Synthesis method of 1, 2, 3-benzotriazine-4-ketone

Abstract

The invention relates to the field of organic synthesis, in particular to a preparation method of 1, 2, 3-benzotriazine-4-ketone, which comprises the following steps: S1, under the catalytic action of a condensing agent T3P, directly carrying out amidation reaction on anthranilic acid and methoxyamine hydrochloride to obtain 2-amino-N-methoxybenzamide; s2, under the condition of a diazotization reaction, the 2-amino-N-methoxybenzamide is converted into 3-methoxy-1, 2, 3-benzotriazine-4-ketone, and the 3-methoxy-1, 2, 3-benzotriazine-4-ketone is converted into 2-methoxy-1, 2, 3-benzotriazine-4-ketone; and S3, reducing the 3-methoxy-1, 2, 3-benzotriazine-4-ketone into the 1, 2, 3-benzotriazine-4-ketone under the condition of palladium on carbon / hydrogen gas, so as to obtain the 1, 2, 3-benzotriazine-4-ketone. The preparation method provided by the invention has the advantages of easily available raw materials, easily separated products and high yield, and is suitable for industrial production.

Description

Technical Field

[0001] The invention relates to the field of organic synthesis, and in particular to a method for preparing 1,2,3-benzotriazine-4-one. Background Art

[0002] 1,2,3-Triazinones are an important class of six-membered aromatic heterocycles containing three nitrogen atoms, characterized by three consecutive nitrogen atoms in the six-membered ring. The 1,2,3-triazinones skeleton has received very little attention, and only a few 1,2,3-triazine skeletons are available to date, which may be partly due to its inherent instability. 1,2,3-Benzotriazin-4-one is an oxo derivative of 1,2,3-triazinone, which is a bicyclic aromatic structure consisting of 7 carbon atoms and 3 nitrogen atoms. This compound is a good pharmacogen and has a variety of biological activities. 1,2,3-Benzotriazin-4-one can be used as a heterocyclic skeleton associated with a wide range of pesticide activities. For example, compound (V) exhibits plant growth regulation and insecticidal activities. Compound (VI) has nematicidal activity against Rhabditis elegans. With the increasing reports on the chemical properties and various applications of 1,2,3-benzotriazine-4-one, the high-yield synthesis route of 1,2,3-benzotriazine-4-one (I) has become a hot topic, which has also prompted us to study its high-yield synthesis route.

[0003]

[0004] At present, there are mainly two reported methods for synthesizing 1,2,3-benzotriazine-4-one (I):

[0005] Method 1: NaNO2 reacts with HCl to obtain nitrous acid, which is then diazotized with o-aminobenzoic acid amide to directly convert into 1,2,3-benzotriazine-4-one (I). This method has the problems of incomplete reaction of the raw materials, the generation of a large number of by-products, and limited tolerance of functional groups (Bioorg.Med.Chem.Lett.2017,27,2641–2644).

[0006]

[0007] Method 2: In 2008, Song Qiuling's research group reported a halogen-mediated oxidative rearrangement reaction to synthesize 1,2,3-benzotriazine-4-one (I) from 3-aminoindazole. This method has a low yield and requires column chromatography to separate the product, which is not suitable for industrial production conditions (Org. Lett. 2018, 20, 6494-6497).

[0008]

[0009] Based on the above problems, a better synthesis route of 1,2,3-benzotriazine-4-one needs to be developed. Summary of the invention

[0010] 1. Technical issues to be resolved

[0011] In view of the above-mentioned shortcomings and deficiencies of the prior art, the present invention provides a method for preparing 1,2,3-benzotriazine-4-one, which has easily available raw materials, easy separation of products and high yield, and solves the technical problems of low reaction completion, low yield, great difficulty in product separation and conditions unsuitable for industrial production in the existing synthesis methods.

