Synthesis method and application of 3-trifluoromethyl-2-pyridine sulfonamide

Abstract

The invention belongs to the technical field of organic chemical synthesis, and relates to a synthesis method and application of 3-trifluoromethyl-2-pyridine sulfonamide. According to the synthesis method, an oxime ester compound derived from 3-trifluoromethyl-2-pyridine carboxylic acid, a sulfur dioxide reagent, an additive and a photocatalyst are subjected to a reaction in a solvent under the photocatalysis condition, and the 3-trifluoromethyl-2-pyridine sulfonamide is obtained. According to the method, the oxime ester compound derived from the 3-trifluoromethyl-2-pyridine carboxylic acid reacts with the sulfur dioxide reagent under the photocatalytic condition, then modification is further carried out, the corresponding 3-trifluoromethyl-2-pyridine sulfonamide can be efficiently constructed, the reaction steps are short, the conditions are mild, operation is easy, and substrate compatibility is good; the reaction post-treatment is convenient, an additional metal reagent is not needed, pyrimidulfuron-methyl can be conveniently and efficiently synthesized, and the method has wide pharmaceutical chemistry and industrial synthesis values.

Description

Technical Field

[0001] The invention belongs to the technical field of organic chemical synthesis, and specifically relates to a synthesis method of 3-trifluoromethyl-2-pyridinesulfonamide and an application of the synthesis method of the herbicide flazasulfuron-methyl. Background Art

[0002] Flazasulfuron, also known as N-((4,6-dimethoxypyrimidin-2-yl)-3-trifluoromethyl-2-pyridinesulfonamide)-urea, is a type of sulfonamide herbicide developed by Ishihara Industrial Chemical Company in Japan in the 1980s. It is widely used as a selective herbicide for grapes, citrus, sugarcane, olives and golf turf. It is mainly used for selective killing of broadleaf weeds, sedges and grass weeds. It is widely used in China, Japan, France, Brazil and other countries.

[0003] There are mainly the following methods for the synthesis of pyrimidinsulfone: one is to obtain it by the reaction of 3-trifluoromethyl-2-pyridinesulfonamide and 2-((phenoxycarbonyl)amino)-4,6-dimethoxypyrimidine (Zhuang, Z.; Sun, Y.; Zhong, Y.; He, Q.; Zhang, X.; Yang, C. Org. Lett. 2024, 26, 713.); the other is to obtain it by the reaction of 3-trifluoromethyl-2-pyridinesulfonamide and phenol carbonate to generate (4,6-dimethoxy Pyrimidine-2-yl)-carbamic acid phenol ester, and then react with 2-amino-4,6-dimethoxypyrimidine to obtain the corresponding pyrimidinsulfuron (Fumio, K.; Takahiro, H.; Nobuyuki, S.; Chimoto, H.; Kouji, H.; Toshio, S.; Kouji, M. EP0184385A2); the third is the reaction of 3-trifluoromethyl-2-pyridinesulfonamide with 2-isocyanato-4,6-dimethoxypyrimidine to obtain pyrimidinsulfuron. The above three synthetic routes all require the use of 3-trifluoromethyl-2-pyridinesulfonamide, and for the synthesis of this compound, currently it is mainly based on 2-chloro-3-trifluoromethylpyridine as a raw material and thiourea, NaHS or Na 2 S 2 O 3The reaction generates 2-mercapto-3-trifluoromethylpyridine; then an oxidation reaction occurs under chlorine conditions to generate the corresponding 3-trifluoromethyl-2-pyridinesulfonyl chloride, which then undergoes an ammonolysis reaction with ammonia water to generate the corresponding 3-trifluoromethyl-2-pyridinesulfonamide. The traditional synthesis route requires multiple steps of violent reactions, which will produce thiol products with a pungent odor, and use toxic chlorine as an oxidant. The last step also requires the use of an irritating reagent, ammonia water. Therefore, there are usually problems such as long synthesis steps, harsh reaction conditions, and post-treatment that produces a large amount of wastewater and waste gas. Based on this, the field still needs to explore a method for synthesizing 3-trifluoromethyl-2-pyridinesulfonamide that is efficient, convenient, mild and green, and has good substrate compatibility and apply it to the synthesis of pyrimidinesulfonamide. Summary of the invention

[0004] The purpose of the present invention is to solve the above technical problems and provide a simple, efficient method for synthesizing 3-trifluoromethyl-2-pyridinesulfonamide in the absence of metal, as well as its application in the synthesis of pyrimidinesulfonamide.

