Diphenyltriazine compound intermediate and its synthesis method and application

Abstract

The present invention belongs to the technical field of drug synthesis, and relates to a diphenyltriazine compound intermediate, a synthesis method and an application thereof. The present invention provides an intermediate, which has the advantages of easy availability of raw materials, mild reaction conditions, low production cost and high safety for synthesizing diphenyltriazine compounds. The present invention also provides a preparation method of the intermediate, which achieves the effects of mild reaction conditions, short reaction time and high product yield by using a mixed solvent of dichloromethane and n-hexane as a reaction solvent and controlling the ratio of the mixed solvent; and an application of synthesizing diphenyltriazine compounds from the intermediate.

Description

Technical Field

[0001] The invention belongs to the technical field of drug synthesis, and in particular relates to a diphenyltriazine compound intermediate and a synthesis method and application thereof. Background Art

[0002] Pulmonary hypertension is a rare and difficult-to-cure pulmonary vascular disease that can gradually lead to right heart failure and eventually death. 75% of PAH patients die within 5 years of diagnosis, and the average survival time after the onset of symptoms is 1.9 years. Therefore, it is also called "malignant tumor in the field of cardiopulmonary vascular disease." PGI2 receptor agonists are the dominant drugs for the treatment of pulmonary hypertension, and the representative variety is selexipag.

[0003] Diphenyltriazine compounds are a new type of long-acting oral PGI2 receptor agonists with strong target selectivity compared with existing drugs.

[0004] Among them, the compound with the chemical name 6-((5,6-diphenyl-1,2,4-triazine-3-yl)(isopropyl)amino)-N-(methylsulfonyl)hexanamide (hereinafter referred to as "SYN045") performed more outstandingly, and its structural formula is shown in Formula V. The agonist activity of SYN045 on the prostacyclin IP receptor is more than 1,000 times that of the other seven prostacyclin receptor targets, with significantly reduced side effects and outstanding clinical advantages.

[0005]

[0006] The prior art discloses the synthetic route of the above-mentioned compound SYN045, as shown below. The process route is long, and multiple intermediates and finished products need to be purified by column chromatography, with a low yield; and the preparation of intermediate II-3 requires reaction at high temperature (140~150°C); Dess-Martin reagent is used in the preparation of intermediate II-4, and the post-processing operation is relatively cumbersome; the preparation of intermediate II-5 uses the dangerous reagent NaH, which poses a safety hazard; the preparation of intermediate II-6 is a hydrogenation reduction reaction, which requires the use of special equipment such as an autoclave, and there are safety hazards, so this route is not suitable for large-scale production.

[0007] Summary of the invention

[0008] The object of the present invention is to provide an intermediate for synthesizing diphenyltriazine compounds and a synthesis method thereof, as well as a preparation method for preparing diphenyltriazine compounds from the intermediate and a synthesis method of compound SYN045, which are suitable for scale-up production.

[0009] In order to solve the above technical problems, the technical solution adopted by the present invention is as follows: The invention provides an intermediate for synthesizing diphenyltriazine compounds, the chemical name of which is 3-isopropylamino-5,6-diphenyl-1,2,4-triazine, and which has a structural formula shown in Formula III.

[0010]

[0011] The intermediate provided by the present invention is used to synthesize diphenyltriazine compounds, especially compound SYN045, which has the advantages of cheap and readily available raw materials, mild reaction conditions, low production cost and high safety.

[0012] The present invention also provides a method for preparing the intermediate, comprising the following steps: mixing a compound shown in formula II, isopropylamine and a reaction solvent A, reacting at room temperature for 3-5 hours, adding water to quench the reaction, and obtaining an intermediate shown in formula III, wherein the reaction solvent A is a mixed solvent of dichloromethane and n-hexane, and X1 in the compound structure shown in formula II is a halogen.

[0013]

[0014] Furthermore, X1 in the compound structure represented by formula II is preferably chlorine or bromine.

[0015] Furthermore, the step also includes a post-treatment process, adding ethyl acetate to the reaction solution obtained after the quenching reaction for extraction, washing the organic phase with water, drying, concentrating to remove ethyl acetate, adding methyl tert-butyl ether, stirring at room temperature for 0.5-1.5h, and filtering to obtain the compound shown in formula III.

[0016] Furthermore, the volume ratio of dichloromethane to n-hexane in the reaction solvent A is 10:1-20:1, preferably 11:1-19:1, and more preferably 13:1.

[0017] Furthermore, in the above steps, the equivalent ratio of the compound represented by formula II to isopropylamine is 1:2-3.

[0018] Furthermore, in the above steps, the mass volume ratio of the compound represented by formula II to the reaction solvent A is 71:300~400g / mL.

