CN116217553B - A triazone compound and its preparation method and application - Google Patents
A triazone compound and its preparation method and application Download PDFInfo
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Abstract
The invention provides a triazinone compound with a structural formula V, a preparation method thereof and an application of the triazinone compound with the structural formula V as a starting material in preparation of S-217622. The invention also provides a novel, efficient and environment-friendly preparation method of the S-217622.
Description
Cross Reference to Related Applications
The present patent application claims the priority benefit of the chinese invention patent application filed at 2022, 3/23, and filed under application number CN202210291040.0, the entire contents of which are incorporated herein by reference.
Technical Field
The invention belongs to the field of organic chemistry, and particularly relates to a novel triazinone compound, and a preparation method and application thereof.
Background
The epidemic situation of novel coronavirus infection (COVID-2019) caused by SARS coronavirus 2 (severe acute respiratorysyndrome coronavirus, SARS-CoV-2) seriously threatens the life and health of human beings. The search for effective antiviral drugs is also of great significance in suppressing epidemic situations while actively developing and popularizing vaccination.
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-triazin-E-2, 4-dione, structural formula shown as I, is a small molecule oral 3CL protease inhibitor developed by salt wild pharmaceutical Co., ltd., north sea duct university.
Structurally, the three groups P1, P1' and P2 attached to the triazinone core are key groups for the activity-related activity of S-217622. S-217622 has a mechanism of action similar to that of COVID-19 oral therapeutic Paxlovid marketed by the fei-shi-ku, plays an important role in the life cycle of various coronaviruses, has the potential advantage of having an effect on all novel coronavirus variants which have been discovered at present, and has a slightly stronger inhibitory activity on the amikappy strain.
The metabolism test of the mice with S-217622 shows that the half-life period is longer, the novel coronavirus pneumonia can be treated by single drug, the curative effect is obvious, and the mice have more advantages than the Paxlovid of the schniz.
Salt wild publication No. 2, month 8 of 2022, phase IIa partial data of phase II/III clinical trials of S-217622. In antiviral terms, the S-217622 group had a significant effect compared to the placebo group.
The synthetic route of S-217622, which has been disclosed so far, is shown below:
The method comprises the steps of preparing a compound A by reacting S-ethyl isothiourea hydrobromide with tert-butyl isocyanate, wherein the yield is 50%, carrying out substitution reaction on the compound A and the compound B to obtain a compound C, wherein the yield is 93%, carrying out deprotection by trifluoroacetic acid to obtain a compound D with 97% yield, carrying out substitution reaction on the compound D and the compound E to obtain a compound F with the yield of 45%, and carrying out substitution reaction on the compound G with strong alkali to remove ethylmercapto and then carrying out reaction on the compound with the compound F to obtain a final compound I with the yield of 25%, namely S-217622.
Obviously, this route has certain problems. Firstly, the raw materials of the reaction in the first step, namely S-ethyl isothiourea hydrobromide and tert-butyl isocyanate, are relatively expensive, which is not beneficial to reducing the cost, secondly, the reaction yield in the fourth step and the fifth step is too low, namely only 45 percent and 25 percent respectively, which is not suitable for industrial mass production, and finally, the ethanethiol stripped in the fifth step is extremely volatile (boiling point is 36.2 ℃), is odorous and toxic, and is not beneficial to environmental protection and safe production.
Therefore, in order to ensure safe production, reduce the cost of mass administration and improve the accessibility of drugs, the inventors have sought to develop a new S-217622 synthetic route which is milder in reaction conditions, moderate in cost and environmentally friendly.
Disclosure of Invention
In order to overcome the defects of the prior art, the invention provides a novel triazinone compound, a preparation method thereof and application of the compound as a key intermediate of S-217622 in synthesizing S-217622. The method for finally obtaining the S-217622 by the novel triazinone compound provided by the invention has the advantages of high yield and low cost.
In order to achieve the above object, the present invention adopts the following technical scheme:
a triazinone compound with a structural formula V,
Wherein r=o or S.