[0005] The technical solution adopted by the present invention to solve its technical problem is:

[0006] A method for synthesizing 3-trifluoromethyl-2-pyridinesulfonamide comprises the following steps: under the protection of an inert gas, using an oxime ester compound derived from 3-trifluoromethyl-2-pyridinecarboxylic acid, a sulfur dioxide reagent, an additive and a photocatalyst, performing a photochemical reaction in a solvent and under illumination conditions, and performing in-situ hydrolysis to obtain the corresponding 3-trifluoromethyl-2-pyridinesulfonamide.

[0007] Preferably, the reaction formula of the reaction is as follows:

[0008]

[0009] In the formula, Ar 1 ,Ar 2 Each independently, or, Ar 1 ,Ar 2 Connected to form a polycyclic ring with C5-C6 being unsubstituted or substituted by O and / or N atoms;

[0010] Ar 1 ,Ar 2At least one selected from phenyl substituted or unsubstituted by a substituent, and a heteroaromatic ring substituted or unsubstituted by a substituent, wherein the heteroaromatic ring is selected from one of a five-membered to six-membered aromatic ring containing a heteroatom, and the heteroatom is selected from at least one of a nitrogen atom, an oxygen atom, and a sulfur atom; the substituent is selected from at least one of an electron-withdrawing group and an electron-donating group; the electron-withdrawing group is selected from at least one of a fluorine, chlorine, bromine, trifluoromethyl, a C1-C16 alkyl acyl, and a C1-C16 alkoxy substituent group, and the electron-donating group is selected from at least one of a C1-C16 alkyl and a C1-C16 alkoxy substituent group;

[0011] “SO 2 " is sulfur dioxide reagent.

[0012] Preferably, the solvent is at least one of ethyl acetate, acetonitrile and dichloromethane, more preferably acetonitrile.

[0013] Preferably, the sulfur dioxide reagent is at least one of sulfur dioxide gas, sulfur dioxide ethyl solution, and bis(sulfur dioxide)-1,4-diazabicyclo[2.2.2]octane adduct. The reaction can be achieved with good results under the sulfur dioxide reagent, while other conventional sulfur dioxide reagents such as K 2 S 2 O 5 、Na 2 S 2 O 5 、NaHSO 3 The above methods do not generate any product, and thus are not suitable for the reaction of the present invention.

[0014] Preferably, the additive is at least one of ammonium fluoride, ammonium chloride, ammonium bromide, ammonium sulfate, ammonium perchlorate, ammonium acetate, ammonium trifluoroacetate, ammonium trifluoromethanesulfonate and potassium dihydrogen phosphate.

[0015] Preferably, the photocatalyst is at least one of BP, DiF-BP, DiCl-BP, DiBr-BP and DiOMe-BP. The catalyst structure is as follows:

[0016]

[0017] Preferably, the molar ratio of the oxime ester compound derived from 3-trifluoromethyl-2-pyridinecarboxylic acid, the sulfur dioxide reagent, the additive and the photocatalyst is 1:(0.7-2):(1-3):(0.01-0.1), more preferably, the molar ratio of the oxime ester compound derived from 3-trifluoromethyl-2-pyridinecarboxylic acid, the sulfur dioxide reagent, the additive and the photocatalyst is 1:(0.8-1.2):(1-2):(0.03-0.05), more preferably, the molar ratio of the oxime ester compound derived from 3-trifluoromethyl-2-pyridinecarboxylic acid, the sulfur dioxide reagent, the additive and the photocatalyst is 1:1:1.5:0.05.

[0018] Preferably, the reaction temperature is 15-80°C, and the reaction time is 10-48h; more preferably, the reaction temperature is 20-50°C, and the reaction time is 24-48h; more preferably, the reaction temperature is 40-50°C, and the reaction time is 36h.

[0019] Preferably, the light source of the reaction is a 360-400nm lamp bead, more preferably a 380-390nm wavelength lamp bead.

