A triazone compound and its preparation method and application

Abstract

The present invention provides a triazine ketone compound of structural formula V and a preparation method thereof, and use of the triazine ketone compound of structural formula V as a starting material in the preparation of S-217622. The present invention also provides a novel, efficient and environmentally friendly preparation method of S-217622. Wherein, R=O or S.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This patent application claims the priority benefit of the Chinese invention patent application with application number CN202210291040.0 filed on March 23, 2022, the entire contents of which are hereby incorporated by reference. Technical Field

[0003] The invention belongs to the field of organic chemistry, and specifically relates to a novel triazine ketone compound and a preparation method and application thereof. Background Art

[0004] The COVID-2019 epidemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has seriously threatened human life and health. While actively developing and promoting vaccination, finding effective antiviral drugs is also important to curb the epidemic.

[0005] S-217622 (CAS: 2647530-73-0), chemical name: (E)-6-((6-chloro-2-methyl-2H-indazol-5-yl)imino)-3-((1-methyl-1H-1,2,4-triazol-3-yl)methyl)-1-(2,4,5-trifluorobenzyl)-1,3,5-triazinane-2,4-dione, structural formula is shown in I; it is a small molecule oral 3CL protease inhibitor developed by Shionogi Pharmaceutical Co., Ltd. and Hokkaido University.

[0006]

[0007] From a structural point of view, the three groups P1, P1' and P2 connected to the triazine ketone core are the key groups related to the activity of S-217622. The mechanism of action of S-217622 is similar to that of Paxlovid, an oral COVID-19 treatment drug approved by Pfizer. It plays an important role in the life cycle of various coronaviruses. Its potential advantage is that it is effective against all the novel coronavirus variants that have been discovered so far, and its inhibitory activity against the Omicron strain is slightly stronger.

[0008] The mouse metabolic test of S-217622 showed that it has a long half-life and can be used as a single drug to treat new coronavirus pneumonia with significant efficacy, which is more advantageous than Pfizer's Paxlovid.

[0009] On February 8, 2022, Shionogi released partial data from Phase IIa of the Phase II / III clinical trial of S-217622. In terms of antiviral effects, the S-217622 group had a significant effect compared with the placebo group.

[0010] The currently disclosed synthesis route of S-217622 is as follows:

[0011]

[0012] In the first step, S-ethylisothiourea hydrobromide reacts with tert-butyl isocyanate to prepare compound A with a yield of 50%; in the second step, compound A and compound B undergo a substitution reaction to obtain compound C with a yield of 93%; in the third step, trifluoroacetic acid is used for deprotection to generate compound D with a yield of 97%; in the fourth step, compound D and compound E undergo a substitution reaction to prepare compound F with a yield of 45%; in the fifth step, compound G is treated with a strong base to remove the ethyl mercapto group, and then reacts with compound F to obtain the final compound I, i.e., S-217622, ​​with a yield of 25%.

[0013] Obviously, this route has certain problems. First, the raw materials for the first step, S-ethylisothiourea hydrobromide and tert-butyl isocyanate, are both expensive, which is not conducive to reducing costs; second, the yields of the fourth and fifth steps are too low, only 45% and 25% respectively, which are not suitable for large-scale industrial production; finally, the ethyl mercaptan removed in the fifth step is highly volatile (boiling point 36.2°C), smelly and toxic, which is not conducive to environmental protection and safe production.

[0014] Therefore, in order to ensure safe production, reduce the cost of medicines for the public and improve the accessibility of medicines, the inventors are committed to developing a new S-217622 synthesis route with milder reaction conditions, moderate costs and environmental friendliness. Summary of the invention

[0015] In order to overcome the deficiencies of the prior art, the present invention provides a new triazine ketone compound and a preparation method thereof, as well as the use of the compound as a key intermediate of S-217622 in the synthesis of S-217622. The method provided by the present invention for finally obtaining S-217622 via the new triazine ketone compound has high yield and low cost.

[0016] In order to achieve the above-mentioned object of the invention, the present invention adopts the following technical solutions:

[0017] A triazine ketone compound of structural formula V,

[0018]

[0019] Wherein, R=O or S.