[0019] The preparation method of the intermediate (compound shown in formula III) provided by the present invention adopts a mixed solvent of dichloromethane and n-hexane as the reaction solvent A, and controls the volume ratio of dichloromethane to n-hexane in the reaction solvent A within the range of 10:1-20:1, so as to achieve a higher reaction yield of 92%-96% under milder reaction conditions at room temperature with a shorter reaction time of 3-5h. The optimized reaction solvent is more conducive to improving the reaction rate and yield, enhancing the reaction selectivity and product purity. And by optimizing the reactant ratio and the amount of reaction solvent A, the product yield is further improved.

[0020] Furthermore, in the above post-treatment step, the mass volume ratio of the compound represented by formula II to the water used for quenching the reaction is 71:400~600g / mL.

[0021] Furthermore, in the above post-treatment step, the mass volume ratio of the compound represented by formula II to the water used for washing the organic phase is 71:400-600 g / mL.

[0022] Furthermore, in the above post-treatment step, the mass volume ratio of the compound represented by formula II to ethyl acetate is 71:400~600g / mL.

[0023] Furthermore, in the above post-treatment step, the mass volume ratio of the compound represented by formula II to methyl tert-butyl ether is 71:200~300g / mL.

[0024] Furthermore, in the above post-treatment step, the drying is to remove moisture using a desiccant, specifically, drying using anhydrous sodium sulfate.

[0025] The present invention provides a method for preparing the intermediate (the compound represented by Formula III), and by optimizing the post-treatment method and conditions, the purity of the product is further improved to ensure the product quality.

[0026] The present invention also provides a method for preparing a diphenyltriazine compound from the intermediate, comprising the following steps: subjecting the compound represented by formula III to a substitution reaction with the compound represented by formula VIII to obtain a diphenyltriazine compound represented by formula IX; wherein X2 in the structure represented by formula VIII is a halogen, and R is a C1-C5 saturated alkane. R in the structure represented by formula IX is the same as R in the structure represented by formula VIII.

[0027]

[0028] Furthermore, in the structure represented by Formula VIII, R is a C1-C5 straight-chain or branched saturated alkane, preferably a C1-C5 straight-chain saturated alkane.

[0029] Furthermore, in the structure represented by Formula VIII, R is a C4-C5 saturated alkane, preferably a C4-C5 straight-chain or branched saturated alkane, and more preferably a C4-C5 straight-chain saturated alkane.

[0030] Furthermore, in the structure represented by formula VIII, X2 is preferably chlorine or bromine.

[0031] Furthermore, the preparation method specifically includes the following steps: mixing the compound shown in formula III, the general compound shown in formula VIII and the reaction solvent B, cooling to 0°C-10°C, adding potassium tert-butoxide, heating to room temperature and stirring for 3-5h, adding water to quench the reaction, extracting with ethyl acetate, taking the organic phase, washing with 1N hydrochloric acid, washing with water, drying, concentrating to remove ethyl acetate to obtain a crude product, recrystallizing the crude product twice with isopropanol to obtain a filter cake, and drying to obtain a diphenyl triazine compound having a structural formula as shown in formula IX; wherein the reaction solvent B is dimethyl sulfoxide.

[0032] Furthermore, the equivalent ratio of the compound represented by formula III to the compound represented by formula VIII is 1:2-5.

[0033] Furthermore, the equivalent ratio of the compound represented by formula III to potassium tert-butoxide is 1:4-6.

[0034] Furthermore, the mass volume ratio of the compound represented by formula III to the reaction solvent B is 70:300-400 g / mL.

[0035] Furthermore, the mass volume ratio of the compound represented by formula III to the water used for quenching the reaction is 70:500~1000g / mL.

[0036] Furthermore, the mass volume ratio of the compound represented by formula III to ethyl acetate is 70:500~1000g / mL.

[0037] Furthermore, the mass volume ratio of the compound represented by formula III to 1N hydrochloric acid used for washing the organic phase is 70:200-500 g / mL.

[0038] Furthermore, the mass volume ratio of the compound represented by formula III to the water used for washing the organic phase is 70:200-500 g / mL.

[0039] Furthermore, the drying after washing the organic phase with water is to remove moisture with a desiccant, specifically, drying with anhydrous sodium sulfate.

[0040] Furthermore, the specific method of recrystallizing the crude product twice with isopropanol is as follows: adding 400-600mL of isopropanol to the crude product, heating to reflux to dissolve, filtering to remove mechanical impurities, cooling the filtrate to 0°C~5°C, keeping warm and stirring for 3-5h, filtering, rinsing the filter cake with 200-500mL of isopropanol, and draining; adding 400-600mL of isopropanol to the filter cake, heating to reflux, slowly cooling to 0°C~5°C for 3-5h after dissolving, keeping warm and stirring for 1-2h, filtering, rinsing the filter cake with 200-500mL of isopropanol, and draining.

