Process for the preparation of a 4-trifluoromethylpyridine intermediate core nucleus and derivatives thereof

Abstract

The application discloses a preparation method of a 4-trifluoromethyl pyridine intermediate core mother nucleus and a derivative thereof, which comprises the following steps: S1: condensation reaction is carried out by taking malononitrile and 4-ethoxy-1,1,1-trifluoro-3-buten-2-one as raw materials, dissolving in an organic solvent and catalyzing by an organic amine or an ammonium salt thereof, so as to obtain a condensate; S2: ring closing reaction is carried out on the condensate under a strong acid system, so as to obtain a ring closing product; and S3: chlorination reaction is carried out on the ring closing product under the action of a chlorination reagent and a chlorination catalyst, so as to prepare the 4-trifluoromethyl pyridine intermediate core mother nucleus (compound I). The starting raw material adopted in the application is cheap and easy to obtain, the reaction condition is mild, the operation is simple, the route is short, and the total amount of three wastes is greatly reduced.

Description

Technical Field

[0001] This application relates to the field of chemical synthesis, and in particular to a method for preparing a 4-trifluoromethylpyridine intermediate core and its derivatives. Background Technology

[0002] The research and applications of 4-trifluoromethylpyridine compounds in pharmaceuticals, pesticides, and new materials are becoming increasingly widespread. For example, 1. Flupyradifurone is a novel neonicotinoid insecticide developed by Ishihara Sangyo Co., Ltd. of Japan. Due to its unique mechanism of action and extremely high biological activity, it is particularly effective against piercing-sucking pests, has low toxicity and high safety, and is effective against pests resistant to other insecticides. The Chinese patent for flupyradifurone, CN1081670, expired on July 22, 2013.

[0003] The 4-trifluoromethylpyridine intermediate related to flonicamid, 4-trifluoromethylnicotinic acid, is mainly prepared via two routes:

[0004] Route 1.

[0005]

[0006] Route 2.

[0007]

[0008] Route 1 has better atom economy, but it uses relatively expensive materials such as methyl 3-methoxyacrylate and flammable and expensive NaH, resulting in higher costs. Route 2 is a longer route with poorer atom economy and higher costs.

[0009] 2. Pyroxsulam, also known as metoxysulfuron, is a triazolopyrimidine amine systemic and selective post-emergence herbicide developed by Corteva. It can effectively control difficult-to-control weeds at extremely low concentrations and has a broad spectrum of weed control. Statistics show that global sales of pyroxsulam reached US$130 million in 2019, indicating a promising market prospect. The Chinese patent for pyroxsulam, CN1398266, expired on July 2, 2022.

[0010] The main preparation route for the 4-trifluoromethylpyridine intermediate related to pyrazosulfanilamide, 2-methoxy-4-trifluoromethylpyridine-3-sulfonyl chloride, is as follows:

[0011] A) First, prepare 2-methoxy-4-trifluoromethylpyridine, then prepare 2-methoxy-4-trifluoromethylpyridine-3-sulfonyl chloride.

[0012] Preparation of 2-methoxy-4-trifluoromethylpyridine:

[0013] Option 1.

[0014]

[0015] Option 2.

[0016]

[0017] Preparation of 2-methoxy-4-trifluoromethylpyridine-3-sulfonyl chloride:

[0018] Option 1.

[0019]

[0020] Option 2.

[0021]

[0022] B) Corteva proposed a completely new route in CN113227052A:

[0023]

[0024] Method A) has a long route for the preparation of 2-methoxy-4-trifluoromethylpyridine, and phosphorus-containing raw materials are not easy to obtain. Method B uses highly toxic fuming liquid chloroacetonitrile. Both methods for preparing 2-methoxy-4-trifluoromethylpyridine-3-sulfonyl chloride require expensive organic lithium and ultra-low temperature reaction. The final step of aqueous phase chlorination also poses a great environmental risk.

[0025] Method B) also uses highly toxic fuming liquid chloroacetonitrile and malodorous liquid propanethiol. The final step is also chlorination with chlorine gas in the aqueous phase, which places high demands on the factory's safe production and environmental protection.

[0026] 3. Flupyroxystrobin is the first methoxyacrylate insecticide (non-acaricide), developed by Syngenta. Flupyroxystrobin was initially discovered as a fungicide, demonstrating excellent control of barley powdery mildew, apple scab, downy mildew in vines, and late blight in tomatoes. As an insecticide (mosquito repellent), Flupyroxystrobin exhibits no cross-resistance with pyrethroid insecticides such as permethrin. The Chinese compound patent for Flupyroxystrobin, CN87103623, expired on April 16, 2007, and it received its ISO generic name as an insecticide in 2022.

[0027] The main preparation routes for the Flupyroxystrobin-related 4-trifluoromethylpyridine intermediate, 2-chloro-4-trifluoromethylpyridine, are as follows:

[0028] Option 1.

[0029] Bioorganic and Medicinal Chemistry Letters, 2001, vol.11, #4, p.475-477;

[0030]

[0031] Scheme 1, Reagents and conditions: (a) Mg, THF, 50℃, 3h, g2%; (b) O3, CH2Cl2 / MeOH, -78℃, 24h, 90%; (c) NH3 / MeOH, reflux, 24h, 70%; (d) MCPBA, CH2Cl2, rt, 10h, 73%; (e) SOCl2, reflux, 3h, 42%;

[0032] Option 2. Corteva Agriculture's patent CN113272277A provides the following method:

[0033]

[0034] In Scheme 1, step a uses the highly toxic bromide-based Glycol coupling reaction, step b requires the use of rare ozone in an ultra-low temperature environment, step d uses the peroxide MCPBA, and step e has a low reaction yield.