[0020] Preferably, the specific reaction conditions of the reaction are as follows:

[0021] The oxime ester compound derived from 3-trifluoromethyl-2-pyridinecarboxylic acid, the sulfur dioxide reagent, the additive and the photocatalyst are charged into a dry reaction tube in a molar ratio of 1:1.0:1.5:0.05, and the solvent acetonitrile is added under the protection of an inert gas, the amount of acetonitrile added is 20 mL / mmol based on the oxime ester compound derived from the carboxylic acid, and the reaction is carried out for 36 hours under irradiation with a lamp bead with a wavelength of 390 nm at 40-50° C., and 3-trifluoromethyl-2-pyridinesulfonamide is obtained after post-treatment.

[0022] More preferably, the specific reaction conditions of the reaction are as follows:

[0023] The oxime ester compounds derived from 3-trifluoromethyl-2-pyridinecarboxylic acid, bis(sulfur dioxide)-1,4-diazabicyclo[2.2.2]octane adduct, ammonium bromide and photocatalyst DiOMe-BP are charged into a dry reaction tube in a molar ratio of 1:1.0:1.5:0.05, and the solvent acetonitrile is added under the protection of inert gas. The amount of acetonitrile added is 20mL / mmol based on the oxime ester compounds derived from carboxylic acid. The reaction is carried out at 40-50°C and irradiated with a lamp bead with a wavelength of 390nm for 36 hours. After post-treatment, 3-trifluoromethyl-2-pyridinesulfonamide is obtained.

[0024] More preferably, the inert gas is any one or more of nitrogen, argon and helium.

[0025] More preferably, the post-treatment is extraction, washing, drying, concentration and subsequent separation and purification by column chromatography of the reaction solution; specifically, the reaction solution is extracted with ethyl acetate three times, the organic phase is collected and washed twice with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure, and a mixture of petroleum ether and ethyl acetate (volume ratio = 1:1) is used as the mobile phase for column chromatography separation to obtain the corresponding sulfonamide compounds.

[0026] The present invention also provides an application of any one of the above-mentioned synthesis methods of 3-trifluoromethyl-2-pyridinesulfonamide in the field of pyrimidinesulfonamide synthesis.

[0027] Preferably, the application is to use 3-trifluoromethyl-2-pyridinesulfonamide synthesized by any of the above-mentioned synthesis methods as a raw material, and react it with 2-((phenoxycarbonyl)amino)-4,6-dimethoxypyrimidine to obtain the corresponding pyrimidosulfuron.

[0028] Preferably, the reaction formula is as follows:

[0029]

[0030] The method of the invention comprises the following steps: in a solvent, an oxime ester compound derived from 3-trifluoromethyl-2-pyridinecarboxylic acid, a sulfur dioxide reagent such as bis(sulfur dioxide)-1,4-diazabicyclo[2.2.2]octane adduct, an additive such as ammonium bromide and a photocatalyst such as DiOMe-BP are used to homolytically split the oxime ester compound derived from 3-trifluoromethyl-2-pyridinecarboxylic acid under photocatalytic conditions to generate an imine-type nitrogen free radical and a 3-trifluoromethyl-2-pyridine free radical intermediate; then, the pyridine free radical undergoes a free radical addition reaction with the sulfur dioxide reagent to generate a corresponding pyridine-substituted sulfonyl free radical; then, the sulfonyl free radical undergoes a free radical-free radical coupling reaction with the imine free radical to generate a corresponding sulfonyl imide structure; and finally, a hydrolysis reaction is carried out under the condition of an additive such as ammonium bromide, so that the corresponding 3-trifluoromethyl-2-pyridine sulfonamide can be efficiently constructed. The resulting 3-trifluoromethyl-2-pyridinesulfonamide reacts with 2-((phenoxycarbonyl)amino)-4,6-dimethoxypyrimidine to give the corresponding pyrimidosulfuron.

