CN116217553A - A kind of triazone compound and its preparation method and application - Google Patents

Abstract

其中，R＝O或S。The present invention provides a triazone compound of structural formula V and a preparation method thereof, as well as the application of the triazone 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

A kind of triazone compound and its preparation method and application

Cross References to Related Applications

This patent application claims the priority of the Chinese invention patent application with application number CN202210291040.0 filed on March 23, 2022, the entire content of which is hereby incorporated by reference.

technical field

The invention belongs to the field of organic chemistry, and specifically relates to a novel triazone compound, a preparation method and application thereof.

Background technique

The outbreak of novel coronavirus infection (COVID-2019) caused by SARS coronavirus 2 (severe acute respiratory syndrome coronavirus 2, SARS-CoV-2) has seriously threatened human life and health. While actively developing and promoting vaccination, it is also of great significance to find effective antiviral drugs to contain the epidemic.

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-diketone, structural formula as shown in I; is a small molecule oral 3CL protease inhibitor developed by Shionogi Pharmaceutical Co., Ltd. and Hokkaido University.

From the structural point of view, the three groups P1, P1' and P2 connected to the triazone 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 treatment drug for COVID-19 approved by Pfizer. It plays an important role in the life cycle of various coronaviruses. Its potential advantage is that it has an effect on all new coronavirus variants that have been discovered so far , and had slightly stronger inhibitory activity against Omicron strains.

The mouse metabolism test of S-217622 shows that it has a longer half-life and can be used as a single drug for the treatment of new coronavirus pneumonia, and the efficacy is significant, which is more advantageous than Pfizer's Paxlovid.

On February 8, 2022, Shionogi announced part of the Phase IIa data of the Phase II/III clinical trial of S-217622. In terms of antiviral, compared with the placebo group, the S-217622 group had a significant effect.

The currently published synthetic route of S-217622 is as follows:

In the first step, compound A is prepared by reacting S-ethylisothiouronium hydrobromide with tert-butyl isocyanate, and the yield is 50%; in the second step, compound A and compound B undergo a substitution reaction to obtain compound C, and the yield is 93%; the third step, deprotection with trifluoroacetic acid, generates compound D with a yield of 97%; the fourth step, compound D and compound E undergo a substitution reaction to prepare compound F, and the yield is 45%; fifth In the first step, compound G removes the thiol group with a strong base, and then reacts with compound F to obtain the final compound I, namely S-217622, with a yield of 25%.

Obviously, there are certain problems with this route. First of all, the first step reaction raw materials——S-ethylisothiouronium hydrobromide and tert-butyl isocyanate are more expensive, which is not conducive to reducing costs; secondly, the fourth step and the fifth step reaction yield are too high. Low, only 45% and 25% respectively, are not suitable for industrialized large-scale production; Finally, the ethanethiol that the 5th step takes off is very volatile (boiling point 36.2 ℃), smelly and poisonous, is unfavorable for environmental protection and safe production.

Therefore, in order to ensure safe production, reduce drug costs for the general public, and improve drug availability, the inventors are committed to developing a new synthetic route for S-217622 with milder reaction conditions, moderate cost, and environmental friendliness.

Contents of the invention

In order to overcome the deficiencies of the prior art, the present invention provides a new triazone compound and its preparation method, as well as the application of the compound as a key intermediate of S-217622 in the synthesis of S-217622. The method for finally obtaining S-217622 through the novel triazone compound provided by the present invention has high yield and low cost.

In order to realize the foregoing invention object, the present invention adopts following technical scheme:

A triazone compound of structural formula V,

Wherein, R=O or S.

The present invention also provides a preparation method of the compound of the above structural formula V, comprising the following steps:

Step A: In the presence of a base, the cyanuric chloride of the structural formula VII is reacted with the compound of the structural formula VIII to obtain the compound of the structural formula VI, which is used for the next reaction after separation or not;

Wherein, R=O or S, R ₁ =C ₁ ~C ₄ alkyl or benzyl;

Step B: in the presence of a catalyst, the compound of structural formula VI is hydrolyzed to obtain the compound of structural formula V;

Wherein, R and R ₁ are as defined above.

