, the 1-haloacetone is one of 1-chloroacetone or 1-bromoacetone.

[0010] Optionally, the catalyst is AlCl 3 , BF 3 , ZnCl 2 SnCl 4 、TiO 2 , polyphosphoric acid or the like.

[0011] Optionally, the molar ratio of the 1,3,5-trihalobenzene to the 1-haloacetone is 1:0.95-3.0.

[0012] Optionally, the molar ratio of the 1,3,5-trihalobenzene to the Lewis acid catalyst is 1:1.0 to 3.0.

[0013] Optionally, the solvent for the Friedel-Crafts reaction is one or more of dichloromethane, 1,2-dichloroethane, petroleum ether, and cyclohexane.

[0014] Optionally, the mass ratio of the 1,3,5-trihalobenzene to the solvent is 1:1-10.

[0015] Optionally, the reaction temperature of the Friedel-Crafts reaction is -5°C to 100°C.

[0016] Optionally, the 1-(2,4,6-trihalophenyl)-propyl-2-one Lewis acid complex is hydrolyzed by acid to 1-(2,4,6-trihalophenyl)-propyl-2-one, the acid is an inorganic acid, and the mass ratio of the inorganic acid to the trihalobenzene is 1.0-5.0:1.0.

[0017] Optionally, the trihalobenzene Friedel-Crafts reaction time is 1 to 10 hours.

[0018] Compared with the prior art, the present invention has the following beneficial effects:

[0019] (1) 1,3,5-trihalobenzene is used as a raw material, and 1-(2,4,6-trihalophenyl)-propyl-2-one is prepared through Friedel-Crafts reaction and hydrolysis reaction. The reaction steps are few, the process flow is simple, the operation is easy, and the process is suitable for industrial production.

[0020] (2) 1,3,5-Trihalobenzene is easy to obtain and inexpensive, thus reducing production costs.

[0021] Based on the following detailed description of specific embodiments of the present invention, those skilled in the art will become more aware of the above and other objects, advantages and features of the present invention. DETAILED DESCRIPTION

[0022] In the description of the present embodiment, it should be understood that the terms "first" and "second" are only used for descriptive purposes and cannot be understood as indicating or implying relative importance or implicitly indicating the number of technical features indicated. Thus, the features defined as "first" and "second" may explicitly or implicitly include at least one of the features, that is, include one or more of the features. In the description of the present invention, the meaning of "multiple" is at least two, such as two, three, etc., unless otherwise clearly and specifically defined. When a feature "includes or contains" one or some of the features it covers, unless otherwise specifically described, this indicates that other features are not excluded and other features may be further included.

[0023] In the description of the present embodiment, the description with reference to the terms "one embodiment", "some embodiments", "illustrative embodiments", "examples", "specific examples", or "some examples" means that the specific features, structures, materials, or characteristics described in conjunction with the embodiment or example are included in at least one embodiment or example of the present invention. In this specification, the schematic representation of the above terms does not necessarily refer to the same embodiment or example. Moreover, the specific features, structures, materials, or characteristics described may be combined in any one or more embodiments or examples in a suitable manner.

[0024] The invention provides a method for preparing 1-(2,4,6-trichlorohalogen)-propyl-2-ketone.

[0025] In some embodiments of the present invention, first, 1,3,5-trichlorobenzene is used as a raw material to prepare 1-(2,4,6-trichlorophenyl)-propyl-2-one Lewis acid complex by Friedel-Crafts reaction. Then, 1-(2,4,6-trichlorophenyl)-propyl-2-one Lewis acid complex is hydrolyzed by acid to obtain 1-(2,4,6-trichlorophenyl)-propyl-2-one.

[0026] In other embodiments of the present invention, first, 1,3,5-tribromobenzene is used as a raw material to obtain 1-(2,4,6-trichlorophenyl)-propyl-2-one Lewis acid complex by Friedel-Crafts reaction. Then, the 1-(2,4,6-trichlorophenyl)-propyl-2-one Lewis acid complex is hydrolyzed by acid to obtain 1-(2,4,6-trichlorophenyl)-propyl-2-one.

[0027] In some other embodiments of the present invention, first, 3,5-dichlorobromobenzene is used as a raw material to obtain 1-(2,4,6-trichlorophenyl)-propyl-2-one Lewis acid complex by Friedel-Crafts reaction. Then, 1-(2,4,6-trichlorophenyl)-propyl-2-one Lewis acid complex is hydrolyzed by acid to obtain 1-(2,4,6-trichlorophenyl)-propyl-2-one.

[0028] In some other embodiments of the present invention, first, 5-chloro-1,3-dibromobenzene is used as a raw material to obtain 1-(2,4,6-trichlorophenyl)-propyl-2-one Lewis acid complex by Friedel-Crafts reaction. Then, the 1-(2,4,6-trichlorophenyl)-propyl-2-one Lewis acid complex is hydrolyzed by acid to obtain 1-(2,4,6-trichlorophenyl)-propyl-2-one.