[0035] In Option 2, the first step of the reaction requires the use of a large amount of expensive n-butyllithium for coupling in an ultra-low temperature reaction, which results in harsh reaction conditions and high costs.

[0036] Other literature preparation routes for related intermediates:

[0037] 1. Core parent nucleus (Compound I)

[0038]

[0039] The routes reported by patents CN101128470 and CN114667167 are as follows:

[0040]

[0041] The starting materials are too expensive. In addition, the total yields of the two steps reported in the two patents are 36.5% and 18% respectively, which are too low to be suitable for commercial production.

[0042] The route reported in patent CN105753778 is as follows:

[0043]

[0044] The reaction conditions are relatively mild, but the final hydrogenation step produces a lot of impurities, which can easily generate impurities that remove chlorine at the 2-position and retain chlorine at the 6-position, as well as impurities where chlorine at both the 2 and 6-positions is removed. The post-processing purification is complicated and increases the difficulty of production.

[0045] 2. Compound II

[0046]

[0047] The following methods were used in the literature European Journal of Organic Chemistry, 2003, #8, pp. 1559-1568 and Tetrahedron, 2004, vol. 60, #51, pp. 11869-11874:

[0048]

[0049] The process involves carbonylation of lithium salts with carbon dioxide at -75°C. However, considering the current literature methods for preparing the raw material 2-chloro-4-trifluoromethylpyridine, the entire process requires two ultra-low temperature reactions, making it unsuitable for commercial production.

[0050] The preparation routes for compounds III, IV, and V mentioned in this application have not been reported in the literature. Summary of the Invention

[0051] To address the aforementioned issues, this application provides a method for preparing a 4-trifluoromethylpyridine intermediate core and its derivatives. The method uses readily available and inexpensive commercial products as starting materials and prepares the intermediate core (compound I) through condensation, cyclization, and chlorination. Simultaneously, it can derive a series of methods for preparing 4-trifluoromethylpyridine intermediate derivatives.

[0052] In a first aspect, this application provides a method for preparing a 4-trifluoromethylpyridine intermediate core, employing the following technical solution:

[0053] A method for preparing a 4-trifluoromethylpyridine intermediate core includes the following steps:

[0054] S1: Using malononitrile and 4-ethoxy-1,1,1-trifluoro-3-buten-2-one as raw materials, a condensation reaction is carried out in an organic solvent and catalyzed by an organic amine or its ammonium salt to obtain a condensate.

[0055]

[0056] S2: The condensate undergoes a cyclization reaction in a strong acid system to yield a cyclized compound;

[0057]

[0058] S3: The cyclized compound undergoes a chlorination reaction under the action of a chlorinating reagent and a chlorination catalyst to obtain the core of the 4-trifluoromethylpyridine intermediate (compound I);

[0059]

[0060] This application describes a method for preparing the core of the 4-trifluoromethylpyridine intermediate (compound I) through condensation, cyclization, and chlorination. The starting materials used are inexpensive and readily available, the reaction conditions are mild, the operation is simple, the route is short, and the total amount of waste is significantly reduced. This method solves a series of problems in the existing technology for preparing the 4-trifluoromethylpyridine intermediate, such as long process routes, difficult or expensive raw materials, harsh reaction conditions, and low yield.

[0061] In step S1, the condensation reaction uses a benzene-based organic solvent that is immiscible with water and easily recyclable, preferably toluene. The organic amine or its ammonium salt is selected from one or more of cyclohexylamine, piperidine, ammonium formate, ammonium acetate, cyclohexylamine acetate, and piperidine acetate, preferably ammonium formate, ammonium acetate, cyclohexylamine acetate, or piperidine acetate, more preferably cyclohexylamine acetate or piperidine acetate. The condensation reaction is carried out at room temperature. After the S1 reaction, before solvent removal, an appropriate amount of polymerization inhibitor is added to prevent self-polymerization of the double bonds on the carbon chain of the condensate. The molar ratio of malononitrile: 4-ethoxy-1,1,1-trifluoro-3-buten-2-one: catalyst: polymerization inhibitor is 1.0:(1.0~1.2):0.05:0.01. In the S2 cyclization reaction, the strong acid system is concentrated sulfuric acid or a mixture of concentrated sulfuric acid and glacial acetic acid. In the S3 chlorination reaction, the chlorinating agent is any one of thionyl chloride, sulfonyl chloride, phosphoryl chloride, oxalyl chloride, and phosphorus oxychloride, preferably thionyl chloride or phosphorus oxychloride; the chlorination catalyst is phosphorus pentachloride or a tertiary amine and its salt; the molar ratio of cyclizer:chlorinating agent:chlorination catalyst is 1:(1-5):(0.02-0.4).

[0062] Secondly, this application provides a method for preparing 4-trifluoromethylpyridine intermediate derivative A, which adopts the following technical solution:

[0063] A method for preparing a 4-trifluoromethylpyridine intermediate derivative A includes the following steps:

[0064] S1 to S3 are carried out according to the above-mentioned preparation method of the core nucleus to obtain the 4-trifluoromethylpyridine intermediate core nucleus (compound I); S4: Compound I is hydrolyzed in an acidic system and quenched in ice water to precipitate compound II;

[0065] S5: Compound II was prepared in an alcohol system and by Pd / C catalytic hydrogenation to produce derivative A, wherein derivative A is 4-trifluoromethylnicotinic acid;

[0066] The reaction pathway is as follows:

[0067]

[0068] In some specific implementations, in step S4, a hydrolysis reaction is carried out in an acidic system to obtain a carboxylic acid at position 3, which is then quenched in ice water and compound II is precipitated.

