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Lifitegrast intermediate and preparation method thereof

A technology for rifiplast and intermediates, applied in the field of rifiplast intermediates and their preparation, can solve the problems of unsuitability for industrialization and high cost

Active Publication Date: 2021-07-06
DEYANG HUAKANG PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0015] This method uses 3-methylsulfonylbromobenzene as starting material, and this route uses precious metal and heavy metal to carry out coupling reaction, and cost is higher, is not suitable for industrialization

Method used

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  • Lifitegrast intermediate and preparation method thereof
  • Lifitegrast intermediate and preparation method thereof
  • Lifitegrast intermediate and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0047] Embodiment 1: the synthesis of intermediate formula II:

[0048] A 2L three-necked flask was successively added m-bromobenzenetoluene (85.5g, 0.5mol, 1eq), sodium methanesulfonate (61.2g, 0.6mol, 0.6eq), cuprous iodide (4.5g), sodium tert-butoxide ( 72g, 0.75mol, 1.5eq), 800ml dry DMF, nitrogen protection, react overnight at 110°C, TLC control, the reaction is complete; post-treatment: the reaction solution is lowered to 0-5°C, add 600ml ice water, add ethyl acetate (300ml*3), the organic phase was combined, the organic phase was extracted with 500ml water and 500ml saturated sodium chloride, the organic phase was dried, filtered, and concentrated under reduced pressure to obtain an oil, which was recrystallized with petroleum ether to obtain 77g of a yellow solid, Yield 90%, purity 98.5%.

Embodiment 2

[0049] Embodiment 2: the synthesis of intermediate formula III:

[0050] A 2L three-neck flask was sequentially added the formula II (85g, 0.5mol, 1eq) obtained in Example 1, 600ml of chloroform, started stirring, and added NBS (106.8g, 0.6mol, 1.2eq) and AIBN (8.2g, 0.05mol, 0.1 eq), 20-25°C, stirring for 5h, controlled by TLC, after the reaction is complete, post-treatment: add 300ml of 10% sodium bisulfite, extract the organic phase with 300ml of water and saturated sodium chloride, dry the organic phase, and filter , and concentrated to obtain 112.05 g of a yellow oil, with a yield of 90% and a purity of 95.4%.

Embodiment 3

[0051] Embodiment 3: the synthesis of intermediate formula III:

[0052] The difference between this embodiment and Example 2 is that the halogenation reagent is selected from NCS, the catalyst is selected from BPO, and the organic solvent A is selected from carbon tetrachloride; other reaction conditions are the same as in Example 2; the yield of the product is 86%, and the purity is 98.60%.

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Abstract

The invention relates to the field of pharmaceutical and chemical production, and discloses a lifitegrast intermediate and a preparation method thereof. A reaction route of the preparation method is as described in the specification. The preparation method is simple to operate, stable and reliable in process, safe in production, suitable for industrial production, and high product conversion rate; and the obtained lifitegrast intermediate is high in purity.

Description

technical field [0001] The invention relates to the field of pharmaceutical and chemical production, in particular to a rifemilast intermediate and a preparation method thereof. Background technique [0002] Lifitegrast is a drug developed by Shire Pharmaceuticals for the treatment of dry eye syndrome. It was approved by the US Food and Drug Administration (FDA) for marketing in the United States on July 11, 2016. The indication patent was granted in May 2026. Due on the 17th. Its structural formula: [0003] [0004] m-thymphenyl-L-phenylalanine is one of the main intermediates of rifelast. [0005] First of all, the Chinese patent application whose publication number is CN104797574A discloses two methods for synthesizing m-thiamphenyl-L-phenylalanine: [0006] a. Synthetic route 3-bromo-L-phenylalanine as the starting material, protected by a protecting group, replaced by a methylsulfonyl group, and then deprotected, the route uses 3-bromo-L-phenylalanine as Startin...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C317/48C07C315/04
CPCC07C317/48
Inventor 李庚李开均黄晓平尹大恒
Owner DEYANG HUAKANG PHARMA
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