The invention also provides a preparation method of the compound with the structural formula V, which comprises the following steps:
step A, in the presence of alkali, cyanuric chloride of a structural formula VII reacts with a compound of a structural formula VIII to obtain a compound of a structural formula VI, and the compound is used for the next reaction after separation or not separation;
Wherein r=o or S, alkyl or benzyl of R 1＝C1～C4;
step B, in the presence of a catalyst, hydrolyzing the compound with the structural formula VI to obtain a compound with the structural formula V;
Wherein R and R 1 are as defined previously.
The synthetic route for the above formula V is as follows:
Preferably, the R 1 is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl or benzyl.
Preferably, 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 (1, 8-diazabicyclo undec-7-ene) and DABCO (1, 4-diazabicyclo [2.2.2] octane), and 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 alkali 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, and more preferably dichloromethane.
Preferably, in the step A, the reaction temperature is-10 ℃ to 60 ℃, and more preferably 0 ℃ to 30 ℃.
Preferably, in the 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, and more preferably N-methylmorpholine.
Preferably, in the step B, the molar ratio of the compound of the 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, and more preferably tetrahydrofuran.
It is a further object of the present invention to provide the use of a compound of formula V as defined above as starting material in the preparation of S-217622.
In addition, the invention also provides a preparation method of the S-217622 in the structural formula I,
Comprising the steps of using the compound of formula V as a starting material:
Step 1, in the presence of alkali, the compound of the structural formula V reacts with 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, reacting the compound with structural formula IV with diethylamine to generate a compound with structural formula III,
Step 3, in the presence of alkali, the compound of the structural formula III reacts with 1- (chloromethyl) -2,4, 5-benzotrifluoride to obtain a compound of the structural formula II,
And 4, reacting the compound shown in the structural formula II with 6-chloro-2-methyl-2H-indol-5-amine in the presence of a catalyst to obtain the S-217622.
The synthetic route for S-217622 of the above structural formula I is as follows:
preferably, the compound of formula V is prepared by the preparation method of the invention.
Preferably, the salt of 3- (chloromethyl) -1-methyl-1H-1, 2, 4-triazole is selected from the group consisting of hydrochloride, sulfate, citrate, maleate, fumarate, hydrobromide or mesylate.
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 to 1:2, more preferably 1:1 to 1:1.2.
Preferably, in the step 1, the base is selected from one of potassium carbonate or sodium carbonate.
Preferably, in the 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.
Preferably, in the step 1, the solvent is selected from one or more of acetonitrile, tetrahydrofuran, ethyl acetate, DMF, DMSO, dichloromethane, acetone, methanol and ethanol, and more preferably acetonitrile.
Preferably, the reaction temperature in the step 1 is 20 to 150 ℃, and more preferably 40 to 100 ℃.
Preferably, in the step 2, the molar ratio of the compound III to the diethylamine is 1:0.8-1:10, more preferably 1:1-1:3.
Preferably, the reaction solvent in the step 2 is selected from one or more of dichloromethane, ethyl acetate, tetrahydrofuran, methanol, ethanol, acetonitrile, acetone, DMF and DMSO, and more preferably dichloromethane.
Preferably, the reaction temperature in the step 2 is 10-100 ℃, and more preferably 20-60 ℃.
Preferably, in the step 3, the molar ratio of the compound of the structural formula III to 1- (chloromethyl) -2,4, 5-benzotrifluoride is 1:1 to 1:2, more preferably 1:1 to 1:1.2.
Preferably, in the step 3, the base is selected from one of 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 the step 3 is selected from one or more of acetonitrile, tetrahydrofuran, ethyl acetate, DMF, DMSO, dichloromethane, acetone, methanol and ethanol, and more preferably acetonitrile.
Preferably, the reaction temperature in the step 3 is selected from 20 to 150 ℃, more preferably 40 to 100 ℃.
Preferably, in the step 4, the catalyst is selected from one or more of N-methylmorpholine, N-methylpiperidine, N-methylpyrrolidine, DABCO, triethylamine, pyridine and 4-dimethylaminopyridine, and 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 the compound II to the 6-chloro-2-methyl-2H-indol-5-amine in the step4 is 1:0.8-1:2, more preferably 1:1-1:1.2.