[0012] (II) Technical solution

[0013] The present invention provides a method for preparing 1,2,3-benzotriazine-4-one, which comprises the following steps:

[0014] S1. Under the catalytic action of condensation agent T3P, anthranilic acid and methoxyamine hydrochloride directly undergo amidation reaction to obtain 2-amino-N-methoxybenzamide;

[0015] S2, under diazotization reaction conditions, 2-amino-N-methoxybenzamide is converted into 3-methoxy-1,2,3-benzotriazine-4-one;

[0016] S3. 3-methoxy-1,2,3-benzotriazine-4-one is reduced to 1,2,3-benzotriazine-4-one under palladium carbon / hydrogen conditions.

[0017] According to a preferred embodiment of the present invention, in S1, the reaction temperature is room temperature, the reaction time is 3-8h (preferably 6h), and the reaction solvent is dichloromethane, chloroform, 1,2-dichloroethane, acetonitrile, cyclohexane, toluene, tetrahydrofuran, MDF or DMSO, among which dichloromethane is most preferred, which has moderate polarity, does not react with raw materials and products and can dissolve them well; preferably, an organic base is also added to the reaction solvent to provide an alkaline environment.

[0018] According to a preferred embodiment of the present invention, in S1, the organic base is pyridine or triethylamine. Such bases can keep anthranilic acid and methoxyamine hydrochloride from reacting and provide an alkaline environment.

[0019] According to a preferred embodiment of the present invention, in S1, the reaction solvent is dichloromethane, the organic base is pyridine, the reaction temperature is room temperature, and the molar ratio of o-aminobenzoic acid, methoxyamine hydrochloride, T3P, and pyridine is 1:1.2-1.25:1.5-1.6:2-2.5, more preferably 1:1.2:1.5:2.

[0020] According to a preferred embodiment of the present invention, in S2, the diazotization reaction conditions are: water is used as the reaction solvent, and the molar ratio of 2-amino-N-methoxybenzamide to NaNO2 and HCl is 1:2-2.1:2.1-2.5, more preferably 1:2:2.5; the reaction temperature is 0-5°C (preferably 0°C, carried out under ice bath conditions); the reaction time is 1.5-2.5h (preferably 2h).

[0021] The diazotization reaction conditions are: This reaction usually involves the reaction of an aromatic primary amine (Ar-NH2) with nitrous acid under acidic conditions to form a diazonium salt (Ar-N2+X-). Sodium nitrite (NaNO2) is dissolved in water, which decomposes into nitrous acid (HNO2) under acidic conditions. Commonly used acids include dilute hydrochloric acid (HCl) to provide the necessary acidic environment to promote the reaction. Diazotium salts are unstable at higher temperatures and are easily decomposed. In order to maintain low temperatures, the reaction is often carried out in an ice bath.

[0022] According to a preferred embodiment of the present invention, in S3, the reaction temperature is room temperature, the reaction time is 1-2h (preferably 1h); the reaction solvent is ethanol, methanol, isopropanol, tetrahydrofuran or dioxane. Considering the safety of the solvent, reaction inertness and easy post-processing, ethanol is most preferred.

[0023] (III) Beneficial effects

[0024] The technical effects of the present invention are:

[0025] (1) The raw materials used in the present invention are o-aminobenzoic acid and methoxyamine hydrochloride, which are easy to obtain, have low raw material costs, are easy to separate the product, and have a high yield (yield of more than 90%). Compared with the prior art method of column chromatography separation, the present invention is more suitable for industrial production. When the present invention separates the target product, after the reaction is completed, Pd / C is filtered and recovered, ethanol is removed by rotary evaporation to obtain a yellow solid, and the light yellow solid is recrystallized with ethyl acetate to obtain the target product, and the purification process is simple.

[0026] (2) Although the synthesis route of 1,2,3-benzotriazine-4-one of the present invention also includes a diazo reaction step, 2-amino-N-methoxybenzamide is more susceptible to diazo reaction than anthranilic acid amide, thereby reducing raw material residues and side reactions and improving product yield. DETAILED DESCRIPTION

[0027] In order to better explain the present invention and facilitate understanding, the present invention is described in detail below in conjunction with specific implementation methods.

