Method for preparing trifluorobenzene pyrimidine

Abstract

The invention belongs to the field of pesticide intermediates and product preparation, and particularly relates to a method for preparing trifluorobenzene pyrimidine. The method disclosed by the invention comprises the following steps: (1) in a first organic solvent, carrying out Schiff base condensation reaction on 2-aminopyridine and pyrimidine-5-formaldehyde under the action of a first moisture scavenger to generate N-2-pyridine-5-pyrimidine methylenimine; (2) in a second organic solvent, carrying out reductive amination reaction on the N-2-pyridine-5-pyrimidine methylenimine and hydrogen under the action of a catalyst to generate N-2-pyridine-5-pyrimidine methylamine; and (3) in a third organic solvent, carrying out cyclization reaction on the N-2-pyridine-5-pyrimidine methylamine and 2-(3-trifluoromethylphenyl) malonyl chloride in the presence of an acid-binding agent, so as to prepare the trifluorobenzene pyrimidine. According to the method disclosed by the invention, the post-treatment operation times and the reaction reagent consumption are greatly reduced, and efficient and green production is realized.

Description

Technical Field

[0001] The invention belongs to the field of pesticide intermediate and product preparation, and specifically relates to a method for preparing trifluanidazole. Background Art

[0002] Triflumezopyrim (TFM) is a pyrido[1,2-α]pyrimidinone mesoionic insecticide developed by DuPont (now Corteva) and registered for marketing in 2017. The drug is a nicotinic acetylcholine receptor inhibitor that acts on the orthosteric site of insect nicotinic acetylcholine receptors (nAChRs) and can effectively inhibit their biological functions. The drug is mainly used to control rice-related pests such as rice planthoppers, brown planthoppers, white-backed planthoppers, leafhoppers, and has no cross-resistance with most insecticides currently on the market, and has good market prospects. In order to further reduce the cost of medication, it is of great significance to continuously optimize the synthesis process of the drug and reduce its production cost and the output of three wastes.

[0003]

[0004] The existing synthetic route of trifluorophenylpyrimidine mainly uses 2-(3-trifluoromethylphenyl)malonic acid derivatives and N-2-pyridine-5-pyrimidinemethylamine as key intermediates. Since 2-(3-trifluoromethylphenyl)malonyl chloride is not suitable for long-term storage, the cyclization reaction using it as a substrate requires low temperature and is easily affected by temperature, resulting in overreaction and low conversion rate. Therefore, it is only suitable for small-scale laboratory research and development. The existing intermittent production process often uses 2,4,6-trichlorophenol as a protective group, and its diester is refluxed with N-2-pyridine-5-pyrimidinemethylamine in toluene to obtain a crude trifluorophenylpyrimidine.

[0005]

[0006] For another key intermediate N-2-pyridine-5-pyrimidinemethylamine, WO2009099929A1 and WO2011017342A2 both disclose the preparation of Schiff base from 2-aminopyridine and pyrimidine-5-carboxaldehyde in chloroform, followed by reduction with sodium borohydride to generate N-2-pyridine-5-pyrimidinemethylamine. This route has the following shortcomings: 1. The Schiff base reaction is a reversible reaction, which requires strict anhydrous conditions, and the use of chloroform as a reaction solvent is more harmful to the environment; 2. The reductive amination reaction uses sodium borohydride as a reducing agent, which is costly and cumbersome to post-process, with a low conversion rate, usually only 65%; 3. The crude product prepared by the reaction needs to be purified before it can be used in the cyclization reaction, and the whole process post-processing uses a large number of solvents and the amount of waste liquid generated is relatively large.

[0007]

[0008] In summary, it is of great value to develop an efficient, economical and environmentally friendly synthesis process for trifluorophenylpyrimidine. Summary of the invention

[0009] The purpose of the present invention is to provide a green, safe and efficient method for preparing trifluorophenylpyrimidine using 2-aminopyridine and pyrimidine-5-carboxaldehyde as starting substrates.

[0010] The first aspect of the present invention provides a method for preparing trifluorobenzene, the method comprising the steps of:

[0011] (1) in a first organic solvent, allowing 2-aminopyridine and pyrimidine-5-carboxaldehyde to undergo a Schiff base condensation reaction under the action of a first dehydrating agent to generate N-2-pyridine-5-pyrimidine imine;

[0012] (2) in a second organic solvent, subjecting N-2-pyridine-5-pyrimidinemethanamine to a reductive amination reaction with hydrogen in the presence of a catalyst to generate N-2-pyridine-5-pyrimidinemethanamine;

[0013] (3) In a third organic solvent, N-2-pyridine-5-pyrimidinemethylamine is reacted with 2-(3-trifluoromethylphenyl)malonyl chloride in the presence of an acid-binding agent to undergo a cyclization reaction to obtain trifluorophenylpyrimidine.

