CN114853741A - Preparation method of novel coronavirus main protease inhibitor - Google Patents
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Abstract
The invention discloses a preparation method of a novel coronavirus main protease inhibitor S-217622, which comprises the following steps: the target compound S-217622 is prepared by taking 6-chloro-2-methyl-5-isothiocyanato-2H-indazole and 2,4, 5-trifluorophenylmethylamine as raw materials and sequentially carrying out condensation reaction, ammoniation reaction, acylation reaction and cyclization reaction. The preparation method has the advantages of simple process, mild conditions, safety and environmental protection, and provides a new way for the industrial production of the product.
Description
Technical Field
The invention belongs to the technical field of organic synthesis route design and preparation of raw material medicines and intermediates thereof, and particularly relates to a preparation method of a novel coronavirus main protease inhibitor S-217622.
Background
S-217622 is an oral medicine for treating new corona developed by Nippon salt Yeyi company, and has high-efficiency inhibiting effect on the main protease 3CLpro of new corona virus and antiviral effect. Preclinical tests show that S-217622 has strong in-vitro effect on 3CLpro activity and IC 50 The value was 0.013. mu.M, EC 50 The value was 0.37. mu.M. Animal experiments have shown that S-217622 is highly effective when administered orally in rats, monkeys, and dogsAbsorption and low clearance, with half-lives in monkeys and dogs of about 10 and 30 hours, respectively. Meanwhile, in vitro experiments also prove that S-217622 has stronger antiviral activity on various new coronavirus variant strains and EC of the Ormcken variant strain 50 The value was about 0.29. mu.M, and no significant decrease occurred. At present, the medicine has completed phase IIb clinical tests, and salt Yeyi company has applied for production and marketing approval from Japan Housheng labour province based on the clinical test results.
The chemical name of S-217622(I) is: (6E) -6- [ (6-chloro-2-methyl-2H-indazol-5-yl) imino ] dihydro-3- [ (1-methyl-1H-1, 2, 4-triazol-3-yl) methyl ] -1- [ (2,4, 5-trifluorophenyl) methyl ] -1,3, 5-triazine-2, 4(1H,3H) -dione having the following structural formula:
analysis of the molecular structure composition of S-217622 shows that the compound is composed of a triazine parent nucleus and three side chains of indazolyl, triazolyl and trifluorobenzyl.
Based on the above analysis, the research literature of salt-wild-type corporation "Discovery of S-217622, a Non-equivalent Oral SARS-CoV-23 CL Protease Inhibitor Clinical diagnosis for Treating COVID-19" (bioRxiv, post January 26,2022) discloses a synthetic route of S-217622 by using the idea of "reverse synthesis method":
firstly, a triazine parent nucleus 3- (1, 1-dimethylethyl) -6- (ethylmercapto) -1,3, 5-triazine-2, 4(1H,3H) -diketone and a fluorobenzyl side chain 2,4, 5-trifluorobenzyl bromide are substituted in the presence of an acid binding agent to obtain an intermediate 1; secondly, carrying out deprotection on the intermediate 1 under a strong acid condition to obtain an intermediate 2; then the intermediate 2 and triazolyl side chain 3- (chloromethyl) -1-methyl-1H-1, 2, 4-triazole carry out substitution reaction again in the presence of an acid-binding agent to obtain an intermediate 3; finally, the intermediate 3 and 6-chloro-2-methyl-2H-indazol-5-amine of the indazolyl side chain are subjected to condensation reaction under a strong alkaline condition to prepare the target product S-217622 (I).
Considering the above synthetic route, in order to selectively perform the substitution reaction between the halogenated side chain and the parent nucleus twice, protection and deprotection steps are inevitably required, so that the whole reaction yield is reduced, and the principle of atom economy cannot be satisfied to the maximum extent. Meanwhile, because the reaction route repeatedly uses the substitution reaction with the same mechanism twice, the situations of selectivity reduction and side reactions increase are bound to occur.
Therefore, in order to realize the preparation of the Xinguan drug S-217622 more efficiently, a modern synthesis technology is adopted, a more economical and practical reaction route is searched, an economic, environment-friendly, green and alternative process route is formed, and the method is very important for enriching the preparation technology of S-217622 and the economic and technical development of the bulk drug.