[0029] In the above embodiment, the reaction process specifically includes two steps of Friedel-Crafts reaction and hydrolysis reaction. 1,3,5-trihalobenzene is used as a raw material by Friedel-Crafts reaction to obtain 1-(2,4,6-trihalophenyl)-propyl-2-ketone Lewis acid complex. Afterwards, the 1-(2,4,6-trihalophenyl)-propyl-2-ketone Lewis acid complex is hydrolyzed to obtain 1-(2,4,6-trihalophenyl)-propyl-2-ketone. It should be noted that the trihalophenyl in the above embodiment is trichlorophenyl or tribromophenyl.

[0030] In the above embodiment, 1,3,5-trihalobenzene is used as a raw material, and 1-(2,4,6-trihalophenyl)-propyl-2-ketone is prepared through Friedel-Crafts reaction and hydrolysis reaction, with fewer reaction steps, simple process flow, easy operation, and suitable for industrial production. At the same time, 1,3,5-trihalobenzene is easy to obtain and the price is not high, which reduces the production cost.

[0031] In some embodiments of the present invention, the above-mentioned method of preparing 1-(2,4,6-trihalogenophenyl)-propyl-2-keto Lewis acid complex by Friedel-Crafts reaction of the raw material 1,3,5-trihalogenophenyl includes: reacting the raw material 1,3,5-trihalogenobenzene with 1-chloroacetone under the action of a Lewis acid catalyst to obtain 1-(2,4,6-trichlorophenyl)-propyl-2-keto Lewis acid complex.

[0032] In other embodiments of the present invention, the above-mentioned method of preparing 1-(2,4,6-trihalophenyl)-propyl-2-keto Lewis acid complex by Friedel-Crafts reaction of the raw material 1,3,5-trihalobenzene includes: reacting the raw material 1,3,5-trihalobenzene with 1-bromoacetone under the action of a Lewis acid catalyst to obtain 1-(2,4,6-tribromophenyl)-propyl-2-keto Lewis acid complex.

[0033] In some embodiments of the present invention, the 1,3,5-trihalobenzene and 1-haloacetone catalyst is AlCl 3 Of course, in other embodiments of the present invention, the catalyst may also be BF 3 , ZnCl 2 SnCl 4 、TiO 2 Or one or more of polyphosphoric acid. Preferably, AlCl 3 , BF3 , ZnCl 2 As a catalyst.

[0034] In some embodiments of the present invention, the molar ratio of 1,3,5-trihalobenzene to 1-haloacetone is 1:0.95-3.0. That is to say, the molar amount of 1-haloacetone weighed in the reaction is 0.95-3.0 times that of 1,3,5-trihalobenzene. Specifically, it can be any value between 0.95 and 3.0, such as 0.95, 1.05, 1.4, 2.3, etc. Preferably, the molar ratio of 1,3,5-trihalobenzene to 1-haloacetone is 1:1.15, at which time the reaction is sufficient and does not cause waste of materials.

[0035] In some embodiments of the present invention, the molar ratio of 1,3,5-trihalobenzene to the Lewis acid catalyst is 1:1.0 to 3.0. That is to say, the molar amount of Lewis acid weighed in the reaction is 1.0 to 3.0 times that of 1,3,5-trihalobenzene. Specifically, it can be any value between 1.0 and 3.0, such as 1.05, 1.2, 1.4, 1.8, 2.5, etc. More preferably, the molar ratio of 1,3,5-trihalobenzene to the Lewis acid catalyst is 1:1.5.

[0036] In some embodiments of the present invention, the solvent used in the Friedel-Crafts reaction is dichloromethane. In this embodiment, dichloromethane is selected as the solvent for the Friedel-Crafts reaction because it has the advantages of low toxicity, high solubility and low cost.

[0037] Of course, in other embodiments of the present invention, the solvent used in the Friedel-Crafts reaction may also be one or more of 1,2-dichloroethane, petroleum ether, and cyclohexane.

[0038] In some embodiments of the present invention, the mass ratio of 1,3,5-trihalobenzene to the solvent is 1:1 to 10. That is, the mass of the solvent weighed in the reaction is 1.0 to 10.0 times that of 1,3,5-trihalobenzene. Specifically, it can be any value between 1.0 and 10.0, such as 1.05, 1.2, 1.4, 1.8, 2.5, 3.0, 5.4, 6.2, etc. More preferably, the mass ratio of 1,3,5-trihalobenzene to the solvent is 1:5.