[0031] Compared with the prior art, the beneficial effects of the present invention are mainly embodied in that: the present invention synthesizes the key intermediate 3-trifluoromethyl-2-pyridinesulfonamide by reacting an oxime ester compound derived from 3-trifluoromethyl-2-pyridinecarboxylic acid and a sulfur dioxide reagent under additive and photocatalytic conditions. The corresponding pyrimidinesulfonamide can then be obtained through a simple reaction. The reaction conditions are mild, the steps are short, the operation is simple, the functional group compatibility is good, no metal reagents are required, it is green and environmentally friendly, and the post-processing is convenient and simple; the reaction only requires two steps, and no expensive catalyst is required, and the commercially available pesticide pyrimidinesulfonamide can be quickly synthesized, which has broad medicinal chemistry and industrial synthesis value. DETAILED DESCRIPTION

[0032] In order to better clarify and understand the purpose, process scheme and advantages of the present invention, the technical scheme and implementation method of the present invention are further described clearly, completely and in detail through specific examples. It should be noted that the embodiments described in the present invention are implemented on the premise of the technical scheme of the present invention, and detailed implementation methods and specific operation processes are given, but they are only part of the embodiments of the present invention, not all of the embodiments. The specific implementation methods described are limited to explaining and interpreting the present invention, and do not limit the present invention. Based on the embodiments in the present invention, all other implementation methods obtained by ordinary technicians in this field without making creative work are within the scope of protection of the present invention.

[0033] The experimental methods and conditions used in the embodiments of the present invention are conventional methods and conventional conditions unless otherwise specified. The materials, reagents or instruments used in the embodiments, unless otherwise specified, can be obtained from commercial sources or prepared by conventional methods. The reaction conditions embodied in the content of the invention of the present invention can achieve the reaction and obtain the product of the expected effect. Due to space limitations, some embodiments are listed below to further illustrate the advantages of the technical solution of the present invention.

[0034] The temperature in the embodiments of the present invention is 20-50°C, including 20°C, 25°C, 30°C, 35°C, 40°C, 50°C, etc.

[0035] Example 1

[0036]

[0037] At room temperature, 0.2 mmol of diphenylmethanone O-(3-(trifluoromethyl)picolinoyl)oxime (1a), 0.2 mmol of bis(sulfur dioxide)-1,4-diazabicyclo[2.2.2]octane adduct, 0.3 mmol of ammonium chloride, and 0.01 mmol of photocatalyst DiOMe-BP were added to a dry test tube. The reaction tube was plugged with a stopper and placed under nitrogen protection. 4.0 mL of acetonitrile was then added. The reaction was irradiated with a 390 nm wavelength lamp at 40-50°C for 36 hours. After TLC monitoring of the complete reaction, the reaction solution was poured into ethyl acetate (20 mL) and extracted (3 times). The organic phase was washed twice with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. A mixture of petroleum ether and ethyl acetate (volume ratio = 1:1) was used as the mobile phase for column chromatography separation to obtain the corresponding 3-trifluoromethyl-2-pyridinesulfonamide (2a) (Example 1) with a yield of 65%.

[0038] Structural characterization of compound example 1 product 2a: 1 HNMR (400 MHz, DMSO-d 6 )δ(ppm)8.97(d,J=4.4Hz,1H),8.46(d,J=7.8Hz,1H),7.88(dd,J=7.8,4.4Hz,1H),7.79(br,2H);

[0039] 13 CNMR (100MHz, DMSO-d 6 )δ (ppm) 157.4, 151.9, 137.5 (q, J = 5.7Hz), 126.9, 122.6 (q, J = 273.5Hz), 122.5 (q, J = 34.5Hz).

[0040] Embodiment 2-25:

[0041] On the basis of Example 1, the reaction conditions were changed. The reaction conditions and results are shown in the following table:

[0042]

[0043]

[0044] The catalyst structure is as follows:

[0045]

