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

Patent metadata

Field	Value
Publication number	US-11479535-B2
Application number	US-202017113540-A
Country	US
Kind code	B2
Filing date	Dec 7, 2020
Priority date	Apr 27, 2012
Publication date	Oct 25, 2022
Grant date	Oct 25, 2022

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 from unisolated and unpurified intermediates allowing for improved yields and reactor throughput.

First claim

What is claimed is:

1. A method of preparing a diketopiperazine of Formula I (n=1-7) comprising:

mixing 4-nitrophenol, an inorganic metallic base, and ethyl fumaryl chloride in an organic solvent to produce a monoethyl fumarate ester;
adding an aminoalkyl-diketopiperazine having two primary amine functional groups;
wherein the mono-ethyl fumarate ester is reacted with the aminoalkyl-diketopiperazine in situ without purification.

2. The method of claim 1 , wherein the am inoalkyl-diketopiperazine is:

wherein n=1-7.

3. The method of claim 1 , wherein the organic solvent is selected from acetone, acetonitrile, ethyl acetate, tetrahydrofuran, and dichloromethane.

4. The method of claim 1 , wherein the inorganic metallic base is provided in an amount of 1 to 2 equivalents based on the amount of 4-nitrophenol.

5. The method of claim 1 , wherein the ethyl fumaryl chloride is provided in an amount of 0.5 to 2 equivalents based on the amount of 4-nitrophenol.

6. The method of claim 1 , wherein the inorganic metallic base is added as an aqueous mixture to a solution of 4-nitrophenol in the organic solvent.

Assignees

• Mannkind Corp

Inventors

• Kraft Kelly Sullivan
• Freeman John J
• Serwinski Paul
• Pavia Vincent
• Phanstiel Otto
• Kaur Navneet

Classifications

• C07C67/30

  by modifying the acid moiety of the ester, such modification not being an introduction of an ester group · CPC title

• C07C201/12

  by reactions not involving the formation of nitro groups · CPC title

• C07C67/39

  by oxidation of groups which are precursors for the acid moiety of the ester · CPC title

• C07D241/08 Primary

  with oxygen atoms directly attached to ring carbon atoms · CPC title

• C07C205/43

  to carbon atoms of the same non-condensed six-membered aromatic ring or to carbon atoms of six-membered aromatic rings being part of the same condensed ring system · CPC title