[0039] In some embodiments of the present invention, the reaction temperature of the Friedel-Crafts reaction is -5°C to 100°C. In this embodiment, the setting of the Friedel-Crafts reaction temperature is conducive to the formation of the complex. Preferably, the Friedel-Crafts reaction temperature can be -5°C to 10°C.

[0040] In some embodiments of the present invention, the above-mentioned 1-(2,4,6-trihalophenyl)-propyl-2-one Lewis acid complex is hydrolyzed into 1-(2,4,6-trihalophenyl)-propyl-2-one by acid hydrolysis, and the acid is an inorganic acid. In this embodiment, the complex hydrolysis is carried out under inorganic acid conditions, which can increase the reaction rate, promote the hydrolysis reaction, and has a higher degree of safety.

[0041] In a further embodiment of the present invention, the mass ratio of the inorganic acid to the trihalobenzene is 1.0-5.0:1.0. That is, the mass of the inorganic acid is 1.0-5.0 times that of the trihalobenzene, and the specific multiple can be a value between 1.0 and 5.0, such as 1.0, 1.2, 1.5, 1.8, 2.0, 2.5, 3.0, 4.5, 5.0, etc. Preferably, the mass ratio of the inorganic acid to the trihalobenzene is 2.0:1.0.

[0042] In some embodiments of the present invention, the time for the Friedel-Crafts reaction of trihalobenzene is 1 to 10 hours. Preferably, the time for the Friedel-Crafts reaction is 2 hours.

[0043] The present invention is specifically explained below using several embodiments, and the technical solutions in the embodiments of the present invention are clearly and completely described. The described embodiments are only a part of the embodiments of the present invention, rather than all the embodiments.

[0044] Example 1

[0045] The preparation method of 1-(2,4,6-trichlorophenyl)-propyl-2-ketone comprises the following steps:

[0046] Step S11, weigh 18.1 g of 1,3,5-trichlorobenzene, 14.4 g of AlCl 3 And measure 200mlCH 2 Cl 2 , add to the container, add 10g of 1-chloroacetone at 0-5℃, and finish the dripping within 1 hour. After the dripping is completed, keep the temperature at 0-5℃ for 1 hour to obtain 1-(2,4,6-trichlorophenyl)-propyl-2-one Lewis acid complex.

[0047] Step S12, dropwise add 10 ml of 10% hydrochloric acid aqueous solution into the above container, after the dropwise addition is completed, heat and stir at 20° C. for 1 hour, separate the layers and remove the lower organic layer.

[0048] Step S13, remove the lower organic layer and wash with water until neutral, add anhydrous sodium sulfate to dry, filter out the anhydrous sodium sulfate after drying, desolventize and evaporate CH 2 Cl 2 Then, 120 ml of a methanol / water solution with a volume ratio of 1:1 was added and recrystallized. After suction filtration, 21.5 g of white needle crystals were obtained with a yield of 91.5% and a purity of 99.3%.

[0049] The specific synthesis formula is as follows:

[0050]

[0051] Example 2

[0052] Preparation method of 1-(2,4,6-trichlorophenyl)-propyl-2-ketone

[0053] Step S21, weigh 18.1 g of 1,3,5-trichlorobenzene, 15 g of ZnCl 2 And measure 200mlCH 2 Cl 2 , add to the container, add 14.6g of 1-bromoacetone dropwise at 0-5°C, and complete the dropwise addition within 1 hour. After the dropwise addition is completed, keep the temperature at 0-5°C for 2 hours to obtain 1-(2,4,6-trichlorophenyl)-propyl-2-one Lewis acid complex.

[0054] Step S22, dropwise add 10 ml of 10% hydrochloric acid aqueous solution into the above container, after the dropwise addition is completed, heat-insulate and stir at 20° C. for 1 hour, and remove the lower organic layer after stratification.

[0055] Step S23, remove the lower organic layer, add 150 ml of dichloroethane three times for extraction, then wash with water until neutral and add 20 g of anhydrous sodium sulfate to dry, filter out the anhydrous sodium sulfate after drying, and remove the dichloroethane under reduced pressure. Add 120 ml of methanol / water solution with a volume ratio of 1:1 to the residue and recrystallize, and obtain 18.5 g of white needle crystals after suction filtration, with a yield of 78% and a purity of 99.7%.

[0056] The specific synthesis formula is as follows:

[0057]

[0058] Example 3

[0059] Preparation method of 1-(2,4,6-tribromophenyl)-propyl-2-ketone

[0060] Step S31, weigh 31.0 g of 1,3,5-tribromobenzene, 20% BF 3 , ether aqueous solution, 200mlCH 2 Cl 2 The solution was added to a container, and 10 g of 1-chloroacetone was added dropwise at 0-5°C for 1 hour. After the addition was completed, the temperature was kept at 0-5°C for 2 hours to obtain 1-(2,4,6-tribromophenyl)-propyl-2-one Lewis acid complex.

