A method for synthesizing 3,5,6-trichloro-[1,2,4]-triazine

Abstract

The invention discloses a method for synthesizing 3,5,6-trichloro-[1,2,4]-triazine, comprising the following steps: S1, 6-azauracil and liquid bromine react at 60°C-70°C to generate 5-bromo-6-azauracil; S2, 5-bromo-6-azauracil and concentrated hydrochloric acid react at 100°C-105°C to generate 5-chloro-6-azauracil; S3, 5-chloro-6-azauracil reacts with phosphorus oxychloride at room temperature to generate 3,5,6-trichloro-[1,2,4]-triazine. The method for synthesizing 3,5,6-trichloro-[1,2,4]-triazine of the invention has the advantages of simple synthesis method, mild reaction conditions, controllable process and convenience for industrial production.

Description

Technical Field

[0001] The invention relates to the technical field of organic chemical synthesis, and in particular to a method for synthesizing 3,5,6-trichloro-[1,2,4]-triazine. Background Art

[0002] The six-membered heterocyclic system containing three nitrogen atoms is called a triazine system. According to the relative positions of the heteroatoms in the molecule, it can be divided into 1,2,3-triazine, 1,2,4-triazine, and 1,3,5-triazine.

[0003] 3,5,6-Trichloro-[1,2,4]-triazine is an important organic compound that is widely used in the treatment of various diseases. For example, it is clinically used in the treatment of various edemas (it has a good effect on cardiac edema), and has a certain therapeutic effect on various stages of hypertension and diabetes insipidus. In addition, the trichlorotriazine compound also plays an important role in the synthesis of compounds such as diuretics for the treatment of kidney disease and compositions for the treatment of autism spectrum disorders. Therefore, the development of an efficient and green synthesis method for 3,5,6-trichloro-[1,2,4]-triazine compounds is an important part of the field of organic chemical synthesis.

[0004] The main method for synthesizing 3,5,6-trichloro-[1,2,4]-triazine at present is: 5-bromo-6-azauracil reacts with phosphorus pentachloride and N,N-diethylaniline in the presence of trichlorophosphate at 120°C to obtain 3,5,6-trichloro-[1,2,4]-triazine. The reaction equation is as follows:

[0005]

[0006] In the process of preparing the target product from compound b, an intermediate compound d is generated, which cannot be completely converted into the final product, so that the obtained product is a mixture of the intermediate compound d and the target product. However, the polarity of the intermediate compound d is very close to that of the target product, and the post-processing is complicated, making it difficult to obtain a purified product. Summary of the invention

[0007] In view of the above-mentioned defects of the prior art, the present invention provides a method for synthesizing 3,5,6-trichloro-[1,2,4]-triazine, which uses 6-azauracil as a reaction raw material, firstly introduces bromine on the uracil ring, introduces the first chlorine by chlorine-bromine replacement, and then chlorinates the hydroxyl groups at two positions in the environment of phosphorus oxychloride to successfully obtain 3,5,6-trichloro-[1,2,4]-triazine. The reaction conditions of the synthesis method are relatively mild and the method has broad application prospects.

[0008] In order to solve the above technical problems, the present invention provides a method for synthesizing 3,5,6-trichloro-[1,2,4]-triazine, comprising the following steps:

[0009] S1, 6-azauracil and liquid bromine react at 60°C-70°C to generate 5-bromo-6-azauracil;

[0010] S2, 5-bromo-6-azauracil and concentrated hydrochloric acid react at 100°C-105°C to generate 5-chloro-6-azauracil;

[0011] S3, 5-chloro-6-azauracil react with phosphorus oxychloride at room temperature to generate 3,5,6-trichloro-[1,2,4]-triazine.

[0012] As a preferred embodiment, the molar ratio of 6-azauracil to liquid bromine in step S1 is 1:(2.5-3).

[0013] As a more preferred embodiment, the molar ratio of 6-azauracil to liquid bromine in step S1 is 1:2.5.

[0014] As a preferred embodiment, water is also added in the step S1.

[0015] As a preferred embodiment, in step S1, the mass volume ratio of 6-azauracil to water is 1 g:(5-10) ml.

[0016] As a preferred embodiment, the mass volume ratio of 5-bromo-6-azauracil to concentrated hydrochloric acid in step S2 is 1 g:(5-10) ml.

