Preparation method of pyrrolotriazine compound

Abstract

The invention belongs to the technical field of medicine synthesis. The invention firstly provides a preparation method of a monochloramine organic solution. On the other hand, the invention provides application of the preparation method in amination reaction or preparation of a compound 4. On the other hand, the invention provides a preparation method of the compound 4. The invention also provides a preparation method of the compounds 2 and 3. The whole process route is short, the cost is low, less three wastes are generated, the post-treatment is simple, the yield is high, the product quality is excellent, and the method is suitable for industrial production.

Description

Preparation method of pyrrolotriazine compound Technical Field

[0001] The invention belongs to the field of drug synthesis, and more specifically relates to a method for preparing a pyrrolotriazine compound. Background Art

[0002] Pyrrolotriazine compounds have attracted significant attention in recent years from pharmaceutical researchers due to their excellent biological activity. 4-Aminopyrrolo[2,1-f][1,2,4]triazine (CAS: 159326-68-8, English name: pyrrolo[2,1-F][1,2,4]triazin-4-amine, compound 4) is a typical representative of this class of compounds. It is an important synthetic precursor for a variety of drugs. Its skeleton has favorable biological properties, leading to its high demand as an early-stage clinical API. For example, avapritinib, a precision targeted drug for gastrointestinal stromal tumors (GIST), the small molecule kinase inhibitor BMS-754807, the fibroblast growth factor receptor (FGFR) inhibitor rogatinib, and remdesivir, recently used to treat COVID-19, all contain a 4-aminopyrrolo[2,1-f][1,2,4]triazine core structure. Therefore, how to use cheap and readily available raw materials and processes suitable for industrial scale-up production to achieve large-scale synthesis of 4-aminopyrrolo[2,1-f][1,2,4]triazine has become a hot topic in industrial research.

[0003] Journal of Heterocyclic Chemistry 1994, 31, 781–786 uses 2-pyrrolecarboxaldehyde as a raw material to react with hydroxylaminesulfonic acid to obtain N-amino-2-cyanopyrrole, which is then reacted with formamidine acetate to obtain compound 1. Although this route has a shorter reaction step, the starting material is expensive and the overall yield is low, making it unsuitable for industrial scale-up production.

[0004] In CN110845502A, 2,5-dimethoxytetrahydrofuran is reacted with tert-butyl carbazate, followed by reaction with chlorosulfonyl isocyanate, and then with formamidine acetate to obtain compound 1. This route has a long reaction step, low atom economy, low overall yield, and requires column chromatography.

[0005] Organic Process Research & Development (2022), 26(1), 82-90 uses pyrrole / DMF / phosphorus oxychloride / hydroxylamine for ortho-cyanidation, followed by deprotonation / amination and cyclization to complete the synthesis of compound 4. This process route can start with a cheap starting material pyrrole and obtain compound 4 with a total yield of 55% after 3 steps. However, this route still has the following problems: the first step of the route is cyanidation reaction, which uses phosphorus oxychloride. The reaction operation is cumbersome, and the reaction liquid is a black liquid after quenching. At the same time, it is mixed with a lot of solids, and extraction and separation are very difficult. The reaction produces a large amount of phosphorus-containing wastewater, which cannot be directly treated biochemically. Specific equipment and processes are required for treatment, which increases the economic cost. The second step requires preparing a monochloramine solution in MTBE as the amination reagent. MTBE, ammonium chloride, and aqueous ammonia are mixed and then added to an 8-10% aqueous sodium hypochlorite solution to obtain a monochloramine-MTBE solution with a monochloramine content of approximately 2.2% (0.33 mol / L). High-concentration aqueous sodium hypochlorite solutions are expensive and have limited concentrations. This process consumes a significant amount of material and generates a large amount of wastewater, severely limiting production capacity. Furthermore, the deprotonation / amination reaction is prone to reverse reactions, and the addition of the final 20% of the monochloramine solution requires precise control of the addition rate and amount, as well as the alkalinity of the system, adding to the complexity of production operations.

[0006] Considering the importance of compound 4 in nucleoside drugs, it is necessary to develop a preparation method for this compound that is more suitable for industrial production.

[0007] Summary of the Invention

[0008] A first aspect of the present invention provides a method for preparing a monochloramine organic solution, comprising the following steps:

[0009] Step b: mixing an organic solvent, water, ammonium chloride and aqueous ammonia, and then adding Ca(ClO)2. After the reaction is completed, the organic phase is separated to obtain an organic solution of monochloramine.

[0010] Ca(ClO)2+NH4Cl+NH3·H2O→NH2Cl.

[0011] Another aspect of the present invention provides a method for preparing compound 3, comprising the following steps:

[0012] Step b: Mix the organic solvent, water, ammonium chloride and ammonia water and then add Ca(ClO)2. After the reaction is completed, separate the organic phase to obtain an organic solution of monochloramine.

[0013] Ca(ClO)2+NH4Cl+NH3·H2O→NH2Cl;

[0014] Step c: Compound 2 is dissolved in DMF, and under the action of NaH, the organic solution of monochloramine prepared in step b is added to react to obtain compound 3.

[0015] Another aspect of the present invention provides a method for preparing compound 4, comprising the following steps:

[0016] Step b: Mix the organic solvent, water, ammonium chloride and ammonia water and then add Ca(ClO)2. After the reaction is completed, separate the organic phase to obtain an organic solution of monochloramine.

[0017] Ca(ClO)2+NH4Cl+NH3·H2O→NH2Cl;

[0018] Step c: Compound 2 is dissolved in DMF, and under the action of NaH, the organic solution of monochloramine prepared in step b is added to react to obtain compound 3.

[0019] Step d: Compound 3 reacts with formamidine acetate in the presence of a base to obtain compound 4.

[0020] In some embodiments of the present invention, in step b, Ca(ClO)2 is added in batches and the system temperature is controlled at -25 to 15°C.

[0021] In some embodiments of the present invention, in step b, Ca(ClO)2 is added in batches and the system temperature is controlled at -25 to -10°C.

[0022] In some embodiments of the present invention, in step b, the organic solvent is one or more of MTBE, diethyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, ethyl acetate, and dichloromethane.

[0023] In some embodiments of the present invention, in step b, the organic solvent is MTBE.

[0024] In some embodiments of the present invention, in step b, the molar ratio of Ca(ClO)2, NH3·H2O and NH4Cl is 1:1-10:1-10.

[0025] In some embodiments of the present invention, in step b, the molar ratio of Ca(ClO)2, NH3·H2O and NH4Cl is 1:2-3:3-4.

[0026] In some embodiments of the present invention, in step b, the molar ratio of Ca(ClO)2, NH3·H2O and NH4Cl is 1:2-2.5:3.5-4.

[0027] In some embodiments of the present invention, in step b, the volume ratio of MTBE, water and aqueous ammonia is 10-30:1-10:1.

[0028] In some embodiments of the present invention, in step b, the volume ratio of MTBE, water and aqueous ammonia is 12-18:1-3:1.

[0029] In some embodiments of the present invention, in step b, the volume ratio of MTBE, water and aqueous ammonia is 13-15:1-2:1.