[0069] Thirdly, this application provides a method for preparing 4-trifluoromethylpyridine intermediate derivative B, using the following technical solution:

[0070] A method for preparing a 4-trifluoromethylpyridine intermediate derivative B includes the following steps:

[0071] First, the preparation method of the core nucleus described above is followed to obtain the 4-trifluoromethylpyridine intermediate core nucleus (compound I); then, using compound I as a raw material, derivative B is prepared by etherification, hydrolysis, Hoffmann degradation, and diazotization. The derivative B is 2-methoxy-4-trifluoromethylpyridine-3-sulfonyl chloride.

[0072] The reaction process follows this route:

[0073]

[0074] In some specific implementations, the hydrolysis reaction of compound III to prepare compound IV is carried out in an acidic system, preferably 98% concentrated sulfuric acid or fuming sulfuric acid.

[0075] In some specific embodiments, compound V is diazotized to prepare 2-methoxy-4-trifluoromethylpyridine-3-sulfonyl chloride. Compound V is reacted with an acid and sodium nitrite at 0°C to prepare a diazonium salt; the acid is preferably concentrated hydrochloric acid. Thionyl chloride is added dropwise to water at 0°C or sulfur dioxide is introduced, preferably thionyl chloride, and cuprous chloride is added. The prepared diazonium salt is then rapidly added dropwise to the system at 0°C under controlled temperature, and the reaction continues until the starting material disappears. A preferred molar ratio of compound V: hydrochloric acid: sodium nitrite: thionyl chloride: cuprous chloride is 1:(3.5–4):(1.0–1.5):(4–4.5):(0.01–0.02).

[0076] Fourthly, this application provides a method for preparing 4-trifluoromethylpyridine intermediate derivative C, using the following technical solution:

[0077] A method for preparing a 4-trifluoromethylpyridine intermediate derivative C includes the following steps:

[0078] First, the preparation method described above is followed to obtain the 4-trifluoromethylpyridine intermediate core (compound I); then, using compound I as a starting material, derivative C is prepared via a decarboxylation reaction. Derivative C is 2-chloro-4-trifluoromethylpyridine. The reaction route is as follows:

[0079]

[0080] In some specific implementations, the decarboxylation reaction is carried out by heating and refluxing in sulfuric acid until no gas is released, the product is washed with liquid alkali until neutral, and 2-chloro-4-trifluoromethylpyridine is prepared by extraction and solvent removal with dichloromethane.

[0081] In summary, this application has at least the following beneficial effects:

[0082] 1. The raw materials used in this application are all commercial products, which are cheap and readily available, and have a significant cost advantage;

[0083] 2. The process route of this application is short, with a high yield and a significant reduction in the total amount of waste.

[0084] 3. The preparation method of this application has generally mild reaction conditions, which reduces the risk to production safety;

[0085] 4. This application provides a method for preparing a core core of a 4-trifluoromethylpyridine intermediate, and uses the synthesized core core as raw material to continue preparing a series of derivatives, thus developing a method for preparing 4-trifluoromethylpyridine intermediates and their derivatives, which is suitable for factories to produce different products according to the peak and off-peak seasons of downstream product sales. Detailed Implementation

[0086] To make the inventive objectives, technical solutions, and beneficial technical effects of this application clearer, this application will be described in detail below. It should be noted that the various aspects, features, embodiments, and advantages described in this application can be compatible and / or combined together.

[0087] The main raw material of this application is 4-ethoxy-1,1,1-trifluoro-3-buten-2-one, which is prepared by the following reaction route:

[0088]

[0089] The above reaction routes have been reported in numerous publications and will not be listed here. In the above conventional reaction routes, the main raw materials are trifluoroacetic anhydride and vinyl ethyl ether, both of which are commercially produced products with wide availability and readily available sources. Unless otherwise specified, the technical terms in this specification have the same meaning as commonly understood by those skilled in the art.

[0090] This application relates to a method for preparing a 4-trifluoromethylpyridine intermediate core and its derivatives.

[0091] The following is a detailed description of this application.

[0092] In a first aspect, this application provides a method for preparing a 4-trifluoromethylpyridine intermediate core, employing the following technical solution:

[0093] A method for preparing a 4-trifluoromethylpyridine intermediate core includes the following steps:

[0094] S1: Using malononitrile and 4-ethoxy-1,1,1-trifluoro-3-buten-2-one as raw materials, the mixture is dissolved in an organic solvent and then undergoes a condensation reaction catalyzed by an organic amine or its ammonium salt to obtain a condensate.

[0095] S2: The condensate undergoes a cyclization reaction under the action of a strong acid to obtain a cyclized compound;

[0096] S3: The cyclized compound undergoes a chlorination reaction under the action of a chlorinating reagent and a chlorination catalyst to obtain the core of the 4-trifluoromethylpyridine intermediate (compound I).

[0097] The reaction route for the 4-trifluoromethylpyridine intermediate core (compound I) of this application is as follows:

[0098] S1. Condensation reaction:

[0099]

[0100] S2. Cyclic reaction:

[0101]

[0102] S3. Chlorination reaction:

[0103]

[0104] In some specific embodiments, in step S1, the organic amine or its ammonium salt catalyst is cyclohexylamine, piperidine, ammonium formate, ammonium acetate, cyclohexylamine acetate or piperidine acetate, preferably ammonium formate, ammonium acetate, cyclohexylamine acetate or piperidine acetate, more preferably cyclohexylamine acetate or piperidine acetate.