[0017] As a preferred embodiment, in the step S3, the mass volume ratio of 5-chloro-6-azauracil to phosphorus oxychloride is 1 g:(5-10) ml.

[0018] As a more preferred embodiment, in step S3, the mass volume ratio of 5-chloro-6-azauracil to phosphorus oxychloride is 1 g:5 ml.

[0019] As a preferred embodiment, N,N-diisopropylethylamine is further added in the step S3.

[0020] As a more preferred embodiment, the molar ratio of 5-chloro-6-azauracil to N,N-diisopropylethylamine in step S3 is 1:(2-5).

[0021] As a more preferred embodiment, the molar ratio of 5-chloro-6-azauracil to N,N-diisopropylethylamine in step S3 is 1:2.

[0022] Compared with the prior art, the present invention has the following beneficial effects:

[0023] (1) The synthesis method of 3,5,6-trichloro-[1,2,4]-triazine of the present invention is simple, has mild reaction conditions, is controllable, and is convenient for industrial production.

[0024] (2) The method for synthesizing 3,5,6-trichloro-[1,2,4]-triazine of the present invention has a relatively high reaction yield and is simple to post-process, making it easy to obtain a purified product.

[0025] (3) The method for synthesizing 3,5,6-trichloro-[1,2,4]-triazine of the present invention uses 6-azauracil as a reaction raw material. The raw material is cheap and easily available, and 5-bromo-6-azauracil can be prepared in large quantities, thereby reducing the synthesis cost of 3,5,6-trichloro-[1,2,4]-triazine.

[0026] The concept, specific structure and technical effects of the present invention will be further described below in conjunction with the accompanying drawings to fully understand the purpose, characteristics and effects of the present invention. BRIEF DESCRIPTION OF THE DRAWINGS

[0027] Figure 1 is the HPLC spectrum of compound b in Example 1 of the present invention;

[0028] Figure 2 is the HPLC spectrum of compound c in Example 1 of the present invention;

[0029] Figure 3 is the LCMS spectrum of compound c in Example 1 of the present invention;

[0030] Figure 4 This is the LCMS spectrum of the target compound in Example 1 of the present invention. DETAILED DESCRIPTION

[0031] In order to make the technical means, creative features, objectives and effects of the invention easier to understand, the invention is further described below with reference to specific diagrams. However, the invention is not limited to the following implementation cases.

[0032] It should be noted that the structures, proportions, sizes, etc. illustrated in the drawings in this specification are only used to match the contents disclosed in the specification so as to facilitate understanding and reading by persons familiar with this technology. They are not used to limit the conditions under which the present invention can be implemented, and therefore have no substantive technical significance. Any structural modification, change in proportion or adjustment of size, without affecting the effects and purposes that can be achieved by the present invention, should still fall within the scope of the technical contents disclosed by the present invention.

[0033] At present, the main method for synthesizing 3,5,6-trichloro-[1,2,4]-triazine is to react 5-bromo-6-azauracil with phosphorus pentachloride and N,N-diethylaniline in trichlorophosphate at 120°C. This synthesis method has two major technical problems: 1) the raw materials are expensive, 25g of 5-bromo-6-azauracil will cost more than 1,000 yuan, and the reaction cost is too high with this as the raw material; 2) the reaction conditions are harsh and the reaction yield is low, and the post-processing is difficult, which is not conducive to obtaining a purified product.

[0034] In order to solve the above technical problems, the inventors of the present application used 6-azauracil as a raw material and introduced bromine on the uracil ring to obtain 5-bromo-6-azauracil. Since 6-azauracil is cheap, 5-bromo-6-azauracil can be synthesized in large quantities, which is convenient for the industrial production of 3,5,6-trichloro-[1,2,4]-triazine.

[0035] The synthetic route of 3,5,6-trichloro-[1,2,4]-triazine is as follows:

[0036]

[0037] S1, compound a (6-azauracil) and liquid bromine react to generate compound b (5-bromo-6-azauracil).

[0038] Reaction mechanism: First, the π electrons on the aromatic ring of compound a attack bromine to generate a non-aromatic carbon cation intermediate, and the bromine anion leaves at the same time; then, the electrons of the CH bond ortho-position of the carbon cation intermediate are introduced into the carbon cation, releasing a proton, and the aromatic bromine product b is obtained again.