[0030] Another aspect of the present invention provides an organic solution of monochloramine prepared by the preparation method of step b.

[0031] In some embodiments of the present invention, the organic solution of monochloramine prepared by the preparation method in step b is an MTBE solution of monochloramine.

[0032] In some embodiments of the present invention, the content of monochloramine in the MTBE solution of monochloramine is 0.44 to 1.32 mol / L.

[0033] In some embodiments of the present invention, the content of monochloramine in the MTBE solution of monochloramine is 0.50-1.00 mol / L.

[0034] In some embodiments of the present invention, the content of monochloramine in the MTBE solution of monochloramine is 0.53 to 0.88 mol / L.

[0035] In some embodiments of the present invention, in step c, the organic solution of monochloramine is a MTBE solution of monochloramine.

[0036] In some embodiments of the present invention, in step c, the molar ratio of compound 2, NaH and NH2Cl is 1:1-3:1-5.

[0037] In some embodiments of the present invention, in step c, the molar ratio of compound 2, NaH and NH2Cl is 1:1-2:1-3.

[0038] In some embodiments of the present invention, in step c, the molar ratio of compound 2, NaH and NH2Cl is 1:1-1.5:1.2-2.5.

[0039] In some embodiments of the present invention, in step c, the mass volume ratio of compound 2 and DMF is 1:2-10.

[0040] In some embodiments of the present invention, in step c, the mass volume ratio of compound 2 and DMF is 1:3-8.

[0041] In some embodiments of the present invention, in step c, the mass volume ratio of compound 2 and DMF is 1:3-6.

[0042] In some embodiments of the present invention, step c comprises the following steps: dissolving compound 2 in DMF, cooling to -5 to 5°C, adding 1 equivalent of NaH for reaction, adding the MTBE solution of monochloramine, and then continuing the reaction by adding the remaining equivalent of NaH.

[0043] In some embodiments of the present invention, in step d, the base is potassium carbonate, sodium bicarbonate, sodium carbonate, triethylamine or diisopropylamine, and the reaction temperature is 70-95°C, preferably 75-85°C.

[0044] In some embodiments of the present invention, in step d, the reaction time is 24 to 96 hours.

[0045] In some embodiments of the present invention, in step d, the reaction time is 60 to 80 hours.

[0046] In some embodiments of the present invention, the preparation method of compound 4 further comprises step a of dissolving pyrrole in an organic solvent, and sequentially adding CSI and DMF to react to obtain compound 2:

[0047] In some embodiments of the present invention, the organic solvent used in step a is MTBE.

[0048] Another aspect of the present invention provides a method for preparing compound 2, comprising the following steps: step a: dissolving pyrrole in MTBE, and sequentially adding CSI and DMF to react to obtain compound 2;

[0049] In some embodiments of the present invention, in step a, the reaction temperature is -20 to 10°C, preferably -15 to -10°C.

[0050] In some embodiments of the present invention, in step a, the molar ratio of pyrrole, CSI and DMF is 1:1-3:1-5, preferably 1:1-1.5:2-4, more preferably 1:1-1.2:2.5-3.5; the mass volume ratio of pyrrole and MTBE is 1:2-20, preferably 1:3-15, more preferably 1:5-8.

[0051] In some embodiments of the present invention, in step a, after the reaction is completed, the reaction is quenched with an alkaline system, extracted with MTBE, and the organic phase is concentrated, dehydrated, and distilled to obtain Compound 2.

[0052] In some embodiments of the present invention, in step a, the alkaline system is a mixture of alkali, water and MTBE.

[0053] In some embodiments of the present invention, in step a, the base in the alkaline system is NaHCO3 or K2CO3.

[0054] In some embodiments of the present invention, in step a, the base in the alkaline system is NaHCO 3 , and the mass volume ratio of the mixed solution of NaHCO 3 , water and MTBE is 1:1-5:0.3-20. Beneficial effects:

[0055] The solvent in step a of the present invention is easily recycled and reused; the reagent cost in step b is low, atom economy is achieved, solvent usage is small, reaction impurities are small, post-processing is simple, and yield is high; the product of the present invention has good properties and high purity; the entire process route is short, cost is low, the solvent can be recycled and reused, three wastes are generated less, post-processing is simple, yield is high, product quality is excellent, and the process is suitable for industrial production. DETAILED DESCRIPTION

[0056] The following specific implementations are further detailed descriptions of this article.

[0057] Unless otherwise specified, the scientific and technical terms used herein have the meanings commonly understood by those skilled in the art. Furthermore, the laboratory procedures used herein are all conventional procedures widely used in the relevant fields.

[0058] When describing the compounds, compositions, methods and processes of the present invention, the following terms have the following meanings unless otherwise indicated. In addition, unless the context of use clearly dictates otherwise, as used herein, the singular forms "a", "an" and "the" include the corresponding plural forms.

[0059] The terms “having,” “comprising,” and “including” should be interpreted as open-ended, indicating the presence of the listed elements but not excluding the existence, occurrence, or addition of any other element or elements that are not listed.

[0060] All ranges recited herein include those endpoints of the range between the two values ​​recited. Regardless of whether stated or not, all values ​​recited herein include the degree of expected experimental error, technical error, and instrumental error for the given technique used to measure the value.

[0061] Herein, % is weight / weight (w / w) percentage unless otherwise stated.

[0062] Unless otherwise indicated, any numerical value, such as a concentration or a range of concentrations recited herein, is to be understood as being modified in all instances by the term "about."

[0063] In this document, unless otherwise indicated, the term "about" is intended to qualify the numerical value it modifies, indicating that such value may vary within a certain range. When no range is stated (e.g., a margin of error or the standard deviation of the mean value given in a graph or data table), the term "about" should be understood to mean a larger range that includes the stated value, as well as a range that is rounded to the nearest integer, taking into account significant figures, and a range that includes plus or minus 10% of the stated value.

[0064] As used herein, the terms "chloramine" and "monochloramine" have the same meaning and refer to NH2Cl.

[0065] Ca(ClO)2

[0066] In the present invention, the calcium hypochlorite used can be industrial calcium hypochlorite having an available chlorine content greater than 20%, wherein the available chlorine content of Ca(ClO)2 can be 20% to 80%, for example, 30%, 38%, 50%, 55%, 62%, 70%, 75%, 80% or any value or range therebetween. The calcium hypochlorite used in the embodiment is calcium hypochlorite having an available chlorine content of 75%. The feed amount is the mass of the reagent used and is not converted into the amount of the active ingredient.

[0067] In some embodiments of the present invention, in step b, the organic solvent, water, NH4Cl and aqueous ammonia are mixed, and Ca(ClO)2 is added in batches. The system temperature is controlled at -25 to 15°C (e.g., -25°C, -20°C, -15°C, -10°C, -5°C, 0°C, 5°C, 10°C, 15°C or any value or range therebetween), preferably at -25 to -10°C (e.g., -25°C, -20°C, -15°C, -10°C or any value or range therebetween). After the reaction is completed, the organic phase is separated to obtain an organic solution of monochloramine.