[0041] Furthermore, the crude product is recrystallized twice with isopropanol to obtain a filter cake and then dried. Specifically, the filter cake obtained by recrystallization is vacuum dried at a temperature of 45° C.-55° C. to constant weight to obtain a diphenyltriazine compound having a structural formula as shown in Formula IX.

[0042] The present invention has found in the research of synthetic route design that the above intermediate (compound shown in formula III) is directly subjected to substitution reaction with 6-bromohexanoic acid to prepare compound II-7 (chemical name: 6-((5,6-diphenyl-1,2,4-triazine-3-yl)(isopropyl)amino)hexanoic acid). This reaction is difficult to carry out, and compound II-7 cannot be obtained. Therefore, compound SYN045 can no longer be prepared by reacting compound II-7 with methylsulfonamide. Therefore, in order to overcome this technical difficulty, the present invention has developed the above synthetic route, and first condenses 6-bromohexanoic acid with methylsulfonamide to prepare a compound shown in formula IV (chemical name is 6-bromo-N-(methylsulfonyl)hexanamide), and then the compound shown in formula IV is subjected to substitution reaction with the intermediate (compound shown in formula III) to prepare the target compound SYN045 (as shown in formula V). The synthetic route designed by the present invention has the advantages of mild reaction conditions, low production cost and high safety, and is conducive to industrial production. This reaction route is also applicable to preparing a diphenyltriazine compound having a structural formula as shown in Formula IX by reacting a compound as shown in Formula III with a compound of the general formula as shown in Formula VIII.

[0043]

[0044] The method for preparing a diphenyltriazine compound having a structural formula as shown in Formula IX from an intermediate (compound shown in Formula III) provided by the present invention, in particular, preparing compound SYN045 (compound shown in Formula V), mainly adopts dimethyl sulfoxide as a reaction solvent B, so as to achieve high yield and high purity of the raw material drug product, and at the same time, the reaction conditions are mild, the reaction time is short, the post-processing process is simplified, and the optimized reaction solvent system is more conducive to improving the reaction rate and yield, enhancing the reaction selectivity and product purity. The present invention further improves the product yield and purity by further optimizing the reaction conditions, such as the ratio of reactants, the amount of solvent, and optimizing the post-processing method and the crude product purification process.

[0045] The present invention also provides a method for synthesizing a diphenyl triazine compound, the structure of the diphenyl triazine compound is shown in Formula V, and the synthesis method comprises the following reaction steps: S1, 4,4'-dimethylbenzil and 2-aminoacetamide hydrochloride undergo cyclization reaction to obtain a compound of formula I; S2, the compound represented by formula I is subjected to chlorination reaction with phosphorus oxychloride to obtain a compound represented by formula II; S3, the compound represented by formula II is subjected to substitution reaction with isopropylamine to obtain a compound represented by formula III; S4, condensing the compound represented by formula IV-1 with methylsulfonamide to obtain a compound represented by formula IV; S5, the compound represented by formula III is subjected to substitution reaction with the compound represented by formula IV to obtain a compound represented by formula V; Wherein, X1 in the compound structure of formula II is a halogen, and X3 in the compound structure of formula IV-1 and the compound structure of formula IV is the same halogen.

[0046] The synthetic route of the compound represented by formula V (ie, SYN045) is as follows.

[0047]

[0048] Furthermore, X1 in the compound structure represented by formula II is preferably chlorine or bromine, and X3 in the compound structure represented by formula IV-1 and the compound structure represented by formula IV is the same halogen, preferably chlorine or bromine.

[0049] Furthermore, in the above step S1, the reaction temperature of the cyclization reaction is 100°C to 110°C.

[0050] Furthermore, in the above step S2, the reaction temperature of the chlorination reaction is 80°C to 90°C.

[0051] Furthermore, in the above step S3, the reaction temperature of the substitution reaction is 20°C to 25°C.

[0052] Furthermore, in the above step S4, the condensation reaction is carried out under reflux conditions.

[0053] Furthermore, in the above step S5, the reaction temperature of the substitution reaction is 20°C to 25°C.

[0054] Furthermore, in the above step S3, the reaction solvent A of the substitution reaction is a mixed solvent of dichloromethane and n-hexane, and the volume ratio of dichloromethane to n-hexane in the reaction solvent A is 10:1-20:1, preferably 11:1-19:1, and more preferably 13:1.

[0055] Furthermore, in the above step S5, the reaction solvent B of the substitution reaction is dimethyl sulfoxide (DMSO).

