Preparation method of lifitegrast intermediate

A phosphorus ligand and compound technology, applied in the field of organic synthesis, can solve the problems of L-3-bromophenylalanine being expensive, unsuitable for industrial production, and long method routes, achieving low cost, suitable for industrial production, and reducing The effect of production costs

Active Publication Date: 2020-07-31
SHANGHAI HAOYUAN CHEMEXPRESS
View PDF4 Cites 3 Cited by
  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The used raw material L-3-bromophenylalanine of these methods is expensive, and self-made route is long, and cost is high
And, the method route of above-mentioned preparation compound (VIII) is long, and cost is high, is not suitable for industrialized production

Method used

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
View more

Image

Smart Image Click on the blue labels to locate them in the text.
Viewing Examples
Smart Image
  • Preparation method of lifitegrast intermediate
  • Preparation method of lifitegrast intermediate
  • Preparation method of lifitegrast intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0028] Add 20mL DMAC and 5.0g zinc powder into 100mL reaction bottle 1, replace with nitrogen three times, add dropwise 0.4g methanesulfonic acid and stir to raise the temperature to 60-70°C, keep it warm for 20-30min, then lower the temperature by 10-20°C, slowly add N- Boc-3-iodo-L-alanine benzyl ester (24.0 g) was dissolved in DMAC (20 mL) for about 4 hours, and the temperature was controlled at 20°C. After the dropwise addition, the reaction was stirred for 0.5-1 h, and the reaction was basically complete as detected by TLC or GC, and the obtained organozinc reagent was ready for use.

[0029] Add 20mL DMAC to 100mL reaction vial 2, add 10g 3-bromophenylmethyl sulfone, 389mg Pd 2 (dba) 3 , 259mg of tris(o-methylphenyl)phosphorus, replaced by nitrogen three times, then heated to 70-80°C, added dropwise the organozinc reagent in reaction bottle 1, after the addition was completed, kept stirring for 1 hour and sent to LC-MS. After the reaction was complete, the reaction sol...

Embodiment 2

[0031] Add 20mL DMAC and 5.0g zinc powder into 100mL reaction bottle 1, replace with nitrogen three times, add dropwise 0.4g methanesulfonic acid and stir to raise the temperature to 60-70°C, keep it warm for 20-30min, then lower the temperature by 10-20°C, slowly add N- Boc-3-iodo-L-alanine benzyl ester (24.0 g) was dissolved in DMAC (20 mL) for about 4 hours, and the temperature was controlled at 20°C. After the dropwise addition, the reaction was stirred for 0.5-1 h, and the reaction was basically complete as detected by TLC or GC, and the obtained organozinc reagent was ready for use.

[0032] Add 20mL DMAC to 100mL reaction vial 2, add 10g 3-bromophenylmethyl sulfone, 135mg Pd(OAc) 2 , 259mg of tris(o-methylphenyl)phosphorus, replaced by nitrogen three times, then heated to 70-80°C, added dropwise the organozinc reagent in reaction bottle 1, after the addition was completed, kept stirring for 1 hour and sent to LC-MS. After the reaction was complete, the reaction solutio...

Embodiment 3

[0034]Add 20mL DMAC and 5g zinc powder to the reaction bottle 1, replace with nitrogen three times, then add 0.4g methanesulfonic acid dropwise and stir to raise the temperature to 60-70°C, keep it warm for 20-30min, then lower the temperature by 10-20°C, slowly add N-Boc- A DMAC solution (20 mL) of 3-iodo-L-alanine methyl ester (19.5 g) was used for about 4 h at a temperature of 20° C. After the dropwise addition was completed, the reaction was stirred for 0.5-1 h. TLC or GC detects that the basic reaction is complete, and the obtained organozinc reagent is ready for use.

[0035] Add 20mL DMAC to reaction flask 2, add 10g 3-bromophenylmethyl sulfone, 389mg Pd 2 (dba) 3 , 259mg of tris(o-methylphenyl)phosphorus, replaced by nitrogen three times, then heated to 70-80°C, added dropwise the organozinc reagent in reaction bottle 1, after the addition was completed, kept stirring for 1 hour and sent to LC-MS. After the reaction was complete, the reaction solution was cooled to r...

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to view more

PUM

No PUM Login to view more

Abstract

The invention relates to a preparation method of a lifitegrast intermediate. The preparation method is implemented by the following route, has the advantages of short synthesis route, high yield and high safety, and is simple and convenient to operate and suitable for industrial production. According to the preparation method, a compound II reacts with metal zinc in an organic solvent to generatean organic zinc reagent, a compound I carries out a coupling reaction with the organic zinc reagent, a palladium reagent and a phosphorus ligand to obtain a compound III, and Boc protecting groups ofthe compound III are removed to obtain a compound IV, wherein R1 and R2 groups are respectively and independently selected from methyl, ethyl, vinyl, n-propyl, isopropyl, propenyl, propynyl, cyclopropyl, n-butyl, isobutyl, tert-butyl, butenyl, cyclobutyl, n-pentyl, iso-pentyl, cyclopentyl, n-hexyl, cyclohexyl, phenyl and benzyl.

Description

Technical field: [0001] The invention belongs to the field of organic synthesis, and relates to the synthesis of a Litahast intermediate, in particular to the synthesis of an amino acid compound. Background technique: [0002] Amino acid compound (IV) is a widely used pharmaceutical intermediate, which can be used in the synthesis of intercellular adhesion factor inhibitors, especially the synthesis of new small molecule integrin (integrin) inhibitor drug ritazast. [0003] [0004] Litamistat (Lifitegrast), developed by Shire Dev LLC, is a new type of small molecule integrin (integrin) inhibitor, which can antagonize lymphocyte function-associated antigen-1 (LFA-1), block Interaction with its cognate ligand, intercellular adhesion molecule-1 (ICAM-1), interferes with the overexpression of ICAM-1 in corneal and conjunctival tissues that cause dry eye disease. Litahast was approved by the FDA on July 11, 2016. It is the first drug to treat the symptoms and signs of dry ey...

Claims

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to view more

Application Information

Patent Timeline
no application Login to view more
Patent Type & Authority Applications(China)
IPC IPC(8): C07C317/48C07C317/50C07C315/04
CPCC07C315/04C07B2200/07C07C317/48C07C317/50Y02P20/55
Inventor 郑保富李硕梁高强马振标刘钢杨成武梅魁孙娟娟黄颖波
Owner SHANGHAI HAOYUAN CHEMEXPRESS
Who we serve
  • R&D Engineer
  • R&D Manager
  • IP Professional
Why Eureka
  • Industry Leading Data Capabilities
  • Powerful AI technology
  • Patent DNA Extraction
Social media
Try Eureka
PatSnap group products

Browse by: Latest US Patents, China's latest patents, Technical Efficacy Thesaurus, Application Domain, Technology Topic.

© 2024 PatSnap. All rights reserved.Legal|Privacy policy|Modern Slavery Act Transparency Statement|Sitemap