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

Methods for the synthesis of ethylfumarates and their use as intermediates

A kind of technology of monoethyl fumarate, monoethyl fumarate acid chloride

Inactive Publication Date: 2018-04-06
MANNKIND CORP
View PDF6 Cites 0 Cited by
  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Ethyl fumarate chloride (EFC) is known and commercially available, however, the disadvantage is the use of the acid chloride on a pharmaceutical scale
Some disadvantages include limited reactivity, purity, possible backlog in commercial availability, etc.

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
  • Methods for the synthesis of ethylfumarates and their use as intermediates
  • Methods for the synthesis of ethylfumarates and their use as intermediates
  • Methods for the synthesis of ethylfumarates and their use as intermediates

Examples

Experimental program
Comparison scheme
Effect test

Embodiment

[0059] Coupling of ethyl fumarate acid chloride and 4-nitrophenol: To a 1 L 4-neck round bottom flask was added 11.20 g (80.51 mmol) of 4-nitrophenol, 90 mL of water and 69 mL of acetone. While stirring under nitrogen, a solution of 12.80 g (120.8 mmol) of sodium carbonate in 90 mL of deionized water was added to the reaction. 21 mL of ethyl fumarate chloride (EFC) (17.0 mL, d=1.16 g / mL, 121 mmol) in acetone was added to the mixture using an addition funnel. A 25-33°C exotherm was observed during the EFC addition. The reaction mixture faded from yellow to colorless as the EFC addition proceeded. At the end of the EFC addition, the reaction pH was 7-7.5. Approximately 15 minutes after the EFC addition was complete, the reaction was diluted with 450 mL of deionized water. A precipitate formed at 27°C. The mixture was kept for 15 minutes, then the solid was separated, washed with deionized water (3x220 mL), and dried in a vacuum oven at 50 °C for 1 hour. The product was anal...

Embodiment 4

[0080] Example 4: For coupling Figure 11 Experimental Preparation 4 from MEF, TFAA and p-NP, NaOH: Part A: Assemble a 250 mL 3-neck round bottom flask with a magnetic stirrer, temperature readout / controller and addition funnel with nitrogen adapter. The vent gas is vented to an alkaline scrubber. Add p-nitrophenol (p-NP, 10 g) and trifluoroacetic anhydride (TFAA, 16.61 g, 11 mL) to the flask, and start stirring. The resulting yellow slurry was treated with triethylamine (TEA, 600 µL). A ~12 °C exotherm was observed after TEA addition. The solution was stirred for about 30 minutes (until clear, indicating complete formation).

[0081] Part B (In situ generation of 4-nitrophenyl ethyl fumarate): Assemble a 250 mL 4-neck round bottom flask with a magnetic stirrer, temperature readout / controller, addition funnel with nitrogen adapter, and reflux condenser . Monoethyl fumarate (MEF, 10.36 g) and acetone (9 mL) were added to the flask. TEA (16.33 mL) was added to the flask an...

Embodiment 5

[0088] A 500 mL 3-neck round bottom flask was fitted with a magnetic stirrer, temperature reader / controller, and addition funnel with nitrogen inlet. The vent gas is vented to an alkaline scrubber. Monoethyl fumarate (MEF, 5 g), anhydrous dichloromethane or THF (10 mL) and triethylamine (TEA, 12 mL) were added to the flask. An exotherm was observed during TEA addition. The clear reaction mixture was cooled to 5°C in an ice bath. A solution of chlorosulfonyl isocyanate (CSI, 4.96 g) in 10 mL of anhydrous dichloromethane was added over 20-30 minutes. After the addition was complete, the reaction mixture was kept below 10 °C for 3 hours. For reactions with DCM, crude MEF anhydride was isolated by removal of solvent in vacuo. For reactions with THF as solvent, MEF anhydride was used without further manipulation.

[0089] A 500 mL 3-neck round bottom flask was assembled with a magnetic stirrer, temperature reader / controller, and addition funnel with nitrogen adapter. The vent...

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

Disclosed embodiments relate to improved methods for the synthesis of activated fumarate intermediates and their use in chemical synthesis. Disclosed embodiments describe the synthesis of activated fumarate esters including those derived from activating groups including: 4-nitrophenyl, diphenylphophoryl azide, pivaloyl chloride, chlorosulfonyl isocyanate, p-nitrophenol, MEF, trifluoroacetyl and chlorine, for example, ethyl fumaroyl chloride and the subsequent use of the activated ester in situ. Further embodiments describe the improved synthesis of substituted aminoalkyl-diketopiperazines fromunisolated and unpurified intermediates allowing for improved yields and reactor throughput.

Description

[0001] This application is a divisional application of an invention patent application with an application date of March 15, 2013, an application number of 201380033409.7, and an invention title of "method for synthesizing ethyl fumarate and its use as an intermediate". technical field [0002] The present invention relates to compositions for the delivery of active agents, particularly bioactive agents. The disclosed embodiments are in the field of chemical synthesis, and more particularly, relate to improved synthetic methods for the preparation of 4-nitrophenyl ethyl fumarate and its use as a chemical intermediate. Background technique [0003] Drug delivery is an ongoing problem in the administration of active agents to patients. Conventional methods of delivering active agents are often severely limited by biological, chemical and physical barriers. Typically these barriers are formed by the environment through which delivery occurs, the environment of the target f...

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
IPC IPC(8): C07C201/12C07C205/43
CPCC07C67/30C07C201/12C07D241/08C07C69/60C07C205/43C07C67/39
Inventor 凯利·克拉夫特约翰·弗里曼保罗·舎温斯基文尼·帕维亚奥托·范特西尔纳夫尼特·考尔
Owner MANNKIND CORP
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