[0056] The diphenyltriazine compound (the structure is shown in Formula V, i.e., SYN045) provided by the present invention has a short synthesis route, and a high-purity raw material drug can be obtained without purification by column chromatography, and the product has a high yield and low cost; by optimizing and screening the reaction conditions, the reaction conditions are mild and the reaction time is short; the required materials and reagents are convenient and easy to obtain, and the product is easy to purify by recrystallization; at the same time, high-temperature reaction and the use of dangerous reagent NaH are avoided, the equipment requirements are simple, the safety of process operation is improved, and the Dess-Martin oxidation reagent is not used in the process, the process is simplified, and it is more suitable for scale-up production. BRIEF DESCRIPTION OF THE DRAWINGS

[0057] Figure 1 For the intermediate in Example 1 of the present invention 1 H-NMR spectrum; Figure 2 is the mass spectrum of the intermediate in Example 1 of the present invention; Figure 3 is the compound SYN045 in Example 5 of the present invention 1 H-NMR spectrum. DETAILED DESCRIPTION

[0058] The present invention is further described in detail below through specific implementation modes, but it is only used to help understand the present invention so that professionals in the field can implement or use the present invention, and does not constitute any limitation to the present invention.

[0059] the term In this application, "eq" means equivalent, and both "eq" and "equivalent" are calculated in molar ratios, and each step can use its own independent equivalent standard. For example, if 0.3 mol (1 eq) of A is used in a reaction, and the amount of B used is 6 times that of A, that is, 6 eq, then the amount of B used is 1.8 mol.

[0060] As used herein, the term "room temperature" or "RT" refers to an ambient temperature of 20°C to 25°C (68-77°F).

[0061] The following is a description with reference to specific embodiments.

[0062] Example 1: Preparation of diphenyltriazine compound intermediate In this example, intermediate 2 is prepared from intermediate 1, and then the intermediate claimed in the present invention is prepared.

[0063] The chemical name of intermediate 1 is 5,6-diphenyl-1,2,4-triazine-3-ol, and the preparation method is as follows: glacial acetic acid (500 mL), benzil (100 g, 1 eq), hydrochloric acid semicarbazide (178 g, 1.5 eq) and purified water (200 mL) are added to the reaction bottle in sequence, stirred evenly, heated to 100°C~110°C, kept warm for 2~3 hours, then cooled to 30°C~40°C, 1L purified water is added, stirred at room temperature for 1~2 hours. Filter, place the filter cake in 400 mL of ethyl acetate, heat and reflux and stir for 1~3 hours, cool to room temperature, filter, and vacuum dry the filter cake to obtain 110 g of the compound shown in formula I, with a yield of 92.8%.

[0064] The reaction formula is as follows:

[0065] The chemical name of intermediate 2 is 3-chloro-5,6-diphenyl-1,2,4-triazine, and the preparation method is as follows: phosphorus oxychloride (185 g, 3 eq) and the compound shown in formula I (100 g, 1 eq) are added to the reaction bottle in sequence, the temperature is raised to 80°C~90°C, stirred to dissolve, kept warm for 1~2 hours, concentrated under reduced pressure to remove phosphorus oxychloride, and 200 mL of toluene is added to continue to concentrate to remove residual phosphorus oxychloride. After concentration, a mixed solvent of toluene (100 mL) and isopropanol (300 mL) is added, and the solid is dispersed by stirring at room temperature, filtered, and the filter cake is vacuum dried to obtain 72 g of the compound shown in formula II, with a yield of 67%.

[0066] The reaction formula is as follows:

[0067] Intermediates This embodiment provides a method for preparing an intermediate. The chemical name of the intermediate is 3-isopropylamino-5,6-diphenyl-1,2,4-triazine, and the structural formula is shown in Formula III.

[0068]

[0069] Reaction solvent A was prepared with dichloromethane and n-hexane, wherein the volume ratio of dichloromethane to n-hexane was 13:1; reaction solvent A (350 mL), the compound represented by formula II (71 g, 1 eq) and isopropylamine (39.2 g, 2.5 eq) were added to the reaction flask, reacted at room temperature for 4 h, and 500 mL of purified water was added to quench the reaction.

[0070] The organic phase was extracted with 500 mL of ethyl acetate, washed once with 500 mL of purified water, dried over anhydrous sodium sulfate, concentrated to remove ethyl acetate, added with 250 mL of methyl tert-butyl ether to remove impurities, stirred at room temperature for 1 h, and filtered to obtain 73.2 g of the compound represented by formula III, with a yield of 95.1%.

[0071] The structural characterization of the intermediates can be found in Figure 1 and Figure 2 , the specific data are as follows.

[0072] 1 H-NMR (400MHz, CDCl3): δ: 1.349~1.362 (d, 6H), 4.393 (brs, 1H), 7.312~7.320 (m, 5H), 7.388~7.430 (m, 3H), 7.475~7.489 (m, 2H) ppm.