The synthetic route of above-mentioned structural formula V is as follows:

Preferably, said R ₁ is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl or benzyl.

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

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

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

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

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

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

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

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

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.

In addition, the present invention also provides a preparation method of S-217622 of structural formula I,

Including using the compound of the structural formula V as a starting material, through the following steps:

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

Wherein, R=O or S;

Step 2: the compound of structural formula IV reacts with diethylamine to generate the compound of structural formula III,

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

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

The synthetic route of S-217622 of above-mentioned structural formula I is as follows:

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

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

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

Preferably, in the step 1, the alkali is selected from potassium carbonate or sodium carbonate.

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

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

Preferably, the reaction temperature in step 1 is 20-150°C, more preferably 40-100°C.

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

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

Preferably, the reaction temperature in step 2 is 10-100°C; more preferably 20-60°C.

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

Preferably, in the step 3, the alkali is selected from potassium carbonate or sodium carbonate.

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

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

Preferably, the reaction temperature in step 3 is selected from 20-150°C, more preferably 40-100°C.

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

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

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.

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

Preferably, the reaction temperature in step 4 is 20-150°C; more preferably 40-100°C.

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

1. The synthetic route of the compound of structural formula V is novel, the starting materials are cheap and easy to obtain, and the expensive reagents and raw materials in the prior art are not used;

2. Including the preparation method of structural formula V, each single-step yield is above 85%, especially the step 2 of adding P2 group and the step 4 of adding P1' when preparing S-217622, so the preparation of S-217622 The total yield is high, which is beneficial to reduce the production cost.

3. Because the compound of structural formula V is used as the starting material for the preparation of S-217622, the production of ethanethiol is avoided; the sulfur-containing compound removed in the above step 4 has a high boiling point, is not volatile, and is convenient for handling. Therefore, the preparation method of S-217622 provided by the present invention is environmentally friendly and beneficial to protect the safety of operators.

4. The reaction is mild, the process is simple, and there is no high-temperature and high-pressure reaction in the whole preparation process, which is very suitable for industrial production.

Detailed ways

The present invention will be described below with reference to specific examples. Those skilled in the art can understand that these examples are only for illustrating the present invention, and they do not limit the scope of the present invention in any way.

The experimental methods in the following examples are conventional methods unless otherwise specified. The raw materials and reagent materials used in the following examples are all commercially available products unless otherwise specified.

The preparation of the compound of embodiment 1 structural formula V-1

Add cyanuric chloride (0.1mol) of 18.4g structural formula VII, 100ml dichloromethane, methyl glycolate (0.1mol) of 9.0g structural formula VIII-1 and 13.8g potassium carbonate powder (0.1mol) in the 500ml reaction bottle, Stir the reaction at room temperature for 2 hours, filter, and rotate the filtrate to dryness under reduced pressure; directly add 24.6g of sodium acetate, 100ml of tetrahydrofuran, 1.3g of N-methylmorpholine (0.01mol) and 2.0g of water to the residue without treatment, and stir at room temperature Reacted for 48 hours, filtered, and the filtrate was rotary evaporated under reduced pressure to the remaining 1/2; cooled to 0-5°C, added 100ml of heptane, stirred for 1 hour, filtered, and dried to obtain 15.5g of the compound of the structural formula V-1 as a white solid, producing The yield is 92%, and the purity is 99%.

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

¹ H-NMR (400M, DMSO-d ₆ ): 12.36 (1H, s), 4.65 (2H, s).

