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

Patent metadata

Field	Value
Publication number	US-10858325-B2
Application number	US-201816126323-A
Country	US
Kind code	B2
Filing date	Sep 10, 2018
Priority date	Apr 27, 2012
Publication date	Dec 8, 2020
Grant date	Dec 8, 2020

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 comprising:

mixing 4-nitrophenol, an inorganic metallic base, and ethyl fumaryl chloride in a mixture of an organic solvent and water to form a mono-ethyl fumarate ester;
adding an aminoalkyl-diketopiperazine according to the following formula:

wherein n=1−7, to the mono-ethyl fumarate ester; and
quenching the reaction mixture with a second solvent.

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

3. The method of claim 1 , wherein the inorganic metallic base is selected from sodium carbonate and sodium hydroxide.

4. The method of claim 1 , wherein the 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.

7. The method of claim 1 , wherein the ethyl fumaryl chloride is added to a mixture of 4-nitrophenol and the inorganic metallic base, with cooling.

8. The method of claim 1 , wherein the aminoalkyl-diketopiperazine is mixed with an organic solvent to form an aminoalkyl-diketopiperazine-containing mixture prior to adding the aminoalkyl-diketopiperazine.

9. The method of claim 8 , wherein the organic solvent in the aminoalkyl-diketopiperazine-containing mixture is the same organic solvent used to form the mono-ethyl fumarate ester.

10. The method of claim 8 , wherein the aminoalkyl-diketopiperazine-containing mixture further comprises an inorganic metallic base.

11. The method of claim 10 , wherein the inorganic metallic base is selected from sodium carbonate and sodium hydroxide.

12. The method of claim 8 , wherein the reaction mixture is heated after addition of the aminoalkyl-diketopiperazine-containing mixture.

13. The method of claim 1 , wherein the second solvent is water.

14. The method of claim 13 , wherein the reaction mixture is cooled prior to quenching.

Assignees

• Mannkind Corp

Inventors

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

Classifications

• C07D241/08 Primary

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

• C07C67/30

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

• C07C67/39

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

• C07C201/12

  by reactions not involving the formation of nitro groups · 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