[0073] ESI-MS (m / z): 291.5[M+H]+.

[0074] Example 2: Preparation of intermediates Reaction solvent A was prepared with dichloromethane and n-hexane, wherein the volume ratio of dichloromethane to n-hexane was 11:1; reaction solvent A (300 mL), the compound represented by formula II (71 g, 1 eq) and isopropylamine (31.4 g, 2.0 eq) were added to the reaction flask, reacted at room temperature for 3 h, and 400 mL of purified water was added to quench the reaction.

[0075] The mixture was extracted with 400 mL of ethyl acetate, and the organic phase was taken. After washing once with 400 mL of purified water, it was dried over anhydrous sodium sulfate and concentrated to remove ethyl acetate. 200 mL of methyl tert-butyl ether was added, and the mixture was stirred at room temperature for 0.5 h. The mixture was filtered to obtain 71.5 g of the compound represented by formula III, with a yield of 92.9%.

[0076] Example 3: Preparation of intermediates Reaction solvent A was prepared with dichloromethane and n-hexane, wherein the volume ratio of dichloromethane to n-hexane was 19:1; reaction solvent A (400 mL), the compound represented by formula II (71 g, 1 eq) and isopropylamine (47.0 g, 3.0 eq) were added to the reaction flask, reacted at room temperature for 5 h, and 600 mL of purified water was added to quench the reaction.

[0077] The mixture was extracted with 600 mL of ethyl acetate, and the organic phase was taken. After washing once with 600 mL of purified water, it was dried over anhydrous sodium sulfate and concentrated to remove ethyl acetate. 300 mL of methyl tert-butyl ether was added, and the mixture was stirred at room temperature for 1.5 h. The mixture was filtered to obtain 72.2 g of the compound represented by formula III, with a yield of 93.8%.

[0078] Example 4: Preparation of diphenyltriazine compounds Dimethyl sulfoxide is used as reaction solvent B; reaction solvent B (350 mL), compound represented by formula III (70 g, 1 eq), and compound represented by formula VI (186.5 g, 3 eq) are added to the reaction flask, the temperature is lowered to 0°C~10°C, preferably 2°C~5°C, potassium tert-butoxide (135.0 g, 5 eq) is added, the temperature is raised to room temperature and stirred for 4 hours, 700 mL of purified water is added to quench the reaction, and the organic phase is extracted with 700 mL of ethyl acetate to obtain an organic phase, the organic phase is washed once with 300 mL of 1N hydrochloric acid, washed once with 300 mL of purified water, dried over anhydrous sodium sulfate, and concentrated to remove ethyl acetate to obtain a crude product.

[0079] Add 500mL of isopropanol to the crude product, heat to reflux to dissolve, filter to remove mechanical impurities, cool the filtrate to 0℃~4℃, keep warm and stir for 4h, filter, rinse the filter cake with 300mL of isopropanol, and drain. Add the filter cake to the reaction bottle, add 500mL of isopropanol, heat to reflux, slowly cool to 1℃~4℃ for 4h after dissolving, keep warm and stir for 1.5h, filter, rinse the filter cake with 300mL of isopropanol, and drain. The filter cake is vacuum dried at 50℃ to constant weight to obtain the compound shown in VII, the chemical name is 5-((5,6-diphenyl-1,2,4-triazine-3-yl)(isopropyl)amino)-N-(methylsulfonyl)pentanamide, 49.1g is obtained in the reaction, the yield is 43.4%, and the purity is 99.7%.

[0080] The reaction formula is as follows:

[0081] The compound of formula VI used in the above preparation method has a chemical name of 5-bromo-N-(methylsulfonyl)pentanamide, and its synthesis route and preparation method are as follows:

[0082] Dichloromethane (5.5L), 5-bromovaleric acid (1kg, 1eq), methylsulfonamide (629g, 1.2eq), 4-dimethylaminopyridine (DMAP; 808g, 1.2eq), 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDCI; 1.27kg, 1.2eq) were added to the reaction flask, refluxed for 8h, cooled to room temperature, added with 5L purified water, separated, the organic phase was washed once with a saturated sodium bicarbonate aqueous solution, dried over anhydrous sodium sulfate, and concentrated to remove dichloromethane. 1L of dichloromethane was added to the residue, stirred to dissolve, 3L of n-hexane was added dropwise at room temperature, cooled to 0℃~10℃, stirred for 2h, filtered, and the filter cake was dried under vacuum to obtain 541g of the compound shown in formula VI, with a yield of 38%.

[0083] Example 5: Preparation of SYN045 This example provides a method for preparing SYN045 (the compound represented by Formula V).

