Preparation method of (S)-2-[1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonyl ethyl]-4-acetyl amino isoindoline-1, 3-diketone isomer

A technology of methylsulfonylethyl and acetylamino, which is applied in the field of medicinal chemistry and can solve problems affecting the effectiveness of drugs

Active Publication Date: 2015-04-22
SUZHOU YABAO PHARMA R&D CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] But in actual operation, (S)-2-(3-ethoxy-4-methoxyphenyl)-1-(methylsulfonyl)-ethan-2-ylamine-N-acetyl-L - The ee value of leucine salt is only 94.6%, and the purity of the final prepared isomer is 94.7%; and the low purity of the isomer will affect the effectiveness of the drug

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0023] Example 1: Patent CN100427085C method

[0024] Resolution of 1-(3-ethoxy-4-methoxy-phenyl)-2-methanesulfonyl-ethylamine

[0025] Add 1-(3-ethoxy-4-methoxy-phenyl)-2-methanesulfonyl-ethylamine (137.0 g , 500 mmol), N-acetyl-L-leucine (52 g, 300 mmol) and methanol (1.0 L). The slurry was heated to reflux with stirring for 1 hour, then the slurry was cooled to ambient temperature with stirring and stirring was continued at ambient temperature for 3 hours. The slurry was filtered and washed with methanol (250ml). The solid was air dried and then vacuum dried at ambient temperature to constant weight to give 100.5 g of crude product (80.9% ee).

[0026] The crude solid (55.0g) was refluxed with methanol (440ml) for 1 hour, then cooled to room temperature and stirred at ambient temperature for 3 hours. The slurry was filtered and the filter cake was washed with methanol (200ml). The solid was air-dried and then dried under vacuum at 30°C to constant weight to obtain 49....

Embodiment 2

[0030] Add 1-(3-ethoxy-4-methoxy-phenyl)-2-methanesulfonyl-ethylamine (137.0 g , 500 mmol), N-acetyl-L-leucine, and methanol (1.0L) were added in different molar ratios. The slurry was heated to reflux with stirring for 1 hour, then the slurry was cooled to ambient temperature with stirring and stirring was continued at ambient temperature for 3 hours. The slurry was filtered and washed with methanol (250ml). The solid was air-dried, and then vacuum-dried to constant weight at ambient temperature to obtain the crude product. The specific results are shown in Table 1.

[0031] Table 1 (S)-1-(3-ethoxy-4-methoxy-phenyl)-2-methanesulfonyl-ethylamine-N-acetyl-L-leucine salts prepared in different molar ratios ee value comparison

[0032] serial number N-acetyl-L-leucine: 3-ethoxy-4-methoxy-phenyl)-2-methanesulfonyl-ethylamine ee value% 1 0.40:1 89.8 2 0.45:1 89.6 3 0.50:1 89.4 4 0.55:1 88.3 5 0.58:1 81.9

Embodiment 3

[0034] Add 1-(3-ethoxy-4-methoxy-phenyl)-2-methanesulfonyl-ethylamine (137.0 g , 500 mmol), N-acetyl-L-leucine (48 g, 275 mmol), and different volumes of methanol in Table 2 were added. The slurry was heated to reflux with stirring for 1 hour, then the slurry was cooled to ambient temperature with stirring and stirring was continued at ambient temperature for 3 hours. The slurry was filtered and washed with methanol (250ml). The solid was dried in the air, and then vacuum-dried to constant weight at ambient temperature to obtain the crude product. The specific results are shown in Table 2:

[0035]Table 2 (S)-1-(3-ethoxy-4-methoxy-phenyl)-2-methanesulfonyl-ethylamine-N-acetyl-L-leucine salt prepared by different volumes of methanol ee value comparison

[0036] serial number volume of methanol ee value% 1 925ml 83.8 2 1110ml 83.5 3 1295ml 89.4 4 1480ml 89.2 5 1665ml 88.9 6 1850ml 89.5

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Abstract

The invention discloses a preparation method of a (S)-2-[1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonyl ethyl]-4-acetyl amino isoindoline-1, 3-diketone isomer. The preparation method comprises the following steps: preparing 1-(3-ethoxy-4-methoxy-phenyl)-2-methylsulfonyl-ethylamine chiral amino acid salt by virtue of a mixed solvent reaction, and then reacting with N-(1,3-dioxo-1,3-dihydrogen-isobenzofuran-4-yl)-acetamide under the condition proper for generate a final product. According to the preparation method disclosed by the invention, the prepared (S)-2-[1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonyl ethyl]-4-acetyl amino isoindoline-1, 3-diketone isomer has the purity of at least 99 percent basically without containing other isomers, so that the effectiveness of a medicament preparation is ensured.

Description

technical field [0001] The invention relates to the field of medicinal chemistry, in particular to a (S)-2-[1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-4-acetylamino Process for the preparation of isomers of isoindoline-1,3-dione. Background technique [0002] (S)-2-[1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-4-acetylaminoisoindoline-1,3-dione , is the first PDE-4 inhibitor developed by Cell Genomics for the treatment of adult patients with active psoriatic arthritis. The chemical structural formula is as follows: [0003] Chinese patent CN100427085C discloses (S)-2-[1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-4-acetylaminoisoindoline- The preparation method of 1,3-diketone, in the resolution process of 2-(3-ethoxyl-4-methoxyphenyl)-1-(methylsulfonyl)-eth-2-yl-amine, React with a resolution reagent, then heat and reflux with methanol to obtain (S)-2-(3-ethoxy-4-methoxyphenyl)-1-(methylsulfonyl)-ethan-2-ylamine -N-acetyl-L-leucine salt, the ee va...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D209/48A61K31/4035A61P19/02A61P17/06
CPCC07D209/48
Inventor 刘保杰彭涛吴玲
Owner SUZHOU YABAO PHARMA R&D CO LTD
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