[0020] The present invention also provides a method for preparing the compound of the above structural formula V, comprising the following steps:

[0021] Step A: In the presence of a base, cyanuric chloride of structural formula VII reacts with a compound of structural formula VIII to obtain a compound of structural formula VI, which is used in the next reaction with or without separation;

[0022]

[0023] Wherein, R=O or S, R1=C1~C4 alkyl or benzyl;

[0024] Step B: In the presence of a catalyst, the compound of formula VI is hydrolyzed to obtain a compound of formula V;

[0025]

[0026] wherein R and R1 are as defined above.

[0027] The synthetic route of the above structural formula V is as follows:

[0028]

[0029] Preferably, R1 is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl or benzyl.

[0030] Preferably, in step A, the base is selected from one or more of potassium carbonate, sodium carbonate, potassium bicarbonate, sodium bicarbonate, potassium hydroxide, sodium hydroxide, triethylamine, pyridine, DBU (1,8-diazabicycloundec-7-ene) and DABCO (1,4-diazabicyclo[2.2.2]octane); more preferably potassium carbonate or sodium carbonate.

[0031] Preferably, in step A, the molar ratio of cyanuric chloride of structural formula VII to the compound of structural formula VIII is 1:0.9 to 1:2; more preferably 1:0.9 to 1:1.2.

[0032] Preferably, in the step A, the molar ratio of cyanuric chloride of structural formula VII to the base is 1:0.5 to 1:5; more preferably 1:0.5 to 1:2.

[0033] Preferably, in step A, the reaction solvent is selected from one or more of dichloromethane, ethyl acetate, isopropyl acetate, tetrahydrofuran, acetonitrile and acetone; more preferably dichloromethane.

[0034] Preferably, in step A, the reaction temperature is -10°C to 60°C; more preferably 0°C to 30°C.

[0035] Preferably, in step B, the catalyst is selected from one of N-methylmorpholine, N-methylpiperidine, N-methylpyrrolidine, DABCO (1,4-diazabicyclo[2.2.2]octane), triethylamine, pyridine and 4-dimethylaminopyridine; more preferably N-methylmorpholine.

[0036] Preferably, in the step B, the molar ratio of the compound of formula VI to the catalyst is 1:0.05 to 1:0.5; more preferably 1:0.05 to 1:0.3.

[0037] Preferably, in step B, the reaction solvent is selected from one or more of tetrahydrofuran, methanol, ethanol, isopropanol, acetonitrile and acetone; more preferably tetrahydrofuran.

[0038] Another object of the present invention is to provide the use of the compound of the above structural formula V as a starting material in the preparation of S-217622.

[0039] In addition, the present invention also provides a method for preparing S-217622 of structural formula I,

[0040]

[0041] The method comprises taking the compound of structural formula V as a starting material and performing the following steps:

[0042] Step 1: In the presence of a base, the compound of formula V is reacted with a salt of 3-(chloromethyl)-1-methyl-1H-1,2,4-triazole to prepare a compound of formula IV.

[0043]

[0044] Wherein, R=O or S;

[0045] Step 2: The compound of formula IV reacts with diethylamine to generate a compound of formula III,

[0046]

[0047] Step 3: In the presence of a base, the compound of formula III is reacted with 1-(chloromethyl)-2,4,5-trifluorotoluene to obtain a compound of formula II.

[0048]

[0049] Step 4: In the presence of a catalyst, the compound of formula II is reacted with 6-chloro-2-methyl-2H-indol-5-amine to obtain the S-217622.

[0050] The synthetic route of S-217622 of the above structural formula I is as follows:

[0051]

[0052] Preferably, the compound of structural formula V is prepared by the preparation method described in the present invention.

[0053] Preferably, the salt of 3-(chloromethyl)-1-methyl-1H-1,2,4-triazole is selected from hydrochloride, sulfate, citrate, maleate, fumarate, hydrobromide or methanesulfonate.

[0054] Preferably, in step 1, the molar ratio of compound V to the salt of 3-(chloromethyl)-1-methyl-1H-1,2,4-triazole is 1:0.8 to 1:2; more preferably 1:1 to 1:1.2.

[0055] Preferably, in step 1, the base is selected from potassium carbonate or sodium carbonate.

[0056] Preferably, in step 1, the molar ratio of the compound V to the base is 1:0.8 to 1:5; more preferably 1:1 to 1:3.

[0057] Preferably, in step 1, the solvent is selected from one or more of acetonitrile, tetrahydrofuran, ethyl acetate, DMF, DMSO, dichloromethane, acetone, methanol and ethanol; more preferably acetonitrile.