[0084] Dimethyl sulfoxide was used as the reaction solvent B; reaction solvent B (350 mL), the compound represented by formula III (70 g, 1 eq), and the compound represented by formula IV (196.8 g, 3 eq) were added to the reaction flask, the temperature was lowered to 2°C~5°C, potassium tert-butoxide (135.3 g, 5 eq) was added, the temperature was raised to room temperature and stirred for 4 h, 700 mL of purified water was added to quench the reaction, and the mixture was extracted with 700 mL of ethyl acetate. The organic phase was washed once with 300 mL of 1N hydrochloric acid and once with 300 mL of purified water, dried over anhydrous sodium sulfate, and concentrated to remove ethyl acetate to obtain a crude product.

[0085] Add 500mL of isopropanol to the crude product, heat to reflux to dissolve, filter to remove mechanical impurities, cool the filtrate to 0℃~4℃, keep warm and stir for 4h, filter, rinse the filter cake with 300mL of isopropanol, and drain. Add the filter cake to the reaction bottle, add 500mL of isopropanol, heat to reflux, slowly cool to 1℃~4℃ for 4h after dissolving, keep warm and stir for 1.5h, filter, rinse the filter cake with 300mL of isopropanol, and drain. The filter cake was vacuum dried at 50℃ to constant weight to obtain 51.5g of compound SYN045, with a yield of 44.4% and a purity of 99.8%.

[0086] The reaction formula is as follows:

[0087] The compound of formula IV used in the above preparation method has a chemical name of 6-bromo-N-(methylsulfonyl)hexanamide, and its synthesis route and preparation method are as follows.

[0088]

[0089] Dichloromethane (5L), 6-bromohexanoic acid (1kg, 1eq), methylsulfonamide (585g, 1.2eq), 4-dimethylaminopyridine (DMAP; 752g, 1.2eq), 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDCI; 1.18kg, 1.2eq) were added to the reaction flask, refluxed for 6h, cooled to room temperature, added with 5L purified water, separated, the organic phase was washed once with a saturated sodium bicarbonate aqueous solution, dried over anhydrous sodium sulfate, and concentrated to remove dichloromethane. 1L of dichloromethane was added to the residue, stirred to dissolve, 3L of n-hexane was added dropwise at room temperature, cooled to 0℃~10℃, stirred for 2h, filtered, and the filter cake was vacuum dried to obtain 572g of the compound shown in formula IV, with a yield of 41%.

[0090] The structural characterization map of compound SYN045 can be found in Figure 3 , the specific data are as follows.

[0091] 1H-NMR (500 MHz, CDCl3): δ: 7.558~7.509 (m, 4H), 7.477~7.442 (m, 1H), 7.391~7.323 (m, 5H), 5.137 (m, 1H), 3.683 (m, 2H), 3.30 6 (s, 3H), 2.460~2.432 (m, 2H), 1.915 (m, 2H), 1.822~1.763 (m, 2H), 1.548~1.522 (m, 2H), 1.367~1.354 (d, 6H), ppm.

[0092] Example 6: Preparation of SYN045 This embodiment provides a method for preparing SYN045.

[0093]

[0094] Dimethyl sulfoxide was used as the reaction solvent B; reaction solvent B (300 mL), compound represented by formula III (70 g, 1 eq), and compound represented by formula IV (131.2 g, 2 eq) were added to the reaction flask, the temperature was lowered to 5°C~10°C, potassium tert-butoxide (108.2 g, 4 eq) was added, the temperature was raised to room temperature and stirred for 3 h, 500 mL of purified water was added to quench the reaction, and 500 mL of ethyl acetate was used for extraction. The organic phase was washed once with 200 mL of 1N hydrochloric acid, once with 200 mL of purified water, dried over anhydrous sodium sulfate, and concentrated to remove ethyl acetate to obtain a crude product. 400 mL of isopropanol was added to the crude product, heated to reflux to dissolve, and mechanical impurities were removed by filtration. The filtrate was cooled to 3°C~5°C, stirred for 3 h, filtered, and the filter cake was rinsed with 200 mL of isopropanol and dried. The filter cake was added to the reaction bottle, 400 mL of isopropanol was added, the temperature was raised to reflux, and after the solution was clear, the temperature was slowly lowered to 0°C~2°C for 3 hours, and the mixture was stirred for 1 hour at this temperature, and the filter cake was rinsed with 200 mL of isopropanol and dried. The filter cake was vacuum dried at 45°C to constant weight to obtain 49.6 g of compound SYN045, with a yield of 42.7% and a purity of 99.6%.

[0095] Example 7: Preparation of SYN045 This embodiment provides a method for preparing SYN045.