[0068] In some embodiments of the present invention, the organic solvent may be one or more of MTBE, diethyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, ethyl acetate, and dichloromethane.

[0069] In some embodiments of the present invention, in step b, the organic solvent is MTBE.

[0070] Ca(ClO)2 is added to the system in batches as a solid. By controlling the amount and frequency of Ca(ClO)2 additions, as well as the agitation and heat transfer rate of the reactor, safe and controllable production can be achieved. At low temperatures, Ca(ClO)2 dissolves very slowly in water. Adding an appropriate amount of ammonium chloride greatly accelerates the dissolution of Ca(ClO)2, rapidly releasing hypochlorous acid, which then oxidizes NH3 to produce monochloramine.

[0071] Since NaH is used in the reaction to prepare compound 3 from compound 2, the water content in the reaction system needs to be strictly controlled. The oxidation of NH3 by solid Ca(ClO)2 with a high effective chlorine content can avoid the participation of a large amount of water in the reaction. After the reaction is completed, the organic phase is allowed to stand and separate, washed, dried, and filtered to remove the desiccant to obtain an MTBE solution of monochloramine. Since the volume of water used in the reaction is small, the water content in the reaction system is also low, and less desiccant is required, which helps to simplify the production steps and increase production capacity.

[0072] In some embodiments of the present invention, the molar ratio of Ca(ClO)2, NH3·H2O and NH4Cl is 1:1-10:1-10, preferably 1:2-3:3-4, and more preferably 1:2-2.5:3.5-4; the volume ratio of MTBE, water and aqueous ammonia is 10-30:1-10:1, preferably 12-18:1-3:1, and more preferably 13-15:1-2:1.

[0073] Excessive calcium hypochlorite is detrimental to the cyclization reaction of compound 3 and formamidine acetate, which will increase the number of reaction impurities and produce a large amount of black viscous material, seriously affecting the product yield and crystallization operation.

[0074] ammonia

[0075] Ammonia water is an aqueous solution of ammonia, wherein the main component is NH3·H2O. The ammonia water used in the present invention is industrial ammonia water, and its ammonia content (NH3) can be 20-30%, for example, 20%, 25%, 26%, 27%, 28%, 29%, 30% or any range or value therebetween.

[0076] Step b: Monochloramine organic solution and its preparation

[0077] Monochloramine is a gas at room temperature and differential pressure, making it difficult to prepare a solution with a high chloramine content in an organic solvent. Org. Lett. 2020, 22, 7656-7661 uses a ~10% NaClO aqueous solution to prepare an aqueous solution of monochloramine, which is then extracted with an organic solvent to obtain an organic solution of monochloramine. To obtain a high-concentration organic solution of monochloramine, a large amount of organic solvent is required for repeated extraction due to the huge amount of aqueous solution.

[0078] The method of the present invention uses a small amount of aqueous solution and does not require repeated extraction with a large amount of organic solvents, thereby obtaining an organic solution of monochloramine with a very high content. For example, the method of the present invention can obtain an MTBE solution with an extremely high content of monochloramine. In some embodiments of the present invention, the content of monochloramine in the obtained MTBE solution is 0.44 to 1.32 mol / L (for example, 0.44 mol / L, 0.45 mol / L, 0.46 mol / L, 0.47 mol / L, 0.48 mol / L, 0.49 mol / L, 0.50 mol / L, 0.60 mol / L, 0.70 mol / L, 0.80 mol / L, 0.90 mol / L, 1.00 mol / L, 1.10 mol / L, 1.20 mol / L, 1 .30 mol / L or any value or range therebetween), in some embodiments of the present invention, the content of monochloramine in the obtained monochloramine MTBE solution is 0.50-1.00 mol / L (for example, 0.50 mol / L, 0.55 mol / L, 0.60 mol / L, 0.65 mol / L, 0.70 mol / L, 0.75 mol / L, 0.80 mol / L, 0.85 mol / L, 0.90 mol / L, 0.95 mol / L, 1.00 mol / L or any value or range therebetween). In some embodiments of the present invention, the monochloramine content in the obtained monochloramine MTBE solution is 0.53-0.88 mol / L (for example, 0.53 mol / L, 0.55 mol / L, 0.58 mol / L, 0.60 mol / L, 0.65 mol / L, 0.70 mol / L, 0.73 mol / L, 0.75 mol / L, 0.80 mol / L, 0.88 mol / L, or any value or range therebetween).

[0079] After the reaction in step b is completed, the organic phase is allowed to stand and decompose, and the organic phase is washed and dried, and the desiccant is filtered to obtain a MTBE solution of monochloramine. The MTBE solution is stored at -15 to 5° C., preferably -15 to -10° C. The content of monochloramine in the MTBE solution may change with a long storage time. The content of monochloramine can be determined by titration before use. The titration method is as follows:

[0080] Titration method (NH2Cl concentration w / w%)

[0081] Solution A: Sodium thiosulfate pentahydrate (6.20 g) and deionized water (250 mL), stir until dissolved.

[0082] Solution B: Starch (0.500 g) and deionized water (50 mL), heat to 70 °C and stir for 1 h to dissolve.

[0083] Solution C: deionized water (200 mL), acetic acid (10 mL), solution B (10 mL) and potassium iodide (0.8 g).

[0084] Titration: In a conical flask, add Solution C (20.0 mL) and sample (1.0 mL) in sequence. While stirring thoroughly, add Solution A dropwise until the mixture turns colorless.

[0085] Calculation formula:

[0086] If the concentration of the monochloramine MTBE solution used in step c is too low, the conversion rate of compound 2 to 3 will be reduced.

[0087] Step c Preparation of Compound 3

[0088] In some embodiments of the present invention, in step c, the base is NaH, and the molar ratio of compound 2, NaH and NH2Cl is 1:1-3:1-5, preferably 1:1-2:1-3, and more preferably 1:1-1.5:1.2-2.5; the mass volume ratio of compound 2 and DMF is 1:2-10, preferably 1:3-8, and more preferably 1:3-6.

[0089] In some embodiments of the present invention, compound 2 is dissolved in DMF, cooled to -5 to 5°C, and 1 equivalent of NaH is added in batches for reaction. The MTBE solution of the chloramine is then added, and the reaction is continued to completion by adding the remaining equivalent of NaH. Failure to add additional NaH reduces the conversion of compound 2 to 3. Adding an excess of NaH all at once accelerates the decomposition of compound 3, producing more unknown impurities and also reducing the conversion of compound 2 to 3.

[0090] In some embodiments of the present invention, step c includes the following steps: first dissolving compound 2 in DMF, adding NaH in batches for reaction, then slowly adding the MTBE solution of monochloramine of the present invention, and finally adding 0.1-0.5 (e.g., 0.1, 0.2, 0.3, 0.4, 0.5 or any value or range therebetween) equivalents of NaH. After the reaction is completed, post-treatment is performed to remove MTBE in the system to obtain a DMF solution of compound 3. At this time, the conversion rate of compound 2 to compound 3 is higher than 95%.