The preparation of embodiment 2 structural formula V-1 compound

Add 18.4g structural formula VII cyanuric chloride (0.1mol), 100ml ethyl acetate, 11.8g structural formula VIII-2 isopropyl glycolate (0.1mol) and 12.2g triethylamine (0.12mol) in the 500ml reaction flask , stirred at room temperature for 2 h, filtered, and the filtrate was rotary evaporated to dryness under reduced pressure; the residue was directly added with 13.8 g of potassium acetate, 100 ml of acetone, 1.5 g of triethylamine (0.014 mol) and 2.0 g of water, and stirred at room temperature for 48 h , filtered, the filtrate was rotary evaporated under reduced pressure to the remaining 1/2, cooled to 0-5°C, added 100ml of heptane, stirred for 1h, filtered, and dried to obtain 14.4g of the compound of the structural formula V-1 as a white solid, with a yield of 85 %, 98% purity.

Mass spectrometry and NMR data are consistent with Example 1.

The preparation of embodiment 3 structural formula V-1 compound

Add 18.4g of cyanuric chloride (0.1mol) of structural formula VII, 100ml of acetonitrile, 16.6g of structural formula VIII-3 benzyl glycolate (0.1mol) and 4.0g of sodium hydroxide (0.1mol) in the 500ml reaction flask, and stir the reaction at room temperature After 2 hours, filter, and the filtrate was rotary evaporated to dryness under reduced pressure; the residue was directly added with 13.8g of potassium carbonate, 100ml of acetonitrile, 1.0g of N-methylpiperidine (0.1mol) and 2.0g of water, and stirred at room temperature for 48h , filtered, the filtrate was rotary evaporated under reduced pressure to the remaining 1/2, cooled to 0-5°C, added 100ml of heptane, stirred for 1h, filtered, and dried to obtain 13.7g of the compound of the structural formula V-1 as a white solid, with a yield of 81 %, 98% purity.

Mass spectrometry and NMR data are consistent with Example 1.

The preparation of embodiment 4 structural formula V-2 compound

Add cyanuric chloride (0.1mol) of 18.4g structural formula VII, 100ml dichloromethane, 10.6g methyl thioglycolate (0.1mol) of structural formula VIII-4 and 13.8g potassium carbonate powder (0.1mol) in the 500ml reaction bottle, Stir the reaction at room temperature for 30 minutes, filter, and rotate the filtrate to dryness under reduced pressure; directly add 24.6g of sodium acetate, 100ml of tetrahydrofuran, 1.0g of N-methylmorpholine (0.01mol) and 2.0g of water to the residue without treatment, and stir at room temperature Reacted for 48 hours, filtered, and the filtrate was rotary evaporated under reduced pressure to the remaining 1/2, cooled to 0-5°C, added 100ml of heptane, stirred for 1 hour, filtered and dried, 16.7g of the compound of structural formula V-2de as a white solid, yield 90 %, 99% purity.

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

¹ H-NMR (400M, DMSO-d ₆ ): 12.48 (1H, s), 4.32 (2H, s).

The preparation of embodiment 5 structural formula V-2 compound

Add 18.4g cyanuric chloride (0.1mol) of structural formula VII, 100ml tetrahydrofuran, 13.4g isopropyl thioglycolate (0.1mol) of structural formula VIII-5 and 13.8g potassium carbonate powder (0.1mol) in the 500ml reaction flask, room temperature Stir the reaction for 1 hour, filter; directly add 24.6g sodium acetate, 1.0g N-methylmorpholine (0.01mol) and 2.0g water to the filtrate, stir and react at room temperature for 48h, filter, and the filtrate is rotary evaporated under reduced pressure to the remaining 1/ 2. Cool down to 0-5°C, add 100ml of heptane, stir for 1h, filter, and dry to obtain 16.3g of the compound of structural formula V-2 as a white solid, with a yield of 88% and a purity of 99%.

Mass spectrometry and NMR data are consistent with Example 4.

The preparation of embodiment 6 structural formula V-2 compound

Add 18.4g cyanuric chloride (0.1mol) of structural formula VII, 100ml acetone, 18.2g benzyl mercaptoacetate (0.1mol) and 13.8g potassium carbonate powder (0.1mol) in the 500ml reaction bottle, stir reaction at room temperature for 2 hours, filter , directly add 24.6g of sodium acetate, 1.0g of N-methylmorpholine (0.01mol) and 2.0g of water to the filtrate, stir and react at room temperature for 48h, filter, and rotate the filtrate to the remaining 1/2 under reduced pressure, and cool to 0～ 5°C, add 100ml of heptane, stir for 1h, filter, and dry to obtain 15.7g of the compound of structural formula V-2 as a white solid, with a yield of 85% and a purity of 98%.