[0061] Step S32, dropwise add 10 ml of 10% hydrochloric acid aqueous solution into the above container, and after the dropwise addition is completed, heat and stir at 25°C for 2 hours to separate into layers, wherein the upper layer is the water layer and the lower layer is the organic layer.

[0062] Step S33, the upper aqueous layer was extracted by adding 150 ml of dichloromethane three times, the organic layers were combined, and dried with 30 g of anhydrous sodium sulfate. After drying, the sodium sulfate was filtered off, and CH 2 Cl 2 The mother liquor was decompressed and desolventized, and the residue after distillation was added with 150 ml of a methanol / water solution with a volume ratio of 1:1, heated to dissolve, cooled to crystallize, and filtered to obtain 26.1 g of white crystals with a yield of 70.5% and a purity of 99.5%.

[0063] The specific synthesis formula is as follows:

[0064]

[0065] It should be noted that the white crystals obtained in Examples 1 to 3 were characterized by nuclear magnetic resonance. The 1-(2,4,6-trichlorophenyl)-propyl-2-one obtained in Example 1 had a hydrogen nuclear magnetic resonance spectrum: (400mHZ, chloroforum-d) 87.36 (S.2H), 4.07 (S.2H), 2.28 (S.3H). The 1-(2,4,6-trichlorophenyl)-propyl-2-one obtained in Example 2 had a hydrogen nuclear magnetic resonance spectrum: (400mHZ, chloroforum-d) 87.36 (S.2H), 4.07 (S.2H), 2.28 (S.3H). The 1-(2,4,6-tribromophenyl)-propyl-2-one obtained in Example 3 had a hydrogen nuclear magnetic resonance spectrum: (400 mHZ, chloroform-d) 87.32 (S.2H), 4.01 (S.2H), 2.24 (S.3H).

[0066] At this point, those skilled in the art should recognize that, although multiple exemplary embodiments of the present invention have been shown and described in detail herein, many other variations or modifications that conform to the principles of the present invention can still be directly determined or derived based on the content disclosed in the present invention without departing from the spirit and scope of the present invention. Therefore, the scope of the present invention should be understood and recognized as covering all these other variations or modifications.

Claims

1. A method for preparing a fluopicolide intermediate, wherein the structural formula of the fluopicolide intermediate is: Wherein X is chlorine or bromine; characterized in that, The preparation method comprises the following steps: The raw material 1,3,5-trihalobenzene is subjected to Friedel-Crafts reaction to obtain 1-(2,4,6-trihalophenyl)-propyl-2-keto Lewis acid complex; The Lewis acid complex of 1-(2,4,6-trihalophenyl)-propyl-2-one is hydrolyzed by acid to obtain 1-(2,4,6-trihalophenyl)-propyl-2-one.

2. The preparation method according to claim 1, characterized in that: The method of preparing 1-(2,4,6-trihalophenyl)-propyl-2-keto Lewis acid complex by Friedel-Crafts reaction of raw material 1,3,5-trihalobenzene comprises: reacting raw material 1,3,5-trihalobenzene with 1-haloacetone under the action of Lewis acid catalyst to obtain 1-(2,4,6-trihalophenyl)-propyl-2-keto Lewis acid complex.

3. The preparation method according to claim 2, characterized in that: The 1-haloacetone is one of 1-chloroacetone and 1-bromoacetone.

4. The preparation method according to claim 2, characterized in that: The catalyst is one or more of AlCl3, BF3, ZnCl2, SnCl4, TiO2, and polyphosphoric acid, and more preferably AlCl3, BF3, and ZnCl2.

5. The preparation method according to claim 2, characterized in that: The molar ratio of the 1,3,5-trihalobenzene to the 1-haloacetone is 1:0.95-3.

0.

6. The preparation method according to claim 2, characterized in that: The molar ratio of the 1,3,5-trihalobenzene to the Lewis acid catalyst is 1:1.0 to 3.

0.

7. The preparation method according to claim 1, characterized in that: The solvent for the Friedel-Crafts reaction is one or more of dichloromethane, 1,2-dichloroethane, petroleum ether, and cyclohexane.

8. The preparation method according to claim 7, characterized in that: The mass ratio of the 1,3,5-trihalobenzene to the solvent is 1:1-10.

9. The preparation method according to claim 1, characterized in that: The reaction temperature of the Friedel-Crafts reaction is -5°C to 100°C.

10. The preparation method according to claim 1, characterized in that: The 1-(2,4,6-trihalophenyl)-propyl-2-one Lewis acid complex is hydrolyzed into 1-(2,4,6-trihalophenyl)-propyl-2-one through acid hydrolysis. The acid is an inorganic acid, and the mass ratio of the inorganic acid to the trihalobenzene is 1.0-5.0:1.0.

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