[0014] The present invention has the following beneficial effects:

[0015] (1) Step (1) In the step of preparing N-2-pyridine-5-pyrimidine azomethine, the method of the present invention adopts a method of drying a water removing agent to replace the water separation method in the prior art, which can effectively remove water from the reaction system in a timely manner and promote the forward reaction. Compared with the prior art, the present method is carried out under normal pressure conditions, without the need for multiple reduced pressure distillations and solvent replacements, and the reaction temperature is reduced from the boiling point temperature of the solvent required for azeotropic dehydration to 60-70°C, the reaction conditions are milder and more energy-saving, and the post-treatment only requires filtration and separation, and the whole process is simple to operate. In addition, the present method can achieve a yield of more than 95% within 10-12 hours, and the recovered water removing agents such as molecular sieves and color-changing silica gel can be recycled after drying and activation, which is more in line with the needs of industrial production.

[0016] (2) In the step (2) of preparing N-2-pyridine-5-pyrimidinemethylamine, the method of the present invention uses a metal palladium catalyst for catalytic hydrogenation to replace the reduction method using sodium borohydride in the prior art. Compared with the sodium borohydride reduction method, the reaction and post-treatment process involve multi-step temperature control and the use of multiple solvents, the operation is cumbersome and the average yield is only 64%. The method uses hydrogen as a reducing agent, and can achieve a conversion rate of more than 95% within 10 to 12 hours. At the same time, only filtering and vacuum distillation are required to obtain a high-purity product, and the reaction process is more green, efficient and easy to operate. At the same time, the separated and recovered palladium catalyst can still be recycled after cleaning and drying, which further reduces the production cost and is more in line with the needs of large-scale production.

[0017] (3) For step (1) and step (2), the methods in the prior art require two separate operations. The method of the present invention does not need to separate the product N-2-pyridine-5-pyrimidinemethanamine of step (1), and can directly apply it to step (2). Therefore, steps (1) and (2) of the method of the present invention can achieve one-pot two-step. In addition, the dehydrating agent used in step (1) can also assist in controlling the water content of the reaction system in step (2), thereby inhibiting the hydrolysis of imine and improving the selectivity of the reaction. Compared with the prior art method, the "one-pot two-step" method can obtain N-2-pyridine-5-pyrimidinemethanamine with a total yield of more than 95% within 20 hours, and the post-treatment process is further simplified to two steps of filtration and reduced pressure distillation. Thanks to the compatibility of the solvent, the method realizes the recycling of a single solvent, further reduces the discharge of three wastes, effectively reduces the production cost, and helps to achieve green and efficient industrial production. DETAILED DESCRIPTION

[0018] In order to enable those skilled in the art to understand the characteristics and effects of the present invention, the following is a general description and definition of the terms and expressions mentioned in the specification and claims. Unless otherwise specified, all technical and scientific terms used in the text are the common meanings understood by those skilled in the art for the present invention. In the event of a conflict, the definition in this specification shall prevail.

[0019] The theories or mechanisms described and disclosed herein, whether correct or incorrect, should not limit the scope of the present invention in any way, that is, the present invention can be implemented without being limited by any specific theory or mechanism.

[0020] Herein, “comprising”, “including”, “containing” and similar terms encompass the meanings of “consisting essentially of” and “consisting of”. For example, when “A comprises B and C” is disclosed herein, “A consists essentially of B and C” and “A consists of B and C” should be deemed to be disclosed herein.

[0021] In this article, all features such as values, quantities, contents and concentrations defined in the form of numerical ranges or percentage ranges are only for brevity and convenience. Accordingly, the description of numerical ranges or percentage ranges should be considered to have included and specifically disclosed all possible secondary ranges and individual values ​​within the range (including integers and fractions).

[0022] In this document, unless otherwise specified, percentage refers to mass percentage and ratio refers to mass ratio.

[0023] Herein, when describing embodiments or examples, it should be understood that they are not used to limit the present invention to these embodiments or examples. On the contrary, all substitutes, improvements and equivalents of the methods and materials described in the present invention can be included in the scope limited by the claims.

[0024] In this document, in order to make the description concise, not all possible combinations of various technical features in various embodiments or examples are described. Therefore, as long as there is no contradiction in the combination of these technical features, the various technical features in various embodiments or examples can be combined arbitrarily, and all possible combinations should be considered to be within the scope of this specification.

[0025] In the present invention, the method for efficiently preparing trifluorobenzene adopts the following reaction route:

[0026]

[0027] The present invention provides a method for preparing trifluorobenzene, which comprises the steps of:

[0028] (1) in a first organic solvent, allowing 2-aminopyridine and pyrimidine-5-carboxaldehyde to undergo a Schiff base condensation reaction under the action of a first dehydrating agent to generate N-2-pyridine-5-pyrimidine imine;

[0029] (2) in a second organic solvent, subjecting N-2-pyridine-5-pyrimidinemethanamine to a reductive amination reaction with hydrogen in the presence of a catalyst to generate N-2-pyridine-5-pyrimidinemethanamine;

[0030] (3) In a third organic solvent, N-2-pyridine-5-pyrimidinemethylamine is reacted with 2-(3-trifluoromethylphenyl)malonyl chloride in the presence of an acid-binding agent to undergo a cyclization reaction to obtain trifluorophenylpyrimidine.