[0091] In some embodiments of the present invention, in step c, when compound 2 is dissolved in DMF, 1.1-1.5 (e.g., 1.1, 1.2, 1.3, 1.4, 1.5 or any value or range therebetween) equivalents of NaH are added in batches for reaction, and then the MTBE solution of monochloramine of the present invention is slowly added. At this time, the conversion rate of compound 2 to compound 3 is less than 80%.

[0092] In some embodiments of the present invention, the mass volume ratio of compound 2 to DMF is 1:2-10, preferably 1:3-8, and more preferably 1:3-6; after compound 2 is dissolved in DMF, the temperature is lowered to -5 to 5°C, and 60% NaH is added in batches.

[0093] In some embodiments of the present invention, the post-treatment step includes: adding potassium carbonate and stirring the reaction. After the reaction is completed, concentrating under reduced pressure to remove MTBE, filtering, rinsing the filter cake with MTBE, combining the filtrate, and concentrating under reduced pressure until no MTBE flows out to obtain a DMF solution of compound 3.

[0094] In some embodiments of the present invention, the molar ratio of compound 2 to potassium carbonate is 1:0.5-3, preferably 1:0.5-1.5.

[0095] When the potassium carbonate equivalent is reduced or no potassium carbonate is used, compound 3 will gradually decompose into compound 2 when MTBE is concentrated.

[0096] Step a Preparation of Compound 2

[0097] J. Am. Chem. Soc. 2007, 129, 3078-3079 (Supporting Information-S6) uses acetonitrile as a solvent to prepare compound 2. The reaction requires a temperature of -78°C, resulting in a 63% yield. Acetonitrile is expensive and difficult to recycle, and deep-cooling reactions require high energy consumption, making it suitable only for small-scale experiments. In step a of the present invention, MTBE is preferred as a solvent because it is inexpensive and easily recyclable. The reaction is quick, simple, and requires minimal waste. The high yield, lack of deep cooling, and low energy consumption make it suitable for large-scale production, with production capacity reaching hundreds of kilograms.

[0098] Step d

[0099] If the reaction temperature in step d is too low, the reaction time of the cyclization reaction of compound 3 and formamidine acetate will be prolonged. If the reaction temperature is too high, the impurities in the cyclization reaction of compound 3 and formamidine acetate will increase, and the amount of black tar will also increase significantly.

[0100] In some embodiments of the present invention, in step d, the base is one or more of potassium carbonate, sodium bicarbonate, sodium carbonate, triethylamine or diisopropylamine, the reaction temperature is 70 to 95° C., preferably 75 to 85° C., the reaction time is 24 to 96 h, preferably 60 to 80 h, and after the reaction is completed, the temperature is lowered to room temperature and water is added for crystallization to obtain a crude product of compound 4, which is then purified to obtain a finished product of compound 4.

[0101] In some embodiments of the present invention, the purification step of step d is as follows: adding methanol to the crude product, stirring and refluxing until the solution is clear, adding activated carbon for decolorization, concentrating to dryness under reduced pressure, adding n-hexane for pulping, filtering, and drying the filter cake to obtain the finished product of compound 4.

[0102] In some embodiments of the present invention, the purification step of step d is: or the crude product is added with n-hexane and citric acid aqueous solution, stirred to dissolve, controlling the pH = 3.0 to 5.0, standing and stratifying, adding activated carbon to the aqueous phase for decolorization, filtering, slowly adding NaOH aqueous solution to the filtrate, stirring and neutralizing to pH = 8.0 to 10.0, filtering, adding water to the filter cake for slurrying, filtering, and drying the filter cake to obtain the finished product of compound 4.

[0103] Production capacity

[0104] The method of the present invention can be used for industrial production of 100 kg. When producing 1 kg of pyrrolotriazineamine, the total volume of materials required for the reaction is 35 L (including water, ammonium chloride, ammonia water, MTBE, and Ca(ClO)2), and the total amount of wastewater generated is 10 kg.

[0105] In Org.Process Res.Dev.2022,26,82-90, a large amount of ~10% NaClO aqueous solution with low effective chlorine content is used to oxidize NH3. The concentration of the prepared chloramine MTBE is about 0.33 mol / L (mass percentage concentration ~2.2%, see Org.Process Res.Dev.2022,26,82-90 page 88), which is actually used for laboratory pilot-scale production of 690 g of pyrrolotriazineamine. When converted to the production of 1 kg of pyrrolotriazineamine, the total volume of materials required for the reaction is 88 L (including ammonium chloride, ammonia water, MTBE, and NaClO aqueous solution), and the total amount of wastewater generated is 65 kg.

[0106] Org.Lett.2020,22,7656-7661 used a large amount of ~10% NaClO aqueous solution with low effective chlorine content to oxidize NH3, and then used a large amount of MTBE to extract chloramine in the aqueous solution. Only gram-level experimental application research was carried out. When converted to the production of 1 kg of pyrrolotriazineamine, the total volume of materials required for the reaction was 50 L (including ammonium chloride, ammonia water, MTBE, and NaClO aqueous solution), and the total amount of wastewater generated was 41 kg.

[0107] It can be seen that the method of the present invention has high production capacity, low solvent consumption, and low three wastes, and is more suitable for industrial production.

[0108] Unless otherwise specified, the raw materials and reagents used in the examples of the present invention are commercially available.

[0109] The abbreviations used in the present invention have the conventional meanings in the art. For example, the following abbreviations have the following meanings:

[0110] Example 1 Preparation of pyrrole-2-carbonitrile (Compound 2) (Step a)

[0111] Example 1-1

[0112] 2000mL four-necked flask, nitrogen protection. Add MTBE (1000mL) and pyrrole (100.6g), stir and mix. Cool to -10℃, add CSI (214.4g) dropwise, complete the dropwise addition, keep warm and stir for 1h, then add DMF (383.7g) dropwise, complete the dropwise addition, keep warm and react for 2h. The reaction system is then added dropwise to a mixed solution of NaHCO3 (504.1g), water (800mL) and MTBE (200mL) to quench, complete the dropwise addition, warm to room temperature, stir for 0.5h, filter, let the filtrate stand and separate, extract the aqueous phase with MTBE (400mL), combine the organic phases, wash with saturated brine (200mL), concentrate the organic phase until no liquid flows out, and use toluene (100mL) for azeotropic dehydration twice. The concentrate was distilled under reduced pressure, and fractions with boiling points between 100 and 120° C. (vacuum degree 10 to 15 mbar) were collected to obtain colorless, transparent liquid pyrrole-2-carbonitrile with a yield of 85% and a purity of 98%.

[0113] Example 1-2

[0114] A 2000mL four-necked flask was placed under nitrogen protection. MTBE (1000mL) and pyrrole (100.6g) were added and stirred to mix. The temperature was lowered to -10°C, CSI (214.4g) was added dropwise, and the mixture was stirred for 1h. DMF (383.7g) was added dropwise, and the mixture was stirred for 2h. The reaction system was then added dropwise to a mixed solution of Na2CO3 (635.9g), water (800mL) and MTBE (200mL) to quench the mixture. After the mixture was added dropwise, the mixture was warmed to room temperature, stirred for 0.5h, filtered, and the filtrate was allowed to stand for separation. The aqueous phase was extracted with MTBE (400mL), the organic phases were combined, washed with saturated brine (200mL), and the organic phase was concentrated until no liquid flowed out. The mixture was azeotropically dehydrated twice with toluene (100mL). The concentrate was distilled under reduced pressure, and fractions with boiling points between 100 and 120° C. (vacuum degree 10 to 15 mbar) were collected to obtain colorless, transparent liquid pyrrole-2-carbonitrile with a yield of 73% and a purity of 97%.

