CN116217553A - Triazinone compound and preparation method and application thereof - Google Patents
Triazinone compound and preparation method and application thereof Download PDFInfo
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- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
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- C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
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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 of chinese invention patent application No. CN202210291040.0 filed 3/23 2022, 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 2, 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 of formula I; is a small-molecule oral 3CL protease inhibitor developed by salt wild pharmaceutical Co., ltd.
Structurally, the three groups P1, P1' and P2 attached to the triazinone core are critical groups for the activity of S-217622. S-217622 has a mechanism of action similar to that of the COVID-19 oral therapeutic drug Paxlovid marketed by the best lot, plays an important role in the life cycle of various coronaviruses, and has the potential advantages of having an effect on all new coronavirus variants which have been discovered so far and having a slightly stronger inhibitory activity on the Omikovia strain.
The metabolism test of the mice of 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 traditional Chinese medicine composition has more advantages than the Paxlovid of the pyroxene.
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 as follows:
firstly, S-ethyl isothiourea hydrobromide reacts with tert-butyl isocyanate to prepare a compound A, and the yield is 50%; step two, carrying out substitution reaction on the compound A and the compound B to obtain a compound C with the yield of 93%; thirdly, deprotection with trifluoroacetic acid produced compound D in 97% yield; fourthly, carrying out substitution reaction on the compound D and the compound E to prepare a compound F with the yield of 45%; and fifthly, removing the ethylmercapto group of the compound G by using strong alkali, and then reacting with the compound F to obtain the final compound I, namely S-217622 in a yield of 25%.
Obviously, this route has certain problems. Firstly, the price of the S-ethyl isothiourea hydrobromide and tert-butyl isocyanate serving as the reaction raw materials in the first step is relatively high, so that the cost is not reduced; secondly, the reaction yield of the fourth step and the fifth step is too low, which is only 45 percent and 25 percent respectively, and the method is not suitable for industrialized mass production; finally, the ethanethiol removed in the fifth step is extremely volatile (boiling point 36.2 ℃), smells and is 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 focused on developing 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 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: reacting cyanuric chloride of a structural formula VII with a compound of a structural formula VIII in the presence of a base to obtain a compound of a structural formula VI, wherein the compound is used for the next reaction after separation or without separation;
wherein r=o or S, R 1 ＝C 1 ～C 4 Alkyl or benzyl;
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 As defined previously.
The synthetic route for the above formula V is as follows:
preferably, said R 1 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); 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 to 1:1.2.
Preferably, in the step A, the molar ratio of cyanuric chloride of the structural formula VII to the alkali is 1:0.5-1:5; more preferably 1:0.5 to 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 between 10 ℃ below zero and 60 ℃; more preferably from 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; 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 to 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.
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 with 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 with the structural formula V reacts with 3- (chloromethyl) -1-methyl-1H-1, 2, 4-triazole to prepare a compound with the structural formula IV,
wherein r=o or S;
step 2: reacting the compound of the structural formula IV with diethylamine to produce a compound of the structural formula III,
step 3: reacting a compound of the structural formula III with 1- (chloromethyl) -2,4, 5-benzotrifluoride in the presence of a base to obtain a compound of the structural formula II,
step 4: reacting a compound of 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 1:0.8-1:2; 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 alkali is 1:0.8-1:5; more preferably 1:1 to 1:3.
Preferably, in the step 1, the solvent is one or more selected from acetonitrile, tetrahydrofuran, ethyl acetate, DMF, DMSO, dichloromethane, acetone, methanol and ethanol; more preferably acetonitrile.
Preferably, the reaction temperature of step 1 is 20 to 150 ℃, 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 to 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; more preferably dichloromethane.
Preferably, the reaction temperature of the step 2 is 10-100 ℃; more preferably 20 to 60 ℃.
Preferably, in the step 3, the molar ratio of the compound of the structural formula III to the 1- (chloromethyl) -2,4, 5-benzotrifluoride is 1:1-1:2; 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 1:0.8-1:5; 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; more preferably acetonitrile.
Preferably, the reaction temperature of 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; 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 to 1:0.2.
Preferably, the molar ratio of the compound II to the 6-chloro-2-methyl-2H-indol-5-amine in the step 4 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; more preferably methanol or ethanol.