Preferably, the solvent in the step 4 is selected from one or more of methanol, ethanol, isopropanol, acetonitrile, tetrahydrofuran, ethyl acetate, DMF, DMSO, dichloromethane and acetone, and more preferably methanol or ethanol.
Preferably, the reaction temperature in the step 4 is 20-150 ℃, and more preferably 40-100 ℃.
Compared with the prior art, the invention has the following beneficial effects:
1. the compound of the structural formula V has novel synthetic route, the initial raw materials are cheap and easy to obtain, and expensive reagents and raw materials in the prior art are not used;
2. The preparation method of the structural formula V comprises more than 85% of each single-step yield, particularly the step 2 of adding the P2 group and the step 4 of adding the P1' in the preparation of the S-217622, so that the total yield of the preparation of the S-217622 is high, and the production cost is reduced.
3. Because the compound with the structural formula V is used as the starting material for preparing S-217622, the generation of ethanethiol is avoided, and the sulfur-containing compound removed in the step 4 has high boiling point, is not easy to volatilize and is convenient to process. Therefore, the preparation method of S-217622 provided by the invention is environment-friendly in reaction, and is beneficial to protecting the safety of operators.
4. The reaction is mild, the process is simple, the whole preparation process has no high-temperature and high-pressure reaction, and the method is very suitable for industrial production.
Detailed Description
The invention is described below with reference to specific examples. It will be appreciated by those skilled in the art that these examples are for illustration of the invention only and are not intended to limit the scope of the invention in any way.
The experimental methods in the following examples are conventional methods unless otherwise specified. The raw materials, reagent materials and the like used in the examples described below are commercially available products unless otherwise specified.
EXAMPLE 1 preparation of Compounds of formula V-1
A500 ml reaction flask was charged with 18.4g of cyanuric chloride of the formula VII (0.1 mol), 100ml of methylene chloride, 9.0g of methyl glycolate of the formula VIII-1 (0.1 mol) and 13.8g of potassium carbonate powder (0.1 mol), stirred at room temperature for 2 hours, filtered, the filtrate was distilled to dryness under reduced pressure, 24.6g of sodium acetate, 100ml of tetrahydrofuran, 1.3g of N-methylmorpholine (0.01 mol) and 2.0g of water were directly added without treatment, stirred at room temperature for 48 hours, filtered, the filtrate was distilled to the remaining 1/2 under reduced pressure, cooled to 0 to 5℃and 100ml of heptane were added, stirred for 1 hour, filtered and dried to give 15.5g of a white solid compound of the formula V-1 in 92% yield and 99% purity.
MS(m/z):[M-1]-168.0。
1H-NMR(400M,DMSO-d6):12.36(1H,s),4.65(2H,s)。
EXAMPLE 2 preparation of Compounds of formula V-1
To a 500ml reaction flask were added 18.4g of cyanuric chloride of formula VII (0.1 mol), 100ml of ethyl acetate, 11.8g of isopropyl glycolate of formula VIII-2 (0.1 mol) and 12.2g of triethylamine (0.12 mol), stirred at room temperature for 2 hours, filtered, the filtrate was distilled to dryness under reduced pressure, the residue was directly added with 13.8g of potassium acetate, 100ml of acetone, 1.5g of triethylamine (0.014 mol) and 2.0g of water without treatment, stirred at room temperature for 48 hours, filtered, the filtrate was distilled to the remaining 1/2 under reduced pressure, cooled to 0to 5℃and 100ml of heptane was added, stirred for 1 hour, filtered and dried to give 14.4g of a white solid compound of formula V-1 in a yield of 85% purity of 98%.
Mass spectrum and nuclear magnetic data are consistent with example 1.
EXAMPLE 3 preparation of Compounds of formula V-1
To a 500ml reaction flask were added 18.4g of cyanuric chloride of formula VII (0.1 mol), 100ml of acetonitrile, 16.6g of benzyl hydroxy acetate of formula VIII-3 (0.1 mol) and 4.0g of sodium hydroxide (0.1 mol), stirred at room temperature for 2 hours, filtered, the filtrate was distilled to dryness under reduced pressure, the residue was directly added with 13.8g of potassium carbonate, 100ml of acetonitrile, 1.0g of N-methylpiperidine (0.1 mol) and 2.0g of water without treatment, stirred at room temperature for 48 hours, filtered, the filtrate was distilled to the remaining 1/2 under reduced pressure, cooled to 0 to 5℃and 100ml of heptane was added, stirred for 1 hour, filtered and dried to give 13.7g of a compound of formula V-1 as a white solid in a yield of 81% purity of 98%.