[0115] Examples 1-3

[0116] A 2000mL four-necked flask was placed under nitrogen protection. MTBE (1000mL) and pyrrole (100.6g) were added and stirred to mix. The temperature was lowered to -10°C, CSI (214.4g) was added dropwise, and after the addition was complete, the mixture was stirred at this temperature for 1h. DMF (383.7g) was added dropwise, and the mixture was stirred at this temperature for 2h. The reaction system was then added dropwise to a mixed solution of NaOH (240g), water (800mL) and MTBE (200mL) to quench the mixture. After the addition was complete, the mixture was warmed to room temperature, stirred for 0.5h, filtered, and the filtrate was allowed to stand for separation. The aqueous phase was extracted with MTBE (400mL), the organic phases were combined, washed with saturated brine (200mL), the organic phase was concentrated until no liquid flowed out, and azeotropically dehydrated twice with toluene (100mL). The concentrate was distilled under reduced pressure, and fractions with boiling points between 100 and 120° C. (vacuum degree 10 to 15 mbar) were collected to obtain colorless, transparent liquid pyrrole-2-carbonitrile with a yield of 49% and a purity of 97%.

[0117] Examples 1-4

[0118] A 2000mL four-necked flask was placed under nitrogen protection. MTBE (1000mL) and pyrrole (100.6g) were added and stirred to mix. The temperature was lowered to -10°C, CSI (214.4g) was added dropwise, and the mixture was stirred for 1h. DMF (191.9g) was added dropwise, and the mixture was stirred for 2h. The reaction system was then added dropwise to a mixed solution of NaHCO3 (504.1g), water (800mL) and MTBE (200mL) to quench the mixture. After the addition was complete, the mixture was warmed to room temperature, stirred for 0.5h, filtered, and the filtrate was allowed to stand for separation. The aqueous phase was extracted with MTBE (400mL). The organic phases were combined and washed with saturated brine (200mL). The organic phases were concentrated until no liquid flowed out, and azeotropically dehydrated twice with toluene (100mL). The concentrate was distilled under reduced pressure, and fractions with boiling points between 100 and 120° C. (vacuum degree 10 to 15 mbar) were collected to obtain colorless, transparent liquid pyrrole-2-carbonitrile with a yield of 70% and a purity of 97%.

[0119] Examples 1-5

[0120] A 2000mL four-necked flask was placed under nitrogen protection. MTBE (1000mL) and pyrrole (100.6g) were added and stirred to mix. The temperature was lowered to 10°C, CSI (214.4g) was added dropwise, and the mixture was stirred for 1h. DMF (383.7g) was added dropwise, and the mixture was stirred for 2h. The reaction system was then quenched by adding dropwise a mixed solution of NaHCO3 (504.1g), water (800mL) and MTBE (200mL). After the addition was complete, the mixture was warmed to room temperature, stirred for 0.5h, filtered, and the filtrate was allowed to stand for separation. The aqueous phase was extracted with MTBE (400mL). The organic phases were combined and washed with saturated brine (200mL). The organic phases were concentrated until no liquid flowed out, and azeotropically dehydrated twice with toluene (100mL). The concentrate was distilled under reduced pressure, and fractions with boiling points between 100 and 120° C. (vacuum degree 10 to 15 mbar) were collected to obtain colorless, transparent liquid pyrrole-2-carbonitrile with a yield of 68% and a purity of 98%.

[0121] Examples 1-6

[0122] A 2000mL four-necked flask was placed under nitrogen protection. MTBE (1000mL) and pyrrole (100.6g) were added and stirred to mix. The temperature was lowered to -10°C, CSI (254.8g) was added dropwise, and the mixture was stirred for 1h. DMF (383.7g) was added dropwise, and the mixture was stirred for 2h. The reaction system was then quenched by adding dropwise a mixed solution of NaHCO3 (504.1g), water (800mL) and MTBE (200mL). After the addition was complete, the mixture was warmed to room temperature, stirred for 0.5h, filtered, and the filtrate was allowed to stand for separation. The aqueous phase was extracted with MTBE (400mL). The organic phases were combined and washed with saturated brine (200mL). The organic phases were concentrated until no liquid flowed out, and azeotropically dehydrated twice with toluene (100mL). The concentrate was distilled under reduced pressure, and fractions with boiling points between 100 and 120° C. (vacuum degree 10 to 15 mbar) were collected to obtain colorless, transparent liquid pyrrole-2-carbonitrile with a yield of 79% and a purity of 98%.

[0123] Example 2 Synthesis of Compound 4

[0124] Step b: Chloramine synthesis

[0125] To a 3000mL four-necked flask, add NH4Cl (111.8g), water (100mL), 25% ammonia water (76.8g), and MTBE (925g) at room temperature and stir to mix. Cool to -10°C and slowly add Ca(ClO)2 (106.8g) in batches. After addition, stir and react for 1h. After the reaction is complete, allow to stand and separate. Wash the organic phase with saturated brine (100mL), dry with anhydrous CaCl2 (101g), and filter to remove CaCl2 to obtain an acyl chloride solution in MTBE. Store at -15 to -10°C.

[0126] Step c: Synthesis of Compound 3

[0127] In a 2000mL four-necked flask, under N2 protection, DMF (190g) and pyrrole-2-carbonitrile (50.7g) were added in sequence at room temperature and stirred to mix. Cool to 0°C, add 60% NaH (22.0g) in batches, and after addition, keep warm and stir for 1h. Slowly add the above-mentioned chloramine MTBE solution dropwise. After addition, keep warm and stir for 2h. Add 60% NaH (4.4g), after addition, keep warm and stir for 1h. Add potassium carbonate (76.0g) and stir and react for 3h. After the reaction is completed, concentrate under reduced pressure to remove MTBE, filter, rinse the filter cake with MTBE (400mL), combine the filtrates, and concentrate under reduced pressure until no MTBE flows out to obtain a DMF solution of compound 3 for later use.

[0128] Step d: Pyrrolotriazineamine synthesis

[0129] To a 2000mL four-necked flask, add the DMF solution of compound 3, Et3N (167.0g), and formamidine acetate (171.8g) at room temperature, stir and mix thoroughly, heat to 75-85°C, and allow to react with stirring for 72 hours. After the reaction is complete, cool to 25°C, add water (400mL) dropwise to crystallize, and stir for 1 hour. Cool to -10°C, and stir for 10 hours. Filter, rinse the filter cake with water, and filter with suction until no liquid remains to obtain crude pyrrolotriazineamine. Add methanol (1500mL) and stir at reflux until the solution becomes clear. Add activated carbon (2.0g), stir at reflux for 2 hours, filter with suction until no liquid remains, concentrate to dryness under reduced pressure, and add n-hexane (150mL) to slurry for 1 hour. Filter and dry the filter cake to obtain a light yellow pyrrolotriazineamine product with a yield of 65% and a purity of 99%.