Preferably, the reaction temperature of the step 4 is 20-150 ℃; more preferably 40 to 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 single-step yield is above 85%, including the preparation method of the structural formula V, particularly the step 2 of the upper P2 group and the step 4 of the upper 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; 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 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), and the mixture was stirred at room temperature to react for 2 hours, filtered, and 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 are directly added without treatment, stirred at room temperature for reaction for 48h, filtered and the filtrate is distilled under reduced pressure until the residual 1/2; cooling to 0-5 ℃, adding 100ml of heptane, stirring for 1h, filtering and drying to obtain 15.5g of white solid compound of structural formula V-1, wherein 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)。
EXAMPLE 2 preparation of Compounds of formula V-1
A500 ml reaction flask was charged with 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), and the reaction mixture was stirred at room temperature for 2 hours, filtered, and the filtrate was distilled to dryness under reduced pressure; 13.8g of potassium acetate, 100ml of acetone, 1.5g of triethylamine (0.014 mol) and 2.0g of water are directly added without treatment to the residue, stirred at room temperature for 48h, filtered, the filtrate is distilled under reduced pressure until 1/2 remains, cooled to 0-5 ℃, 100ml of heptane is added, stirred for 1h, filtered and dried to obtain 14.4g of a white solid compound of the structural formula V-1, the yield is 85%, and the purity is 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), and the mixture was stirred at room temperature to react for 2 hours, filtered, and the filtrate was distilled to dryness under reduced pressure; 13.8g of potassium carbonate, 100ml of acetonitrile, 1.0g of N-methylpiperidine (0.1 mol) and 2.0g of water are directly added without treatment, the mixture is stirred at room temperature for 48h, the mixture is filtered, the filtrate is distilled under reduced pressure until the residual content is 1/2, the temperature is reduced to 0-5 ℃, 100ml of heptane is added, the mixture is stirred for 1h, the mixture is filtered and dried, and 13.7g of white solid compound of the structural formula V-1 is obtained, and the yield is 81% and the purity is 98%.
Mass spectrum and nuclear magnetic data are consistent with example 1.
EXAMPLE 4 preparation of Compounds of formula V-2
Into a 500ml reaction flask were charged 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 are directly added without treatment, the mixture is stirred at room temperature for 48h, the mixture is filtered, the filtrate is distilled under reduced pressure until the residue is 1/2, the temperature is reduced to 0 to 5 ℃, 100ml of heptane is added, the mixture is stirred for 1h, the mixture is filtered and dried, 16.7g of white solid compound of the structural formula V-2de is obtained, and the yield is 90% and the purity is 99%.
MS(m/z)：[M-1] - 184.0。
1 H-NMR(400M，DMSO-d 6 )：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), and the mixture was stirred at room temperature to react for 1 hour and filtered; 24.6g of sodium acetate, 1.0g of N-methylmorpholine (0.01 mol) and 2.0g of water are directly added into the filtrate, stirred at room temperature for 48h, filtered, distilled to the rest of 1/2 under reduced pressure, cooled to 0-5 ℃, 100ml of heptane is added, stirred for 1h, filtered, dried and 16.3g of white solid compound with the structural formula V-2 is obtained, and the yield is 88% and the purity is 99%.
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 the 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 white solid compound of the formula V-2 was obtained, 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 of formula I (S-217622)
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 flask, and the mixture is heated to 80 ℃ for reaction for 3 hours; the reaction solution was evaporated to dryness under reduced pressure, the residue was stirred with 200ml of water, extracted with ethyl acetate (three times each with 200 ml), the organic phases were combined, dried over anhydrous sodium sulfate, and filtered; concentrating the filtrate to about 50ml by rotary evaporation under reduced pressure, cooling to 0-5 ℃ by ice water bath, dropwise adding 100ml of heptane, stirring for 2h, filtering and drying to obtain 24.6g of compound (white solid) with structural formula IV-1, and the yield is 93% and the purity is 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 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。
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 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-benzotrifluoride, 4.5g (32.6 mmol) of potassium carbonate powder and 100ml of acetonitrile are added into a reaction bottle, the mixture is reacted for 3 hours at 80 ℃, the reaction solution is decompressed and distilled to dryness, 100ml of water is added, the mixture is extracted with ethyl acetate (three times each 100 ml), the organic phases are combined, dried with anhydrous sodium sulfate and filtered; concentrating the filtrate to about 30ml by rotary evaporation under reduced pressure, cooling to 0-5 ℃ by ice water bath, dripping 90ml of heptane, stirring for 2h, filtering and drying to obtain 12.6g of compound (white solid) with the structural formula II-1, wherein the yield is 88% and the purity is 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 formula I
5.0g (11.0 mmol) of the compound of formula II-1 obtained 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, and the temperature is raised to 70 ℃ for reaction for 15 hours; the reaction solution was distilled off under reduced pressure to dryness and recrystallized from 2-methyltetrahydrofuran to give 4.6g of the compound of the formula I (white solid), namely S-217622, yield 83% and purity 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)。
EXAMPLE 8 preparation of Compound of formula I (S-217622)
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 introduced into a reaction flask, and the mixture is heated to 80℃for reaction for 3 hours; spin-drying the solvent, adding 200ml of water, extracting with ethyl acetate (three times each with 200 ml), combining the organic phases, drying over anhydrous sodium sulfate, and filtering; the filtrate was concentrated to about 50ml in volume, cooled to 0-5℃in an ice-water bath, 100ml of heptane was added dropwise, stirred for 2h, filtered and dried to give 26.9g of the compound of formula IV-2 (white solid) in 96% yield and 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 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℃for reaction for 5 hours and dried by spinning 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。
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 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-benzotrifluoride, 4.3g (40.6 mmol) of sodium carbonate and 100ml of methylene chloride are added to the flask, the reaction is carried out at 80℃for 3 hours, the solvent is evaporated off, 100ml of water is added, extraction with ethyl acetate is carried out (three times each of 100 ml), the organic phases are combined, dried over anhydrous sodium sulfate and filtered; the filtrate was concentrated to about 30ml in volume, cooled to 0-5℃in an ice-water bath, 90ml of heptane was added dropwise, stirred for 2h, filtered and dried to give 13.0g of the compound of formula II-2 (white solid) in 92% yield and 99% purity.