[0105] In some specific embodiments, in step S1, the condensation reaction temperature is preferably carried out at 20–30°C.

[0106] In some specific embodiments, in step S1, the organic solvent is selected from benzene-based solvents that are immiscible with water and easily recyclable, with toluene being preferred.

[0107] In some specific embodiments, in step S1, after the condensation reaction is completed, an inhibitor is added before the organic solvent is desolvated to prevent the double bond portion on the carbon chain of the condensate from undergoing self-polymerization; for this purpose, in step S1, the molar ratio of raw material malononitrile: 4-ethoxy-1,1,1-trifluoro-3-buten-2-one: catalyst: inhibitor is 1:(1~1.2):0.05:0.01.

[0108] In some specific embodiments, the polymerization inhibitor is selected from any one or a combination of hydroquinone, p-benzoquinone, methylhydroquinone, 2-tert-butylhydroquinone, 2,5-di-tert-butylhydroquinone, and 2,6-di-tert-butyl-p-cresol.

[0109] In some specific embodiments, in step S2, the strong acid is concentrated sulfuric acid, or a mixture of concentrated sulfuric acid and glacial acetic acid; preferably, a mixture of concentrated sulfuric acid and glacial acetic acid.

[0110] In some specific embodiments, in step S3, the chlorinating agent is thionyl chloride, sulfonyl chloride, phosphoryl chloride, oxalyl chloride, phosphorus oxychloride, preferably thionyl chloride or phosphorus oxychloride.

[0111] In some specific embodiments, in step S3, the chlorination catalyst is phosphorus pentachloride or a tertiary amine and its salt.

[0112] In some specific embodiments, in step S3, the molar ratio of the cyclizer: chlorinating agent: chlorinating catalyst is 1:(1-5):(0.02-0.4).

[0113] Secondly, this application provides a method for preparing 4-trifluoromethylpyridine intermediate derivative A, which adopts the following technical solution:

[0114] A method for preparing a 4-trifluoromethylpyridine intermediate derivative A includes the following steps:

[0115] S1 to S3 are carried out according to the above-mentioned preparation method of the core nucleus to obtain the 4-trifluoromethylpyridine intermediate core nucleus (compound I); S4: Compound I is hydrolyzed in an acidic system and quenched in ice water to precipitate compound II;

[0116] S5: Compound II is prepared in an alcohol system and by Pd / C catalytic hydrogenation to prepare derivative A, wherein derivative A is 4-trifluoromethylnicotinic acid.

[0117] A method for preparing a 4-trifluoromethylpyridine intermediate derivative A, the reaction route of which is as follows:

[0118] In some specific implementations, in step S4, a hydrolysis reaction is carried out in an acidic system to obtain a carboxylic acid at position 3, which is then quenched in ice water and compound II is precipitated.

[0119] Thirdly, this application provides a method for preparing 4-trifluoromethylpyridine intermediate derivative B, using the following technical solution:

[0120] A method for preparing a 4-trifluoromethylpyridine intermediate derivative B includes the following steps:

[0121] First, the core nucleus was prepared according to the above-mentioned method to obtain the 4-trifluoromethylpyridine intermediate core nucleus (compound I); then, using compound I as raw material, derivative B was prepared by etherification, hydrolysis, Hoffmann degradation, and diazotization. The derivative B is 2-methoxy-4-trifluoromethylpyridine-3-sulfonyl chloride.

[0122] A method for preparing a 4-trifluoromethylpyridine intermediate derivative B, the reaction route of which is as follows:

[0123]

[0124] In some specific implementations, the hydrolysis reaction of compound III to prepare compound IV is carried out in an acidic system, preferably 98% concentrated sulfuric acid or fuming sulfuric acid.

[0125] In some specific embodiments, compound V is diazotized to prepare 2-methoxy-4-trifluoromethylpyridine-3-sulfonyl chloride. Compound V is reacted with an acid and sodium nitrite at 0°C to prepare a diazonium salt; the acid is preferably concentrated hydrochloric acid. Thionyl chloride is added dropwise to water at 0°C or sulfur dioxide is introduced, preferably thionyl chloride, and cuprous chloride is added. The prepared diazonium salt is then rapidly added dropwise to the system at 0°C under controlled temperature, and the reaction continues until the starting material disappears. A preferred molar ratio of compound V: hydrochloric acid: sodium nitrite: thionyl chloride: cuprous chloride is 1:(3.5–4):(1.0–1.5):(4–4.5):(0.01–0.02).

[0126] Fourthly, this application provides a method for preparing 4-trifluoromethylpyridine intermediate derivative C, using the following technical solution:

[0127] A method for preparing a 4-trifluoromethylpyridine intermediate derivative C includes the following steps:

[0128] First, the preparation method of the core nucleus described above is followed to obtain the 4-trifluoromethylpyridine intermediate core nucleus (compound I); then, derivative C is prepared by decarboxylation reaction using compound I as raw material, wherein derivative C is 2-chloro-4-trifluoromethylpyridine.

[0129] In some specific implementations, the decarboxylation reaction is carried out by heating and refluxing in sulfuric acid until no gas is released, the product is washed with liquid alkali until neutral, and 2-chloro-4-trifluoromethylpyridine is prepared by extraction and solvent removal with dichloromethane.

[0130] Example

[0131] To make the objectives, technical solutions, and advantages of this invention clearer, the invention will be further described in detail below with reference to embodiments. It should be understood that the specific embodiments described herein are merely illustrative and not intended to limit the invention.