[0130] Example 3

[0131] Step b: Chloramine synthesis

[0132] To a 3000mL four-necked flask, add NH4Cl (111.8g), water (100mL), 25% aqueous ammonia (76.8g), and MTBE (925g) at room temperature and stir to mix. Cool to 0°C and slowly add Ca(ClO)2 (106.8g) in portions. After addition, stir and react for 1 hour. After the reaction is complete, allow the flask to stand and separate. Wash the organic phase with saturated brine (100mL), dry it with anhydrous CaCl2 (101g), and filter to remove the CaCl2 to obtain a solution of acyl chloride in MTBE. Store at 0°C.

[0133] Step c: Synthesis of Compound 3

[0134] To a 2000mL four-necked flask, under N2 protection, add DMF (190g) and pyrrole-2-carbonitrile (50.7g) in sequence at room temperature and stir to mix. Cool to 0°C and add 60% NaH (22.0g) in batches. After addition, keep warm and stir for 1 hour. Slowly add the above chloramine solution in MTBE dropwise. After addition, keep warm and stir for 2 hours. Add an additional 60% NaH (4.4g). After addition, keep warm and stir for 1 hour. Add potassium carbonate (76.0g) and stir and react for 3 hours. After the reaction is complete, concentrate under reduced pressure to remove MTBE, filter, rinse the filter cake with MTBE (400mL), combine the filtrates, and concentrate under reduced pressure until no MTBE flows out to obtain a DMF solution of compound 3 for later use.

[0135] Step d: Pyrrolotriazineamine synthesis

[0136] To a 2000mL four-necked flask, add the DMF solution of compound 3, Et3N (167.0g), and formamidine acetate (171.8g) at room temperature, stir and mix thoroughly, heat to 75-85°C, and allow to react with stirring for 72 hours. After the reaction is complete, cool to 25°C, add water (400mL) dropwise to crystallize, and stir for 1 hour. Cool to -10°C, and stir for 10 hours. Filter, rinse the filter cake with water, and filter with suction until no liquid remains to obtain crude pyrrolotriazineamine. Add methanol (1500mL) and stir at reflux until the solution becomes clear. Add activated carbon (2.0g), stir at reflux for 2 hours, filter with suction until no liquid remains, concentrate to dryness under reduced pressure, and add n-hexane (150mL) to slurry for 1 hour. Filter and dry the filter cake to obtain a light yellow pyrrolotriazineamine product with a yield of 42% and a purity of 99%.

[0137] Example 4

[0138] Step b: Chloramine synthesis

[0139] To a 3000mL four-necked flask, add NH4Cl (111.8g), water (100mL), 25% ammonia water (76.8g), and MTBE (925g) at room temperature and stir to mix. Cool to -10°C and slowly add Ca(ClO)2 (106.8g) in batches. After addition, stir and react for 1h. After the reaction is complete, allow to stand and separate. Wash the organic phase with saturated brine (100mL), dry with anhydrous CaCl2 (101g), and filter to remove CaCl2 to obtain an acyl chloride solution in MTBE. Store at -15 to -10°C.

[0140] Step c: Synthesis of Compound 3

[0141] In a 2000mL four-necked flask, under N2 protection, DMF (190g) and pyrrole-2-carbonitrile (50.7g) were added in sequence at room temperature and stirred to mix. Cool to 0°C, add 60% NaH (22.0g) in batches, and after addition, keep warm and stir for 1h. Slowly add the above-mentioned chloramine MTBE solution dropwise. After addition, keep warm and stir for 2h. Add 60% NaH (4.4g), after addition, keep warm and stir for 1h. Add potassium carbonate (76.0g) and stir and react for 3h. After the reaction is completed, concentrate under reduced pressure to remove MTBE, filter, rinse the filter cake with MTBE (400mL), combine the filtrates, and concentrate under reduced pressure until no MTBE flows out to obtain a DMF solution of compound 3 for later use.

[0142] Step d: Pyrrolotriazineamine synthesis

[0143] To a 2000mL four-necked flask, add the DMF solution of compound 3, Et3N (167.0g), and formamidine acetate (171.8g) at room temperature, stir and mix thoroughly, heat to 95°C, and maintain stirring for 48 hours. After the reaction is complete, cool to 25°C, add water (400mL) dropwise to induce crystallization, maintain stirring for 1 hour, cool to -10°C, maintain stirring for 10 hours, filter, rinse the filter cake with water, and filter with suction until no liquid remains to obtain crude pyrrolotriazineamine. Add methanol (1500mL) and stir under reflux until the solution becomes clear. Add activated carbon (2.0g), stir under reflux for 2 hours, filter under reflux until no liquid remains, concentrate under reduced pressure to dryness, and add n-hexane (150mL) and beat for 1 hour. Filter and dry the filter cake to obtain a light yellow pyrrolotriazineamine product with a yield of 51% and a purity of 99%.

[0144] Example 5

[0145] Step b: Chloramine synthesis

[0146] To a 3000mL four-necked flask, add NH4Cl (111.8g), water (100mL), 25% ammonia water (76.8g), and MTBE (925g) at room temperature and stir to mix. Cool to -10°C and slowly add Ca(ClO)2 (106.8g) in batches. After addition, stir and react for 1h. After the reaction is complete, allow to stand and separate. Wash the organic phase with saturated brine (100mL), dry with anhydrous CaCl2 (101g), and filter to remove CaCl2 to obtain an acyl chloride solution in MTBE. Store at -15 to -10°C.

[0147] Step c: Synthesis of Compound 3

[0148] In a 2000mL four-necked flask, under N2 protection, DMF (190g) and pyrrole-2-carbonitrile (50.7g) were added in sequence at room temperature and stirred to mix. Cool to 0°C, add 60% NaH (22.0g) in batches, and after addition, keep warm and stir for 1h. Slowly add the above-mentioned chloramine MTBE solution dropwise. After addition, keep warm and stir for 2h. Add 60% NaH (4.4g), after addition, keep warm and stir for 1h. Add potassium carbonate (76.0g) and stir and react for 3h. After the reaction is completed, concentrate under reduced pressure to remove MTBE, filter, rinse the filter cake with MTBE (400mL), combine the filtrates, and concentrate under reduced pressure until no MTBE flows out to obtain a DMF solution of compound 3 for later use.