[0028] The present invention provides a method for preparing 1,2,3-benzotriazine-4-one, which comprises the following steps:

[0029] S1. Under the catalytic action of condensing agent T3P, anthranilic acid (structure of formula II) and methoxyamine hydrochloride directly undergo amidation reaction to obtain 2-amino-N-methoxybenzamide (structure of formula III);

[0030] S2. Under diazotization reaction conditions, 2-amino-N-methoxybenzamide is converted into 3-methoxy-1,2,3-benzotriazine-4-one (Formula IV);

[0031] S3. 3-methoxy-1,2,3-benzotriazine-4-one is reduced to 1,2,3-benzotriazine-4-one (structure of formula I) under palladium carbon / hydrogen conditions.

[0032]

[0033] Preferably, in S1: the reaction temperature is room temperature, the reaction time is 3-8h, the reaction solvent is dichloromethane, an organic base is also added to the reaction solvent to provide an alkaline environment, the organic base is pyridine, and the molar ratio of o-aminobenzoic acid, methoxyamine hydrochloride, T3P, and pyridine is 1:1.2-1.25:1.5-1.6:2-2.5, preferably 1:1.2:1.5:2.

[0034] During the reaction, the reaction progress was detected by TLC. After the reaction was completed, post-treatment was started. Dilute hydrochloric acid solution was added to the system to adjust the pH of the reaction system to neutral, and then the system was extracted with dichloromethane for more than 3 times, and the organic phase was taken, dried with anhydrous Na2SO4 to remove moisture, and dichloromethane was removed by rotary evaporation to obtain a solid, namely 2-amino-N-methoxybenzamide.

[0035] Preferably, in S2: the diazotization reaction conditions are: water is used as the reaction solvent, and the molar ratio of 2-amino-N-methoxybenzamide to NaNO2 and HCl is 1:2-2.1:2.1-2.5, more preferably 1:2:2.5; the reaction temperature is 0-5°C (preferably 0°C); the reaction time is 1.5-2.5h (preferably 2h).

[0036] The operation of S2 is as follows: 2-amino-N-methoxybenzamide and sodium nitrite are dissolved in water, the reaction system is placed in an ice bath, then the reaction system is cooled to 0°C, HCl and water are mixed to prepare an HCl aqueous solution, the HCl aqueous solution is added dropwise to the system, and after the addition is completed, the reaction is carried out at 0°C for 1.5-2.5 hours. The degree of reaction is detected by TLC, and after the reaction is completed, post-treatment is started, ammonia water is added to adjust the system pH to 8, and then the system is extracted with dichloromethane for more than 3 times, the organic phase is taken, dried with anhydrous Na2SO4 to remove moisture, and dichloromethane is removed by rotary evaporation to obtain a solid, namely 3-methoxy-1,2,3-benzotriazine-4-one.

[0037] Preferably, in S3: the reaction temperature is room temperature, the reaction time is 1-2 h (preferably 1 h); and the reaction solvent is ethanol.

[0038] The operation of S3 is: take compound (IV) and catalyst Pd / C and dissolve them in ethanol, then evacuate the system, take a hydrogen balloon to replace the gas in the system, repeat this operation 2-4 times to make the hydrogen fill the entire reaction system, then start the reaction at room temperature, after 1-2 hours of reaction, use TLC to detect the extent of the reaction, after the reaction is completed, start post-treatment, filter the reaction system, separate Pd / C from the system, then remove ethanol to obtain a yellow solid, and recrystallize the light yellow solid with ethyl acetate to obtain a light yellow solid 1,2,3-benzotriazine-4-one.

[0039] In the prior art method 1, anthranilic acid amide undergoes a diazotization reaction to directly convert into 1,2,3-benzotriazine-4-one. However, the ortho-carboxyl group (-COOH) of anthranilic acid amide is close to the amine group (-NH2), which affects the nitrite ion (NO 2- ) Diazotization is carried out close to the amine group, which is likely to result in incomplete reaction and residual raw materials. The carboxyl group is a strong electron-withdrawing group, which will reduce the electron density of the adjacent amine group, making the amine group more difficult to be attacked by nitrite, thereby slowing down or hindering the diazotization reaction, resulting in lower reaction efficiency, and may promote the occurrence of side reactions. Under acidic conditions, the carboxyl group in anthranilic acid will also be partially protonated, further reducing its supporting effect on the amine group, increasing the complexity of the reaction and the possibility of by-product formation. Due to the above factors, the diazotization reaction of anthranilic acid amide may be more sensitive to other functional groups, such as esters, ketones, etc., which may undergo hydrolysis or other side reactions under acidic conditions, limiting the tolerance of the functional groups, making it more likely that the raw materials will not be completely reacted and by-products will be generated, and the tolerance to the functional groups is also subject to certain restrictions.