Disclosure of Invention
The invention aims to provide an improved preparation method of (6E) -6- [ (6-chloro-2-methyl-2H-indazol-5-yl) imino ] dihydro-3- [ (1-methyl-1H-1, 2, 4-triazol-3-yl) methyl ] -1- [ (2,4, 5-trifluorophenyl) methyl ] -1,3, 5-triazine-2, 4(1H,3H) -diketone (S-217622, I) according to the synthesis concept of green chemistry by adopting the development result of modern synthesis technology. The preparation method is simple, convenient, economic and environment-friendly, is beneficial to industrial production of the medicine, and can promote the development of economic technology of the raw material medicine.
In order to achieve the purpose, the main technical scheme provided by the invention is as follows: a process for preparing S-217622(I),
the method comprises the following steps: the 6-chloro-2-methyl-5-isothiocyanato-2H-indazole (II) and 2,4, 5-trifluorophenylmethylamine (III) are subjected to condensation reaction to generate N- [ (6-chloro-2-methyl) -2H-indazol-5-yl ] -N '- [1- (2,4, 5-trifluorophenyl) methyl ] thiourea (IV), and the N- [ (6-chloro-2-methyl) -2H-indazol-5-yl ] -N' - [1- (2,4, 5-trifluorophenyl) methyl ] thiourea (IV) and ammonia are subjected to amination reaction under the action of 2-iodophenylbenzoic acid to obtain N- [ (6-chloro-2-methyl) -2H-indazol-5-yl ] -N 'indazol-5-yl' - [1- (2,4, 5-trifluorophenyl) methyl ] guanidine (V); the N- [ (6-chloro-2-methyl) -2H-indazol-5-yl ] -N' - [1- (2,4, 5-trifluorophenyl) methyl ] guanidine (V) and 1-methyl-3-isocyanate methyl-1H-1, 2, 4-triazole (VI) are subjected to acylation reaction to generate 1- [ [1- (2,4, 5-trifluorophenyl) methyl ] [ (6-chloro-2-methyl) -2H-indazol-5-amino ] methylene ] -3- [ (1-methyl-1H-1, 2, 4-triazol-3-yl) methyl ] urea (VII), wherein 1- [ [1- (2,4, 5-trifluorophenyl) methyl [ (6-chloro-2-methyl) -2H-indazole-5-amino ] methylene ] -3- [ (1-methyl-1H-1, 2, 4-triazol-3-yl) methyl ] urea (VII) and phosgene are subjected to cyclization reaction under the action of an acid-binding agent to prepare (6E) -6- [ (6-chloro-2-methyl-2H-indazol-5-yl) imino ] dihydro-3- [ (1-methyl-1H-1, 2, 4-triazol-3-yl) methyl ] -1- [ (2,4, 5-trifluorophenyl) methyl ] -1,3, 5-triazine-2, 4(1H,3H) -dione (S-217622, I).
The reaction scheme is schematically as follows:
in addition, the invention also provides the following auxiliary technical scheme:
the feeding molar ratio of the raw material 6-chloro-2-methyl-5-isothiocyanato-2H-indazole (II) and 2,4, 5-trifluorophenylmethylamine (III) in the condensation reaction is 1: 1-1.5, preferably 1: 1.1-1.3.
The solvent of the condensation reaction is tetrahydrofuran, acetonitrile, dioxane, isopropanol, n-butanol or tert-butanol, preferably tert-butanol.
The condensation reaction temperature is 50-120 ℃, and preferably 80-90 ℃.
The solvent for the ammoniation reaction is tetrahydrofuran, acetonitrile, dioxane, dimethyl sulfoxide, N-dimethylformamide or acetonitrile, preferably acetonitrile.
The temperature of the ammoniation reaction is-10-35 ℃, and preferably 25-30 ℃.
The feeding molar ratio of the acylation reaction raw material N- [ (6-chloro-2-methyl) -2H-indazol-5-yl ] -N' - [1- (2,4, 5-trifluorophenyl) methyl ] guanidine (V) to 1-methyl-3-isocyanate methyl-1H-1, 2, 4-triazole (VI) is 1: 0.9-1.3, preferably 1: 1.0-1.2.