Mass spectrometry and NMR data are consistent with Example 4.

Preparation of Embodiment 7 Structural Formula I Compound (S-217622)

Step 1: Preparation of the compound of structural formula IV-1

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

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

¹ H-NMR (400M, DMSO-d ₆ ): 8.73 (1H, s), 4.69 (2H, s), 4.51 (2H, s), 3.73 (3H, s).

Step 2: Preparation of the compound of structural formula III-1

Add 10.0g (37.9mmol) of compound IV-1, 3.0g (41.0mmol) of diethylamine, and 50ml of dichloromethane prepared in the previous step into the reaction flask, heat up to 40°C for 5 hours, and then rotary evaporate to dryness under reduced pressure. 12.8 g of the compound of formula III-1 (white solid) was obtained, with a yield of 100% and a purity of 98%.

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

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

Step 3. Preparation of the compound of structural formula II-1

Add 10.0g (32.3mmol) of the compound of structural formula III-1, 5.9g (32.7mmol) of 1-(chloromethyl)-2,4,5-trifluorotoluene, 4.5g (32.6mmol) potassium carbonate powder and 100ml acetonitrile, heated to 80°C for 3h reaction, the reaction solution was rotary evaporated to dryness under reduced pressure, added 100ml water, extracted with ethyl acetate (three times, 100ml each time), combined the organic phases, anhydrous Dry over sodium sulfate, filter; concentrate the filtrate to about 30ml by rotary evaporation under reduced pressure, cool down to 0-5°C in an ice-water bath, add 90ml of heptane dropwise, stir for 2h, filter, and dry to obtain 12.6g of the compound of formula II-1 ( White solid), yield 88%, purity 99%.

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

¹ H-NMR (400M, DMSO-d ₆ ): 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).

Step 4. Preparation of compounds of structural formula I

Add the compound of 5.0g (11.0mmol) structural formula II-1 prepared in the previous step, 2.1g (11.6mmol) of 6-chloro-2-methyl-2H-indol-5-amine, 0.21g ( 2.1mmol) of N-methylmorpholine and 30ml of methanol, heated to 70 ° C for 15h; the reaction solution was rotary evaporated to dryness under reduced pressure, and recrystallized with 2-methyltetrahydrofuran to obtain 4.6g of the compound of structural formula I (white solid ), namely S-217622, with a yield of 83% and a purity of 99%.

MS (m/z): [M+1] ⁺ 532.2, 533.7.

¹ H-NMR (400M, DMSO-d ₆ ): 10.55 (1H, s), 8.73 (1H, s), 8.11 (1H, s), 7.95 (1H, s), 6.85 (1H, 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).

Preparation of Embodiment 8 Structural Formula I Compound (S-217622)

Step 1. Preparation of the compound of structural formula IV-2

Add 18.5g (100mmol) of the compound of structural formula V-2, 18.5g (110mmol) of 3-(chloromethyl)-1-methyl-1H-1,2,4-triazole hydrochloride, 30.4 g (220mmol) potassium carbonate powder and 200ml tetrahydrofuran, heat up to 80°C and react for 3h; spin to dry the solvent, add 200ml water, extract with ethyl acetate (three times, 200ml each time), combine organic phases, dry over anhydrous sodium sulfate, filter Concentrate the volume of the filtrate to about 50ml, cool to 0-5°C in an ice-water bath, add dropwise 100ml of heptane, stir for 2h, filter, and dry to obtain 26.9g of the compound of structural formula IV-2 (white solid), yield 96% , 99% purity.

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

¹ H-NMR (400M, DMSO-d ₆ ): 8.73 (1H, s), 4.50 (2H, s), 4.36 (2H, s), 3.73 (3H, s).