[0031] In some embodiments, in step (1), the first dehydrating agent is selected from one or more of molecular sieves, anhydrous sodium sulfate, anhydrous magnesium sulfate and color-changing silica gel. Preferably, the first dehydrating agent is a molecular sieve.

[0032] The present invention has no particular restrictions on the type of the first organic solvent, as long as it has no adverse effect on the reaction. Exemplary first organic solvents are selected from one or more of n-hexane, n-heptane, petroleum ether, cyclohexane, carbon tetrachloride, methyl tert-butyl ether, isopropyl ether, toluene, xylene, dichloromethane, dichloroethane, tetrahydrofuran, ethyl acetate, chloroform, dioxane, ethanol, methanol, isopropanol and acetonitrile. In some embodiments, the first organic solvent is toluene.

[0033] In some embodiments, in step (1), the amount of the first dehydrating agent added is 0.1 to 10% of the total mass of the first organic solvent, 2-aminopyridine and pyrimidine-5-carboxaldehyde, for example, 0.5%, 0.8%, 1%, 1.5%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, preferably 3 to 5%.

[0034] In some embodiments, in step (1), the molar ratio of 2-aminopyridine to pyrimidine-5-carboxaldehyde is 1:(0.9-1.1), for example 1:1.

[0035] In some embodiments, in step (1), the reaction temperature is 20-120°C, for example, 20°C, 30°C, 40°C, 50°C, 60°C, 70°C, 80°C, 90°C, 100°C, 110°C, preferably 50-100°C.

[0036] In some embodiments, in step (1), the reaction time is 1 to 24 h, for example, 1 h, 2 h, 4 h, 5 h, 8 h, 10 h, 12 h, 16 h, 18 h, 20 h, 22 h, preferably 8 to 24 h.

[0037] In some embodiments, in step (1), the initial concentration of 2-aminopyridine in the first organic solvent is 0.01 to 2.0 mol / L, for example, 0.02 mol / L, 0.05 mol / L, 0.08 mol / L, 0.1 mol / L, 0.2 mol / L, 0.3 mol / L, 0.5 mol / L, 0.8 mol / L, 1.0 mol / L, 1.2 mol / L, 1.5 mol / L, 1.8 mol / L, preferably 0.01 to 0.5 mol / L.

[0038] In step (2), the catalyst may be selected from one or more of 5-20wt% Pd(OH)2 / C, 5-20wt% Pd / C, 5wt% Pd / Al2O3 / C, Pd(OCOCH3)2, PdCl2, Ranney Ni, NiCl2, Ni(OH)2, Al-Ni and Ni / Al2O3 / SiO2. Preferably, the catalyst is 5-20wt% Pd(OH)2 / C, such as 5wt% Pd(OH)2 / C, 10wt% Pd(OH)2 / C, 15wt% Pd(OH)2 / C, 20wt% Pd(OH)2 / C.

[0039] In some embodiments, in step (2), a second dehydrating agent may be added to the reductive amination reaction to inhibit the reverse reaction. In some embodiments, the second dehydrating agent is selected from one or more of molecular sieves, anhydrous sodium sulfate, anhydrous magnesium sulfate and color-changing silica gel. Preferably, the second dehydrating agent is a molecular sieve.

[0040] The present invention has no particular limitation on the type of the second organic solvent, as long as it has no adverse effect on the reaction. Exemplary second organic solvents are selected from one or more of toluene, xylene, dichloromethane, dichloroethane, tetrahydrofuran, ethyl acetate, dioxane, ethanol, methanol, isopropanol and acetonitrile; preferably, the second organic solvent is selected from one or more of toluene, tetrahydrofuran, acetonitrile, methanol and ethanol; preferably, the second organic solvent is toluene.

[0041] In step (2), the hydrogen pressure may be 0.1 to 5.0 MPa, for example, 0.2 MPa, 0.5 MPa, 0.8 MPa, 1.0 MPa, 1.5 MPa, 2.0 MPa, 2.5 MPa, 3.0 MPa, 4.0 MPa, preferably 0.1 to 3.0 MPa.

[0042] In step (2), the amount of the catalyst added is 0.5-10% of the mass of N-2-pyridine-5-pyrimidinemethamine, for example, 0.8%, 1%, 1.5%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, preferably 1.0-8%.

[0043] In step (2), the amount of the second dehydrating agent added is 0.1 to 10% of the total mass of the second organic solvent and N-2-pyridine-5-pyrimidinemethamine, for example, 0.5%, 0.8%, 1%, 1.5%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, preferably 3 to 5%.

[0044] In step (2), the reaction temperature may be 20-130°C, for example 30°C, 40°C, 50°C, 60°C, 70°C, 80°C, 90°C, 100°C, 120°C, preferably 60-100°C.