[0040] Step S2 of the present invention carries out diazo reaction with 2-amino-N-methoxybenzamide, and N-methoxy (-OCH3) is located at the ortho position of benzene ring, but it is relatively small and relatively flexible, and will not significantly hinder nitrite ion from approaching amine group, so diazotization can usually occur more smoothly.Methoxy is an electron-donating group, and it can enhance the nucleophilicity of amine group by resonance stabilization, and is conducive to the progress of diazotization reaction.This helps to improve the selectivity and efficiency of reaction, and reduces the generation of by-products.Methoxy is relatively stable under acidic conditions, and is not easy to be hydrolyzed, so the diazotization reaction of 2-amino-N-methoxybenzamide can be carried out under more extensive conditions, and reduces the risk of side reactions.Because the existence of methoxy provides additional electronic effect support, and itself is relatively stable under acidic conditions, so the diazotization reaction of the compound has better tolerance for other functional groups.The electronic effect support provided by methoxy and its own stability, therefore, diazotization reaction is more efficient and more selective in step S2 of the present invention, and diazotization reaction can be completed more effectively, and by-products are less.

[0041] The following are preferred embodiments of the present invention. The sources of the reagents in the embodiments and the related descriptions are as follows:

[0042] 1. Anthranilic acid is commercially available 99% anthranilic acid. Methoxyamine hydrochloride is commercially available 99% methoxyamine hydrochloride. Sodium nitrite is commercially available 99% sodium nitrite. Pd / C is commercially available 5% Pd / C. Dichloromethane, pyridine, concentrated hydrochloric acid and ethanol are commercially available analytical grade.

[0043] 2. The condensation agent T3P is 99% T3P purchased commercially. T3P is an active ester formed by triethylamine and propionic acid. Its full name is 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline propionate (Propylphosphonic anhydride). The commercially available product is usually provided in the form of a 50% acetonitrile solution. It is a highly efficient condensation agent and is currently mainly used in the field of peptide synthesis. The main features of T3P include: (1) High reactivity: T3P can effectively activate carboxylic acids, making them more easily react with nucleophiles such as amines and alcohols to form amide or ester bonds. (2) Mild reaction conditions: Compared with some other condensation agents, such as DCC (N,N'-dicyclohexylcarbodiimide) or EDC (1-ethyl-(3-dimethylaminopropyl)carbodiimide), T3P can work under relatively mild conditions, does not require low temperature or special equipment, and reduces the difficulty of the experiment. (3) Water solubility and stability: T3P has a certain solubility in both organic solvents and water, and is relatively stable and can be stored for a long time without decomposition. In addition, it also exhibits good chemical stability under acidic and alkaline conditions. (4) Easy to handle by-products: After the condensation reaction using T3P, the by-products produced are mainly phosphates, which are generally harmless and easy to remove by conventional methods, reducing the complexity of post-processing steps. (5) Good functional group tolerance: T3P has good tolerance to a variety of functional groups and will not easily induce unnecessary side reactions, which helps to maintain the integrity of the target molecular structure.

[0044] Example 1

[0045] This embodiment provides a method for preparing 1,2,3-benzotriazine-4-one, comprising the following steps:

[0046] (1) A process in which anthranilic acid (structure of formula II) and methoxyamine hydrochloride are directly subjected to an amidation reaction to obtain 2-amino-N-methoxybenzamide (structure of formula III).