[0149] Step d: Pyrrolotriazineamine synthesis

[0150] To a 2000mL four-necked flask, a DMF solution of compound 3, Et3N (167.0g), and formamidine acetate (171.8g) were added at room temperature and stirred. The mixture was then heated to 70°C and stirred for 96 hours. After the reaction was complete, the temperature was lowered to 25°C, and water (400mL) was added dropwise to induce crystallization. The mixture was stirred for 1 hour, then cooled to -10°C and stirred for 10 hours. The mixture was filtered, the filter cake rinsed with water, and suction filtered until no liquid remained to obtain the crude pyrrolotriazineamine. The crude product was added to methanol (1500mL), stirred and refluxed until the solution became clear. Activated carbon (2.0g) was added, stirred and refluxed for 2 hours, suction filtered until no liquid remained to obtain the crude product. The product was concentrated to dryness under reduced pressure, and then slurried in n-hexane (150mL) for 1 hour. The filter cake was filtered and dried to obtain a light yellow pyrrolotriazineamine product with a yield of 46% and a purity of 99%.

[0151] Example 6

[0152] Step b: Chloramine synthesis

[0153] To a 3000mL four-necked flask, add NH4Cl (111.8g), water (100mL), 25% ammonia water (76.8g), and MTBE (925g) at room temperature and stir to mix. Cool to -10°C and slowly add Ca(ClO)2 (160.2g) in batches. After addition, stir and react for 1h. After the reaction is complete, allow to stand and separate. Wash the organic phase with saturated brine (100mL), dry with anhydrous CaCl2 (101g), and filter to remove CaCl2 to obtain an acyl chloride solution in MTBE. Store at -15 to -10°C.

[0154] Step c: Synthesis of Compound 3

[0155] In a 2000mL four-necked flask, under N2 protection, DMF (190g) and pyrrole-2-carbonitrile (50.7g) were added in sequence at room temperature and stirred to mix. Cool to 0°C, add 60% NaH (22.0g) in batches, and after addition, keep warm and stir for 1h. Slowly add the above-mentioned chloramine MTBE solution dropwise. After addition, keep warm and stir for 2h. Add 60% NaH (4.4g), after addition, keep warm and stir for 1h. Add potassium carbonate (76.0g) and stir and react for 3h. After the reaction is completed, concentrate under reduced pressure to remove MTBE, filter, rinse the filter cake with MTBE (400mL), combine the filtrates, and concentrate under reduced pressure until no MTBE flows out to obtain a DMF solution of compound 3 for later use.

[0156] Step d: Pyrrolotriazineamine synthesis

[0157] To a 2000mL four-necked flask, add the DMF solution of compound 3, Et3N (167.0g), and formamidine acetate (171.8g) at room temperature, stir and mix thoroughly, heat to 75-85°C, and allow to react with stirring for 72 hours. After the reaction is complete, cool to 25°C, add water (400mL) dropwise to crystallize, and stir for 1 hour. Then cool to -10°C and stir for 10 hours. Filter, rinse the filter cake with water, and filter with suction until no liquid remains to obtain crude pyrrolotriazineamine. Add methanol (1500mL) and stir under reflux until the solution becomes clear. Add activated carbon (2.0g), stir under reflux for 2 hours, filter with suction until no liquid remains, concentrate to dryness under reduced pressure, and add n-hexane (150mL) to slurry for 1 hour. Filter and dry the filter cake to obtain a light yellow pyrrolotriazineamine product with a yield of 28% and a purity of 99%.

[0158] Example 7

[0159] Step b: Chloramine synthesis

[0160] To a 3000mL four-necked flask, add NH4Cl (111.8g), water (100mL), 25% ammonia water (76.8g), and MTBE (925g) at room temperature and stir to mix. Cool to -10°C and slowly add Ca(ClO)2 (106.8g) in batches. After addition, stir and react for 1h. After the reaction is complete, allow to stand and separate. Wash the organic phase with saturated brine (100mL), dry with anhydrous CaCl2 (101g), and filter to remove CaCl2 to obtain an acyl chloride solution in MTBE. Store at -15 to -10°C.

[0161] Step c: Synthesis of Compound 3

[0162] In a 2000mL four-necked flask, under N2 protection, DMF (190g) and pyrrole-2-carbonitrile (50.7g) were added in sequence at room temperature and stirred to mix. Cool to 0°C, add 60% NaH (22.0g) in batches, and after addition, keep warm and stir for 1h. Slowly add the above-mentioned chloramine MTBE solution dropwise. After addition, keep warm and stir for 2h. Add 60% NaH (4.4g), after addition, keep warm and stir for 1h. Add potassium carbonate (76.0g) and stir and react for 3h. After the reaction is completed, concentrate under reduced pressure to remove MTBE, filter, rinse the filter cake with MTBE (400mL), combine the filtrates, and concentrate under reduced pressure until no MTBE flows out to obtain a DMF solution of compound 3 for later use.

[0163] Step d: Pyrrolotriazineamine synthesis

[0164] To a 2000mL four-necked flask, add the DMF solution of compound 3, Et3N (167.0g), and formamidine acetate (171.8g) at room temperature, stir and mix, heat to 75-85°C, and stir and react for 72 hours. After the reaction is complete, cool to 45°C, concentrate under reduced pressure until no liquid flows out, add water (400mL) dropwise to crystallize, and stir and maintain for 1 hour. Cool to -10°C, stir and maintain for 10 hours, filter, and rinse the filter cake with water to obtain the crude product of pyrrolotriazineamine. The crude product was added with n-hexane (100 mL) and 10% aqueous citric acid solution (86.7 g of citric acid monohydrate and 780 mL of water), stirred to dissolve, and the pH was controlled to 3.0-5.0. The mixture was allowed to stand for stratification, and the organic phase was discarded. Activated carbon (2.0 g) was added to the aqueous phase for decolorization, and the mixture was stirred for 2.0 h. The mixture was filtered and the filter cake was rinsed with water (50 mL). The filtrate was slowly added dropwise with 30% aqueous NaOH solution (49.5 g of NaOH + 116 mL of H2O), stirred and neutralized to pH 8.0-10.0, filtered, the filter cake was slurried with water for 1.0 h, filtered, the filter cake was rinsed with water (50 mL), and the filter cake was dried to obtain a white pyrrolotriazineamine product with a yield of 59% and a purity of 99%.

[0165] Example 8

[0166] Step b: Chloramine synthesis

[0167] To a 3000mL four-necked flask, add NH4Cl (111.8g), water (100mL), 25% ammonia water (76.8g), and MTBE (925g) at room temperature and stir to mix. Cool to -10°C and slowly add Ca(ClO)2 (53.4g) in batches. After addition, stir and react for 1h. After the reaction is complete, allow to stand and separate. Wash the organic phase with saturated brine (100mL), dry with anhydrous CaCl2 (101g), and filter to remove CaCl2 to obtain an acyl chloride solution in MTBE. Store at -15 to -10°C.

[0168] Step c: Synthesis of Compound 3

[0169] In a 2000mL four-necked flask, under N2 protection, DMF (190g) and pyrrole-2-carbonitrile (50.7g) were added in sequence at room temperature and stirred to mix. Cool to 0°C, add 60% NaH (22.0g) in batches, and after addition, keep warm and stir for 1h. Slowly add the above-mentioned chloramine MTBE solution dropwise. After addition, keep warm and stir for 2h. Add 60% NaH (11g), after addition, keep warm and stir for 1h. Add potassium carbonate (76.0g) and stir and react for 3h. After the reaction is completed, concentrate under reduced pressure to remove MTBE, filter, rinse the filter cake with MTBE (400mL), combine the filtrates, and concentrate under reduced pressure until no MTBE flows out to obtain a DMF solution of compound 3 for standby use.