[0132] Example 1:

[0133] A method for preparing a 4-trifluoromethylpyridine intermediate core (compound I) includes the following steps:

[0134] S1. Condensation reaction:

[0135]

[0136] 200 mL of toluene, 84 g (0.5 mol) of 4-ethoxy-1,1,1-trifluoro-3-buten-2-one, and 33.0 g (0.5 mol) of malononitrile were added to a reaction flask. The mixture was stirred at room temperature, and 7.3 g of 0.05 mol piperidine acetate was added in portions over 30 minutes. The reaction was continued for 24 hours at room temperature with stirring. The reaction was monitored until the spot of the starting material 4-ethoxy-1,1,1-trifluoro-3-buten-2-one disappeared. 150 mL of water was added to the flask to wash away the piperidine acetate, and the mixture was allowed to stand to separate into layers. The organic phase was collected, and 0.005 mol of hydroquinone was added and stirred until homogeneous. The organic phase was concentrated under reduced pressure, and toluene was recovered to give 96 g of the condensate, with a molar yield of 88.8%. LC / MS: [M+H]+=217.

[0137] S2. Cyclic reaction:

[0138]

[0139] 143.7 g (1.465 mol) of concentrated sulfuric acid and 29.4 g (0.488 mol) of glacial acetic acid were added to a reaction flask and stirred. 96 g of the S1 step condensate was slowly added to the system while maintaining the temperature at room temperature. The temperature was then raised to 60 °C and reacted at this temperature for 4 hours. After the reaction was complete, the temperature was lowered to room temperature, and 150 ml of ice water was added. The mixture was stirred vigorously, and a large amount of off-white solid precipitated. The solid was filtered, dried, and recrystallized from a 2:1 methanol-water solution to obtain 66.5 g of the cyclic compound, with a molar yield of 79.6% and LC / MS [M+H]+ = 189.

[0140] S3. Chlorination reaction:

[0141]

[0142] 162.6 g (1.06 mol) of phosphorus oxychloride and 22.1 g (0.106 mol) of chlorination catalyst (phosphorus pentachloride) were added to the reaction flask and stirred. Then, 66.5 g of the cyclized compound prepared in the previous step was added, and the mixture was heated to reflux (approximately 115 °C) and reacted at this temperature for 5 hours. Excess phosphorus oxychloride (to be reused) was distilled off under reduced pressure. 150 mL of dichloromethane was added under ice bath conditions, followed by the addition of 200 mL of water. The mixture was allowed to stand and separate. The aqueous phase was washed with dichloromethane and allowed to stand and separate. The organic phases were combined and dried with sodium sulfate. After drying, a transparent oily substance, i.e., chloride, was obtained in 61.6 g, with a molar yield of 84.4%. LC / MS: [M+H]+=208, 1H NMR (400 MHz, CDCl3): δ 7.6 (d, 1H), 8.7 (d, 1H).

[0143] Example 2:

[0144] A method for preparing a 4-trifluoromethylpyridine intermediate core (compound I) differs from Example 1 in that only the S1 condensation reaction is studied, and the 0.05 mol piperidine acetate in the S1 step is replaced with 0.05 mol cyclohexylamine acetate.

[0145] Example 3:

[0146] A method for preparing a 4-trifluoromethylpyridine intermediate core (compound I) differs from Example 1 in that only the S1 condensation reaction is studied, and the 0.05 mol piperidine acetate in the S1 step is replaced with 0.05 mol ammonium formate.

[0147] Example 4:

[0148] A method for preparing a 4-trifluoromethylpyridine intermediate core (compound I) differs from Example 1 in that only the S1 condensation reaction is studied, and the 0.05 mol piperidine acetate in the S1 step is replaced with 0.05 mol ammonium acetate.

[0149] Example 5:

[0150] A method for preparing a 4-trifluoromethylpyridine intermediate core (compound I) differs from Example 1 in that only the S2 cyclization reaction is studied, and the 143.7 g (1.465 mol) concentrated sulfuric acid and 29.4 g (0.488 mol) glacial acetic acid in the S2 step are replaced with 1.953 mol of concentrated sulfuric acid.

[0151] Example 6:

[0152] A method for preparing a 4-trifluoromethylpyridine intermediate core (compound I) differs from Example 1 in that only the S2 cyclization reaction is studied, and the 143.7 g (1.465 mol) concentrated sulfuric acid and 29.4 g (0.488 mol) glacial acetic acid in the S2 step are replaced with 1.953 mol glacial acetic acid.

[0153] Example 7:

[0154] A method for preparing a 4-trifluoromethylpyridine intermediate core (compound I) differs from Example 1 in that only the S3 cyclization reaction is studied, and the chlorination catalyst (phosphorus pentachloride) of 162.6 g (1.06 mol) and 22.1 g (0.106 mol) of phosphorus oxychloride in the S3 step is replaced with 162.6 g (1.06 mol) of phosphorus oxychloride.

[0155] Example 8:

[0156] A method for preparing a 4-trifluoromethylpyridine intermediate core (compound I) differs from Example 1 in that only the S3 cyclization reaction is studied. 200 g of toluene and 66.5 g (0.353 mol) of the cyclized compound are added to a reaction flask, stirred, heated to 105 °C, refluxed to remove water, and approximately 0.014 mol (0.04 eq) of DMF is added. Over 2 hours, 0.39 mol (1.1 eq) of thionyl chloride is added dropwise, and the mixture is refluxed at 105 °C overnight. After cooling to room temperature, the mixture is washed with 200 ml of water, and the layers are separated. The organic layer is collected, dried with sodium sulfate, and after drying, a transparent oily substance, i.e., the chloride, is obtained.