[0045] In step (2), the reaction time may be 1 to 24 h, for example 2 h, 5 h, 8 h, 10 h, 12 h, 15 h, 18 h, 20 h, 24 h, preferably 8 to 24 h.

[0046] In step (2), the initial concentration of N-2-pyridine-5-pyrimidinemethamine in the second organic solvent is 0.01 to 2.0 mol / L, for example, 0.02 mol / L, 0.05 mol / L, 0.08 mol / L, 0.1 mol / L, 0.2 mol / L, 0.3 mol / L, 0.5 mol / L, 0.8 mol / L, 1.0 mol / L, 1.2 mol / L, 1.5 mol / L, 1.8 mol / L, preferably 0.05 to 1.0 mol / L.

[0047] The present invention has no particular restrictions on the third organic solvent, as long as it has no adverse effect on the reaction. The third organic solvent can be selected from one or more of n-hexane, n-heptane, petroleum ether, cyclohexane, carbon tetrachloride, toluene, xylene, dichloromethane, dichloroethane and tetrahydrofuran. Preferably, the third organic solvent is selected from one or more of toluene, dichloromethane and tetrahydrofuran.

[0048] In some embodiments, the acid binding agent is selected from one or more of triethylamine, ethylenediamine, pyridine, piperidine, N,N-diisopropylethylamine, 1,8-diazobispiro[5.4.0]undec-7-ene (DBU), sodium carbonate, sodium acetate, potassium carbonate, calcium carbonate, sodium hydroxide, potassium hydroxide and AMBERSEP 900(OH); preferably, the acid binding agent is triethylamine.

[0049] In step (3), the molar ratio of the acid binding agent to N-2-pyridine-5-pyrimidinemethamine is (1.0-4.0):1, for example, 1.0:1, 2.0:1, 3.0:1, 4.0:1, preferably (2.0-3.0):1.

[0050] In step (3), the initial concentration of N-2-pyridine-5-pyrimidinemethylamine in the third organic solvent is 0.01 to 5.0 mol / L, for example, 0.02 mol / L, 0.05 mol / L, 0.08 mol / L, 0.1 mol / L, 0.2 mol / L, 0.3 mol / L, 0.5 mol / L, 0.8 mol / L, 1.0 mol / L, 1.2 mol / L, 1.5 mol / L, 1.8 mol / L, 2.5 mol / L, 3.0 mol / L, 4.0 mol / L, 4.5 mol / L, preferably 0.1 to 2.0 mol / L.

[0051] In step (3), the reaction temperature may be -10 to 50°C, for example -5°C, 0°C, 10°C, 20°C, 30°C, 40°C, preferably 0 to 30°C.

[0052] In step (3), the reaction time is 0.5 to 8 h, for example, 0.5 h, 1 h, 1.5 h, 2 h, 2.5 h, 3 h, 3.5 h, 4 h, 5 h, 6 h, 7 h, preferably 0.5 to 3 h.

[0053] In some embodiments, 2-(3-trifluoromethylphenyl)malonyl chloride is prepared by reacting 2-(3-trifluoromethylphenyl)malonic acid and oxalyl chloride. 2-(3-trifluoromethylphenyl)malonyl chloride can be prepared by 2-(3-trifluoromethylphenyl)malonic acid and oxalyl chloride according to the methods in the prior art. In some embodiments, 2-(3-trifluoromethylphenyl)malonyl chloride is prepared and used immediately.

[0054] In some embodiments, the product N-2-pyridine-5-pyrimidine imine of step (1) is directly reacted in step (2) without separation. That is, step (1) and step (2) can realize a "one-pot multi-step" reaction in the same reactor. The reaction solution of step (2) does not need to be purified, and after separation, the reaction of step (3) can be directly carried out to obtain a crude trifluorophenylpyrimidine.

[0055] The present invention will be further described below in conjunction with specific examples. It should be understood that these examples are only used to illustrate the present invention and are not intended to limit the scope of the present invention. The experimental methods in the following examples without specifying specific conditions are usually based on conventional conditions or the conditions recommended by the manufacturer. Unless otherwise stated, percentages and parts are calculated by weight.

[0056] Based on the attempts in the art, the above-mentioned preferred conditions can be combined arbitrarily to obtain the preferred embodiments of the present invention.

[0057] The reagents and raw materials used in the present invention are commercially available.

[0058] All reagents used in the experiments were of AR grade.

[0059] All dehydrating agents involved in the experiment should be activated before use. The activation method is: place the dehydrating agent in a muffle furnace, heat to 450°C and keep it warm for 2 hours, then cool it naturally and store it in a sealed container.

[0060] In the present invention, the conversion rate is calculated based on GC-MS or HPLC analysis; the yield is calculated based on the mass of the product after separation and purification; NR means no reaction.

[0061] Herein, room temperature refers to the reaction being carried out at 20 to 25°C.