[0096]

[0097] Dimethyl sulfoxide was used as the reaction solvent B; reaction solvent B (400 mL), compound represented by formula III (70 g, 1 eq), and compound represented by formula IV (328.0 g, 5 eq) were added to the reaction flask, the temperature was lowered to 0°C~3°C, potassium tert-butoxide (162.4 g, 6 eq) was added, the temperature was raised to room temperature and stirred for 5 h, 1000 mL of purified water was added to quench the reaction, and 1000 mL of ethyl acetate was used for extraction, the organic phase was washed once with 500 mL of 1N hydrochloric acid, once with 500 mL of purified water, dried over anhydrous sodium sulfate, and concentrated to remove ethyl acetate to obtain a crude product. 600 mL of isopropanol was added to the crude product, heated to reflux to dissolve, mechanical impurities were removed by filtration, the filtrate was cooled to 0°C~3°C, stirred for 5 h, filtered, the filter cake was rinsed with 500 mL of isopropanol, and dried. The filter cake was added to the reaction bottle, 600 mL of isopropanol was added, the temperature was raised to reflux, and after the solution was clear, the temperature was slowly lowered to 3°C~5°C for 5 hours, and the mixture was stirred for 2 hours at this temperature, and the filter cake was rinsed with 500 mL of isopropanol and dried. The filter cake was vacuum dried at 55°C to constant weight to obtain 50.2 g of compound SYN045, with a yield of 43.2% and a purity of 99.7%.

[0098] Comparative Example 1: Preparation of intermediate Comparative Example 1 The method for preparing the compound represented by formula III by reacting the compound represented by formula II with isopropylamine in Example 1 was carried out, except that the reaction solvent A was replaced with chloroform (350 mL), to obtain 47.4 g of the compound represented by formula III, with a yield of 61.6%.

[0099] Comparative Example 2: Preparation of intermediate Comparative Example 2 was carried out according to the method for preparing the compound represented by formula III by reacting the compound represented by formula II and isopropylamine in Example 1, except that the reaction solvent A was changed to dichloromethane (350 mL), to obtain 54.1 g of the compound represented by formula III, with a yield of 70.3%.

[0100] Comparative Example 3: Preparation of intermediate Comparative Example 3 was carried out according to the method for preparing the compound represented by Formula III by reacting the compound represented by Formula II and isopropylamine in Example 1, except that the volume ratio of dichloromethane to n-hexane in the reaction solvent A was adjusted to 4:1, to obtain 42.8 g of the compound represented by Formula III, with a yield of 55.6%.

[0101] The results show that in the preparation method of the intermediates of Examples 1-3 of the present invention, by selecting reaction solvent A and further controlling the volume ratio of dichloromethane to n-hexane in the range of 10:1-20:1, preferably 11:1-19:1, more preferably 13:1, the reaction time is 3-5 hours, and the yield can reach more than 92%, especially up to 96%, achieving a higher reaction yield under milder reaction conditions and with a shorter reaction time. It can be seen from the study of Comparative Examples 1-3 that the yield of the reaction under the same conditions is only 55%-70%, which is much lower than the yield of the present invention, and the reaction solvent A of the present invention is more conducive to the reaction.

[0102] Comparative Example 4: Preparation of SYN045 Comparative Example 4 The method for preparing compound SYN045 by reacting the compound represented by formula III and the compound represented by formula IV in Example 5 was carried out, except that the reaction solvent B was changed to tetrahydrofuran (350 mL), to obtain 53.6 g of compound SYN045 with a yield of 32.2% and a purity of 98.6%.

[0103] Comparative Example 5: Preparation of SYN045 Comparative Example 5 The method for preparing compound SYN045 by reacting the compound represented by formula III and the compound represented by formula IV in Example 5 was carried out, except that the reaction solvent B was changed to acetonitrile (350 mL), to obtain 35.2 g of compound SYN045 with a yield of 20.3% and a purity of 98.9%.

[0104] Comparative Example 6: Preparation of SYN045 Comparative Example 6 The method for preparing compound SYN045 by reacting the compound represented by formula III and the compound represented by formula IV in Example 5 was carried out, except that the reaction solvent B was changed to N,N-dimethylformamide (DMF, 350 mL), to obtain 38.9 g of compound SYN045 with a yield of 23.5% and a purity of 98.8%.

[0105] The results show that in the preparation method of compound SYN045 in Examples 5-7, the selection of reaction solvents is different, which has a greater impact on the final product yield. The present invention selects reaction solvent B to obtain a higher final product yield of 42%-45%. Comparative Examples 4-6 use DMF, acetonitrile, and tetrahydrofuran as reaction solvents, respectively. The reaction yield and purity are lower after the reaction under the same conditions. The present invention has simpler steps, higher yield and purity, and the purity is as high as 99.5% or more.