The solvent for the acylation reaction is toluene, xylene, dioxane, dimethyl sulfoxide, N-dimethylformamide or acetonitrile, and toluene is preferred.
The temperature of the acylation reaction is-5-45 ℃, preferably 25-30 ℃.
The charging molar ratio of the raw material 1- [ [1- (2,4, 5-trifluorophenyl) methyl ] [ (6-chloro-2-methyl) -2H-indazole-5-amino ] methylene ] -3- [ (1-methyl-1H-1, 2, 4-triazol-3-yl) methyl ] urea (VII) for the cyclization reaction to phosgene is 1: 1.0-1.5, preferably 1: 1.2.
The acid-binding agent for the cyclization reaction is sodium hydride, potassium hydride, sodium hydroxide, potassium hydroxide, sodium tert-butoxide, potassium tert-butoxide, sodium methoxide, sodium ethoxide, sodium carbonate, potassium carbonate or cesium carbonate, preferably potassium carbonate.
The solvent of the cyclization reaction is tetrahydrofuran, acetonitrile, dioxane, dimethyl sulfoxide, N-dimethylformamide or acetonitrile, and tetrahydrofuran is preferred.
The temperature of the cyclization reaction is 5-45 ℃, and preferably 30-35 ℃.
Advantageous effects
The preparation method of the anti-neocorolla drug S-217622 provided by the invention is characterized in that a target product is conveniently prepared by sequentially carrying out condensation, ammoniation, acylation, cyclization and other common unit reactions on known or available raw materials. The preparation process has the characteristics of simple process, safety, environmental protection and the like, can improve the quality and yield of the product, and is suitable for industrial production.
Detailed Description
The following non-limiting detailed description of the present invention is provided in connection with several preferred embodiments.
The first embodiment is as follows:
in reaction of6-chloro-2-methyl-2H-indazol-5-amine (18.1g,0.1mol), potassium carbonate (27.6g,0.2mol) and water (200mL) were added to a bottle, and carbon disulfide (15.2g, 0.2mol) was added dropwise with stirring and stirred at room temperature for 3 to 4 hours. And (3) cooling to 0-5 ℃, dropwise adding a dichloromethane (100mL) solution of cyanuric chloride (9.2g, 50mmol) while stirring, slowly raising the temperature to room temperature after dropwise adding, continuously stirring for 4-6 hours, and finishing the TLC detection reaction. The pH was adjusted to 11 with sodium hydroxide. Standing for layering, separating out organic phase, extracting water phase with dichloromethane for 3 times, combining organic phases, and drying with anhydrous sodium sulfate. Vacuum concentrating to obtain oily 6-chloro-2-methyl-5-isothiocyanato-2H-indazole (II)20.6g with yield 92.4%, EI-MS M/z 224[ M + H ] -] + 。
Example two:
in a reaction flask, (2,4, 5-trifluorophenyl) methyl bromide (22.5g,0.1mmol), sodium azide (16.2g,0.25mol) and hexadecyltributyl phosphonium bromide (5.1g,0.01mol) were added to water (100mL) and stirred until dissolved. Heating to 80-85 ℃, and stirring for reaction for 8-10 hours. After cooling and standing for separation, the organic layer was collected, and the aqueous phase was extracted with toluene (50mL) and combined with the organic phase. And (3) dropwise adding a water (30mL) solution of sodium borohydride (11.7g,0.3mol) into the organic phase, heating to 80-85 ℃, stirring for reaction for 12-16 hours, and detecting by TLC to finish the reaction. The organic phase was separated off and washed 2 times with water and dried over anhydrous sodium sulfate. Vacuum concentrating to obtain light brown oily 2,4, 5-trifluorophenylmethylamine (III)13.3g, yield 82.6%, EI-MS M/z 162[ M + H ]] + 。