[0062] Example 1 (Schiff base reaction, step 1)

[0063] 2-Aminopyridine (0.095g, 1.0mmol), pyrimidine-5-carboxaldehyde (0.110g, 1.0mmol), anhydrous sodium sulfate (100.0mg) and methanol (2.0mL) were placed in a dry test tube, reacted at room temperature, and sealed for 8h; after the reaction, filtered, and the filter cake was washed with dry dichloromethane (2.0mL) 3 times; after the organic phase was combined, the solvent was evaporated under reduced pressure; the residue was vacuum dried and sealed in a nitrogen environment. The residue was detected by GC-MS, and the conversion rate was 27.54%.

[0064] Examples 2 to 18 (Schiff base reaction, step 1)

[0065] The operation is similar to that of Example 1, except for the type of dehydrating agent, the type of solvent, the reaction temperature and the reaction time. The specific conditions and conversion rates of each example are shown in Table 1 below.

[0066] Table 1

[0067]

[0068]

[0069] Example 19 (Reductive amination reaction, step 2)

[0070] 100mg Molecular sieves, N-2-pyridine-5-pyrimidine imine (0.185g, 1.0mmol), 5% Pd(OH)2 / C (10.0mg) and toluene (2.0mL) were placed in a Shrek reaction tube. Nitrogen was replaced 3 times, followed by hydrogen replacement 3 times, and hydrogen was continuously supplied to the reaction system using a hydrogen balloon. The reaction temperature was 50°C and the reaction was closed for 24h. After the reaction, nitrogen was replaced three times. Diatomaceous earth was used to assist the filter, and the filter cake was washed with toluene (2.0mL) 3 times. The organic phases were combined and the solvent was removed by rotary evaporation to obtain a pale yellow solid crude product. The crude product was purified by column chromatography, and the eluent was dichloromethane: methanol = 30:1 to 20:1, and a small amount of ammonia or triethylamine was added at the same time. The pure product was a light yellow solid, and the yield was 31% after GC-MS detection.

[0071] Examples 20 to 32 (reductive amination reaction, step 2)

[0072] The method of Example 19 was repeated, except that different types of catalysts were used. The types, amounts and conversion rates of the catalysts used in each example are shown in Table 2 below.

[0073] Table 2

[0074]

[0075]

[0076] Examples 33-41 (reductive amination reaction, step 2)

[0077] The method of Example 19 was repeated, except that 20 wt% Pd(OH)2 / C (10.0 mg) was used as the catalyst. The type of solvent used in the reaction was different. A solvent with a boiling point below 50°C was used. The reaction temperature was based on the reflux temperature. The specific solvents used in each example and the conversion rate are shown in Table 3 below.

[0078] Table 3

[0079] Example Solvents Conversion rate [%] 33 Methanol 75.38 34 Ethanol 79.84 35 Ethyl acetate 68.72 36 Acetonitrile 69.54 37 Tetrahydrofuran 65.37 38 Dichloromethane 33.65 39 Ethylene dichloride 45.38 40 n-Heptane 21.57 41 Xylene 83.51

[0080] Examples 42-47 (reductive amination reaction, step 2)

[0081] The method of Example 19 was repeated, except that 20 wt% Pd(OH)2 / C (10.0 mg) was used as a catalyst, the reaction temperature was 70°C, and the reaction time was different. The reaction time and conversion rate of each example are shown in Table 4 below.

[0082] Table 4

[0083] Example Reaction time [h] Conversion rate [%] 42 4.0 73.53 43 6.0 86.68 44 8.0 94.11 45 10.0 96.36 46 12.0 97.93 47 24.0 98.75

[0084] Example 48 (Cyclization reaction, step 3)

[0085] In a 25mL flask, 2-(3-trifluoromethylphenyl)malonic acid (0.276 g, 1.0 mmol), N,N-dimethylformamide (1 drop), and dichloromethane (5.0 mL) were added, and stirred in an ice-water bath for 15 min; oxalyl chloride (1.27 g, 10.0 mmol) was slowly added dropwise to the reaction flask, and after the addition, stirring was continued for 30 min in an ice-water bath, and then the temperature was slowly raised to room temperature and stirred at room temperature for 1 h; after the reaction was completed, all solvents and unreacted oxalyl chloride were removed using a rotary evaporator, and then dichloromethane (3.0 mL) was added to prepare a 2-(3-trifluoromethylphenyl)malonyl chloride solution, which was temporarily stored under a nitrogen environment.

[0086] Stir N-2-pyridine-5-pyrimidinemethylamine (0.186g, 1.0mmol), triethylamine (0.204g, 2.0mmol), and dichloromethane (5.0mL) in an ice-water bath; when the temperature drops to 0-3°C, keep the temperature unchanged, add 2-(3-trifluoromethylphenyl)malonyl chloride solution, and continue stirring for 2h; after the reaction is completed, add 10.0mL of ice water, use a separatory funnel to separate the organic phase; extract the aqueous phase with ethyl acetate (5mL) three times, combine the organic phases, and dry with anhydrous sodium sulfate for 1h; filter, rinse the filter cake with ethyl acetate (5mL) three times; distill the filtrate under reduced pressure to obtain a crude trifluorophenylpyrimidine; separate and purify by column chromatography, and the eluent is ethyl acetate → ethyl acetate: methanol = 20:1-5:1. After separation and purification, vacuum dry for 24h and seal for storage. According to HPLC detection, the conversion rate is 54.49% and the yield is 43%.