Mass spectrum and nuclear magnetic data are consistent with example 1.
EXAMPLE 4 preparation of Compounds of formula V-2
To a 500ml reaction flask were added 18.4g of cyanuric chloride of the formula VII (0.1 mol), 100ml of methylene chloride, 10.6g of methyl thioglycolate of the formula VIII-4 (0.1 mol) and 13.8g of potassium carbonate powder (0.1 mol), and the mixture was stirred at room temperature to react for 30 minutes, filtered, and the filtrate was distilled to dryness under reduced pressure, 24.6g of sodium acetate, 100ml of tetrahydrofuran, 1.0g of N-methylmorpholine (0.01 mol) and 2.0g of water were directly added without treatment, stirred at room temperature to react for 48 hours, filtered, and the filtrate was distilled to the remaining 1/2 under reduced pressure, cooled to 0 to 5℃and 100ml of heptane was added, stirred for 1 hour, filtered, dried and 16.7g of the white solid compound of the formula V-2de was obtained in a yield of 90% and a purity of 99%.
MS(m/z):[M-1]-184.0。
1H-NMR(400M,DMSO-d6):12.48(1H,s),4.32(2H,s)。
EXAMPLE 5 preparation of Compounds of formula V-2
A500 ml reaction flask was charged with 18.4g of cyanuric chloride of the formula VII (0.1 mol), 100ml of tetrahydrofuran, 13.4g of isopropyl thioglycolate of the formula VIII-5 (0.1 mol) and 13.8g of potassium carbonate powder (0.1 mol), stirred at room temperature for reaction for 1 hour, filtered, 24.6g of sodium acetate, 1.0g of N-methylmorpholine (0.01 mol) and 2.0g of water were directly added to the filtrate, stirred at room temperature for reaction for 48 hours, filtered, the filtrate was distilled under reduced pressure until 1/2 remained, cooled to 0 to 5 ℃,100 ml of heptane was added, stirred for 1 hour, filtered, dried and 16.3g of a compound of the formula V-2 as a white solid was obtained in 88% yield and 99% purity.
Mass and nuclear magnetic data are consistent with example 4.
EXAMPLE 6 preparation of Compounds of formula V-2
To a 500ml reaction flask were added 18.4g of cyanuric chloride of formula VII (0.1 mol), 100ml of acetone, 18.2g of benzyl mercaptoacetate (0.1 mol) and 13.8g of potassium carbonate powder (0.1 mol), stirred at room temperature for 2 hours, filtered, 24.6g of sodium acetate, 1.0g of N-methylmorpholine (0.01 mol) and 2.0g of water were directly added to the filtrate, stirred at room temperature for 48 hours, filtered, the filtrate was distilled under reduced pressure until the remaining 1/2 was cooled to 0 to 5 ℃, 100ml of heptane was added, stirred for 1 hour, filtered, dried, 15.7g of a compound of formula V-2 as a white solid was added, and the yield was 85% and the purity was 98%.
Mass and nuclear magnetic data are consistent with example 4.
EXAMPLE 7 preparation of Compound (S-217622) of formula I
Step 1 preparation of Compounds of formula IV-1
16.9G (0.1 mol) of compound V-1, 18.5g of 3- (chloromethyl) -1-methyl-1H-1, 2, 4-triazole hydrochloride (0.11 mol), 30.4g of potassium carbonate (0.22 mol) and 200ml of acetonitrile are added into a reaction bottle, the mixture is heated to 80 ℃ for reaction for 3 hours, the reaction solution is distilled to dryness under reduced pressure, the residue is added with 200ml of water for stirring, ethyl acetate is used for extraction (three times, 200ml each time), the organic phases are combined, anhydrous sodium sulfate is dried and filtered, the filtrate is distilled to be concentrated to about 50ml under reduced pressure, the temperature is reduced to 0-5 ℃ by an ice water bath, 100ml of heptane is added dropwise, the mixture is stirred for 2 hours, filtered and dried, and 24.6g of the compound (white solid) with the structural formula IV-1 is obtained, and the yield is 93% and the purity is 99%.