Example three:
adding 6-chloro-2-methyl-5-isothiocyanato-2H-indazole (II) (11.2g, 50mmol) and 2,4, 5-trifluorophenylmethylamine (III) (9.7g, 60mmol) into tert-butanol (200mL) in a three-neck flask, heating to reflux, reacting for 8-10 hours, and detecting the reaction by TLC. Concentrated under reduced pressure, dichlorohexane (250mL) was added to the residue, washed 3 times with 5% dilute hydrochloric acid, the organic phase was separated, dried over anhydrous sodium sulfate, and the solvent was recovered by distillation under reduced pressure. Recrystallizing the residue with ethyl acetate to obtain light gray solid N- [ (6-chloro-2-methyl) -2H-indazol-5-yl)]-N' - [1- (2,4, 5-trifluorophenyl) methyl]16.2g of thiourea (IV), yield 84.2%, EI-MS M/z 385 [ M + H ]] + ； 1 H NMR(DMSO d 6 )δ9.12(s,1H),8.16(brs,1H),7.54(m,2H),7.45(m,2H),6.04(brs, 1H),5.06(s,2H),4.09(s,3H)。
Example four:
adding N- [ (6-chloro-2-methyl) -2H-indazol-5-yl) into a three-neck bottle]-N' - [1- (2,4, 5-trifluorophenyl) methyl]Thiourea (IV) (11.5g, 30mmol) and acetonitrile (150mL) were added dropwise, with stirring at room temperature, to a solution of 2-iodoxybenzoic acid (9.3g, 33mmol) in 28-30% aqueous ammonia (60 mL). And after finishing dropping, continuously stirring and reacting for 1-2 hours, and detecting by TLC to finish the reaction. Extracted 3 times with ethyl acetate. The organic phases were combined, washed 3 times with 10% sodium bicarbonate solution, the organic phase was separated and dried over anhydrous sodium sulfate. Vacuum distilling to recover solvent, recrystallizing the residue with ethyl acetate to obtain light gray solid N- [ (6-chloro-2-methyl) -2H-indazol-5-yl)]-N' - [1- (2,4, 5-trifluorophenyl) methyl]10g of guanidine (V), yield 90.7%, EI-MS M/z 368[ M + H ]] + ； 1 H NMR(DMSO d 6 )δ9.58(brs, 1H),9.13(s,1H),8.96(brs,1H),8.14(brs,1H),7.50(m,4H),5.03(s,2H),4.09(s,3H)。
Example five:
triphosgene (29.6g,0.1mol) and dichloromethane (200mL) were added to a reaction flask at room temperature, and a solution of 1-methyl-1H-1, 2, 4-triazole-3-methylamine (11.2g, 0.1mol) and dichloromethane (200mL) was added dropwise with stirring. After the dropwise addition is complete, the temperature is reduced to 0-5 ℃, triethylamine (15.2g, 0.15mol) is continuously dropwise added while stirring, the temperature is slowly raised to the room temperature, and the stirring is continuously carried out for 4 hours. Vacuum concentrating to obtain oily 1-methyl-3-isocyanate methyl-1H-1, 2, 4-triazole (VI)12.6g with yield of 91.3%, EI-MS M/z:139[ M + H ]] + 。
Example six:
adding N- [ (6-chloro-2-methyl) -2H-indazol-5-yl) into a three-neck bottle]-N' - [1- (2,4, 5-trifluorophenyl) methyl]Guanidine (V) (7.4g, 20mmol) and 100mL of toluene are cooled to 0-5 ℃ and a solution of 1-methyl-3-isocyanatomethyl-1H-1, 2, 4-triazole (VI) (3.04g, 22mmol) in 10mL of toluene is added dropwise. Stirring for 15 minutes, heating to room temperature, reacting for 18-20 hours, and detecting by TLC to finish the reaction. Concentrating under reduced pressure to obtain gray solid 1- [ [1- (2,4, 5-trifluorophenyl) methyl][ (6-chloro-2-methyl) -2H-indazol-5-amino]Methylene group]-3- [ (1-methyl-1H-1, 2, 4-triazol-3-yl) methyl group]Urea (A), (B) and (C)VII)9.6g, yield 94.9%; the product can be directly used for the next reaction without further treatment; EI-MS M/z 506[ M + H ]] + 。
Example seven:
