Preparation method of 3-tert-butyl-6-ethylthio-1, 3, 5-triazine-2, 4 (1H, 3H)-diketone

An ethylthio and tert-butyl technology, applied in the field of organic synthesis, can solve the problems of low yield and limited purity of the target product, and achieve the effects of improving product yield and yield

Pending Publication Date: 2022-07-22
杭州布朗生物医药科技有限公司
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0004] In order to solve the low yield of the target product obtained in the existing 3-tert-butyl-6-ethylthio-1,3,5-triazine-2,4(1H,3H)-dione preparation proces

Method used

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  • Preparation method of 3-tert-butyl-6-ethylthio-1, 3, 5-triazine-2, 4 (1H, 3H)-diketone
  • Preparation method of 3-tert-butyl-6-ethylthio-1, 3, 5-triazine-2, 4 (1H, 3H)-diketone
  • Preparation method of 3-tert-butyl-6-ethylthio-1, 3, 5-triazine-2, 4 (1H, 3H)-diketone

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0056] A preparation method of 3-tert-butyl-6-ethylthio-1,3,5-triazine-2,4(1H,3H)-dione, the specific steps are:

[0057]1 mol (185 g) S-ethylisothiourea was added to 300 g acetonitrile, the temperature of the water bath was controlled at 32-36 °C, and 1.2 mol (100 g) tert-butyl isocyanate was slowly added dropwise within 1 h After the reaction was kept for 2.5 h, 2.17 mol (220 g) triethylamine was added, then the temperature was increased and the temperature was also controlled to 53-56 °C with a water bath, and 0.40 mol (120 g) triphosgene was dissolved in 500 g of acetonitrile to prepare a solution, Slowly added dropwise within 150 min and incubated for 4.5 h to obtain a crude product solution after the reaction was completed;

[0058] Under the pressure of 1.5 atm, it was heated to 90 °C and concentrated until the crude product solution volume was about 71% of the original volume. Then 1000 mL of dilute hydrochloric acid with a concentration of 1 wt% was slowly added dropw...

Embodiment 2

[0067] A preparation method of 3-tert-butyl-6-ethylthio-1,3,5-triazine-2,4(1H,3H)-dione, the specific steps are:

[0068] 1 mol (185 g) S-ethylisothiourea was added to 300 g acetonitrile, the temperature of the water bath was controlled at 10-20 °C, and 1.15 mol (96 g) tert-butyl isocyanate was slowly added dropwise within 45 min After the reaction was completed, 2.00 mol (202 g) of triethylamine was added after 4 h of incubation, and then the temperature was increased and the temperature was also controlled to 10-20 °C in a water bath, and 0.35 mol (104 g) of triphosgene was dissolved in 500 g of acetonitrile to prepare a solution. Slowly added dropwise within 90 min and incubated for 6 h to obtain a crude product solution after the reaction was completed;

[0069] Under the pressure of 1.5 atm, it was heated to 90 °C and concentrated until the crude product solution volume was about 74% of the original volume. Then 1000 mL of dilute hydrochloric acid with a concentration of ...

Embodiment 3

[0073] A preparation method of 3-tert-butyl-6-ethylthio-1,3,5-triazine-2,4(1H,3H)-dione, the specific steps are:

[0074] 1 mol (185 g) S-ethylisothiourea was added to 300 g acetonitrile, the temperature was controlled at 0-10 °C in a water bath, and 1.25 mol (104 g) tert-butyl isocyanate was slowly added dropwise within 75 min After the reaction was kept for 2 h, 2.6 mol (263 g) triethylamine was added, and then the temperature was increased and the temperature was controlled to 0-10 °C in a water bath. 1.0 mol (297 g) triphosgene was dissolved in 500 g of dichloromethane to prepare The solution was slowly added dropwise within 180 min and incubated for 4 h to obtain a crude product solution after the reaction was completed;

[0075] Under the pressure of 1.5 atm, it was heated to 90 °C and concentrated until the crude product solution volume was about 72% of the original volume, then 1000 mL of dilute hydrochloric acid with a concentration of 1 wt% was slowly added dropwise,...

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Abstract

The invention belongs to the field of organic synthesis, and particularly relates to a preparation method of 3-tert-butyl-6-ethylthio-1, 3, 5-triazine-2, 4 (1H, 3H)-diketone. The method comprises the following steps: adding S-ethyl isothiourea into an organic solvent, slowly dropwise adding tert-butyl isocyanate, then carrying out a first-stage heat preservation reaction, then adding triethylamine and dropwise adding an organic solution of triphosgene, carrying out a second-stage heat preservation reaction after slowly dropwise adding to obtain a stock solution, and carrying out a second-stage heat preservation reaction after slowly dropwise adding; and carrying out post-treatment on the stock solution to obtain the target product 3-tert-butyl-6-ethylthio-1, 3, 5-triazine-2, 4 (1H, 3H)-diketone. The preparation of the 3-tert-butyl-6-ethylthio-1, 3, 5-triazine-2, 4 (1H, 3H)-diketone is realized in a milder and more efficient manner, and compared with the existing preparation scheme, the purity can reach 99% or above, and the product yield is also obviously improved to 84% or above.

Description

technical field [0001] The invention belongs to the field of organic synthesis, in particular to a preparation method of 3-tert-butyl-6-ethylthio-1,3,5-triazine-2,4(1H,3H)-dione. Background technique [0002] Ensitrelvir (S-217622), the first orally active, non-covalent, non-peptide SARS-Cov-23CL protease inhibitor, was announced at the end of February 2022 by Shionogi to complete the Phase IIb clinical trial of the oral drug S-217622 Analyzed and applied for a production and sales license to the Japanese Ministry of Health, Labour and Welfare based on Phase IIb clinical data. It is an oral drug of great and special significance. [0003] And 3-tert-butyl-6-ethylthio-1,3,5-triazine-2,4(1H,3H)-dione is an important intermediate for the preparation of Ensitrelvir (S-217622), 3 - The yield and product quality of tert-butyl-6-ethylthio-1,3,5-triazine-2,4(1H,3H)-dione in the industrial production process directly affect Ensitrelvir (S-217622) production progress and product qu...

Claims

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Application Information

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IPC IPC(8): C07D251/38
CPCC07D251/38
Inventor 马肖克黄国祥徐华新
Owner 杭州布朗生物医药科技有限公司
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