[0170] Step d: Pyrrolotriazineamine synthesis

[0171] To a 2000mL four-necked flask, add the DMF solution of compound 3, Et3N (167.0g), and formamidine acetate (171.8g) at room temperature, stir and mix, heat to 75-85°C, and stir and react for 72 hours. After the reaction is complete, cool to 45°C, concentrate under reduced pressure until no liquid flows out, add water (400mL) dropwise to crystallize, and stir and maintain for 1 hour. Cool to -10°C, stir and maintain for 10 hours, filter, and rinse the filter cake with water to obtain the crude product of pyrrolotriazineamine. The crude product was added with n-hexane (100 mL) and 10% aqueous citric acid solution (86.7 g of citric acid monohydrate and 780 mL of water), stirred to dissolve, and the pH was controlled to 3.0-5.0. The mixture was allowed to stand for stratification, and the organic phase was discarded. Activated carbon (2.0 g) was added to the aqueous phase for decolorization, and the mixture was stirred for 2.0 h. The mixture was filtered and the filter cake was rinsed with water (50 mL). The filtrate was slowly added dropwise with 30% aqueous NaOH solution (49.5 g of NaOH + 116 mL of H2O), stirred and neutralized to pH 8.0-10.0, filtered, the filter cake was slurried with water for 1.0 h, filtered, the filter cake was rinsed with water (50 mL), and the filter cake was dried to obtain a white pyrrolotriazineamine product with a yield of 37% and a purity of 99%.

[0172] All documents mentioned in this application are incorporated herein by reference, just as if each document were incorporated individually by reference. Furthermore, it should be understood that the preferred embodiments described above are merely illustrative of the technical concepts and features of the present invention, intended to facilitate understanding of the present invention by those skilled in the art, and are not intended to limit the scope of protection of the present invention. Any equivalent variations or modifications made in accordance with the spirit and substance of the present invention are intended to fall within the scope of protection of the present invention.

Claims

1. A method for preparing a monochloramine organic solution, characterized in that: The following steps are involved: Step b: Mix the organic solvent, water, ammonium chloride and ammonia water, then add Ca(ClO)2, separate the organic phase after the reaction is completed, and obtain an organic solution of monochloramine. Ca(ClO)2+NH4Cl+NH3·H2O→NH2Cl.

2. A method for preparing compound 3, characterized in that: The following steps are involved: Step b: Mix the organic solvent, water, ammonium chloride and ammonia water, then add Ca(ClO)2, separate the organic phase after the reaction is completed, and obtain an organic solution of monochloramine. Ca(ClO)2+NH4Cl+NH3·H2O→NH2Cl; Step c: dissolving compound 2 in DMF, adding the organic solution of monochloramine prepared in step b to react under the action of NaH to obtain compound 3.

3. A method for preparing compound 4, characterized in that: The following steps are involved: Step b: Mix the organic solvent, water, ammonium chloride and ammonia water, then add Ca(ClO)2, separate the organic phase after the reaction is completed, and obtain an organic solution of monochloramine. Ca(ClO)2+NH4Cl+NH3·H2O→NH2Cl; Step c: dissolving compound 2 in DMF, adding the organic solution of monochloramine prepared in step b to react under the action of NaH to obtain compound 3. Step d: Compound 3 and formamidine acetate react under the action of a base to obtain compound 4.

4. The preparation method according to any one of claims 1 to 3, characterized in that: In step b, the Ca(ClO)2 is added in batches, and the system temperature is controlled at -25 to 15°C, preferably -25 to -10°C.

5. The preparation method according to any one of claims 1 to 3, characterized in that: In step b, the organic solvent is one or more of MTBE, ether, tetrahydrofuran, 2-methyltetrahydrofuran, ethyl acetate, and dichloromethane, preferably MTBE.

6. The preparation method according to claim 5, characterized in that: The molar ratio of Ca(ClO)2, NH3·H2O and NH4Cl is 1:1-10:1-10, preferably 1:2-3:3-4, more preferably 1:2-2.5:3.5-4; the volume ratio of MTBE, water and ammonia water is 10-30:1-10:1, preferably 12-18:1-3:1, more preferably 13-15:1-2:

1.

7. The MTBE solution of monochloramine prepared by the preparation method according to claim 1, wherein the content of monochloramine is 0.44-1.32 mol / L, preferably 0.50-1.00 mol / L, and more preferably 0.53-0.88 mol / L.

8. The preparation method according to claim 2 or 3, characterized in that: In step c, the organic solution of monochloramine is a MTBE solution of monochloramine, and preferably, the content of monochloramine in the MTBE solution of monochloramine is 0.44 to 1.32 mol / L, preferably 0.50 to 1.00 mol / L, and more preferably 0.53 to 0.88 mol / L; The molar ratio of the compound 2, NaH and NH2Cl is 1:1-3:1-5, preferably 1:1-2:1-3, more preferably 1:1-1.5:1.2-2.5; The mass volume ratio of compound 2 to DMF is 1:2-10, preferably 1:3-8, and more preferably 1:3-6.

9. The preparation method according to claim 8, characterized in that: Step c comprises the following steps: dissolving compound 2 in DMF, cooling to -5 to 5°C, adding 1 equivalent of NaH for reaction, adding the MTBE solution of monochloramine, and then continuing the reaction by adding the remaining equivalent of NaH.

10. The preparation method according to claim 3, characterized in that: In step d, the base is potassium carbonate, sodium bicarbonate, sodium carbonate, triethylamine or diisopropylamine, the reaction temperature is 70 to 95° C., preferably 75 to 85° C., and the reaction time is 24 to 96 h, preferably 60 to 80 h.

11. The preparation method according to claim 2 or 3, characterized in that: The method further comprises dissolving pyrrole in an organic solvent, and sequentially adding CSI and DMF to react to obtain compound 2: Preferably, the organic solvent is MTBE.

12. A method for preparing compound 2, characterized in that: The method comprises the following steps: dissolving pyrrole in MTBE, adding CSI and DMF in sequence to react to obtain compound 2, 13. The preparation method according to claim 11 or 12, characterized in that: In step a, the reaction temperature is -20 to 10°C, preferably -15 to -10°C; Preferably, the molar ratio of pyrrole, CSI and DMF is 1:1-3:1-5, preferably 1:1-1.5:2-4, more preferably 1:1-1.2:2.5-3.5; the mass volume ratio of pyrrole and MTBE is 1:2-20, preferably 1:3-15, more preferably 1:5-8; Preferably, after the reaction is completed, the reaction is quenched with an alkaline system, extracted with MTBE, and the organic phase is concentrated, dehydrated, and distilled to obtain compound 2; Preferably, the alkaline system is a mixture of alkali, water and MTBE; Preferably, the base in the alkaline system is NaHCO3 or K2CO3; More preferably, the base in the alkaline system is NaHCO3, and the mass volume ratio of the mixed solution of NaHCO3, water and MTBE is 1:1-5:0.3-20.

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