[0039] Specific reaction process: Add water and compound a (6-azauracil) to the reaction bottle, add liquid bromine dropwise at below 30°C, heat to 60°C-70°C after the addition is complete, react for 18 hours, and monitor the end of the reaction using TLC spot plate. After the reaction is complete, concentrate the reaction solution, extract with ethyl acetate, wash the organic phase with brine, dry with anhydrous sodium sulfate, filter and concentrate. Add the crude product to a mixed solvent of petroleum ether and ethyl acetate (1:1), stir and filter, and the filter residue is compound b (5-bromo-6-azauracil).

[0040] In this step, the molar ratio of compound a (6-azauracil) to liquid bromine is 1:(2.5-3).

[0041] The reaction of compound a (6-azauracil) with liquid bromine requires a sufficient excess of liquid bromine. When the amount of liquid bromine is relatively small, such as when the molar ratio of compound a (6-azauracil) to liquid bromine is 1:1.5, even if the reaction time is extended, compound a (6-azauracil) still cannot react completely. Of course, the amount of liquid bromine used is not the more the better. On the one hand, an increase in the amount of liquid bromine will increase production costs; on the other hand, too much liquid bromine leads to side reactions and post-processing difficulties. The inventors of the present application repeatedly explored in the experiment and finally determined that when the molar ratio of compound a (6-azauracil) to liquid bromine is 1:(2.5-3), compound a reacts completely and has fewer side reactions.

[0042] In this step, the mass (g) to volume (ml) ratio of compound a (6-azauracil) to water is 1:8 (ie, 1 g of compound a corresponds to 8 ml of water).

[0043] S2, compound b (5-bromo-6-azauracil) and concentrated hydrochloric acid react to generate compound c (5-chloro-6-azauracil).

[0044] The concentrated hydrochloric acid here is hydrochloric acid with a mass concentration of 36%-38%.

[0045] Reaction mechanism: This reaction is an SN2 reaction. The chloride anion attacks the carbon connected to the bromine atom, and the bromide anion leaves at the same time to form a chlorinated product.

[0046] Specific reaction process: Compound b (5-bromo-6-azauracil) and concentrated hydrochloric acid were added to the reaction flask, and the reaction was carried out at 100°C-105°C for 18 hours. After the reaction of the raw materials was basically completed by LCMS detection, the temperature was lowered to room temperature, extracted with ethyl acetate, and the organic phase was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated to obtain compound c (5-chloro-6-azauracil).

[0047] In this step, the mass (g) volume (ml) ratio of compound b (5-bromo-6-azauracil) to concentrated hydrochloric acid is 1:(5-10).

[0048] The addition of concentrated hydrochloric acid, in addition to being a reaction raw material, also has the function of a solvent. When the amount of concentrated hydrochloric acid used is relatively small, compound B is difficult to stir, the reaction system is uneven, the reaction rate is slow, or even cannot react completely. When the amount of concentrated hydrochloric acid used is too much, a large amount of wastewater will be generated. Taking all factors into consideration, the mass (g) volume (ml) ratio of compound B (5-bromo-6-azauracil) to concentrated hydrochloric acid is set to 1: (5-10).

[0049] S3, compound c (5-chloro-6-azauracil) and phosphorus oxychloride react to generate the compound shown in formula I.

[0050] Reaction mechanism: First, the phenolic hydroxyl group generates an alkoxy anion under the action of the base, which attacks phosphorus oxychloride to generate dichlorophosphate aryl ester, and the generated chloride anion leaves at the same time; then, the chloride anion attacks the carbon connected to the oxygen of dichlorophosphate aryl ester to generate a chlorinated product, and at the same time leaves a molecule of dichlorophosphoric acid.

[0051] Specific reaction process: First add compound c (5-chloro-6-azauracil) and DIEA (N,N-diisopropylethylamine) to the reaction bottle, and then slowly add phosphorus oxychloride. After the reaction is completed, the phosphorus oxychloride is distilled off under reduced pressure, and purified by column with neutral aluminum trioxide to obtain the compound shown in formula I, namely 3,5,6-trichloro-[1,2,4]-triazine.

[0052] In this step, N,N-diisopropylethylamine is added to neutralize the HCl generated by the reaction, and the molar ratio of compound c (5-chloro-6-azauracil) to N,N-diisopropylethylamine is set to 1:(2-5).