[0058] Preferably, the reaction temperature of step 1 is 20-150°C, more preferably 40-100°C.

[0059] Preferably, in step 2, the molar ratio of compound III to diethylamine is 1:0.8 to 1:10; more preferably 1:1 to 1:3.

[0060] Preferably, the reaction solvent of step 2 is selected from one or more of dichloromethane, ethyl acetate, tetrahydrofuran, methanol, ethanol, acetonitrile, acetone, DMF and DMSO; more preferably dichloromethane.

[0061] Preferably, the reaction temperature of step 2 is 10-100°C; more preferably 20-60°C.

[0062] Preferably, in step 3, the molar ratio of the compound of formula III to 1-(chloromethyl)-2,4,5-trifluorotoluene is 1:1 to 1:2; more preferably 1:1 to 1:1.2.

[0063] Preferably, in step 3, the base is selected from potassium carbonate or sodium carbonate.

[0064] Preferably, in step 3, the molar ratio of the compound of formula III to the base is 1:0.8 to 1:5; more preferably 1:1 to 1:2.

[0065] Preferably, the solvent in step 3 is selected from one or more of acetonitrile, tetrahydrofuran, ethyl acetate, DMF, DMSO, dichloromethane, acetone, methanol and ethanol; more preferably acetonitrile.

[0066] Preferably, the reaction temperature of step 3 is selected from 20 to 150°C, more preferably 40 to 100°C.

[0067] Preferably, in step 4, the catalyst is selected from one or more of N-methylmorpholine, N-methylpiperidine, N-methylpyrrolidine, DABCO, triethylamine, pyridine and 4-dimethylaminopyridine; more preferably, N-methylmorpholine.

[0068] Preferably, in step 4, the molar ratio of the compound of structural formula II to the catalyst is 1:0.05 to 1:2; more preferably 1:0.05 to 1:0.2.

[0069] Preferably, the molar ratio of compound II to 6-chloro-2-methyl-2H-indol-5-amine in step 4 is 1:0.8 to 1:2, more preferably 1:1 to 1:1.2.

[0070] Preferably, the solvent in step 4 is selected from one or more of methanol, ethanol, isopropanol, acetonitrile, tetrahydrofuran, ethyl acetate, DMF, DMSO, dichloromethane and acetone; more preferably methanol or ethanol.

[0071] Preferably, the reaction temperature of step 4 is 20-150°C; more preferably 40-100°C.

[0072] Compared with the prior art, the present invention has the following beneficial effects:

[0073] 1. The synthesis route of the compound of structural formula V is novel, the starting materials are cheap and readily available, and no expensive reagents and raw materials used in the prior art are used;

[0074] 2. Including the preparation method of structural formula V, the yield of each single step is above 85%, especially step 2 of adding P2 group and step 4 of adding P1' when preparing S-217622. Therefore, the total yield of preparing S-217622 is high, which is conducive to reducing production costs.

[0075] 3. Since the compound of structural formula V is used as the starting material for preparing S-217622, ​​the generation of ethyl mercaptan is avoided; the sulfur-containing compound removed in the above step 4 has a high boiling point, is not easy to volatilize, and is easy to handle. Therefore, the method for preparing S-217622 provided by the present invention is environmentally friendly and is conducive to protecting the safety of operators.

[0076] 4. The reaction is mild, the process is simple, and there is no high temperature or high pressure reaction in the entire preparation process, which is very suitable for industrial production. DETAILED DESCRIPTION

[0077] The present invention is described below with reference to specific examples. It will be appreciated by those skilled in the art that these examples are only used to illustrate the present invention and are not intended to limit the scope of the present invention in any way.

[0078] The experimental methods in the following examples are conventional methods unless otherwise specified. The raw materials, reagents, etc. used in the following examples are commercially available products unless otherwise specified.

[0079] Example 1 Preparation of the compound of formula V-1

[0080]

[0081] 18.4 g of cyanuric chloride (0.1 mol) of structural formula VII, 100 ml of dichloromethane, 9.0 g of methyl glycolate (0.1 mol) of structural formula VIII-1 and 13.8 g of potassium carbonate powder (0.1 mol) were added to a 500 ml reaction bottle, and the mixture was stirred at room temperature for 2 h, filtered, and the filtrate was evaporated to dryness under reduced pressure; 24.6 g of sodium acetate, 100 ml of tetrahydrofuran, 1.3 g of N-methylmorpholine (0.01 mol) and 2.0 g of water were directly added to the residue without treatment, and the mixture was stirred at room temperature for 48 h, filtered, and the filtrate was evaporated to a remaining 1 / 2 under reduced pressure; the temperature was lowered to 0-5 ° C, 100 ml of heptane was added, stirred for 1 h, filtered, and dried to obtain 15.5 g of a white solid compound of structural formula V-1 with a yield of 92% and a purity of 99%.