[0087] Examples 49-62 (Cyclization reaction, step 3)

[0088] The operation is similar to that of Example 48. The difference is that the type and amount of the base, the reaction temperature, the reaction time, the type and amount of the reaction solvent are different. The conversion rate is shown in Table 5 below.

[0089] Table 5

[0090]

[0091]

[0092] Example 63 (Cyclization reaction, step 3)

[0093] In a 25mL flask, 2-(3-trifluoromethylphenyl)malonic acid (0.276 g, 1.0 mmol), N,N-dimethylformamide (1 drop), and dichloromethane (5.0 mL) were added, and stirred in an ice-water bath for 15 min; oxalyl chloride (1.27 g, 10.0 mmol) was slowly added dropwise to the reaction flask, and after the addition, stirring was continued for 30 min in an ice-water bath, and then the temperature was slowly raised to room temperature and stirred at room temperature for 1 h; after the reaction was completed, all solvents and unreacted oxalyl chloride were removed using a rotary evaporator, and then dichloromethane (3.0 mL) was added to prepare a 2-(3-trifluoromethylphenyl)malonyl chloride solution, which was temporarily stored under a nitrogen environment.

[0094] Stir N-2-pyridine-5-pyrimidinemethylamine (0.186g, 1.0mmol), triethylamine (0.204g, 2.0mmol), and tetrahydrofuran (5.0mL) in an ice-water bath; when the temperature drops to 0-3°C, keep the temperature unchanged, add 2-(3-trifluoromethylphenyl)malonyl chloride solution, and continue stirring for 2h; after the reaction is completed, add 10.0mL of ice water, use a separatory funnel to separate the organic phase; extract the aqueous phase with ethyl acetate (5mL) three times, combine the organic phases, and dry with anhydrous sodium sulfate for 1h; filter, rinse the filter cake with ethyl acetate (5mL) three times; distill the filtrate under reduced pressure to obtain a crude trifluorophenylpyrimidine; separate and purify by column chromatography, and the eluent is ethyl acetate → ethyl acetate: methanol = 20:1-5:1. After separation and purification, vacuum dry for 24h and seal for storage. The yield is 36% as determined by HPLC.

[0095] Example 64 (Schiff base reaction-reductive amination reaction, steps 1 and 2)

[0096] 2-aminopyridine (0.95 g, 10.0 mmol), pyrimidine-5-carboxaldehyde (1.10 g, 10.0 mmol), Molecular sieve (500.0 mg) and toluene (100.0 mL) were placed in a pre-dried 250 mL flask; the flask was sealed and heated to 60 ° C in an oil bath for 12 h. After the reaction was completed, the temperature was naturally lowered to room temperature, 50.0 mg of 20 wt% Pd (OH) 2 / C catalyst was added to the flask, nitrogen replaced the gas 3 times, and then hydrogen replaced 3 times; a hydrogen balloon was used to continuously supply hydrogen to the reaction system; heated to 70 ° C and kept warm for 12 h. After the reaction was completed, nitrogen replaced 3 times, filtered, and diatomaceous earth was used for filtration, and the filter cake was washed three times with toluene (5 mL); after combining the organic phases, the solvent was removed by reduced pressure distillation to obtain a light yellow solid with a yield of 97%, and the solvent was recycled after recovery.

[0097] Example 65 (Schiff base reaction-reductive amination reaction, steps 1 and 2)

[0098] 2-aminopyridine (0.95 g, 10.0 mmol), pyrimidine-5-carboxaldehyde (1.10 g, 10.0 mmol), Molecular sieve (500.0 mg) and anhydrous tetrahydrofuran (100.0 mL) were placed in a pre-dried 250 mL flask; the flask was sealed and heated to 60 ° C in an oil bath and kept warm for 12 hours. After the reaction was completed, the temperature was naturally lowered to room temperature, 50.0 mg of 20wt% Pd(OH)2 / C catalyst was added to the flask, nitrogen replaced the gas 3 times, and then hydrogen replaced 3 times; a hydrogen balloon was used to continuously supply hydrogen to the reaction system; heated to 70 ° C and kept warm for 12 hours. After the reaction was completed, nitrogen was replaced 3 times, filtered, and diatomaceous earth was used for filtration. The filter cake was washed three times with anhydrous tetrahydrofuran (5 mL); after combining the organic phases, the solvent was removed by vacuum distillation to obtain a light yellow solid with a yield of 85%. The solvent was recovered and recycled. .