MS(m/z):[M+1]+265.1。
1H-NMR(400M,DMSO-d6):8.73(1H,s),4.69(2H,s),4.51(2H,s),3.73(3H,s)。
Step 2 preparation of Compounds of formula III-1
10.0G (37.9 mmol) of the compound IV-1 prepared in the previous step, 3.0g (41.0 mmol) of diethylamine and 50ml of dichloromethane are added into a reaction bottle, the temperature is raised to 40 ℃ for reaction for 5 hours, and the mixture is distilled to dryness under reduced pressure, so that 12.8g of the compound (white solid) of the structural formula III-1 is obtained, the yield is 100%, and the purity is 98%.
MS(m/z):[M+1]+310.2。
1H-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).
Step 3 preparation of Compounds of formula II-1
10.0G (32.3 mmol) of the compound of formula III-1 obtained in the previous step, 5.9g (32.7 mmol) of 1- (chloromethyl) -2,4, 5-trifluorotoluene, 4.5g (32.6 mmol) of potassium carbonate powder and 100ml of acetonitrile are added into a reaction bottle, the mixture is heated to 80 ℃ for reaction for 3 hours, the reaction liquid is decompressed and distilled to dryness, 100ml of water is added, the mixture is extracted with ethyl acetate (three times, 100ml each time), the organic phases are combined, anhydrous sodium sulfate is dried and filtered, the filtrate is decompressed and distilled to be concentrated to about 30ml, the ice water bath is cooled to 0-5 ℃, 90ml of heptane is added dropwise, the mixture is stirred for 2 hours, the filtration and the drying are carried out, and 12.6g of the compound of formula II-1 (white solid) is obtained, the yield is 88%, and the purity is 99%.
MS(m/z):[M+1]+454.2。
1H-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).
Step 4 preparation of Compounds of formula I
5.0G (11.0 mmol) of the compound of formula II-1 prepared in the previous step, 2.1g (11.6 mmol) of 6-chloro-2-methyl-2H-indol-5-amine, 0.21g (2.1 mmol) of N-methylmorpholine and 30ml of methanol are added into a reaction flask, the temperature is raised to 70 ℃ for 15H, the reaction solution is distilled to dryness under reduced pressure, and the compound of formula I (white solid) is recrystallized by 2-methyltetrahydrofuran, namely S-217622, the yield is 83% and the purity is 99%.
MS(m/z):[M+1]+532.2,533.7。
1H-NMR(400M,DMSO-d6)：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).
EXAMPLE 8 preparation of Compound (S-217622) of formula I
Step 1 preparation of Compounds of formula IV-2
18.5G (100 mmol) of the compound of formula V-2, 18.5g (110 mmol) of 3- (chloromethyl) -1-methyl-1H-1, 2, 4-triazole hydrochloride, 30.4g (220 mmol) of potassium carbonate powder and 200ml of tetrahydrofuran are added to a reaction flask, the reaction is carried out for 3 hours at 80℃C, 200ml of water is added, extraction is carried out with ethyl acetate (three times each 200 ml), the organic phases are combined, dried over anhydrous sodium sulfate and filtered, the filtrate volume is concentrated to about 50ml, the ice water bath is cooled to 0-5℃C, 100ml of heptane is added dropwise, stirring is carried out for 2 hours, filtration and drying are carried out, and 26.9g of the compound of formula IV-2 (white solid) is obtained in 96% yield and 99% purity.
MS(m/z):[M+1]+281.1。
1H-NMR(400M,DMSO-d6):8.73(1H,s),4.50(2H,s),4.36(2H,s),3.73(3H,s)。
Step 2 preparation of Compounds of formula III-2
10.0G (35.7 mmol) of the compound of formula IV-2 prepared in the previous step, 2.9g (39.7 mmol) of diethylamine and 50ml of ethyl acetate were added into a bottle, and the mixture was heated to 40 ℃ to react for 5 hours and spin-dried to obtain 12.6g of the compound of formula III-2 (white solid) in a yield of 100% and a purity of 98%.