[0053] In this step, the mass (g) volume (ml) ratio of compound c (5-chloro-6-azauracil) to phosphorus oxychloride is 1: (5-10). Phosphorus oxychloride, on the one hand, is used as a reaction raw material, and on the other hand, as a reaction solvent, the amount of phosphorus oxychloride added is relatively small, resulting in the inability to mix the materials evenly; but too much phosphorus oxychloride leads to an increase in the amount of wastewater. In this application, the mass (g) volume (ml) ratio of compound c (5-chloro-6-azauracil) to phosphorus oxychloride is set to 1: (5-10).

[0054] The yield calculation formula involved in the following examples is as follows: yield = product mass * product purity / (product molecular weight * raw material mass / raw material molecular weight), where the raw material is a raw material that has been completely reacted.

[0055] Example 1

[0056] Add water (560mL) and compound a (6-azauracil) (70g) to a 1.0L reaction bottle, and add liquid bromine (247.3g) dropwise at below 30°C. After the addition is complete, react at 60°C for 18 hours. After the reaction is completed by TLC spot plate detection, the reaction solution is concentrated, extracted with ethyl acetate, the organic phase is washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. The crude product is added to a mixed solvent of petroleum ether and ethyl acetate (1:1), stirred at room temperature for 1h, filtered, and the filter residue is compound b (5-bromo-6-azauracil), a total of 108g, a yield of 89% (product mass is 108g, product purity is 98.4%, product molecular weight is 191.97, raw material mass is 70g, raw material molecular weight is 113.08, calculated according to the formula), and purity is 98.4%. 1 H NMR (DMSO-d 6):12.5(s,1H),12.3(s,1H), its HPLC spectrum is as follows Figure 1 shown.

[0057] Compound b (5-bromo-6-azauracil) (108 g) and concentrated hydrochloric acid (540 mL) were added to a 1.0 L reaction bottle and reacted at 100° C. for 18 hours. After the reaction of the raw materials was basically completed by LCMS detection, the temperature was lowered to room temperature, extracted with ethyl acetate, the organic phase was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated to obtain 74.7 g of compound c (5-chloro-6-azauracil), with a yield of 90% and a purity of 99.3%. Its HPLC spectrum is shown as follows Figure 2 As shown, the LCMS spectrum is as Figure 3 shown.

[0058] Figure 3 The residence time is 0.589 min, corresponding to Ms of 148 and 150, which is the peak position of compound c.

[0059] First, add 74.7 g of compound c (5-chloro-6-azauracil) and DIEA (N,N-diisopropylethylamine) (130.9 g) to a 1000 mL reaction bottle, and then slowly add phosphorus oxychloride (374 mL). After the reaction, distill off the phosphorus oxychloride under reduced pressure, purify with neutral aluminum oxide column, and obtain 70.1 g of the target compound 3,5,6-trichloro-[1,2,4]-triazine, with a yield of 69% and a purity of 92.6%. Its LCMS spectrum is as follows: Figure 4 As shown in the figure. Since the chlorine at the 5-position of the product is very active and is converted into a hydroxyl group in the LCMS mobile phase, the MS spectrum cannot show the target product with chlorine at the 5-position. Figure 3 The presence of compound c was confirmed in the above analysis. In this case, the chlorine at the 5-position was converted into a hydroxyl group in the mobile phase, but the target product with chlorine at the 5-position was not obtained.

[0060] Example 2

[0061] Add water (25mL) and compound a (6-azauracil) (5g) to the reaction flask, and add liquid bromine (21.2g, 3eq) dropwise at below 30°C. After the addition is complete, react at 60°C for 18 hours. After the reaction is completed by TLC spot plate detection, the reaction solution is concentrated, extracted with ethyl acetate, the organic phase is washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. The crude product is added to a mixed solvent of petroleum ether and ethyl acetate (1:1), stirred at room temperature for 1h, filtered, and the filter residue is compound b (5-bromo-6-azauracil), a total of 7.45g, a yield of 86%, and a purity of 98%.

[0062] Compound b (5-bromo-6-azauracil) (5 g) and concentrated hydrochloric acid (50 mL) were added to the reaction flask and reacted at 100° C. for 18 hours. After the reaction of the raw materials was basically completed by LCMS, the temperature was lowered to room temperature, extracted with ethyl acetate, and the organic phase was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated to obtain 3.46 g of compound c (5-chloro-6-azauracil) with a purity of 99.3% and a yield of 90%.

