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Preparation method of oral medicine for treating new coronal pneumonia

A pneumonia and drug technology, applied in organic chemistry, antiviral agents, etc., can solve the problems of "atom economy, reduced reaction yield, and increased side reactions" to the maximum, and achieve the reduction of protection and deprotection steps , The preparation process is simple, and the effect of increasing selectivity

Pending Publication Date: 2022-07-15
SUZHOU LIXIN PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0010] Investigating the above synthetic route, in order to selectively carry out the substitution reaction between the halogenated side chain and the mother nucleus twice, it is inevitable to take protection and deprotection steps, thereby reducing the overall reaction yield and not being able to maximize Satisfy the principle of "atom economy"
At the same time, since the reaction route repeats the substitution reaction of the same mechanism twice, it will inevitably lead to a decrease in selectivity and an increase in side reactions.

Method used

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  • Preparation method of oral medicine for treating new coronal pneumonia
  • Preparation method of oral medicine for treating new coronal pneumonia
  • Preparation method of oral medicine for treating new coronal pneumonia

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0035] At room temperature, 1-(2,4,5-trifluorophenyl)methylthiourea (11.0 g, 50 mmol) and methanol (100 mL) were added to the reaction flask, and after stirring to dissolve, iodoethane (9.36 g) was added. g, 60 mmol), and continued to stir and drop the reaction for 6 to 8 hours. Concentrated under reduced pressure, the obtained residue was recrystallized from ethyl acetate to obtain 10.6 g of [N-(2.4.5-trifluorophenyl)methyl]ethylcarbamoylthiocyanate hydroiodide (II), which was obtained The rate is 56.4%, EI-MS m / z: 249 [M+H] + .

Embodiment 2

[0037] [N-(2.4.5-trifluorophenyl)methyl]carbamoylthiocyanate ethyl ester hydroiodide (II) (7.52g, 20mmol), diisopropylethylamine ( 7.74 g, 60 mmol) and dichloromethane (100 mL), stirred until dissolved. The ice bath was cooled to 0~5°C, and the solution of N-(chloroformyl)isocyanate (3.2g, 30mmol) in dichloromethane (15mL) was slowly added dropwise. After the addition was completed, the temperature was slowly raised to room temperature, and the reaction was stirred for 1~2 hours. , TLC detection reaction completed. Stand for crystallization, filter, wash the filter cake with dichloromethane, and recrystallize from ethyl acetate to obtain an off-white solid 6-ethylmercapto-1-(2,,4,5-trifluorophenyl)methyl]-1, 3,5-Triazine-2,4(1H,3H)-dione (III) 5.5g, 86.8% yield, EI-MS m / z: 318[M+H] + ; 1 H NMR (DMSO d 6 ) δ 11.60 (brs, 1H), 7.09 (m, 2H), 5.07 (s, 2H), 3.13 (q, J=7.4Hz, 2H), 1.29 (t, J=7.4Hz, 3H).

Embodiment 3

[0039] 6-Ethylmercapto-1-(2,,4,5-trifluorophenyl)methyl]-1,3,5-triazine-2,4(1H,3H)-dione ( III) (5.73 g, 20 mmol) and 3-chloromethyl-1-methyl-1H-1,2,4-triazole hydrochloride (5.04 g, 30 mmol) were dissolved in acetonitrile (100 mL) and added in portions Acid binding agent cesium carbonate (16.3 g, 50 mmol), heated to reflux, and reacted for 2 to 4 hours. Cool to room temperature, quench the reaction with saturated ammonium chloride solution, extract 3 times with ethyl acetate, combine the organic phases, dry over anhydrous sodium sulfate, recover the solvent by distillation under reduced pressure, and recrystallize the residue from ethyl acetate to obtain a white solid 6- Ethylmercapto-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 (IV) 4.8g, 58.1% yield, EI-MS m / z: 413[M+H] + ; 1 H NMR (DMSO d 6 )δ7.93(s,1H),7.14(m,1H),6.95(m,1H),5.23(s,2H),5.16(s,2H),3.84(s,3H),3.20(q,, J=7.4Hz, 2H), 1.34 (t, J=7.4Hz, 3H). ...

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Abstract

The invention discloses a preparation method of an oral drug S-217622 for treating new coronal pneumonia, which comprises the following steps: carrying out cyclization reaction on [N-(2.4. 5-trifluorophenyl) methyl] carbamyl ethyl thiocyanate hydriodate and N-(chloroformyl) isocyanate, and further sequentially reacting with 3-chloromethyl-1-methyl-1H-1, 2, 3, 4-tetramethyl-1, 3, 4-tetramethyl-1, 3, 4-tetramethyl-1, 3, 4-tetramethyl-1, 3, 4-tetramethyl-1, 3, 4-tetramethyl-1, 3, 4-tetramethyl-1, 3, 4-tetramethyl-1, 3, 4-tetramethyl-1, 3, 4- The preparation method comprises the following steps: respectively carrying out substitution reaction and condensation reaction on 1, 2, 4-triazole hydrochloride and 6-chloro-2-methyl-2H-indazole-5-amine to prepare a target compound S-217622. The preparation method is simple in process, mild in condition, safe and environment-friendly, and a new way is provided for industrial production of the product.

Description

technical field [0001] The invention belongs to the technical field of organic synthesis route design and preparation of raw materials and intermediates, in particular to a preparation method of S-217622, ​​an oral medicine for treating new coronary pneumonia. Background technique [0002] S-217622 is an oral drug developed by Shionogi Company of Japan for the treatment of new coronary pneumonia, which can effectively inhibit the new coronavirus 3CL enzyme and play an antiviral role. Preclinical tests show that S-217622 has a strong effect on 3CL enzyme activity in vitro, and IC 50 Value is 0.013 μM, EC 50 The value was 0.37 μM. Animal experiments show that S-217622 has high absorption rate and low clearance rate when administered orally in rats, monkeys and dogs, and its half-lives in monkeys and dogs are about 10 and 30 hours, respectively. At the same time, in vitro tests also confirmed that S-217622 has strong antiviral activity against a variety of new coronavirus va...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D403/14A61P31/14
CPCC07D403/14A61P31/14
Inventor 许学农曾得利包志坚冷秀云王喆孙祥
Owner SUZHOU LIXIN PHARMA