[0157] Table 1. Effect of the choice of condensation catalyst on the yield of condensation reaction in step S1 of Examples 1-4

[0158] Condensation catalyst Condensation reaction yield Example 1 Piperidine acetate 88.8％ Example 2 Cyclohexylamine acetate 83.3％ Example 3 Ammonium formate 69.2％ Example 4 ammonium acetate 76.2％

[0159] Table 2. Effect of the choice of cyclizing acid on the cyclization reaction yield in step S2 of Examples 1 and 5-6

[0160] Cyclic acids Cyclization reaction yield Example 1 Concentrated sulfuric acid + glacial acetic acid 79.6％ Example 5 concentrated sulfuric acid 63.7％ Example 6 glacial acetic acid 39.2％

[0161] Table 3. Effect of the choice of chlorination system on the chlorination reaction yield in step S3 of Examples 1 and 7-8

[0162] chlorination system Chlorination reaction yield Example 1 <![CDATA[POCl3+PCl5]]> 84.4％ Example 7 <![CDATA[POCl3]]> 56.1％ Example 8 <![CDATA[SOCl2+DMF]]> 64.7％

[0163] Based on the results of Examples 1-4 and Table 1, it can be seen that the choice of condensation catalyst has a significant impact on the condensation yield. For example, when cyclohexylamine acetate or piperidine acetate is selected, the condensation yield can reach more than 83%; while when ammonium acetate is selected, the condensation yield is 76.2%; and when ammonium formate is selected, the condensation yield is only 69.2%.

[0164] Based on the results of Examples 1, 5-6 and Table 2, it can be seen that the choice of cyclizing acid is the key factor affecting the cyclization yield in the cyclization reaction. The mixed acid composed of concentrated sulfuric acid and glacial acetic acid has the best effect as the cyclizing acid, while neither concentrated sulfuric acid alone nor glacial acetic acid alone can achieve a large cyclization yield.

[0165] Based on the results of Examples 1, 7-8, and Table 3, it can be seen that the choice of chlorination system has a significant impact on the chlorination yield in the chlorination reaction. The chlorination system of phosphorus oxychloride + phosphorus pentachloride is the better choice, with a chlorination yield of up to 84.4%. However, when phosphorus oxychloride is used alone, the chlorination yield is below 60%. The chlorination system of thionyl chloride + N,N-dimethylformamide has a chlorination yield close to 65%.

[0166] Example 9:

[0167] A method for preparing a 4-trifluoromethylpyridine intermediate derivative A is as follows:

[0168]

[0169] Following the preparation method of the core nucleus in Example 1, a 4-trifluoromethylpyridine intermediate core nucleus (compound I) was obtained. Under ice bath conditions, 50 ml of concentrated sulfuric acid was added to the reaction flask, and 12 ml of concentrated nitric acid was slowly added under controlled temperature conditions. The mixture was stirred, and after the addition was complete, the temperature was raised to 70°C. Within 30 minutes, 20.7 g of compound I (0.1 mol) was added in portions under controlled temperature. The temperature was raised to 100°C, and the reaction continued for 3 hours until the starting material disappeared. The reaction system was then cooled to room temperature and slowly added to ice water. The mixture was stirred rapidly to precipitate a solid, which was then filtered and dried to obtain 20.7 g of a white solid, compound II, with a molar yield of 91.6%. LC / MS: [M+H]+=227;

[0170] S5: 20.7 g of compound II (0.0916 mol), 15.0 g of sodium acetate (0.183 mol), and 1.5 g of 10% palladium on carbon were added sequentially to a hydrogenation flask. Then, 100 ml of ethanol was added. The mixture was stirred at room temperature. The air in the hydrogenation flask was replaced with nitrogen three times, followed by replacement with hydrogen three times. The pressure was increased to 5 kg under a hydrogen atmosphere, and the reaction was stirred at room temperature until no hydrogen absorption occurred, approximately 8 hours later. After the reaction was complete, the mixture was filtered, the filter cake was washed with ethanol, the palladium on carbon was recovered, and the solvent ethanol was distilled off under reduced pressure. 100 ml of water was added and stirred. Concentrated hydrochloric acid was slowly added dropwise to adjust the pH to 2-3. The mixture was extracted with ethyl acetate and allowed to stand for separation. The organic phase was washed twice with saturated brine, dried over sodium sulfate, and the solvent ethyl acetate was distilled off under reduced pressure to obtain 16.4 g of a yellowish solid, 4-trifluoromethylnicotinic acid, with a molar yield of 93.7%. LC / MS: [M+H]+=192, 1H NMR (400MHz, CDCl3): δ9.1 (s, 1H), 8.9 (d, J 5.2Hz, 1H), 7.8 (d, J 5.2Hz, 1H).