[0106] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modification, equivalent substitution or improvement made within the spirit and principle of the present invention should be included in the protection scope of the present invention.

Claims

1. An intermediate for synthesizing diphenyltriazine compounds, whose chemical name is 3-isopropylamino-5,6-diphenyl-1,2,4-triazine, and has the structural formula shown in formula III: 。 2. The method for preparing the intermediate according to claim 1, characterized in that: The following steps are involved: The compound represented by formula II and isopropylamine are added to the reaction solvent A, and the reaction is carried out at room temperature for 3-5 hours. Water is added to quench the reaction to obtain a mixed solution containing the intermediate represented by formula III, wherein the reaction solvent A is a mixed solvent of dichloromethane and n-hexane, and X1 in the structure of the compound represented by formula II is a halogen. 。 3. The preparation method according to claim 2, characterized in that After the step of quenching the reaction, a purification step is also included: adding ethyl acetate to the reaction solution for extraction, washing the organic phase with water, drying, concentrating to remove ethyl acetate, adding methyl tert-butyl ether, stirring at room temperature for 0.5-1.5h, filtering, and filtering the filter cake to obtain the intermediate shown in formula III.

4. The preparation method according to any one of claims 2 to 3, characterized in that: The volume ratio of dichloromethane to n-hexane in the reaction solvent A is 10:1-20:1; and / or The equivalent ratio of the compound represented by formula II to isopropylamine is 1:2-3; and / or The mass volume ratio of the compound represented by formula II to the reaction solvent A is 71:300-400 g / mL.

5. A method for preparing diphenyltriazine compounds from the intermediate according to claim 1, characterized in that: The following steps are involved: The compound represented by formula III is subjected to substitution reaction with the compound represented by formula VIII to obtain a diphenyl triazine compound represented by formula IX; ， Wherein, X2 in the structure shown in Formula VIII is a halogen, and R is a C1-C5 saturated alkane.

6. The preparation method according to claim 5, characterized in that: R is a C4-C5 saturated alkane; and / or X2 is chlorine or bromine.

7. The preparation method according to any one of claims 5 to 6, characterized in that: The specific steps of the substitution reaction are: adding the compound represented by formula III and the compound represented by formula VIII to the reaction solvent B, cooling to 0°C-10°C, adding potassium tert-butoxide, heating to room temperature and stirring for 3-5h, adding water to quench the reaction, extracting the organic phase, acid-washing, water-washing, drying, and concentrating in sequence to obtain a crude product, and recrystallizing the crude product to obtain a diphenyl triazine compound having a structural formula represented by formula IX; Wherein, the reaction solvent B is dimethyl sulfoxide.

8. The preparation method according to claim 7, characterized in that The equivalent ratio of the compound represented by formula III to the compound represented by formula VIII is 1:2-5; and / or The equivalent ratio of the compound represented by formula III to potassium tert-butoxide is 1:4-6; and / or The mass volume ratio of the compound represented by formula III to the reaction solvent B is 70:300-400 g / mL.

9. A method for synthesizing a diphenyltriazine compound, characterized in that: The structure of the diphenyltriazine compound is shown in Formula V, and comprises the following reaction steps: S1, 4,4'-dimethylbenzil and 2-aminoacetamide hydrochloride undergo cyclization reaction to obtain a compound of formula I; S2, the compound represented by formula I is subjected to chlorination reaction with phosphorus oxychloride to obtain a compound represented by formula II; S3, the compound represented by formula II is subjected to substitution reaction with isopropylamine to obtain a compound represented by formula III; S4, condensing the compound represented by formula IV-1 with methylsulfonamide to obtain a compound represented by formula IV; S5, the compound represented by formula III is subjected to substitution reaction with the compound represented by formula IV to obtain a compound represented by formula V; ， Wherein, X1 in the compound structure of formula II is a halogen, and X3 in the compound structure of formula IV-1 and the compound structure of formula IV is the same halogen.

10. The synthesis method according to claim 9, characterized in that Step S1, the reaction temperature of the cyclization reaction is 100°C to 110°C; and / or Step S2, the reaction temperature of the chlorination reaction is 80°C to 90°C; and / or Step S3, the reaction temperature of the substitution reaction is 20°C to 25°C; and / or Step S4, the condensation reaction is carried out under reflux conditions; and / or Step S5, the reaction temperature of the substitution reaction is 20°C to 25°C; and / or Step S3, the substitution reaction uses a reaction solvent A, wherein the reaction solvent A is a mixed solvent of dichloromethane and n-hexane in a volume ratio of 10:1-20:1; and / or Step S5, the substitution reaction adopts a reaction solvent B, and the reaction solvent B is dimethyl sulfoxide.

Images