adding 1- [ [1- (2,4, 5-trifluorophenyl) methyl into a reaction bottle][ (6-chloro-2-methyl) -2H-indazol-5-amino]Methylene group]-3- [ (1-methyl-1H-1, 2, 4-triazol-3-yl) methyl group]Urea (VII) (5.1g,10mmol) and 50mL of tetrahydrofuran were added as a solution of phosgene (1.2g,12mol) in 15mL of tetrahydrofuran with stirring in an ice bath. Heating to 30-35 ℃, and stirring for reaction for 12-14 hours. And cooling to room temperature, adding potassium carbonate (3.3g, 24mmol), slowly heating to reflux, stirring for reaction for 2-4 hours, and detecting by TLC to finish the reaction. The reaction solution was poured into ethyl acetate, and washed 2 times with saturated brine. Separating organic phase, drying with anhydrous sodium sulfate, distilling under reduced pressure to recover solvent, and recrystallizing the residue with ethanol to obtain light brown solid (6E) -6- [ (6-chloro-2-methyl-2H-indazol-5-yl) imino]Dihydro-3- [ (1-methyl-1H-1, 2, 4-triazol-3-yl) methyl group]-1- [ (2,4, 5-trifluorophenyl) methyl group]2.8g of (S-217622, I) -1,3, 5-triazine-2, 4(1H,3H) -dione (S-217622, I) in 52.7% yield, EI-MS M/z:532[ M + H ]] + ； 1 H NMR(DMSO d 6 )δ9.31(s,1H),8.40(s,1H),7.73(s,1H),7.53(m,1H),7.67(m,1H),7.44(m,1H),5.26(s,2H), 5.04(s,2H),4.15(s,3H),3.90(s,3H)。
It should be noted that the above-mentioned preferred embodiments are merely illustrative of the technical concepts and features of the present invention, and are intended to enable those skilled in the art to understand the contents of the present invention and implement the present invention, and not to limit the scope of the present invention. All equivalent changes and modifications made according to the spirit of the present invention should be covered within the protection scope of the present invention.
Claims (9)
1. A preparation method of a novel coronavirus main protease inhibitor S-217622 (chemical name of the novel coronavirus main protease inhibitor is (6E) -6- [ (6-chloro-2-methyl-2H-indazol-5-yl) imino ] dihydro-3- [ (1-methyl-1H-1, 2, 4-triazol-3-yl) methyl ] -1- [ (2,4, 5-trifluorophenyl) methyl ] -1,3, 5-triazine-2, 4(1H,3H) -diketone):
the preparation method is characterized by comprising the following steps: the condensation reaction of 6-chloro-2-methyl-5-isothiocyanato-2H-indazole and 2,4, 5-trifluorophenylmethylamine is carried out to generate N- [ (6-chloro-2-methyl) -2H-indazol-5-yl ] -N ' - [1- (2,4, 5-trifluorophenyl) methyl ] thiourea, the amination reaction of the N- [ (6-chloro-2-methyl) -2H-indazol-5-yl ] -N ' - [1- (2,4, 5-trifluorophenyl) methyl ] thiourea and ammonia is carried out under the action of 2-iodoxybenzoic acid to obtain the N- [ (6-chloro-2-methyl) -2H-indazol-5-yl ] -N ' - [1- (2,4, 5-trifluorophenyl) methyl ] guanidine; the N- [ (6-chloro-2-methyl) -2H-indazol-5-yl ] -N' - [1- (2,4, 5-trifluorophenyl) methyl ] guanidine and 1-methyl-3-isocyanate methyl-1H-1, 2, 4-triazole are subjected to acylation reaction to generate 1- [ [1- (2,4, 5-trifluorophenyl) methyl ] [ (6-chloro-2-methyl) -2H-indazol-5-amino ] methylene ] -3- [ (1-methyl-1H-1, 2, 4-triazol-3-yl) methyl ] urea, and the 1- [ [1- (2,4, 5-trifluorophenyl) methyl ] [ (6-chloro-2-methyl) -2H-indazol Oxazole-5-amino ] methylene ] -3- [ (1-methyl-1H-1, 2, 4-triazole-3-yl) methyl ] urea and phosgene are subjected to cyclization reaction under the action of an acid-binding agent to prepare (6E) -6- [ (6-chloro-2-methyl-2H-indazol-5-yl) imino ] dihydro-3- [ (1-methyl-1H-1, 2, 4-triazole-3-yl) methyl ] -1- [ (2,4, 5-trifluorophenyl) methyl ] -1,3, 5-triazine-2, 4(1H,3H) -diketone (S-217622).
