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Synthesis method of lifitegrast intermediate

A technology of intermediates and ster, which is applied in the field of medicinal chemistry, can solve the problems of unfavorable industrial production, difficult control of Grignard reaction, and low reaction yield, and achieve the effects of simplified reaction steps, mild reaction conditions and high purity

Inactive Publication Date: 2018-06-08
CHONGQING SHENGHUAXI PHARMA CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0015] The shortcoming of this method is that with 6-bromobenzofuran as starting raw material, the Grignard reaction is difficult to control, and the reaction yield is low, and the literature report yield is only 24%, which is unfavorable for suitability for industrialized production

Method used

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  • Synthesis method of lifitegrast intermediate
  • Synthesis method of lifitegrast intermediate
  • Synthesis method of lifitegrast intermediate

Examples

Experimental program
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Effect test

Embodiment 1

[0031] 1) Preparation of 6-methyl formate benzofuran:

[0032] Add 5.28g (0.0268mol) of 6-bromobenzofuran into a 250mL three-necked flask, add 80ml of dry tetrahydrofuran, stir to dissolve, put it in a freezer and cool it down to -65°C, add dropwise n-butyllithium (2M ) 14.74mL, keep the temperature below -60°C during the dropwise addition process, the dropwise addition is completed in 1h, continue to react for 3 hours, under this reaction condition, add 2.89g (0.0321mol) of dimethyl carbonate dropwise After the addition is complete, control the reaction temperature to -65°C. After 4 hours of reaction, the reaction is complete. Add saturated ammonium chloride solution dropwise at low temperature to quench the reaction. After evaporating the solvent under reduced pressure, add 100 mL of water and 100 mL of dichloromethane to stir After layering, the organic layer was washed twice with saturated brine, 100 mL each time, the dichloromethane layer was dried with anhydrous magnesiu...

Embodiment 2

[0036] 1) Preparation of 6-methyl formate benzofuran:

[0037] Add 4.55g (0.0231mol) of 6-bromobenzofuran into a 250mL three-neck flask, add 80ml of dry tetrahydrofuran, stir to dissolve, put it in a freezer and cool it down to -65°C, add n-butyllithium (2M ) 15mL, keep the temperature below -60°C during the dropwise addition process, the dropwise addition is completed in 1h, continue to react for 3 hours, under this reaction condition, add 2.28g (0.0254mol) of dimethyl carbonate dropwise After completion, control the reaction temperature to -65°C. After 4 hours of reaction, the reaction is complete. Add saturated ammonium chloride solution dropwise at low temperature to quench the reaction. After evaporating the solvent under reduced pressure, add 100mL of water and 100mL of methylene chloride to dissolve After layering, the organic layer was washed twice with saturated brine, 100 mL each time, the dichloromethane layer was dried with anhydrous magnesium sulfate and filtered,...

Embodiment 3

[0041] 1) Preparation of 6-methyl formate benzofuran:

[0042]Add 8.28g (0.042mol) of 6-bromobenzofuran into a 250mL three-neck flask, add 100ml of dry tetrahydrofuran, stir to dissolve, put it in a freezer and cool it down to -65°C, add dropwise n-butyllithium (2M ) 23.1mL, keep the temperature below -60°C during the dropwise addition process, the dropwise addition is completed in 1h, continue to react for 3 hours, under this reaction condition, add 4.9g (0.054mol) of dimethyl carbonate dropwise After the addition is complete, control the reaction temperature to -65°C. After 4 hours of reaction, the reaction is complete. Add saturated ammonium chloride solution dropwise at low temperature to quench the reaction. After evaporating the solvent under reduced pressure, add 120 mL of water and 120 mL of dichloromethane to stir After layering, the organic layer was washed twice with saturated brine, 100 mL each time, the dichloromethane layer was dried with anhydrous magnesium sulf...

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Abstract

The invention provides a preparation method of a lifitegrast intermediate I. The method comprises steps as follows: 6-bromobenzo[b]furan is taken as a starting raw material and subjected to a halogen-lithium exchange reaction under the action of n-butyllithium, a product is subjected to a reaction with dimethyl carbonate, methyl benzofuran-6-carboxylate is prepared and hydrolyzed, and the lifitegrast intermediate I is obtained. The raw materials are cheap and easily available, few reaction by-products are produced, yield and purity of a final product are high, meanwhile, the step (1) an the step (2) can be subjected to the one-pot reaction, so that steps of the reaction are simplified, furthermore, the reaction conditions are mild, the product does not need separation on columns, and industrialization is easy to realize.

Description

technical field [0001] The invention relates to lintaglast (lifitegrast), in particular to a preparation method of a lintaglast intermediate, and belongs to the technical field of medicinal chemistry. Background technique [0002] Litahast (lifitegrast) ((S)-2-[2-(benzofuran-6-carbonyl)-5,7-dichloro-1,2,3,4-tetrahydroisoquinoline-6- Formamido]-3-(3-methylsulfonylphenyl)propionic acid) is a new type of small molecule integrin inhibitor designed and developed by SARcode Bioscience, which is made into a preservative-free topical ophthalmic solution for use in For dry eye disease in adults, it is the first treatment for signs of chronic inflammatory diseases of the eye. In 2015, a new drug application was submitted to the FDA, and on July 11, 2016, the FDA approved the drug to be marketed and used for ocular dry syndrome. [0003] The structural formula of Litahast is as follows: [0004] [0005] Through reverse synthesis analysis, the structure of Litahast is composed of...

Claims

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Application Information

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IPC IPC(8): C07D307/79
CPCC07D307/79
Inventor 翁明君王忠玉余欢
Owner CHONGQING SHENGHUAXI PHARMA CO LTD
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