[0046] As can be seen from the above table, in terms of materials: a combination of multiple materials such as photocatalysts, solvents and bis(sulfur dioxide)-1,4-diazabicyclo[2.2.2]octane adducts is required to obtain product 2a. In terms of the amount of bis(sulfur dioxide)-1,4-diazabicyclo[2.2.2]octane adducts, as shown in Examples 2-6, good yields can be achieved, but 1.0 equivalents have the best effect. In terms of additive selection, as shown in Examples 7-12, other additives such as ammonium fluoride, ammonium chloride, ammonium sulfate, and potassium dihydrogen phosphate can also have good effects, but ammonium bromide has the best effect, and it is basically difficult to detect the target product without adding additives. In terms of photocatalyst selection, as shown in Examples 13-16, other photocatalysts such as BP, DiF-BP, DiCl-BP and DiBr-BP can also react, but DiOMe-BP has the best effect. In terms of solvent selection, as shown in Examples 17 and 18, acetonitrile has the best effect. In terms of the selection of the sulfur dioxide reagent source, as shown in Examples 19 and 20, SO 2The acetonitrile solution and gaseous sulfur dioxide were used to replace the bis(sulfur dioxide)-1,4-diazabicyclo[2.2.2]octane adduct, and the reaction still had a good effect. When other conventional sulfur dioxide reagents such as K 2 S 2 O 5 、Na 2 S 2 O 5 、NaHSO 3 In terms of light source selection, for example, as shown in Example 21, replacing the 390nm light source with a 427nm light source has a very poor effect. In terms of temperature selection, for example, as shown in Examples 21-25, lowering the temperature and raising the temperature still have good effects.

[0047] Examples 26-35

[0048] At room temperature, 0.2 mmol of oxime ester substrate 1, 0.2 mmol of bis(sulfur dioxide)-1,4-diazabicyclo[2.2.2]octane adduct, 0.3 mmol of ammonium bromide, and 0.01 mmol of photocatalyst DiOMe-BP were added to a dry test tube, and the reaction tube was plugged with a stopper and placed under nitrogen protection. Then 4.0 mL of acetonitrile was added, and the reaction was irradiated with a 390 nm wavelength lamp bead at 40-50°C for 36 hours. After TLC monitoring of the complete reaction, the reaction solution was poured into ethyl acetate (20 mL) for extraction (3 times), and the organic phase was washed twice with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. A mixture of petroleum ether and ethyl acetate (volume ratio = 1:1) was used as the mobile phase for column chromatography separation to obtain the corresponding 3-trifluoromethyl-2-pyridinesulfonamide (2a) (Examples 26-35).

[0049]

[0050] It can be seen from the above results that in terms of substrate adaptability, whether it is an unprotected oxime substrate (Example 26, 1b), or an oxime substituted with a dimethyl group on an imine (Example 27, 1c) or an oxime substituted with an arylmethyl group (Examples 28 and 29, 1d and 1e), the reaction effect is very poor, and no obvious product is generated. When other oxime substrates (Examples 30-37, 1f-1m) are used, the reaction can be carried out with good yields.

[0051] Embodiment 38

[0052]

[0053] At room temperature, 1.0 mmol of 3-trifluoromethyl-2-pyridinesulfonamide (2a), 1.0 mmol of 2-((phenoxycarbonyl)amino)-4,6-dimethoxypyrimidine (3a), and 1.0 mmol of triethylamine were added to a dry test tube, followed by the addition of 2 ml of acetonitrile as solvent. The mixture was stirred at room temperature and monitored by TLC. After the reaction was completed, acetonitrile and triethylamine were removed by distillation under reduced pressure. 10 mL of water was added, the pH was adjusted to 3-4 with 2N HCl, and pyrimidosulfuron (3a, 327 mg, yield 80%) was obtained by filtration.

[0054] Structural characterization of compound example 38: 1 HNMR (400 MHz, DMSO-d 6 )δ(ppm)13.00(br,1H),8.80(dd,J=4.6,1.0Hz,1H),8.32-8.18(m,1H),7.68(dd,J=7.6,4.6,Hz,1H),7.43(br,1H),5.82(s,1H),3.95(s,6H),

[0055] 13 CNMR (100MHz, DMSO-d 6 )δ(ppm)171.4,156.1,153.2,152.6,149.2,138.3(q,J=5.5Hz),128.3,123.5(q,J=35.3Hz),122.2(q,J=273.9Hz),83.8,54.6.

[0056] The above-described embodiments are only preferred solutions of the present invention and are not intended to limit the present invention in any form. Other variations and modifications are possible without exceeding the technical solutions described in the claims.