2. The method of claim 1, wherein the step of preparing S-217622 comprises: the feeding molar ratio of a raw material 6-chloro-2-methyl-5-isothiocyanato-2H-indazole and 2,4, 5-trifluorophenylmethylamine in the condensation reaction is 1: 1-1.5.
3. The method of claim 1, wherein the step of preparing S-217622 comprises: the solvent of the condensation reaction is tetrahydrofuran, acetonitrile, dioxane, isopropanol, n-butanol or tert-butanol; the temperature of the condensation reaction is 50-120 ℃.
4. The method of claim 1 for preparing S-217622, wherein: the solvent of the ammoniation reaction is tetrahydrofuran, acetonitrile, dioxane, dimethyl sulfoxide, N-dimethylformamide or acetonitrile; the temperature of the ammoniation reaction is-10 to 35 ℃.
5. The method of claim 1, wherein the step of preparing S-217622 comprises: the feeding molar ratio of the acylation reaction raw material N- [ (6-chloro-2-methyl) -2H-indazol-5-yl ] -N' - [1- (2,4, 5-trifluorophenyl) methyl ] guanidine (V) to 1-methyl-3-isocyanate methyl-1H-1, 2, 4-triazole (VI) is 1: 0.9-1.3.
6. The method of claim 1, wherein the step of preparing S-217622 comprises: the solvent of the acylation reaction is toluene, xylene, dioxane, dimethyl sulfoxide, N-dimethylformamide or acetonitrile; the temperature of the acylation reaction is-5-45 ℃.
7. The method of claim 1, wherein the step of preparing S-217622 comprises: the charging molar ratio of the raw material 1- [ [1- (2,4, 5-trifluorophenyl) methyl ] [ (6-chloro-2-methyl) -2H-indazole-5-amino ] methylene ] -3- [ (1-methyl-1H-1, 2, 4-triazol-3-yl) methyl ] urea and phosgene in the cyclization reaction is 1: 1.0-1.5.
8. The method of claim 1, wherein the step of preparing S-217622 comprises: the acid-binding agent for the cyclization reaction is sodium hydride, potassium hydride, sodium hydroxide, potassium hydroxide, sodium tert-butoxide, potassium tert-butoxide, sodium methoxide, sodium ethoxide, sodium carbonate, potassium carbonate or cesium carbonate.
9. The method of claim 1, wherein the step of preparing S-217622 comprises: the solvent of the cyclization reaction is tetrahydrofuran, acetonitrile, dioxane, dimethyl sulfoxide, N-dimethylformamide or acetonitrile; the temperature of the cyclization reaction is 35-75 ℃.
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| CN114805314A (en) * | 2022-04-20 | 2022-07-29 | 杭州国瑞生物科技有限公司 | Synthesis method of Ensaitevir |
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| WO2022035911A2 (en) * | 2020-08-11 | 2022-02-17 | Tutela Pharmaceuticals, Inc. | Methods of treating coronavirus infections by co-administering an fkbp ligand and an antiviral agent |
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| WO2022035911A2 (en) * | 2020-08-11 | 2022-02-17 | Tutela Pharmaceuticals, Inc. | Methods of treating coronavirus infections by co-administering an fkbp ligand and an antiviral agent |
Non-Patent Citations (1)
| Title |
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| YUTO UNOH等: "Discovery of S‑ 217622, a Noncovalent Oral SARS-CoV ‑ 2 3CL Protease Inhibitor Clinical Candidate for Treating COVID-19", 《J. MED. CHEM.》, pages 6499 - 6512 * |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114805314A (en) * | 2022-04-20 | 2022-07-29 | 杭州国瑞生物科技有限公司 | Synthesis method of Ensaitevir |
| CN114805314B (en) * | 2022-04-20 | 2023-12-15 | 杭州国瑞生物科技有限公司 | Synthesis method of Entecavir |
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