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Preparation method of lifitegrast and intermediate compound of lifitegrast

A compound and solvate technology, applied in the field of organic compound synthesis, can solve problems such as unfavorable purification of ritamilast, and achieve the effects of less impurities, overcoming low ee value and reducing cost

Pending Publication Date: 2022-01-04
THE FIRST AFFILIATED HOSPITAL ZHEJIANG UNIV COLLEGE OF MEDICINE +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although the process seems simple, in actual production, the chiral amino acid derivatives are prone to racemization of the chiral configuration under strong alkaline conditions to produce impurity A, which is very unfavorable for the purification of ritazast

Method used

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  • Preparation method of lifitegrast and intermediate compound of lifitegrast
  • Preparation method of lifitegrast and intermediate compound of lifitegrast
  • Preparation method of lifitegrast and intermediate compound of lifitegrast

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0104] Embodiment 1: the preparation method of formula III compound

[0105]

[0106] method 1:

[0107] 46g of compound VI, 4.5g of compound V14.5g, and 34.2g of HATU were dissolved in 460g of DMF, and the temperature was lowered to -5 to 5°C. 9.6 g of triethylamine was added dropwise, and after the drop was completed, the mixture was incubated for 4-6 hours to react. After the reaction was completed, the reaction solution was added dropwise into 500 g of ice water to quench, and filtered. The filter cake was dissolved with 300g of dichloromethane and washed with water. The organic layer was collected and concentrated to dryness to obtain 55.5 g of the crude compound of formula III, with a yield of 100% and a purity of 95.6%.

[0108] Method 2:

[0109] Dissolve 4.2g of compound V1 and 0.1g DMF in 45g of dichloromethane, raise the temperature to reflux, add 10.8g of thionyl chloride dropwise, concentrate to dryness after the reaction is completed, add 30g of dichlorome...

Embodiment 2

[0110] Embodiment 2: the preparation of formula IV compound

[0111]

[0112] method 1:

[0113] Weigh 20g of the crude compound of formula III into a round-bottomed flask, add 30g of tetrahydrofuran, heat up and reflux to dissolve, then add 10g of methyl tert-butyl ether, keep warm for 20-30 minutes, cool down naturally for crystallization, and continue at 5-10°C After stirring for 1.0-1.5 h, it was filtered to obtain a white crystalline powder solid. Dry at 45-55°C to obtain 18.9g with a yield of 94.5%, a purity of 99.7%, and the largest single impurity of less than 0.1%.

[0114] Method 2:

[0115] Weigh 30g of the crude compound of formula III and place it in a reaction flask, add 30g of tetrahydrofuran and 30g of isopropyl ether, heat and stir to dissolve, continue to stir for 10-20 minutes, program cooling and crystallization, cooling down 5-10°C per hour, 30-40 The crystallization was carried out at ℃ for 1 hour. Then continue to cool down and stir to crystallize...

Embodiment 3

[0118] Example 3: Preparation of Litamiast from Compound of Formula II (ie, R=Bn in Compound of Formula I)

[0119]

[0120] Method 1 (inorganic base):

[0121] Add 70.6 g of the compound of formula II into 600 g of acetonitrile, stir to dissolve, and set aside. Add 11.2g of potassium hydroxide into 1000g of purified water, stir to dissolve. Control the reaction temperature from -10 to 30°C, add the reaction solution prepared above into the aqueous sodium hydroxide solution dropwise, and stir until the reaction is complete. Concentrate under reduced pressure to remove the reaction solvent, extract the concentrated solution with 2×200 g of isopropyl acetate, add hydrochloric acid to adjust the pH=1-4, and precipitate a solid, filter, wash with 1000 g of water, and dry at 50-60° C. to obtain 55.6 g of ritazast. Yield 90.4%, purity 95.8%, ee value 95.6%, impurity A 4.4%.

[0122] Method 2 (inorganic base + organic base):

[0123] Add 70.6 g of the compound of formula II in...

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Abstract

The invention relates to a preparation method of lifitegrast and an intermediate compound of the lifitegrast. Specifically, the invention relates to a synthesis method of the lifitegrast, a key intermediate for synthesizing the lifitegrast, a solvate of the lifitegrast and a method for preparing the lifitegrast by hydrolyzing the lifitegrast under an alkaline condition.

Description

technical field [0001] The present invention relates to the field of organic compound synthesis. Specifically, the present invention relates to a synthesis method of ritahast, a key intermediate for synthesizing ritahast and a preparation method thereof. Background technique [0002] Litamistat (Lifitegrast), developed by Shire Pharmaceuticals, is a new type of small-molecule integrin inhibitor that can antagonize lymphocyte-associated antigens, block their interaction with their cognate ligands, intercellular adhesion molecules, and interfere with stem cells. The overexpression of corneal and conjunctival tissues of eye diseases was approved by the US Food and Drug Administration (FDA) for marketing in the United States on July 11, 2016. [0003] [0004] The common preparation method of ritazast includes ester group hydrolysis or hydrogenation reaction of its precursor. As shown in Scheme 1, WO2009139817A2, WO2011050175A1 and WO2019096996A1 disclose that the compound ...

Claims

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Application Information

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IPC IPC(8): C07D405/06
CPCC07D405/06C07B2200/13C07B2200/07
Inventor 王夏蔚郑志国
Owner THE FIRST AFFILIATED HOSPITAL ZHEJIANG UNIV COLLEGE OF MEDICINE
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