Claims

1. A method for synthesizing 3-trifluoromethyl-2-pyridinesulfonamide, characterized in that: The synthesis method is to use oxime ester compounds derived from 3-trifluoromethyl-2-pyridinecarboxylic acid, sulfur dioxide reagent, additives and photocatalysts under a protective atmosphere, perform photochemical reactions in a solvent and under light conditions, and perform in-situ hydrolysis to obtain the corresponding 3-trifluoromethyl-2-pyridinesulfonamide. The reaction formula of the reaction is shown below: In the formula, Ar 1 ,Ar 2 Each independently, or, Ar 1 ,Ar 2 Connected to form a polycyclic ring with C5-C6 being unsubstituted or substituted by O and / or N atoms; Ar 1 ,Ar 2 They are respectively selected from at least one of a phenyl group substituted or unsubstituted by a substituent, and a heteroaromatic ring substituted or unsubstituted by a substituent, wherein the heteroaromatic ring is selected from one of a five-membered to six-membered aromatic ring containing a heteroatom, and the heteroatom is selected from at least one of a nitrogen atom, an oxygen atom, and a sulfur atom; the substituent is selected from at least one of an electron-withdrawing group and an electron-donating group; the electron-withdrawing group is selected from at least one of a fluorine, a chlorine, a bromine, a trifluoromethyl, a C1-C16 alkyl acyl, and a C1-C16 alkoxy acyl substituent group, and the electron-donating group is selected from at least one of a C1-C16 alkyl and a C1-C16 alkoxy group.

2. A method for synthesizing 3-trifluoromethyl-2-pyridinesulfonamide according to claim 1, characterized in that: The solvent is at least one of ethyl acetate, acetonitrile and dichloromethane.

3. A method for synthesizing 3-trifluoromethyl-2-pyridinesulfonamide according to claim 1, characterized in that: The sulfur dioxide reagent is at least one of sulfur dioxide gas, sulfur dioxide ethyl solution, and bis(sulfur dioxide)-1,4-diazabicyclo[2.2.2]octane adduct.

4. A method for synthesizing 3-trifluoromethyl-2-pyridinesulfonamide according to claim 1, characterized in that: The additive is at least one of ammonium fluoride, ammonium chloride, ammonium bromide, ammonium sulfate, ammonium perchlorate, ammonium acetate, ammonium trifluoroacetate, ammonium trifluoromethanesulfonate and potassium dihydrogen phosphate.

5. A method for synthesizing 3-trifluoromethyl-2-pyridinesulfonamide according to claim 1, characterized in that: The photocatalyst is at least one of BP, DiF-BP, DiCl-BP, DiBr-BP and DiOMe-BP.

6. A method for synthesizing 3-trifluoromethyl-2-pyridinesulfonamide according to claim 1, characterized in that: The molar ratio of the oxime ester compound derived from 3-trifluoromethyl-2-pyridinecarboxylic acid, the sulfur dioxide reagent, the additive and the photocatalyst is 1:(0.7-2):(1-3):(0.01-0.1).

7. A method for synthesizing 3-trifluoromethyl-2-pyridinesulfonamide according to claim 1, characterized in that: The reaction temperature is 15-80°C, the light source is 360-400nm, and the reaction time is 10-48h.

8. A method for synthesizing 3-trifluoromethyl-2-pyridinesulfonamide according to claim 1, characterized in that: The specific reaction conditions are as follows: the oxime ester compounds derived from 3-trifluoromethyl-2-pyridinecarboxylic acid, bis(sulfur dioxide)-1,4-diazabicyclo[2.2.2]octane adduct, ammonium bromide and photocatalyst DiOMe-BP are charged into a dry reaction tube in a molar ratio of 1:1.0:1.5:0.05, and the solvent acetonitrile is added under the protection of inert gas. The amount of acetonitrile added is 20 mL / mmol based on the oxime ester compounds derived from carboxylic acid. The reaction is carried out at 40-50°C and at a wavelength of 390 nm for 36 hours to obtain 3-trifluoromethyl-2-pyridinesulfonamide.

9. Use of the synthesis method of 3-trifluoromethyl-2-pyridinesulfonamide according to any one of claims 1 to 8 in the field of pyrimidinesulfonamide synthesis.

10. Application of the synthesis method of 3-trifluoromethyl-2-pyridinesulfonamide according to claim 9 in the field of pyrimidinesulfonamide synthesis, characterized in that: The application is to use 3-trifluoromethyl-2-pyridinesulfonamide synthesized by the synthesis method as a raw material, and react it with 2-((phenoxycarbonyl)amino)-4,6-dimethoxypyrimidine to obtain pyrimidosulfuron.

Images