[0063] First, compound c (5-chloro-6-azauracil) (5 g) and DIEA (N,N-diisopropylethylamine) (13.1 g, 3 eq) were added to the reaction flask, and then phosphorus oxychloride (50 mL) was slowly added. After the reaction, phosphorus oxychloride was distilled off under reduced pressure, and purified by column with neutral aluminum oxide to obtain 4.55 g of the target compound 3,5,6-trichloro-[1,2,4]-triazine, with a yield of 67% and a purity of 92%.

[0064] Example 3

[0065] Add water (35mL) and compound a (6-azauracil) (5g) to the reaction flask, and add liquid bromine (17.7g, 2.5eq) dropwise at below 30°C. After the addition is complete, react at 60°C for 18 hours. After the reaction is complete, the reaction solution is concentrated, extracted with ethyl acetate, and the organic phase is washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. The crude product is added to a mixed solvent of petroleum ether and ethyl acetate (1:1), stirred at room temperature for 1h, filtered, and the filter residue is compound b (5-bromo-6-azauracil), a total of 7.63g, a yield of 88%, and a purity of 98%.

[0066] Compound b (5-bromo-6-azauracil) (5 g) and concentrated hydrochloric acid (30 mL) were added to the reaction flask and reacted at 105° C. for 18 hours. After the reaction of the raw materials was basically completed by LCMS, the temperature was lowered to room temperature, extracted with ethyl acetate, and the organic phase was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated to obtain 3.40 g of compound c (5-chloro-6-azauracil) with a purity of 99.0% and a yield of 87%.

[0067] First, add compound c (5-chloro-6-azauracil) (5 g) and DIEA (N,N-diisopropylethylamine) (17.4 g, 4 eq) to the reaction flask, and then slowly add phosphorus oxychloride (50 mL). After the reaction, distill the phosphorus oxychloride under reduced pressure, purify it with neutral aluminum oxide column, and obtain the target compound 3,5,6-trichloro-[1,2,4]-triazine 4.48 g, with a yield of 66% and a purity of 92%.

[0068] The preferred specific embodiments of the present invention are described in detail above. It should be understood that ordinary technicians in the field can make many modifications and changes based on the concept of the present invention without creative work. Therefore, all technical solutions that can be obtained by technicians in the technical field based on the concept of the present invention through logical analysis, reasoning or limited experiments on the basis of the prior art should be within the scope of protection determined by the claims.

Claims

1. A method for synthesizing 3,5,6-trichloro-[1,2,4]-triazine, It is characterized in that The steps include: S1, 6-azauracil and liquid bromine react at 60°C-70°C to generate 5-bromo-6-azauracil; S2, 5-bromo-6-azauracil and concentrated hydrochloric acid react at 100°C-105°C to generate 5-chloro-6-azauracil; S3, 5-chloro-6-azauracil reacts with phosphorus oxychloride at room temperature to generate 3,5,6-trichloro-[1,2,4]-triazine; Water is also added in step S1, and the molar ratio of 6-azauracil to liquid bromine is 1:(2.5-3); the mass volume ratio of 6-azauracil to water in step S1 is 1g:(5-10)ml; the mass volume ratio of 5-bromo-6-azauracil to concentrated hydrochloric acid in step S2 is 1g:(5-10)ml; the mass volume ratio of 5-chloro-6-azauracil to phosphorus oxychloride in step S3 is 1g:(5-10)ml; N,N-diisopropylethylamine is also added in step S3.

2. The method for synthesizing 3,5,6-trichloro-[1,2,4]-triazine according to claim 1, It is characterized in that In the step S3, the mass volume ratio of 5-chloro-6-azauracil to phosphorus oxychloride is 1 g:5 ml.

3. The method for synthesizing 3,5,6-trichloro-[1,2,4]-triazine according to claim 1, It is characterized in that In the step S3, the molar ratio of 5-chloro-6-azauracil to N,N-diisopropylethylamine is 1:(2-5).

4. The method for synthesizing 3,5,6-trichloro-[1,2,4]-triazine according to claim 3, It is characterized in that In the step S3, the molar ratio of 5-chloro-6-azauracil to N,N-diisopropylethylamine is 1:2.

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