[0099] Example 66 (Schiff base reaction-reductive amination reaction, steps 1 and 2)

[0100] 2-aminopyridine (0.95 g, 10.0 mmol), pyrimidine-5-carboxaldehyde (1.10 g, 10.0 mmol), Molecular sieves (500.0 mg) and toluene (100.0 mL) were placed in a pre-dried 250 mL flask; the flask was sealed and heated to 60 ° C in an oil bath for 12 hours. After the reaction was completed, the solvent was evaporated under reduced pressure. Anhydrous methanol (100.0 mL) and 50.0 mg of 20wt% Pd(OH)2 / C catalyst were added to the residue, and the gas was replaced with nitrogen 3 times, followed by hydrogen replacement 3 times; a hydrogen balloon was used to continuously supply hydrogen to the reaction system; heated to 70 ° C and kept warm for 12 hours. After the reaction was completed, nitrogen was replaced 3 times, filtered, and diatomaceous earth was used for filtration. The filter cake was washed three times with anhydrous methanol (5 mL); after combining the organic phases, the solvent was removed by reduced pressure distillation to obtain a light yellow solid with a yield of 83%. The solvent was recovered and recycled.

[0101] Example 67 (Schiff base reaction-reductive amination reaction-cyclization reaction, steps 1, 2, 3)

[0102] In a 25mL flask, 2-(3-trifluoromethylphenyl)malonic acid (0.276 g, 1.0 mmol), N,N-dimethylformamide (1 drop), and dichloromethane (5.0 mL) were added, and stirred in an ice-water bath for 15 min; oxalyl chloride (1.27 g, 10.0 mmol) was slowly added dropwise to the reaction flask, and after the addition, stirring was continued for 30 min in an ice-water bath, and then the temperature was slowly raised to room temperature and stirred at room temperature for 1 h; after the reaction was completed, all solvents and unreacted oxalyl chloride were removed using a rotary evaporator, and then toluene (3.0 mL) was added to prepare a 2-(3-trifluoromethylphenyl)malonyl chloride solution, which was temporarily stored under a nitrogen environment.

[0103] 2-aminopyridine (0.095 g, 1.0 mmol), pyrimidine-5-carboxaldehyde (0.110 g, 1.0 mmol), Molecular sieve (100.0 mg) and toluene (10.0 mL) were placed in a pre-dried 25 mL flask; the flask was sealed and heated to 60°C in an oil bath for 12 h. After the reaction was completed, the temperature was naturally lowered to room temperature, 10.0 mg of 20 wt% Pd(OH)2 / C catalyst was added to the flask, the gas was replaced with nitrogen 3 times, and then replaced with hydrogen 3 times, and hydrogen balloons were used to continuously supply hydrogen to the reaction system; the flask was heated to 70°C and kept warm for 12 h. After the reaction, nitrogen was replaced three times, and the mixture was filtered with diatomaceous earth as the filter aid. The filtrate was transferred to a pre-dried 25 mL flask, triethylamine (0.204 g, 2.0 mmol) was added, and the mixture was cooled to 0-3 °C in an ice-water bath. The temperature was kept constant, and 2-(3-trifluoromethylphenyl)malonyl chloride solution was added thereto, and stirring was continued for 2 h. After the reaction was completed, 10.0 mL of ice water was added, and the organic phase was separated using a separatory funnel. The aqueous phase was extracted with ethyl acetate (5 mL) three times, and the organic phases were combined and dried with anhydrous sodium sulfate for 1 h. The mixture was filtered, and the filter cake was rinsed with ethyl acetate (5 mL) three times. The filtrate was distilled under reduced pressure to obtain a crude trifluorophenylpyrimidine. The mixture was separated and purified by column chromatography, and the eluent was ethyl acetate → ethyl acetate: methanol = 20:1-5:1. After separation and purification, a yellow solid was obtained, which was vacuum dried for 24 h and sealed for storage, with a yield of 41%.

[0104] Related compound analysis data

[0105]

[0106]

[0107]

Claims

1. A method for preparing trifluorobenzoic acid, characterized in that: The method comprises the steps of: (1) in a first organic solvent, allowing 2-aminopyridine and pyrimidine-5-carboxaldehyde to undergo a Schiff base condensation reaction under the action of a first dehydrating agent to generate N-2-pyridine-5-pyrimidine imine; (2) in a second organic solvent, subjecting N-2-pyridine-5-pyrimidinemethanamine to a reductive amination reaction with hydrogen in the presence of a catalyst to generate N-2-pyridine-5-pyrimidinemethanamine; (3) In a third organic solvent, N-2-pyridine-5-pyrimidinemethylamine is reacted with 2-(3-trifluoromethylphenyl)malonyl chloride in the presence of an acid-binding agent to undergo a cyclization reaction to obtain trifluorophenylpyrimidine.

2. The method according to claim 1, characterized in that The first dehydrating agent is selected from one or more of molecular sieves, anhydrous sodium sulfate, anhydrous magnesium sulfate and color-changing silica gel; preferably, the first dehydrating agent is a molecular sieve.