[0082] MS (m / z): [M-1] - 168.0.

[0083] 1 H-NMR (400M, DMSO-d6): 12.36 (1H, s), 4.65 (2H, s).

[0084] Example 2 Preparation of the compound of formula V-1

[0085]

[0086] 18.4 g of cyanuric chloride (0.1 mol) of structural formula VII, 100 ml of ethyl acetate, 11.8 g of isopropyl glycolate (0.1 mol) of structural formula VIII-2 and 12.2 g of triethylamine (0.12 mol) were added to a 500 ml reaction bottle, and the mixture was stirred at room temperature for 2 h, filtered, and the filtrate was evaporated to dryness under reduced pressure; 13.8 g of potassium acetate, 100 ml of acetone, 1.5 g of triethylamine (0.014 mol) and 2.0 g of water were directly added to the residue without treatment, and the mixture was stirred at room temperature for 48 h, filtered, and the filtrate was evaporated to a remaining 1 / 2 under reduced pressure, cooled to 0-5 ° C, 100 ml of heptane was added, stirred for 1 h, filtered, and dried to obtain 14.4 g of a white solid compound of structural formula V-1 with a yield of 85% and a purity of 98%.

[0087] The mass spectrum and NMR data are consistent with those in Example 1.

[0088] Example 3 Preparation of compound of formula V-1

[0089]

[0090] 18.4 g of cyanuric chloride (0.1 mol) of structural formula VII, 100 ml of acetonitrile, 16.6 g of benzyl hydroxyacetate (0.1 mol) of structural formula VIII-3 and 4.0 g of sodium hydroxide (0.1 mol) were added to a 500 ml reaction bottle, and the reaction was stirred at room temperature for 2 hours, filtered, and the filtrate was evaporated to dryness under reduced pressure; 13.8 g of potassium carbonate, 100 ml of acetonitrile, 1.0 g of N-methylpiperidine (0.1 mol) and 2.0 g of water were directly added to the residue without treatment, and the reaction was stirred at room temperature for 48 hours, filtered, and the filtrate was evaporated to a remaining 1 / 2 under reduced pressure, cooled to 0-5°C, 100 ml of heptane was added, stirred for 1 hour, filtered, and dried to obtain 13.7 g of a white solid compound of structural formula V-1 with a yield of 81% and a purity of 98%.

[0091] The mass spectrum and NMR data are consistent with those in Example 1.

[0092] Example 4 Preparation of the compound of formula V-2

[0093]

[0094] In a 500 ml reaction bottle, 18.4 g of cyanuric chloride (0.1 mol) of structural formula VII, 100 ml of dichloromethane, 10.6 g of methyl thioglycolate (0.1 mol) of structural formula VIII-4 and 13.8 g of potassium carbonate powder (0.1 mol) were added, and the reaction was stirred at room temperature for 30 min, filtered, and the filtrate was evaporated to dryness under reduced pressure; 24.6 g of sodium acetate, 100 ml of tetrahydrofuran, 1.0 g of N-methylmorpholine (0.01 mol) and 2.0 g of water were directly added to the residue without treatment, and the reaction was stirred at room temperature for 48 h, filtered, and the filtrate was evaporated to 1 / 2 under reduced pressure, cooled to 0-5 ° C, 100 ml of heptane was added, stirred for 1 h, filtered, and dried to obtain 16.7 g of white solid compound of structural formula V-2de, with a yield of 90% and a purity of 99%.

[0095] MS (m / z): [M-1] - 184.0.

[0096] 1 H-NMR (400M, DMSO-d6): 12.48 (1H, s), 4.32 (2H, s).