[0171] Example 10:

[0172] A method for preparing a 4-trifluoromethylpyridine intermediate derivative B, comprising the following steps:

[0173]

[0174] The preparation of the core nucleus was carried out according to the method in Example 1 to obtain the 4-trifluoromethylpyridine intermediate core nucleus (compound I). 45 g of 30% sodium methoxide methanol solution (0.25 mol) and 20.7 g (0.1 mol) of compound I were added to a reaction flask. The mixture was heated to reflux for approximately 4 hours, monitored until the starting material spot disappeared. After the reaction was completed, the mixture was cooled to room temperature, filtered, and the methanol was recovered. The mixture was washed with 100 ml of water, then extracted with 100 ml of dichloromethane. After standing and separating the layers, the organic phase was concentrated under reduced pressure to obtain 18.0 g of a yellowish transparent liquid, namely compound III, with a molar yield of 89.1%. LC / MS: [M+H]+=203;

[0175] 26.5 g of concentrated sulfuric acid (0.27 mol) was added to a reaction flask, and the temperature was raised to 70 °C. Over one hour, 18.0 g of the product from the previous step was added in portions to the flask. After the addition was complete, the temperature was raised to 90 °C, and the reaction was stirred for approximately 2 hours. The mixture was then cooled and slowly added to ice water. Sodium carbonate was added to adjust the pH to neutral, and the mixture was stirred rapidly to precipitate a solid. The solid was filtered and dried to obtain a white, near-white solid compound. The product was recrystallized from a methanol-water solution in a 2:1 ratio to obtain 18.3 g of a white, near-white solid, namely compound IV, with a molar yield of 93.3%; LC / MS: [M+H]+=221;

[0176] Under ice bath conditions, 3.7 g of sodium hydroxide (0.091 mol) and 90 ml of water were added to the reaction flask. The mixture was stirred, and the temperature was controlled while 13.3 g of bromine (0.083 mol) was added dropwise. The product from the previous step was added to the reaction flask and the mixture was stirred and heated to 70 °C. The reaction was monitored until the starting material disappeared, and the reaction was allowed to proceed for 3 hours. The mixture was then cooled to room temperature and filtered under reduced pressure. 50 ml of dichloromethane was added to the flask for extraction. The mixture was allowed to stand and separate into layers. The organic phase was collected, dried over sodium sulfate, and the solvent was distilled off under reduced pressure to give 13.7 g of a yellowish-white transparent liquid, compound V, with a molar yield of 85.8%; LC / MS: [M+H]+=193;

[0177] Under ice bath conditions, 30g of 30% hydrochloric acid (0.25mol) and 13.7g (0.0713mol) of the product from the previous step were added to reaction flask A. The mixture was stirred and dissolved at 0°C, and then 16.5g (0.0713mol) of 30% sodium nitrite aqueous solution was added dropwise at this temperature. After the addition was complete, the temperature was maintained at 0°C to prepare the diazonium solution for later use. Under ice bath conditions, 100ml of water and 34.0g (0.285mol) of thionyl chloride were added to reaction flask B. The mixture was stirred and added at 0°C, and then 0.07g of cuprous chloride was added. The diazonium solution from reaction flask A was then added dropwise to reaction flask B, with the temperature maintained at 0°C throughout the addition process. The addition was completed within 20 minutes, and the reaction was stirred while maintaining the temperature for 2 hours. After the reaction was completed, 150 ml of dichloromethane was added to the system for extraction. The mixture was allowed to stand and separate into layers. The organic phase was collected, dried over sodium sulfate, and the solvent was distilled under reduced pressure to obtain 16.0 g of a light yellow transparent oily liquid, namely 2-methoxy-4-trifluoromethylpyridine-3-sulfonyl chloride, with a molar yield of 81.4%, [M+H]+=276, 1H NMR (400 MHz, CDCl3): δ 8.5 (d, 1H), 7.3 (d, 1H), 4.2 (s, 3H).

[0178] Example 11:

[0179] A method for preparing a 4-trifluoromethylpyridine intermediate derivative C, the preparation process is as follows:

[0180]

[0181] First, the preparation method for the core nucleus described above was followed to obtain the 4-trifluoromethylpyridine intermediate core nucleus (compound I). 56g of 70% sulfuric acid (0.4mol) was added to the reaction flask, and the temperature was raised to 100℃. After about 1 hour, 20.7g (0.1mol) of compound I was added in portions, and the temperature was raised to 160℃. The mixture was then kept at 160-170℃ with stirring for 24 hours. After the reaction was completed, the temperature was cooled to 100℃, and 50ml of water was added dropwise while stirring, completing the addition over about 2 hours. The temperature was then further lowered to below 60℃. The reaction solution was poured into a... Add 30% sodium hydroxide solution dropwise to 00 ml of ice water while stirring, and adjust the pH to 8-9; add 100 ml of dichloromethane for extraction, allow to stand and separate into layers, take the organic phase, dry with sodium sulfate, and distill the organic phase under reduced pressure to obtain a colorless oily substance, namely 14.8 g of 2-chloro-4-trifluoromethylpyridine, with a molar yield of 81.5%; LC / MS: [M+H]+=183, 1H NMR (400 MHz, CDCl3): δ 8.53 (d, J=5.0 Hz, 1H), 7.54 (s, 1H), 7.42 (m, 1H).

[0182] Comparative Example 1:

[0183] Preparation of Compound II (Alkali Method):

[0184] 125 ml (100.0 g) of 70% ethanol, 20.7 g (0.1 mol) of compound I, and 16 g (0.4 mol) of caustic soda were added to a reaction flask. The mixture was stirred and heated to reflux for 2.5 hours, until the starting material disappeared. The reaction system was cooled to room temperature, concentrated hydrochloric acid was added, and the pH of the system was adjusted to 2. The mixture was filtered and dried to obtain 18.9 g of a white solid, compound II, with a molar yield of 83.8%.