[0047] The reaction is expressed as follows:

[0048]

[0049] The experimental operation is as follows:

[0050] Take anthranilic acid (13.71g, 100mmol) and dissolve it in 200mL dichloromethane, then add T3P (150mmol) and pyridine (15.82g, 200mmol) to the reaction system, and start stirring at room temperature for 10min. Take methoxyamine hydrochloride (10.02g, 120mmol) and add it to the reaction system in 10 batches, 1g per batch, and start stirring at room temperature after the addition is completed. After the reaction is completed for 6h, TLC detection is performed. After the reaction is completed, the post-treatment is started. Add 1mol / L HCl to the system to adjust the pH to 7, and then extract the system with 30mL dichloromethane for 5 times, take the organic phase, dry it with anhydrous Na2SO4, and rotary evaporate to obtain a solid (16.0g, 96.38mmol), with a yield of 96.4%.

[0051] (2) Under diazo reaction conditions, 2-amino-N-methoxybenzamide is converted into 3-methoxy-1,2,3-benzotriazine-4-one (Formula IV). The reaction is shown below:

[0052]

[0053] The experimental operation is as follows:

[0054] Take compound (III) (16.0 g, 96.38 mmol) and sodium nitrite (13.3 g, 192.76 mmol), dissolve them in 150 mL of water, place the reaction system in an ice bath, prepare 3 mol / L HCl aqueous solution with HCl (8.79 g, 240.95 mmol), then cool the reaction system to 0°C, add 3 mol / L HCl aqueous solution to the system, and after the addition is complete, react at 0°C for 2 h. TLC detects the extent of the reaction. After the reaction is completed, post-treatment is started, and ammonia water is added to adjust the system pH to 8, and then the system is extracted 5 times with 30 mL of dichloromethane, and the organic phase is taken, dried over anhydrous Na2SO4, and rotary evaporated to obtain a solid (16.34 g, 94.45 mmol) with a yield of 98%.

[0055] (3) 3-methoxy-1,2,3-benzotriazine-4-one is reduced to 1,2,3-benzotriazine-4-one (Formula I) under palladium carbon / hydrogen conditions.

[0056] The reaction is expressed as follows:

[0057]

[0058] The experimental operation is as follows:

[0059] Compound (IV) (16.34 g, 94.45 mmol) and Pd / C (3.48 g) were dissolved in ethanol, and then the system was evacuated, and a hydrogen balloon was used to replace the gas in the system. The operation was repeated 3 times so that the hydrogen filled the entire reaction system, and then the reaction was started at room temperature. After the reaction was completed for 1 hour, the degree of reaction was detected by TLC. After the reaction was completed, post-treatment was started, the reaction system was filtered, Pd / C was separated from the system, and then ethanol was removed to obtain a yellow solid. The light yellow solid was recrystallized with ethyl acetate to obtain a light yellow solid 1,2,3-benzotriazine-4-one (13.75 g, 93.54 mmol), and the yield reached 99%. The total yield of the above three steps was 93.53%.

[0060] Product structure characterization: 1 H NMR (600MHz, DMSO-d6) δ14.94(s,1H),8.19(dd,J=7.9,1.5Hz,1H),8.16–8.11(m,1H),8.05(td,J=7.7,1.5Hz,1H),7.92–7.84(m,1H). 13 C NMR (151MHz, DMSO-d6) δ156.1,144.6,135.9,132.9,128.3,124.7,120.6.

[0061] Example 2

[0062] This embodiment provides a method for preparing 1,2,3-benzotriazine-4-one, comprising the following steps:

[0063] (1) Take anthranilic acid (13.71 g, 100 mmol) and dissolve it in 200 mL of dichloromethane. Then add T3P (160 mmol) and pyridine (19.77 g, 250 mmol) to the reaction system and stir at room temperature for 10 min. Take methoxyamine hydrochloride (10.63 g, 125 mmol) and add it to the reaction system in 10 batches, 1.06 g per batch. After the addition is completed, stir at room temperature. After reacting for 6 h, TLC detection is performed. After the reaction is completed, post-treatment is started. Add 1 mol / L HCl to the system to adjust pH=7, then extract the system with 35 mL of dichloromethane for 5 times, take the organic phase, dry it with anhydrous Na2SO4, and rotary evaporate to obtain a solid (16.05 g, 96.69 mmol), with a yield of 96.7%.