[0097] Example 5 Preparation of the compound of formula V-2

[0098]

[0099] In a 500 ml reaction bottle, 18.4 g of cyanuric chloride (0.1 mol) of structural formula VII, 100 ml of tetrahydrofuran, 13.4 g of isopropyl thioglycolate (0.1 mol) of structural formula VIII-5 and 13.8 g of potassium carbonate powder (0.1 mol) were added, the reaction was stirred at room temperature for 1 hour, and filtered; 24.6 g of sodium acetate, 1.0 g of N-methylmorpholine (0.01 mol) and 2.0 g of water were directly added to the filtrate, the reaction was stirred at room temperature for 48 hours, filtered, and the filtrate was evaporated under reduced pressure to the remaining 1 / 2, cooled to 0-5 ° C, 100 ml of heptane was added, stirred for 1 hour, filtered, and dried to obtain 16.3 g of a white solid compound of structural formula V-2, with a yield of 88% and a purity of 99%.

[0100] The mass spectrum and NMR data are consistent with those of Example 4.

[0101] Example 6 Preparation of the compound of formula V-2

[0102]

[0103] In a 500 ml reaction bottle, 18.4 g of cyanuric chloride (0.1 mol) of structural formula VII, 100 ml of acetone, 18.2 g of benzyl thioglycolate (0.1 mol) and 13.8 g of potassium carbonate powder (0.1 mol) were added, and the mixture was stirred at room temperature for 2 hours. The mixture was filtered, and 24.6 g of sodium acetate, 1.0 g of N-methylmorpholine (0.01 mol) and 2.0 g of water were directly added to the filtrate. The mixture was stirred at room temperature for 48 hours, filtered, and the filtrate was evaporated under reduced pressure to a remaining 1 / 2. The mixture was cooled to 0-5°C, 100 ml of heptane was added, the mixture was stirred for 1 hour, filtered, and dried to obtain 15.7 g of a white solid compound of structural formula V-2 with a yield of 85% and a purity of 98%.

[0104] The mass spectrum and NMR data are consistent with those of Example 4.

[0105] Example 7 Preparation of Compound of Formula I (S-217622)

[0106]

[0107] Step 1: Preparation of compound of formula IV-1

[0108] 16.9 g (0.1 mol) of compound V-1, 18.5 g of 3-(chloromethyl)-1-methyl-1H-1,2,4-triazole hydrochloride (0.11 mol), 30.4 g of potassium carbonate (0.22 mol) and 200 ml of acetonitrile were added to the reaction flask, and the temperature was raised to 80°C for reaction for 3 h; the reaction solution was evaporated to dryness under reduced pressure, 200 ml of water was added to the residue and stirred, and extracted with ethyl acetate (three times, 200 ml each time), the organic phases were combined, dried over anhydrous sodium sulfate, and filtered; the filtrate was concentrated to about 50 ml by rotary evaporation under reduced pressure, cooled to 0-5°C in an ice-water bath, 100 ml of heptane was added dropwise, stirred for 2 h, filtered, and dried to obtain 24.6 g of a compound of formula IV-1 (white solid) with a yield of 93% and a purity of 99%.

[0109] MS (m / z): [M+1] + 265.1.

[0110] 1 H-NMR (400M, DMSO-d6): 8.73 (1H, s), 4.69 (2H, s), 4.51 (2H, s), 3.73 (3H, s).

[0111] Step 2: Preparation of compound of formula III-1

[0112] Add 10.0 g (37.9 mmol) of compound IV-1 prepared in the previous step, 3.0 g (41.0 mmol) of diethylamine and 50 ml of dichloromethane into the reaction flask, heat to 40 °C and react for 5 h. Vacuum evaporate to dryness to obtain 12.8 g of compound III-1 (white solid), with a yield of 100% and a purity of 98%.

[0113] MS (m / z): [M+1] + 310.2.

[0114] 1 H-NMR (400M, DMSO-d6): 11.27 (1H, s), 8.73 (1H, s), 4.60 (2H, s), 4.50 (2H, s), 3.73 (3H, s), 3.52 (6H, s).

[0115] Step 3. Preparation of compound of formula II-1

[0116] 10.0 g (32.3 mmol) of the compound of formula III-1 prepared in the previous step, 5.9 g (32.7 mmol) of 1-(chloromethyl)-2,4,5-trifluorotoluene, 4.5 g (32.6 mmol) of potassium carbonate powder and 100 ml of acetonitrile were added to the reaction flask, and the temperature was raised to 80°C for reaction for 3 h. The reaction solution was evaporated to dryness under reduced pressure, 100 ml of water was added, and extracted with ethyl acetate (three times, 100 ml each time). The organic phases were combined, dried over anhydrous sodium sulfate, and filtered; the filtrate was concentrated to about 30 ml by rotary evaporation under reduced pressure, cooled to 0-5°C in an ice-water bath, 90 ml of heptane was added dropwise, stirred for 2 h, filtered, and dried to obtain 12.6 g of the compound of formula II-1 (white solid) with a yield of 88% and a purity of 99%.