[0185] Comparative Example 2:

[0186] The preparation route and process of 4-trifluoromethylnicotonitrile are as follows:

[0187]

[0188] 18.9 g of compound I (0.0916 mol), 15.0 g of sodium acetate (0.183 mol), and 1.5 g of 10% palladium on carbon were added sequentially to a hydrogenation flask, followed by 100 ml of ethanol. The mixture was stirred at room temperature, and the air in the flask was purged with nitrogen three times, followed by purging with hydrogen three times. The pressure was increased to 5 kg under a hydrogen atmosphere, and the reaction was stirred at room temperature until no hydrogen absorption occurred, which took approximately 8 hours. After the reaction was complete, 50 g of ice water was added and stirred for 30 min. The palladium on carbon catalyst was filtered out. Most of the ethanol and water were distilled off, and the mixture was extracted with 100 ml of toluene. The mixture was allowed to stand and separate into layers. The organic phase was collected, dried over sodium sulfate, and desolventized to obtain a colorless, transparent liquid containing 13.8 g of 4-trifluoromethyl nicotinonitrile, with a molar yield of 87.5%. LC / MS: [M+H]+=173, 1H NMR (400 MHz, CDCl3): δ 9.2 (s, 1H), 9.0 (d, J) 5.2Hz,1H),7.8(d,J 5.2Hz,1H).

Claims

1. A method for preparing a 4-trifluoromethylpyridine intermediate core, characterized in that, Includes the following steps: S1: Using malononitrile and 4-ethoxy-1,1,1-trifluoro-3-buten-2-one as raw materials, a condensation reaction is carried out in an organic solvent and catalyzed by an organic amine or its ammonium salt to obtain a condensate. ； S2: The condensate undergoes a cyclization reaction in a strong acid system to yield a cyclized compound; ； S3: The cyclized compound undergoes a chlorination reaction under the action of a chlorinating reagent and a chlorination catalyst to obtain the core of the 4-trifluoromethylpyridine intermediate, which is compound I; ； The organic amine or its ammonium salt in step S1 is selected from one or more of cyclohexylamine, piperidine, ammonium formate, ammonium acetate, cyclohexylamine acetate, and piperidine acetate; the condensation reaction is carried out at room temperature; After the S1 reaction is completed, before the organic solvent is removed, an appropriate amount of polymerization inhibitor is added, wherein the molar ratio of malononitrile: 4-ethoxy-1,1,1-trifluoro-3-buten-2-one: catalyst: polymerization inhibitor is 1.0:(1.0~1.2):0.05:0.01; In step S2, the strong acid system is a mixture of concentrated sulfuric acid and glacial acetic acid; In the S3 chlorination reaction, the molar ratio of cyclized compound: chlorinating reagent: chlorination catalyst is 1:(1~5):(0.02~0.4); The chlorination reagent is any one of thionyl chloride, sulfonyl chloride, phosphoryl chloride, oxalyl chloride, and phosphorus oxychloride; the chlorination catalyst is phosphorus pentachloride or a tertiary amine and its salt.

2. The method for preparing a 4-trifluoromethylpyridine intermediate core according to claim 1, characterized in that: In step S1, the organic solvent is selected from benzene-based solvents that are immiscible with water and easily recyclable.

3. A method for preparing a 4-trifluoromethylpyridine intermediate derivative A, characterized in that... Includes the following steps: ； S1~S3 are carried out according to the preparation method of the core parent nucleus as described in any one of claims 1~2 to obtain compound I; S4: Compound I undergoes hydrolysis in an acidic system and is quenched in ice water to precipitate carboxylic acid compound II at the 3-position; S5: Carboxylic acid compound II at the 3-position is hydrogenated in an alcohol system using Pd / C catalysis to prepare derivative A, wherein derivative A is 4-trifluoromethylnicotinic acid.

4. A method for preparing a 4-trifluoromethylpyridine intermediate derivative B, characterized in that... Includes the following steps: ； Compound I is prepared by the method described in any one of claims 1 to 2; then, using compound I as a raw material, derivative B is prepared by etherification, hydrolysis, Hoffmann degradation, and diazotization, wherein derivative B is 2-methoxy-4-trifluoromethylpyridine-3-sulfonyl chloride.

5. The method for preparing a 4-trifluoromethylpyridine intermediate derivative B according to claim 4, characterized in that: The preparation of the 3-position amide by hydrolysis is carried out in an acidic system, with the acid being 98% concentrated sulfuric acid or fuming sulfuric acid.

6. The method for preparing a 4-trifluoromethylpyridine intermediate derivative B according to claim 4, characterized in that: A diazonium salt was prepared by reacting Hoffmann degradation products, concentrated hydrochloric acid, and sodium nitrite at 0°C. Thionyl chloride was added dropwise to water at 0°C or sulfur dioxide was introduced, and cuprous chloride was added. The prepared diazonium salt was then rapidly added dropwise to the system at 0°C under controlled temperature, and the reaction continued until the starting material disappeared. The molar ratio of Hoffmann degradation products: concentrated hydrochloric acid: sodium nitrite: thionyl chloride: cuprous chloride was 1:(3.5~4):(1.0~1.5):(4~4.5):(0.01~0.02).

7. A method for preparing a 4-trifluoromethylpyridine intermediate derivative C, characterized in that, Includes the following steps: ； Compound I is prepared by the method of any one of claims 1 to 2; then, derivative C is prepared by decarboxylation reaction using compound I as raw material, wherein derivative C is 2-chloro-4-trifluoromethylpyridine.

8. The method for preparing a 4-trifluoromethylpyridine intermediate derivative C according to claim 7, characterized in that: The decarboxylation reaction was carried out by heating and refluxing in sulfuric acid until no gas was released. The product was washed with liquid alkali until neutral, and then extracted with dichloromethane to prepare 2-chloro-4-trifluoromethylpyridine.

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