3. The method according to claim 1, characterized in that Step (1) has one or more of the following characteristics: The first organic solvent is selected from one or more of n-hexane, n-heptane, petroleum ether, cyclohexane, carbon tetrachloride, methyl tert-butyl ether, isopropyl ether, toluene, xylene, dichloromethane, dichloroethane, tetrahydrofuran, ethyl acetate, chloroform, dioxane, ethanol, methanol, isopropanol and acetonitrile; preferably, the first organic solvent is toluene; The addition amount of the first dehydrating agent is 0.1 to 10% of the total mass of the first organic solvent, 2-aminopyridine and pyrimidine-5-carboxaldehyde, preferably 3 to 5%; The molar ratio of 2-aminopyridine to pyrimidine-5-carboxaldehyde is 1:(0.9-1.1), preferably 1:1; The reaction temperature is 20 to 120°C, preferably 50 to 100°C; The reaction time is 1 to 24 hours, preferably 8 to 24 hours; The initial concentration of 2-aminopyridine in the first organic solvent is 0.01 to 2.0 mol / L, preferably 0.01 to 0.5 mol / L.

4. The method according to claim 1, characterized in that In step (2), the catalyst is selected from one or more of 5-20wt% Pd(OH)2 / C, 5-20wt% Pd / C, 5wt% Pd / Al2O3 / C, Pd(OCOCH3)2, PdCl2, Ranney Ni, NiCl2, Ni(OH)2, Al-Ni and Ni / Al2O3 / SiO2; preferably, the catalyst is 5-20wt% Pd(OH)2 / C.

5. The method according to claim 1, characterized in that In step (2), a second water removal agent is also added to the reductive amination reaction.

6. The method according to claim 5, characterized in that The second dehydrating agent is selected from one or more of molecular sieves, anhydrous sodium sulfate, anhydrous magnesium sulfate and color-changing silica gel; preferably, the second dehydrating agent is a molecular sieve; and / or The added amount of the second dehydrating agent is 0.1 to 10% of the total mass of the second organic solvent and N-2-pyridine-5-pyrimidinemethoxyimine, preferably 3 to 5%.

7. The method according to claim 1, characterized in that Step (2) has one or more of the following characteristics: The second organic solvent is selected from one or more of toluene, xylene, dichloromethane, dichloroethane, tetrahydrofuran, ethyl acetate, dioxane, ethanol, methanol, isopropanol and acetonitrile; preferably, the second organic solvent is selected from one or more of toluene, tetrahydrofuran, acetonitrile, methanol and ethanol; preferably, the second organic solvent is toluene; The hydrogen pressure is 0.1 to 5.0 MPa, preferably 0.1 to 3.0 MPa; The amount of the catalyst added is 0.5-10% of the mass of N-2-pyridine-5-pyrimidinemethoxyimine, preferably 1-8%; The reaction temperature is 20 to 130°C, preferably 60 to 100°C; The reaction time is 1 to 24 hours, preferably 8 to 24 hours; The initial concentration of N-2-pyridine-5-pyrimidinemethanimine in the second organic solvent is 0.01 to 2.0 mol / L, preferably 0.05 to 1.0 mol / L.

8. The method according to claim 1, characterized in that The step (3) has one or more of the following features: The third organic solvent is selected from one or more of n-hexane, n-heptane, petroleum ether, cyclohexane, carbon tetrachloride, toluene, xylene, dichloromethane, dichloroethane and tetrahydrofuran; preferably, the third organic solvent is selected from one or more of toluene, dichloromethane and tetrahydrofuran; The acid-binding agent is selected from one or more of triethylamine, ethylenediamine, pyridine, piperidine, N,N-diisopropylethylamine, 1,8-diazobispiro[5.4.0]undec-7-ene, sodium carbonate, sodium acetate, potassium carbonate, calcium carbonate, sodium hydroxide, potassium hydroxide and AMBERSEP 900(OH); preferably, the acid-binding agent is triethylamine; The molar ratio of the acid binding agent to N-2-pyridine-5-pyrimidinemethoxyimine is (1-4):1, preferably (2-3):1; The initial concentration of N-2-pyridine-5-pyrimidinemethylamine in the third organic solvent is 0.01 to 5.0 mol / L, preferably 0.1 to 2.0 mol / L; The reaction temperature is -10 to 50°C, preferably 0 to 30°C; The reaction time is 0.5 to 8 hours, preferably 0.5 to 3 hours.

9. The method according to claim 9, characterized in that 2-(3-trifluoromethylphenyl)malonyl chloride is prepared by reacting 2-(3-trifluoromethylphenyl)malonic acid and oxalyl chloride; and / or, 2-(3-trifluoromethylphenyl)malonyl chloride is prepared and used immediately.

10. The method according to claim 1, characterized in that The product N-2-pyridine-5-pyrimidinemethanimine of step (1) is directly introduced into step (2) for reaction without separation.

Images