[0117] MS (m / z): [M+1] + 454.2.

[0118] 1 H-NMR (400M, DMSO-d6): 8.73 (1H, s), 6.85 (1H, s), 6.67 (1H, s), 5.11 (2H, s), 4.60 (2H, s), 4.50 (2H, s), 3.73 (3H, s), 3.52 (6H, s).

[0119] Step 4. Preparation of the compound of formula I

[0120] 5.0 g (11.0 mmol) of the compound of structural formula II-1 prepared in the previous step, 2.1 g (11.6 mmol) of 6-chloro-2-methyl-2H-indole-5-amine, 0.21 g (2.1 mmol) of N-methylmorpholine and 30 ml of methanol were added to the reaction flask, and the temperature was raised to 70°C for reaction for 15 h; the reaction solution was evaporated to dryness under reduced pressure and recrystallized from 2-methyltetrahydrofuran to obtain 4.6 g of the compound of structural formula I (white solid), i.e. S-217622, ​​with a yield of 83% and a purity of 99%.

[0121] MS (m / z): [M+1] + 532.2, 533.7.

[0122] 1 H-NMR (400M, DMSO-d6): 10.55 (1H, s), 8.73 (1H, s), 8.11 (1H, s), 7.95 (1H, s), 6.85 (1 H, s), 6.67 (1H, s), 6.07 (1H, s), 5.11 (2H, s), 4.50 (2H, s), 3.91 (3H, s), 3.73 (3H, s).

[0123] Example 8 Preparation of Compound of Formula I (S-217622)

[0124]

[0125] Step 1. Preparation of the compound of formula IV-2

[0126] 18.5 g (100 mmol) of the compound of formula V-2, 18.5 g (110 mmol) of 3-(chloromethyl)-1-methyl-1H-1,2,4-triazole hydrochloride, 30.4 g (220 mmol) of potassium carbonate powder and 200 ml of tetrahydrofuran were added to the reaction flask, and the temperature was raised to 80°C for reaction for 3 h; the solvent was spin-dried, 200 ml of water was added, and the mixture was extracted with ethyl acetate (three times, 200 ml each time), the organic phases were combined, dried over anhydrous sodium sulfate, and filtered; the filtrate was concentrated to about 50 ml, cooled to 0-5°C in an ice-water bath, 100 ml of heptane was added dropwise, stirred for 2 h, filtered, and dried to obtain 26.9 g of the compound of formula IV-2 (white solid), with a yield of 96% and a purity of 99%.

[0127] MS (m / z): [M+1] + 281.1.

[0128] 1 H-NMR (400M, DMSO-d6): 8.73 (1H, s), 4.50 (2H, s), 4.36 (2H, s), 3.73 (3H, s).

[0129] Step 2. Preparation of the compound of formula III-2

[0130] Add 10.0 g (35.7 mmol) of the compound of formula IV-2 prepared in the previous step, 2.9 g (39.7 mmol) of diethylamine, and 50 ml of ethyl acetate into the bottle, heat to 40°C and react for 5 hours. Rotate dry to obtain 12.6 g of the compound of formula III-2 (white solid), with a yield of 100% and a purity of 98%.

[0131] MS (m / z): [M+1] + 326.1.

[0132] 1 H-NMR (400M, DMSO-d6): 11.32 (1H, s), 8.73 (1H, s), 4.59 (2H, s), 4.11 (2H, s), 3.73 (3H, s), 3.51 (6H, s).

[0133] Step 3. Preparation of compound of formula II-2

[0134] Add 10.0 g (30.7 mmol) of the compound of formula III-2 prepared in the previous step, 5.6 g (31.0 mmol) of 1-(chloromethyl)-2,4,5-trifluorotoluene, 4.3 g (40.6 mmol) of sodium carbonate and 100 ml of dichloromethane into the bottle, heat to 80 ° C and react for 3 hours, evaporate the solvent, add 100 ml of water, extract with ethyl acetate (three times, 100 ml each time), combine the organic phases, dry over anhydrous sodium sulfate, and filter; concentrate the filtrate to about 30 ml, cool to 0-5 ° C in an ice-water bath, add 90 ml of heptane dropwise, stir for 2 hours, filter, and dry to obtain 13.0 g of the compound of formula II-2 (white solid), with a yield of 92% and a purity of 99%.