[0064] (2) Compound (III) (16.05 g, 96.69 mmol) and sodium nitrite (14.01 g, 203.05 mmol) were dissolved in 150 mL of water, and the reaction system was placed in an ice bath. HCl (8.82 g, 241.7 mmol) was prepared into a 3 mol / L HCl aqueous solution. The reaction system was then cooled to 2°C, and a 3 mol / L HCl aqueous solution was added dropwise to the system. After the addition was complete, the reaction was allowed to react at 2°C for 2 h. The degree of the reaction was detected by TLC. After the reaction was completed, post-treatment was started, and ammonia water was added to adjust the system pH to 8. The system was then extracted 5 times with 30 mL of dichloromethane. The organic phase was taken, dried over anhydrous Na2SO4, and rotary evaporated to obtain a solid (16.85 g, 95.12 mmol) with a yield of 98.4%.

[0065] (3) Compound (IV) (16.85 g, 95.12 mmol) and Pd / C (4.2 g) were dissolved in ethanol, and then the system was evacuated. A hydrogen balloon was used to replace the gas in the system. This operation was repeated 3 times so that the hydrogen filled the entire reaction system. Then the reaction was started at room temperature. After the reaction was completed for 1 hour, the degree of reaction was detected by TLC. After the reaction was completed, post-treatment was started, the reaction system was filtered, Pd / C was separated from the system, and then ethanol was removed to obtain a yellow solid. The light yellow solid was recrystallized from ethyl acetate to obtain a light yellow solid 1,2,3-benzotriazine-4-one (13.85 g), with a yield of 99.1%. The total yield of the above three steps was 94.30%.

[0066] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention, rather than to limit it. Although the present invention has been described in detail with reference to the above embodiments, those skilled in the art should understand that the technical solutions described in the above embodiments may still be modified, or some or all of the technical features therein may be replaced by equivalents. These modifications or replacements, or the technical features in the above embodiments may be combined in the manner described in the embodiments if they do not conflict with each other, and these modifications, replacements or combinations do not cause the essence of the corresponding technical solutions to deviate from the scope of the technical solutions of the embodiments of the present invention.

Claims

1. A method for preparing 1,2,3-benzotriazine-4-one, characterized in that: Includes steps: S1. Under the catalytic action of condensation agent T3P, anthranilic acid and methoxyamine hydrochloride directly undergo amidation reaction to obtain 2-amino-N-methoxybenzamide; S2, under diazotization reaction conditions, 2-amino-N-methoxybenzamide is converted into 3-methoxy-1,2,3-benzotriazine-4-one; S3. 3-methoxy-1,2,3-benzotriazine-4-one is reduced to 1,2,3-benzotriazine-4-one under palladium carbon / hydrogen conditions.

2. The preparation method according to claim 1, characterized in that: In S1, the reaction temperature is room temperature; the reaction solvent is dichloromethane, chloroform, 1,2-dichloroethane, acetonitrile, cyclohexane, toluene, tetrahydrofuran, MDF or DMSO, and an organic base is also added to the reaction solvent to provide an alkaline environment.

3. The preparation method according to claim 1, characterized in that: In S1, the organic base is pyridine or triethylamine.

4. The preparation method according to claim 1, characterized in that: In S1, the reaction solvent is dichloromethane, the organic base is pyridine, the reaction temperature is room temperature, and the molar ratio of o-aminobenzoic acid, methoxyamine hydrochloride, T3P, and pyridine is 1:1.2-1.25:1.5-1.6:2-2.

5.

5. The preparation method according to claim 1, characterized in that: In S2, the diazotization reaction conditions are: water is used as the reaction solvent, and the molar ratio of 2-amino-N-methoxybenzamide to NaNO2 and HCl is 1:2-2.1:2.1-2.

5.

6. The preparation method according to claim 5, characterized in that: In S2, the reaction temperature is 0-5°C; the reaction time is 1.5-2.5h.

7. The preparation method according to claim 1, characterized in that: In S3, the reaction temperature is room temperature; the reaction solvent is ethanol, methanol, isopropanol, tetrahydrofuran or dioxane.

8. The preparation method according to claim 1, characterized in that: In S3, the reaction solvent is ethanol.

Images