Step 2. Preparation of the compound of structural formula III-2

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

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

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

Step 3. Preparation of the compound of structural formula II-2

Add 10.0g (30.7mmol) of the compound of structural formula III-2 prepared in the previous step, 5.6g (31.0mmol) of 1-(chloromethyl)-2,4,5-trifluorotoluene, 4.3g (40.6mmol) in the bottle ) sodium carbonate and 100ml of dichloromethane, heated to 80°C for 3 hours, evaporated to dryness, added 100ml of water, extracted with ethyl acetate (three times, each 100ml), combined organic phases, dried over anhydrous sodium sulfate, filtered; The volume of the filtrate was concentrated to about 30ml, cooled to 0-5°C in an ice-water bath, 90ml of heptane was added dropwise, stirred for 2h, filtered, and dried to obtain 13.0g of a compound of structural formula II-2 (white solid), with a yield of 92%, purity 99%.

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

¹ H-NMR (400M, DMSO-d ₆ ): 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).

Step 4. Preparation of the compound of structural formula I

Add the compound of 5.0g (10.6mmol) structural formula II-2 prepared in the previous step, 2.0g (11.0mmol) of 6-chloro-2-methyl-2H-indol-5-amine, 0.20g (2.0mmol) in the bottle ) of N-methylmorpholine and 30ml of ethanol, heated to 70°C for 15 hours; evaporated to dryness, and recrystallized with 2-methyltetrahydrofuran to obtain 4.5g of a compound of structural formula I (white solid), namely S-217622, produced The yield is 85%, and the purity is 99%.

Mass spectrometry and NMR data are consistent with Example 7.

Claims (10)

1. A triazone compound of structural formula V,

Wherein, R=O or S. 2. the preparation method of the compound of structural formula V described in claim 1, comprises the steps: Step A: In the presence of a base, the cyanuric chloride of the structural formula VII is reacted with the compound of the structural formula VIII to obtain the compound of the structural formula VI, which is used for the next reaction after separation or not;

Wherein, R=O or S, R ₁ =C ₁ ~C ₄ alkyl or benzyl; Step B: in the presence of a catalyst, the compound of structural formula VI is hydrolyzed to obtain the compound of structural formula V;

Wherein, R and R ₁ are as defined above. 3. preparation method according to claim 2, is characterized in that, described _R is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl or benzyl. 4. according to the described preparation method of claim 2 or 3, it is characterized in that, in described step A, described alkali is selected from potassium carbonate, sodium carbonate, potassium bicarbonate, sodium bicarbonate, potassium hydroxide, sodium hydroxide , one or more of triethylamine, pyridine, DBU and DABCO; more preferably potassium carbonate or sodium carbonate; Preferably, in the step A, the molar ratio of the cyanuric chloride of the structural formula VII to the compound of the structural formula VIII is 1:0.9～1:2; more preferably 1:0.9～1:1.2; Preferably, in the step A, the molar ratio of cyanuric chloride of structural formula VII to the base is 1:0.5-1:5; more preferably 1:0.5-1:2; Preferably, in the step A, the reaction solvent is selected from one or more of dichloromethane, ethyl acetate, isopropyl acetate, tetrahydrofuran, acetonitrile and acetone; more preferably dichloromethane; Preferably, in the step A, the reaction temperature is -10°C to 60°C; more preferably 0°C to 30°C; Preferably, in the step B, the catalyst is selected from N-methylmorpholine, N-methylpiperidine, N-methylpyrrolidine, DABCO, triethylamine, pyridine and 4-dimethylaminopyridine A kind of; More preferably N-methylmorpholine; Preferably, in the step B, the molar ratio of the compound of structural formula VI to the catalyst is 1:0.05-1:0.5; more preferably 1:0.05-1:0.3; Preferably, in the step B, the reaction solvent is selected from one or more of tetrahydrofuran, methanol, ethanol, isopropanol, acetonitrile and acetone; more preferably tetrahydrofuran. 5. The compound of structural formula V as claimed in claim 1 is used as a starting material in the preparation of S-217622. 6. A preparation method of S-217622 of structural formula I,

