Looking for breakthrough ideas for innovation challenges? Try Patsnap Eureka!

Green production method of low-cost lenalidomide

A lenalidomide and green production technology, applied in the field of medicinal chemistry, can solve problems such as unfavorable safety production and environmental protection, difficulty in realizing large-scale production, difficulty in large-scale production, etc., and achieve cost reduction, mild process conditions and low price Effect

Active Publication Date: 2019-03-01
XINFA PHARMA
View PDF5 Cites 0 Cited by
  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0011] This synthetic route is catalyzed by a strong base such as sodium amide, which is not easy to prepare and store, and the reaction requires ultra-low temperature -40°C. The reaction conditions are harsh, the steps are lengthy, the process is complicated, the energy consumption is large, the yield is not high, and large-scale production is difficult.
[0012] In summary, in the existing synthetic technology of lenalidomide, the price of raw materials used is high and the reaction conditions are harsh, which is not conducive to safe production and environmental protection, and the steps are lengthy, the process is complicated, the energy consumption is large, and the yield is not high. Difficult to achieve mass 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
  • Green production method of low-cost lenalidomide
  • Green production method of low-cost lenalidomide
  • Green production method of low-cost lenalidomide

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0051] Embodiment 1: the preparation of 2-chloro-4-nitro n-butyraldehyde

[0052] Under nitrogen protection, into a 500 ml four-necked flask connected with stirring, a thermometer and a reflux condenser, add 90.5 g (1.0 mol) of 2-chloroacrolein, 91.5 g (1.5) of nitromethane, 2.0 g of DBU (1, 8-diazabicycloundec-7-ene), stirred and reacted at 90~95°C for 8 hours, after the excess nitromethane was recovered by atmospheric distillation, 144.3 grams of product 2-chloro-4-nitro was obtained by vacuum distillation N-butyraldehyde, yield 95.2%, gas phase purity 99.6%.

Embodiment 2

[0053] Embodiment 2: Preparation of 2-bromo-4-nitro-n-butyraldehyde

[0054] Under nitrogen protection, add 135 g (1.0 mol) of 2-bromoacrolein, 91.5 g (1.5) of nitromethane, 2.0 g of DBU, 95 to The reaction was stirred at 100° C. for 4 hours. After the excess nitromethane was recovered by atmospheric distillation, 175.5 g of product 2-bromo-4-nitro-n-butyraldehyde was obtained by distillation under reduced pressure, with a yield of 89.5% and a gas phase purity of 99.3%.

Embodiment 3

[0055] Example 3: Preparation of 3-(7-nitro-3-oxo-1H-isoindol-2-yl)piperidine-2,6-dione (formula VI)

[0056] Under nitrogen protection, add 120 g of N,N-dimethylformamide, 12.8 g (0.1 mol) of 3-aminopiperidine-2,6 - diketone, 16.5 grams (0.11 moles) of methyl 1-chloroacetoacetate, 40 grams of potassium carbonate, stirred and reacted at 40 to 45 ° C for 4 hours, then stirred and reacted at 90 to 95 ° C for 3 hours, and steamed out the methanol generated by the amidation reaction ; Cool to 40°C, add 16.5 (0.11 mole) 2-chloro-4-nitro-n-butyraldehyde, stir and react at 40-45°C for 5 hours, filter, and wash the filter cake with 40 grams of N,N-dimethylformamide , combined the filtrates, recovered N,N-dimethylformamide by distillation, added 90 grams of isopropanol, and recrystallized to obtain 27.1 grams of 3-(7-nitro-3-oxo-1H-isoindole-2- base) piperidine-2,6-dione, the yield is 93.7%, and the liquid phase purity is 99.7%.

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 green production method of low-cost lenalidomide. According to the method, in presence of a solvent and an alkali, 3-aminopiperidine-2,6-dione and 1-halo-acetoacetate are subjected to dehydrogenation halogen acid condensation, dealcoholizing amidation, 2-halo-4-nitrobutanal dehydration and dehydrochlorination or dehydrobromination, 3-(7-nitro-3-oxo-1H-isoindol-2-yl)piperidine-2,6-dione is obtained, the process is completed with a one-pot method, nitro is reduced into amino by catalytic hydrogenation of 3-(7-nitro-3-oxo-1H-isoindol-2-yl)piperidine-2,6-dione, and lenalidomide is prepared. The method has the advantages of cheap and easily available raw materials, short technological process, simple operation and environmental protection and is a production method beneficial to industrialization.

Description

technical field [0001] The invention relates to a preparation method of lenalidomide, which belongs to the technical field of medicinal chemistry. Background technique [0002] Lenalidomide is an analogue of thalidomide. Compared with thalidomide, it has fewer adverse reactions and lower teratogenicity. With immunomodulatory, anti-angiogenic and anti-tumor properties, it is clinically used in the treatment of myelodysplastic / dysplastic syndrome, mantle cell lymphoma and multiple myeloma. The trade name of lenalidomide is revlimid, and its chemical name is 3-(7-amino-3-oxo-1H-isoindol-2-yl)piperidine-2,6-dione. The structural formula is shown in the figure below. [0003] [0004] Lenalidomide is a second-generation new immunomodulator developed by Celgene Corporation of the United States for the treatment of fatal blood diseases and cancers. June 14), Japan (June 25, 2010) and China (January 23, 2013). Lenalidomide has effects on multiple biological pathways in cells. ...

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): C07D401/04
CPCC07D401/04
Inventor 戚聿新王胜吕强三鞠立柱
Owner XINFA PHARMA
Who we serve
  • R&D Engineer
  • R&D Manager
  • IP Professional
Why Patsnap Eureka
  • Industry Leading Data Capabilities
  • Powerful AI technology
  • Patent DNA Extraction
Social media
Patsnap Eureka Blog
Learn More
PatSnap group products

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

© 2024 PatSnap. All rights reserved.Legal|Privacy policy|Modern Slavery Act Transparency Statement|Sitemap|About US| Contact US: help@patsnap.com