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 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, and the mixture is heated to 70 ℃ for reaction for 15 hours; the solvent was evaporated and recrystallized from 2-methyltetrahydrofuran to give 4.5g of the compound of formula I (white solid), S-217622 in 85% yield and 99% purity.
Mass and nuclear magnetic data are consistent with example 7.
Claims (10)
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: reacting cyanuric chloride of a structural formula VII with a compound of a structural formula VIII in the presence of a base to obtain a compound of a structural formula VI, wherein the compound is used for the next reaction after separation or without separation;
wherein r=o or S, R 1 ＝C 1 ～C 4 Alkyl or benzyl;
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 As defined previously.
3. The method of claim 2, wherein R is 1 Selected from methyl, ethyl, n-propyl, isopropyl, n-butyl or benzyl.
4. A process according to claim 2 or 3, wherein 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 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 to 1:1.2;
preferably, in the step A, the molar ratio of cyanuric chloride of the structural formula VII to the alkali is 1:0.5-1:5; more preferably 1:0.5 to 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 between 10 ℃ below zero and 60 ℃; more preferably from 0℃to 30 ℃;
preferably, in the step B, the catalyst is selected from one of N-methylmorpholine, N-methylpiperidine, N-methylpyrrolidine, DABCO, triethylamine, pyridine and 4-dimethylaminopyridine; 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 to 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 use of a compound of formula V according to claim 1 as starting material in the preparation of S-217622.
6. A preparation method of S-217622 with a 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 with the structural formula V reacts with 3- (chloromethyl) -1-methyl-1H-1, 2, 4-triazole to prepare a compound with the structural formula IV,
wherein r=o or S;
step 2: reacting the compound of the structural formula IV with diethylamine to produce a compound of the structural formula III,
step 3: reacting a compound of the structural formula III with 1- (chloromethyl) -2,4, 5-benzotrifluoride in the presence of a base to obtain a compound of the structural formula II,
step 4: reacting a compound of the structural formula II with 6-chloro-2-methyl-2H-indol-5-amine in the presence of a catalyst to obtain the S-217622.
7. The preparation method according to claim 6, wherein the compound of 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 3- (chloromethyl) -1-methyl-1H-1, 2, 4-triazole is selected from hydrochloride, sulfate, citrate, maleate, 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 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 alkali is 1:0.8-1:5; more preferably 1:1 to 1:3;
preferably, in the step 1, the solvent is one or more selected from acetonitrile, tetrahydrofuran, ethyl acetate, DMF, DMSO, dichloromethane, acetone, methanol and ethanol; more preferably acetonitrile;
preferably, the reaction temperature of step 1 is 20 to 150 ℃, more preferably 40 to 100 ℃.
8. The process according to claim 6 or 7, wherein 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;
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; more preferably dichloromethane;
preferably, the reaction temperature of the step 2 is 10-100 ℃; more preferably 20 to 60 ℃.
9. The process according to any one of claims 6 to 8, wherein in step 3, the molar ratio of the compound of formula III to 1- (chloromethyl) -2,4, 5-trifluorotoluene is from 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 1:0.8-1:5; 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; more preferably acetonitrile;
preferably, the reaction temperature of step 3 is selected from 20 to 150 ℃, more preferably 40 to 100 ℃.
10. The preparation method according to any one of claims 6 to 9, wherein 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; 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 to 1:0.2;
preferably, the molar ratio of the compound II to the 6-chloro-2-methyl-2H-indol-5-amine in the step 4 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; more preferably methanol or ethanol;
preferably, the reaction temperature of the step 4 is 20-150 ℃; more preferably 40 to 100 ℃.
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| CN2022102910400 | 2022-03-23 |
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