Including using the compound of the structural formula V as a starting material, through the following steps: Step 1: In the presence of a base, the compound of the structural formula V is reacted with a salt of 3-(chloromethyl)-1-methyl-1H-1,2,4-triazole to prepare a compound of the structural formula IV,

Wherein, R=O or S; Step 2: the compound of structural formula IV reacts with diethylamine to generate the compound of structural formula III,

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

Step 4: In the presence of a catalyst, the compound of structural formula II is reacted with 6-chloro-2-methyl-2H-indol-5-amine to obtain the S-217622. 7. The preparation method according to claim 6, wherein the compound of the structural formula V is prepared by the preparation method according to any one of claims 2 to 4; Preferably, in the step 1, the salt of the 3-(chloromethyl)-1-methyl-1H-1,2,4-triazole is selected from hydrochloride, sulfate, citrate, horse forate, fumarate, hydrobromide or methanesulfonate; Preferably, in the step 1, the molar ratio of the compound V to the salt of 3-(chloromethyl)-1-methyl-1H-1,2,4-triazole is 1:0.8～1:2 ; More preferably 1:1～1:1.2; Preferably, in the step 1, the alkali is selected from potassium carbonate or sodium carbonate; Preferably, in the step 1, the molar ratio of the compound V to the base is 1:0.8-1:5; more preferably 1:1-1:3; Preferably, in step 1, the solvent is selected from one or more of acetonitrile, tetrahydrofuran, ethyl acetate, DMF, DMSO, methylene chloride, acetone, methanol and ethanol; more preferably acetonitrile; Preferably, the reaction temperature in step 1 is 20-150°C, more preferably 40-100°C. 8. The preparation method according to claim 6 or 7, characterized in that, in the step 2, the molar ratio of the compound III to diethylamine is 1:0.8 to 1:10; more preferably 1:1 ~1:3; Preferably, the reaction solvent in step 2 is selected from one or more of dichloromethane, ethyl acetate, tetrahydrofuran, methanol, ethanol, acetonitrile, acetone, DMF and DMSO; more preferably dichloromethane; Preferably, the reaction temperature in step 2 is 10-100°C; more preferably 20-60°C. 9. according to the preparation method described in any one in claim 6-8, it is characterized in that, in described step 3, the compound of described structural formula III and 1-(chloromethyl)-2,4,5-tri The molar ratio of fluorotoluene is 1:1～1:2; more preferably 1:1～1:1.2; Preferably, in the step 3, the alkali is selected from potassium carbonate or sodium carbonate; Preferably, in the step 3, the molar ratio of the compound of the structural formula III to the base is 1:0.8 to 1:5; more preferably 1:1 to 1:2; Preferably, the solvent in step 3 is selected from one or more of acetonitrile, tetrahydrofuran, ethyl acetate, DMF, DMSO, methylene chloride, acetone, methanol and ethanol; more preferably acetonitrile; Preferably, the reaction temperature in step 3 is selected from 20-150°C, more preferably 40-100°C. 10. according to the preparation method described in any one in claim 6-9, it is characterized in that, in described step 4, described catalyst is selected from N-methylmorpholine, N-methylpiperidine, N-methyl One or more of ylpyrrolidine, DABCO, triethylamine, pyridine and 4-dimethylaminopyridine; more preferably N-methylmorpholine; Preferably, in the step 4, the molar ratio of the compound of the structural formula II to the catalyst is 1:0.05-1:2; more preferably 1:0.05-1:0.2; 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; Preferably, the solvent in step 4 is selected from one or more of methanol, ethanol, isopropanol, acetonitrile, tetrahydrofuran, ethyl acetate, DMF, DMSO, methylene chloride and acetone; more preferably methanol or ethanol ; Preferably, the reaction temperature in step 4 is 20-150°C; more preferably 40-100°C.