[0135] MS (m / z): [M+1] + 470.1.

[0136] 1 H-NMR (400M, DMSO-d6): 8.73 (1H, s), 6.85 (1H, s), 6.67 (1H, s), 5.09 (2H, s), 4.60 (2H, s), 4.11 (2H, s), 3.73 (3H, s), 3.51 (6H, s).

[0137] Step 4. Preparation of compound of formula I

[0138] Add 5.0 g (10.6 mmol) of the compound of structural formula II-2 prepared in the previous step, 2.0 g (11.0 mmol) of 6-chloro-2-methyl-2H-indol-5-amine, 0.20 g (2.0 mmol) of N-methylmorpholine and 30 ml of ethanol into the bottle, heat to 70 ° C and react for 15 hours; evaporate the solvent and recrystallize with 2-methyltetrahydrofuran to obtain 4.5 g of the compound of structural formula I (white solid), i.e. S-217622, ​​with a yield of 85% and a purity of 99%.

[0139] The mass spectrum and NMR data are consistent with those of Example 7.

Claims

1. A triazine ketone compound of structural formula V, in, R=O or S.

2. A method for preparing the compound of structural formula V according to claim 1, comprising the following steps: Step A: In the presence of a base, cyanuric chloride of structural formula VII reacts with a compound of structural formula VIII to obtain a compound of structural formula VI, which is used in the next reaction with or without separation; in, R=O or S, R1=C1~C4 alkyl or benzyl; Step B: In the presence of a catalyst, the compound of formula VI is hydrolyzed to obtain a compound of formula V; Wherein, R and R1 are as defined above; The catalyst is selected from one of the following combinations: sodium acetate and N-methylmorpholine, potassium acetate and triethylamine, potassium carbonate and N-methylpiperidine.

3. The preparation method according to claim 2, characterized in that: The R1 is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl or benzyl.

4. The preparation method according to claim 2, characterized in that: In the step A, the base is selected from one or more of potassium carbonate, sodium carbonate, potassium bicarbonate, sodium bicarbonate, potassium hydroxide, sodium hydroxide, triethylamine, pyridine, DBU and DABCO.

5. The preparation method according to claim 4, characterized in that: In the step A, the base is potassium carbonate or sodium carbonate.

6. The preparation method according to claim 2, 4 or 5, characterized in that: In the step A, the molar ratio of cyanuric chloride of structural formula VII to the base is 1:0.5 to 1:

5.

7. The preparation method according to claim 6, characterized in that: In the step A, the molar ratio of cyanuric chloride of structural formula VII to the base is 1:0.5 to 1:

2.

8. The preparation method according to claim 2, characterized in that: In the step A, the molar ratio of cyanuric chloride of structural formula VII to the compound of structural formula VIII is 1:0.9 to 1:

2.

9. The preparation method according to claim 8, characterized in that: In the step A, the molar ratio of cyanuric chloride of structural formula VII to the compound of structural formula VIII is 1:0.9 to 1:1.

2.

10. The preparation method according to claim 2, characterized in that: In the step A, the reaction solvent is selected from one or more of dichloromethane, ethyl acetate, isopropyl acetate, tetrahydrofuran, acetonitrile and acetone.

11. The preparation method according to claim 10, characterized in that: In the step A, the reaction solvent is dichloromethane.

12. The preparation method according to claim 2, characterized in that: In the step A, the reaction temperature is -10°C to 60°C.

13. The preparation method according to claim 12, characterized in that: In the step A, the reaction temperature is 0°C to 30°C.

14. The preparation method according to claim 2, characterized in that: In the step B, the molar ratio of the compound of formula VI to the catalyst is 1:0.05 to 1:0.

5.

15. The preparation method according to claim 14, characterized in that: In the step B, the molar ratio of the compound of formula VI to the catalyst is 1:0.05 to 1:0.

3.

16. The preparation method according to claim 2, characterized in that: In the step B, the reaction solvent is selected from one or more of tetrahydrofuran, methanol, ethanol, isopropanol, acetonitrile and acetone.

17. The preparation method according to claim 16, characterized in that: In the step B, the reaction solvent is tetrahydrofuran.

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