MS(m/z):[M+1]+326.1。
1H-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).
Step 3 preparation of Compounds of formula II-2
10.0G (30.7 mmol) of the compound of formula III-2 prepared in the previous step, 5.6g (31.0 mmol) of 1- (chloromethyl) -2,4, 5-trifluorotoluene, 4.3g (40.6 mmol) of sodium carbonate and 100ml of methylene chloride are added to the flask, the reaction is carried out for 3 hours at 80℃and the solvent is evaporated off, 100ml of water is added, extraction is carried out with ethyl acetate (three times each 100 ml), the organic phases are combined, dried over anhydrous sodium sulfate and filtered, the filtrate volume is concentrated to about 30ml, the ice water bath is cooled to 0-5℃and 90ml of heptane are added dropwise, stirred for 2 hours, filtered and dried to obtain 13.0g of the compound of formula II-2 (white solid) in 92% yield and 99% purity.
MS(m/z):[M+1]+470.1。
1H-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).
Step 4 preparation of Compounds of formula I
5.0G (10.6 mmol) of the compound of formula II-2 prepared in the previous step, 2.0g (11.0 mmol) of 6-chloro-2-methyl-2H-indol-5-amine, 0.20g (2.0 mmol) of N-methylmorpholine and 30ml of ethanol are added to the flask, the mixture is heated to 70℃for 15H, the solvent is evaporated off, and 4.5g of the compound of formula I (white solid) are obtained by recrystallization from 2-methyltetrahydrofuran, S-217622, yield 85% and purity 99%.
Mass and nuclear magnetic data are consistent with example 7.
Claims (17)
1. A triazinone compound with a structural formula V,
Wherein r=o or S.
2. A process for the preparation of a compound of formula V according to claim 1, comprising the steps of:
step A, in the presence of alkali, cyanuric chloride of a structural formula VII reacts with a compound of a structural formula VIII to obtain a compound of a structural formula VI, and the compound is used for the next reaction after separation or not separation;
Wherein r=o or S, alkyl or benzyl of R 1＝C1～C4;
step B, in the presence of a catalyst, hydrolyzing the compound with the structural formula VI to obtain a compound with the structural formula V;
wherein R and R 1 are as previously defined;
The catalyst is selected from one of sodium acetate and N-methylmorpholine, potassium acetate and triethylamine, potassium carbonate and N-methylpiperidine.
3. The method of claim 2, wherein R 1 is selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, and benzyl.
4. The preparation method according to claim 2, wherein 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 method according to claim 4, wherein in the step A, the base is potassium carbonate or sodium carbonate.
6. The method according to claim 2,4 or 5, wherein in the step a, the molar ratio of cyanuric chloride of the structural formula VII to the base is 1:0.5 to 1:5.
7. The method according to claim 6, wherein in the step A, the molar ratio of cyanuric chloride of the structural formula VII to the base is 1:0.5-1:2.
8. The method according to claim 2, wherein in the step a, the molar ratio of cyanuric chloride of the structural formula VII to the compound of the structural formula VIII is 1:0.9 to 1:2.
9. The method according to claim 8, wherein in the step A, the molar ratio of cyanuric chloride of the structural formula VII to the compound of the structural formula VIII is 1:0.9 to 1:1.2.
10. The preparation method according to claim 2, wherein 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 method according to claim 10, wherein in the step a, the reaction solvent is methylene chloride.
12. The method according to claim 2, wherein in the step a, the reaction temperature is-10 ℃ to 60 ℃.
13. The method according to claim 12, wherein in the step a, the reaction temperature is 0 ℃ to 30 ℃.
14. The method according to claim 2, wherein in the step B, the molar ratio of the compound of structural formula VI to the catalyst is 1:0.05 to 1:0.5.
15. The method of claim 14, wherein in 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, wherein in the step B, the reaction solvent is one or more selected from tetrahydrofuran, methanol, ethanol, isopropanol, acetonitrile and acetone.
17. The method according to claim 16, wherein in the step B, the reaction solvent is tetrahydrofuran.
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